Dataset Viewer
id
stringlengths 2
20
| ch_id
stringlengths 2
20
| keywords
listlengths 0
162
| title
stringlengths 0
130
| authors
stringlengths 0
245
| abstract
stringlengths 0
4.05k
| content
stringlengths 0
197k
| references
listlengths 0
142
| created_date
stringlengths 0
10
| updated_date
stringlengths 0
10
| revised_date
stringlengths 0
10
| journal
stringclasses 1
value | source_url
stringclasses 1
value | publication_types
listlengths 2
2
|
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
a-mannosidosis
|
a-mannosidosis
|
[
"α-Mannosidosis",
"a-Mannosidosis",
"Lysosomal alpha-mannosidase",
"MAN2B1",
"Alpha-Mannosidosis"
] |
Alpha-Mannosidosis
|
Can Ficicioglu, Karolina M Stepien
|
Summary The clinical phenotype of alpha-mannosidosis varies considerably, with a wide spectrum of clinical findings and broad variability in individual presentation. At least three clinical types have been suggested in untreated individuals: mild (clinically recognized after age ten years, with myopathy, slow progression, and absence of skeletal abnormalities); moderate (clinically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities); and severe (obvious progression leading to early death from primary central nervous system involvement or infection). Core features of untreated individuals generally include early childhood-onset non-progressive hearing loss, frequent infections due to immunodeficiency, rheumatologic symptoms (especially systemic lupus erythematosus), developmental delay / intellectual disability, low tone, ataxia, spastic paraplegia, psychiatric findings, bone disease (ranging from asymptomatic osteopenia to focal lytic or sclerotic lesions and osteonecrosis), gastrointestinal dysfunction (including diarrhea, swallowing issues / aspiration, and enlarged liver and spleen), poor growth, eye issues (including tapetoretinal degeneration and optic nerve atrophy), cardiac complications in adults, and pulmonary issues (including parenchymal lung disease). However, with the advent of enzyme replacement therapy, the natural history of this condition may change. Long-term velmanase alfa (VA) treatment outcomes are still being elucidated, but may include improvement in hearing, immunologic profile, and quality of life (improved clinical outcomes for muscle strength). Similarly, affected individuals who underwent hematopoietic stem cell transplantation (HSCT) experienced improvement in development (with preservation of previously learned skills), ability to participate in activities of daily living, stabilization or improvement in skeletal abnormalities, and improvement in hearing ability, although expressive speech and hearing deficiencies remained the most significant clinical problems after HSCT. The diagnosis of alpha-mannosidosis is established in a proband by identification of deficiency of lysosomal enzyme acid alpha-mannosidase (typically 5%-10% of normal activity) in leukocytes or other nucleated cells AND/OR by the identification of biallelic pathogenic variants in Alpha-mannosidosis is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants in the family are known. Prenatal testing for a pregnancy at increased risk is possible by assay of acid alpha-mannosidase enzymatic activity or molecular genetic testing once the pathogenic variants have been identified in the family.
|
Mild form (type 1): typically recognized after age ten years, with myopathy, slow progression, and no skeletal abnormalities
Moderate form (type 2): typically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities
Severe form (type 3): Obvious progression leading to early death from primary central nervous system involvement or infection
For synonyms and outdated names, see
For other genetic causes of these phenotypes, see
• Mild form (type 1): typically recognized after age ten years, with myopathy, slow progression, and no skeletal abnormalities
• Moderate form (type 2): typically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities
• Severe form (type 3): Obvious progression leading to early death from primary central nervous system involvement or infection
## Diagnosis
A proposed diagnostic algorithm for alpha-mannosidosis has been published, but clinical findings alone are not enough to establish the diagnosis because they overlap with clinical findings in other storage disorders [
Alpha-mannosidosis
Macrocephaly with coarsening facial features. The facial features may progress to include:
Prominent forehead
Highly arched eyebrows
Depressed nasal bridge
Widely spaced teeth
Macroglossia
Prognathism
Hearing loss (sensorineural or mixed)
Frequent infections
Developmental delay / intellectual disability
Ataxia
Dysostosis multiplex
Focal lytic or sclerotic lesions
Osteonecrosis
Osteopenia
Note: Histopathologic evaluation of peripheral blood lymphocytes is not required to make the diagnosis and absence of this finding does not preclude the diagnosis.
The diagnosis of alpha-mannosidosis
In affected individuals, alpha-mannosidase enzyme activity in peripheral blood leukocytes is 5%-10% of normal activity.
This "residual" enzyme activity appears to represent mannosidase from other organelles or compartments (e.g., Golgi apparatus or cytosol), since they also show some activity at low pH.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of alpha-mannosidosis, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of alpha-mannosidosis is not considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Alpha-Mannosidosis
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
More than 130
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A few affected individuals were found to have a deletion of one or more exons [
• Macrocephaly with coarsening facial features. The facial features may progress to include:
• Prominent forehead
• Highly arched eyebrows
• Depressed nasal bridge
• Widely spaced teeth
• Macroglossia
• Prognathism
• Prominent forehead
• Highly arched eyebrows
• Depressed nasal bridge
• Widely spaced teeth
• Macroglossia
• Prognathism
• Hearing loss (sensorineural or mixed)
• Frequent infections
• Developmental delay / intellectual disability
• Ataxia
• Prominent forehead
• Highly arched eyebrows
• Depressed nasal bridge
• Widely spaced teeth
• Macroglossia
• Prognathism
• Dysostosis multiplex
• Focal lytic or sclerotic lesions
• Osteonecrosis
• Osteopenia
• In affected individuals, alpha-mannosidase enzyme activity in peripheral blood leukocytes is 5%-10% of normal activity.
• This "residual" enzyme activity appears to represent mannosidase from other organelles or compartments (e.g., Golgi apparatus or cytosol), since they also show some activity at low pH.
• For an introduction to multigene panels click
## Suggestive Findings
Alpha-mannosidosis
Macrocephaly with coarsening facial features. The facial features may progress to include:
Prominent forehead
Highly arched eyebrows
Depressed nasal bridge
Widely spaced teeth
Macroglossia
Prognathism
Hearing loss (sensorineural or mixed)
Frequent infections
Developmental delay / intellectual disability
Ataxia
Dysostosis multiplex
Focal lytic or sclerotic lesions
Osteonecrosis
Osteopenia
Note: Histopathologic evaluation of peripheral blood lymphocytes is not required to make the diagnosis and absence of this finding does not preclude the diagnosis.
• Macrocephaly with coarsening facial features. The facial features may progress to include:
• Prominent forehead
• Highly arched eyebrows
• Depressed nasal bridge
• Widely spaced teeth
• Macroglossia
• Prognathism
• Prominent forehead
• Highly arched eyebrows
• Depressed nasal bridge
• Widely spaced teeth
• Macroglossia
• Prognathism
• Hearing loss (sensorineural or mixed)
• Frequent infections
• Developmental delay / intellectual disability
• Ataxia
• Prominent forehead
• Highly arched eyebrows
• Depressed nasal bridge
• Widely spaced teeth
• Macroglossia
• Prognathism
• Dysostosis multiplex
• Focal lytic or sclerotic lesions
• Osteonecrosis
• Osteopenia
## Establishing the Diagnosis
The diagnosis of alpha-mannosidosis
In affected individuals, alpha-mannosidase enzyme activity in peripheral blood leukocytes is 5%-10% of normal activity.
This "residual" enzyme activity appears to represent mannosidase from other organelles or compartments (e.g., Golgi apparatus or cytosol), since they also show some activity at low pH.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of alpha-mannosidosis, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of alpha-mannosidosis is not considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Alpha-Mannosidosis
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
More than 130
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A few affected individuals were found to have a deletion of one or more exons [
• In affected individuals, alpha-mannosidase enzyme activity in peripheral blood leukocytes is 5%-10% of normal activity.
• This "residual" enzyme activity appears to represent mannosidase from other organelles or compartments (e.g., Golgi apparatus or cytosol), since they also show some activity at low pH.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of alpha-mannosidosis, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of alpha-mannosidosis is not considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Alpha-Mannosidosis
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
More than 130
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A few affected individuals were found to have a deletion of one or more exons [
## Clinical Characteristics
The clinical phenotype of alpha-mannosidosis varies considerably, with a wide spectrum of clinical findings and broad variability in individual presentation. Designating clinical types can be useful in prognosis and management. At least three clinical types (mild, moderate, and severe) have been suggested [
However, with the advent of ERT, the natural history of this condition may change.
Treatment with VA reduced serum oligosaccharide levels and elevated serum immunoglobulin G levels in affected individuals [
With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs).
Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status.
In a study of six individuals younger than age six years who received 1 mg/kg of VA intravenously (IV) once a week for at least 24 months [
All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment;
It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years.
The prognosis for individuals receiving VA treatment is not yet known.
Post-transplant mannosidase activity was within normal limits in all eight affected individuals tested [
Developmental improvement in all affected individuals, though none have reached typical development levels for age;
Preservation of previously learned skills in all affected individuals;
Ability to participate in activities of daily living, with one affected plerson reported to be able to live independently;
Stabilization or improvement in skeletal abnormalities, despite difficulties in quantifying changes in a growing skeleton [
Improvement in hearing ability in some affected individuals, though hearing disability was not completely resolved.
HSCT has shown beneficial effects on the central nervous system pathology in individuals with alpha-mannosidosis, as follows [
Diminished white matter abnormalities, reduced demyelination, and decreased gliosis compared to untreated affected individuals
Normalization of abnormal signals on cerebral magnetic resonance spectroscopy (MRS) that are present in untreated affected individuals
The morbidity and mortality rate associated with HSCT must be balanced against the benefits and is comparable to other non-malignant disases (88% survival rate). The benefits are greater in younger affected individuals before disease-related complications have developed.
The first decade of life is characterized by a high incidence of recurrent infections, including the common cold, pneumonia, gastroenteritis, and, more rarely, infections of the urinary tract. Serous otitis media is common and is usually not bacterial [
The infections diminish in the second and third decade, when ataxia and muscular weakness are more prominent. However, many individuals are able to ski, ride a bike, or play soccer up to the third decade. At any time, individuals risk setbacks in the form of acute necrotizing arthritis or acute hydrocephalus, both requiring surgery. Worsening of the myopathy has also been described and can be seen in affected individuals post-HSCT as an immune-mediated mechanism [
Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [
Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies.
Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections.
Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80.
The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests.
Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty.
In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [
In a longitudinal study of a brother and sister over a period of 25 years, decreased speech capacity was seen in one sib but not the other [
Follow-up observations have also suggested progressive impairment of motor function with age (see also
A longitudinal study of a brother and sister indicated no progression over a period of 25 years [
Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy."
Muscular hypotonia is common.
Communicating hydrocephalus can occur at any age.
Spastic paraplegia has also been described [
In nine individuals with alpha-mannosidosis and psychiatric symptoms, a physical or psychological stressor preceded the rapid development of confusion, delusions, hallucinations, anxiety, and often depression, leading to severe loss of function usually lasting three to 12 weeks, and followed by a period of somnolence, asthenia, and prolonged sleep [
Genu valgum is common and contributes to the gait disturbance.
Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [
Conventional radiographs may reveal:
Thickened calvaria;
Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
Hypoplasia of the inferior portions of the ilia;
Mild expansion of the short tubular bones of the hands.
Cranial MRI, including sagittal T
Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations].
D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary.
The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines.
Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean.
Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm.
In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals.
Narrow shoulders and convex chest were characteristic of the individuals in the study populations.
Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population.
A number of other ocular findings have also been reported in affected individuals, including hyperopia, myopia, strabismus, lenticular changes, superficial corneal opacities, and blurred discs.
Fortunately, many ophthalmologic findings can be remedied (see
Parenchymal lung disease was evident in three of five individuals with alpha-mannosidosis on CT [
In a literature review,
No genotype-phenotype correlations are known.
Alpha-mannosidosis may also be referred to as lysosomal alpha-d-mannosidase deficiency.
General estimates for the prevalence of alpha-mannosidosis vary. The most recent study estimated the prevalence to be 1:1,000,000 [
A study from Australia reported a prevalence of 1:500,000 [
Studies from Norway reported six individuals in a population of 4.5 million [
A prevalence of 1:300,000 was reported in the Czech Republic [
The disease is not specific to individuals of any specific ancestry; individuals from all parts of the world have been described [
• Treatment with VA reduced serum oligosaccharide levels and elevated serum immunoglobulin G levels in affected individuals [
• With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs).
• Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status.
• With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs).
• Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status.
• In a study of six individuals younger than age six years who received 1 mg/kg of VA intravenously (IV) once a week for at least 24 months [
• All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment;
• It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years.
• All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment;
• It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years.
• The prognosis for individuals receiving VA treatment is not yet known.
• With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs).
• Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status.
• All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment;
• It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years.
• Developmental improvement in all affected individuals, though none have reached typical development levels for age;
• Preservation of previously learned skills in all affected individuals;
• Ability to participate in activities of daily living, with one affected plerson reported to be able to live independently;
• Stabilization or improvement in skeletal abnormalities, despite difficulties in quantifying changes in a growing skeleton [
• Improvement in hearing ability in some affected individuals, though hearing disability was not completely resolved.
• Diminished white matter abnormalities, reduced demyelination, and decreased gliosis compared to untreated affected individuals
• Normalization of abnormal signals on cerebral magnetic resonance spectroscopy (MRS) that are present in untreated affected individuals
• Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [
• Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies.
• Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections.
• Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80.
• The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests.
• Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty.
• In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [
• Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy."
• Muscular hypotonia is common.
• Communicating hydrocephalus can occur at any age.
• Spastic paraplegia has also been described [
• Genu valgum is common and contributes to the gait disturbance.
• Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [
• Conventional radiographs may reveal:
• Thickened calvaria;
• Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
• Hypoplasia of the inferior portions of the ilia;
• Mild expansion of the short tubular bones of the hands.
• Thickened calvaria;
• Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
• Hypoplasia of the inferior portions of the ilia;
• Mild expansion of the short tubular bones of the hands.
• Cranial MRI, including sagittal T
• Thickened calvaria;
• Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
• Hypoplasia of the inferior portions of the ilia;
• Mild expansion of the short tubular bones of the hands.
• Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations].
• D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
• In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
• D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
• In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
• Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary.
• The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines.
• D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
• In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
• Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean.
• Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm.
• In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals.
• Narrow shoulders and convex chest were characteristic of the individuals in the study populations.
• Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population.
• A study from Australia reported a prevalence of 1:500,000 [
• Studies from Norway reported six individuals in a population of 4.5 million [
• A prevalence of 1:300,000 was reported in the Czech Republic [
## Clinical Description
The clinical phenotype of alpha-mannosidosis varies considerably, with a wide spectrum of clinical findings and broad variability in individual presentation. Designating clinical types can be useful in prognosis and management. At least three clinical types (mild, moderate, and severe) have been suggested [
However, with the advent of ERT, the natural history of this condition may change.
Treatment with VA reduced serum oligosaccharide levels and elevated serum immunoglobulin G levels in affected individuals [
With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs).
Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status.
In a study of six individuals younger than age six years who received 1 mg/kg of VA intravenously (IV) once a week for at least 24 months [
All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment;
It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years.
The prognosis for individuals receiving VA treatment is not yet known.
Post-transplant mannosidase activity was within normal limits in all eight affected individuals tested [
Developmental improvement in all affected individuals, though none have reached typical development levels for age;
Preservation of previously learned skills in all affected individuals;
Ability to participate in activities of daily living, with one affected plerson reported to be able to live independently;
Stabilization or improvement in skeletal abnormalities, despite difficulties in quantifying changes in a growing skeleton [
Improvement in hearing ability in some affected individuals, though hearing disability was not completely resolved.
HSCT has shown beneficial effects on the central nervous system pathology in individuals with alpha-mannosidosis, as follows [
Diminished white matter abnormalities, reduced demyelination, and decreased gliosis compared to untreated affected individuals
Normalization of abnormal signals on cerebral magnetic resonance spectroscopy (MRS) that are present in untreated affected individuals
The morbidity and mortality rate associated with HSCT must be balanced against the benefits and is comparable to other non-malignant disases (88% survival rate). The benefits are greater in younger affected individuals before disease-related complications have developed.
The first decade of life is characterized by a high incidence of recurrent infections, including the common cold, pneumonia, gastroenteritis, and, more rarely, infections of the urinary tract. Serous otitis media is common and is usually not bacterial [
The infections diminish in the second and third decade, when ataxia and muscular weakness are more prominent. However, many individuals are able to ski, ride a bike, or play soccer up to the third decade. At any time, individuals risk setbacks in the form of acute necrotizing arthritis or acute hydrocephalus, both requiring surgery. Worsening of the myopathy has also been described and can be seen in affected individuals post-HSCT as an immune-mediated mechanism [
Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [
Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies.
Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections.
Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80.
The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests.
Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty.
In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [
In a longitudinal study of a brother and sister over a period of 25 years, decreased speech capacity was seen in one sib but not the other [
Follow-up observations have also suggested progressive impairment of motor function with age (see also
A longitudinal study of a brother and sister indicated no progression over a period of 25 years [
Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy."
Muscular hypotonia is common.
Communicating hydrocephalus can occur at any age.
Spastic paraplegia has also been described [
In nine individuals with alpha-mannosidosis and psychiatric symptoms, a physical or psychological stressor preceded the rapid development of confusion, delusions, hallucinations, anxiety, and often depression, leading to severe loss of function usually lasting three to 12 weeks, and followed by a period of somnolence, asthenia, and prolonged sleep [
Genu valgum is common and contributes to the gait disturbance.
Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [
Conventional radiographs may reveal:
Thickened calvaria;
Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
Hypoplasia of the inferior portions of the ilia;
Mild expansion of the short tubular bones of the hands.
Cranial MRI, including sagittal T
Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations].
D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary.
The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines.
Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean.
Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm.
In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals.
Narrow shoulders and convex chest were characteristic of the individuals in the study populations.
Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population.
A number of other ocular findings have also been reported in affected individuals, including hyperopia, myopia, strabismus, lenticular changes, superficial corneal opacities, and blurred discs.
Fortunately, many ophthalmologic findings can be remedied (see
Parenchymal lung disease was evident in three of five individuals with alpha-mannosidosis on CT [
In a literature review,
• Treatment with VA reduced serum oligosaccharide levels and elevated serum immunoglobulin G levels in affected individuals [
• With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs).
• Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status.
• With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs).
• Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status.
• In a study of six individuals younger than age six years who received 1 mg/kg of VA intravenously (IV) once a week for at least 24 months [
• All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment;
• It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years.
• All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment;
• It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years.
• The prognosis for individuals receiving VA treatment is not yet known.
• With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs).
• Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status.
• All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment;
• It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years.
• Developmental improvement in all affected individuals, though none have reached typical development levels for age;
• Preservation of previously learned skills in all affected individuals;
• Ability to participate in activities of daily living, with one affected plerson reported to be able to live independently;
• Stabilization or improvement in skeletal abnormalities, despite difficulties in quantifying changes in a growing skeleton [
• Improvement in hearing ability in some affected individuals, though hearing disability was not completely resolved.
• Diminished white matter abnormalities, reduced demyelination, and decreased gliosis compared to untreated affected individuals
• Normalization of abnormal signals on cerebral magnetic resonance spectroscopy (MRS) that are present in untreated affected individuals
• Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [
• Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies.
• Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections.
• Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80.
• The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests.
• Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty.
• In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [
• Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy."
• Muscular hypotonia is common.
• Communicating hydrocephalus can occur at any age.
• Spastic paraplegia has also been described [
• Genu valgum is common and contributes to the gait disturbance.
• Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [
• Conventional radiographs may reveal:
• Thickened calvaria;
• Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
• Hypoplasia of the inferior portions of the ilia;
• Mild expansion of the short tubular bones of the hands.
• Thickened calvaria;
• Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
• Hypoplasia of the inferior portions of the ilia;
• Mild expansion of the short tubular bones of the hands.
• Cranial MRI, including sagittal T
• Thickened calvaria;
• Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
• Hypoplasia of the inferior portions of the ilia;
• Mild expansion of the short tubular bones of the hands.
• Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations].
• D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
• In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
• D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
• In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
• Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary.
• The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines.
• D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
• In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
• Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean.
• Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm.
• In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals.
• Narrow shoulders and convex chest were characteristic of the individuals in the study populations.
• Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population.
## Clinical Features in Treatment-Naïve Individuals
The first decade of life is characterized by a high incidence of recurrent infections, including the common cold, pneumonia, gastroenteritis, and, more rarely, infections of the urinary tract. Serous otitis media is common and is usually not bacterial [
The infections diminish in the second and third decade, when ataxia and muscular weakness are more prominent. However, many individuals are able to ski, ride a bike, or play soccer up to the third decade. At any time, individuals risk setbacks in the form of acute necrotizing arthritis or acute hydrocephalus, both requiring surgery. Worsening of the myopathy has also been described and can be seen in affected individuals post-HSCT as an immune-mediated mechanism [
Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [
Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies.
Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections.
Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80.
The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests.
Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty.
In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [
In a longitudinal study of a brother and sister over a period of 25 years, decreased speech capacity was seen in one sib but not the other [
Follow-up observations have also suggested progressive impairment of motor function with age (see also
A longitudinal study of a brother and sister indicated no progression over a period of 25 years [
Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy."
Muscular hypotonia is common.
Communicating hydrocephalus can occur at any age.
Spastic paraplegia has also been described [
In nine individuals with alpha-mannosidosis and psychiatric symptoms, a physical or psychological stressor preceded the rapid development of confusion, delusions, hallucinations, anxiety, and often depression, leading to severe loss of function usually lasting three to 12 weeks, and followed by a period of somnolence, asthenia, and prolonged sleep [
Genu valgum is common and contributes to the gait disturbance.
Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [
Conventional radiographs may reveal:
Thickened calvaria;
Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
Hypoplasia of the inferior portions of the ilia;
Mild expansion of the short tubular bones of the hands.
Cranial MRI, including sagittal T
Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations].
D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary.
The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines.
Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean.
Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm.
In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals.
Narrow shoulders and convex chest were characteristic of the individuals in the study populations.
Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population.
A number of other ocular findings have also been reported in affected individuals, including hyperopia, myopia, strabismus, lenticular changes, superficial corneal opacities, and blurred discs.
Fortunately, many ophthalmologic findings can be remedied (see
Parenchymal lung disease was evident in three of five individuals with alpha-mannosidosis on CT [
In a literature review,
• Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [
• Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies.
• Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections.
• Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80.
• The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests.
• Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty.
• In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [
• Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy."
• Muscular hypotonia is common.
• Communicating hydrocephalus can occur at any age.
• Spastic paraplegia has also been described [
• Genu valgum is common and contributes to the gait disturbance.
• Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [
• Conventional radiographs may reveal:
• Thickened calvaria;
• Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
• Hypoplasia of the inferior portions of the ilia;
• Mild expansion of the short tubular bones of the hands.
• Thickened calvaria;
• Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
• Hypoplasia of the inferior portions of the ilia;
• Mild expansion of the short tubular bones of the hands.
• Cranial MRI, including sagittal T
• Thickened calvaria;
• Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies;
• Hypoplasia of the inferior portions of the ilia;
• Mild expansion of the short tubular bones of the hands.
• Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations].
• D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
• In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
• D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
• In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
• Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary.
• The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines.
• D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis.
• In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [
• Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean.
• Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm.
• In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals.
• Narrow shoulders and convex chest were characteristic of the individuals in the study populations.
• Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
## Nomenclature
Alpha-mannosidosis may also be referred to as lysosomal alpha-d-mannosidase deficiency.
## Prevalence
General estimates for the prevalence of alpha-mannosidosis vary. The most recent study estimated the prevalence to be 1:1,000,000 [
A study from Australia reported a prevalence of 1:500,000 [
Studies from Norway reported six individuals in a population of 4.5 million [
A prevalence of 1:300,000 was reported in the Czech Republic [
The disease is not specific to individuals of any specific ancestry; individuals from all parts of the world have been described [
• A study from Australia reported a prevalence of 1:500,000 [
• Studies from Norway reported six individuals in a population of 4.5 million [
• A prevalence of 1:300,000 was reported in the Czech Republic [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Alpha-Mannosidosis
Coarse facial features
Thickened ribs
Heart defects
Hypertrichosis
Coarse facial features
Dysostosis multiplex
ID
Short stature
Contractures
Hypotonia
Coarse facial features
DD
Frequent upper respiratory infections
Joint stiffness
Seizures
Microcytic anemia
Coarse facial features
Dysostosis multiplex
Short stature
Failure to thrive
Short stature
Normal-to-mildly impaired cognitive development
Coarse facial features
Dysostosis multiplex
ID
Similar to MPS II
DD
Poor feeding
Retinopathy
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
The mucopolysaccharidoses are inherited in an autosomal recessive manner with the exception of mucopolysaccharidosis type II, which is associated with pathogenic variants in
• Coarse facial features
• Thickened ribs
• Heart defects
• Hypertrichosis
• Coarse facial features
• Dysostosis multiplex
• ID
• Short stature
• Contractures
• Hypotonia
• Coarse facial features
• DD
• Frequent upper respiratory infections
• Joint stiffness
• Seizures
• Microcytic anemia
• Coarse facial features
• Dysostosis multiplex
• Short stature
• Failure to thrive
• Short stature
• Normal-to-mildly impaired cognitive development
• Coarse facial features
• Dysostosis multiplex
• ID
• Similar to MPS II
• DD
• Poor feeding
• Retinopathy
## Management
No clinical practice guidelines for alpha-mannosidosis have been published.
To establish the extent of disease and needs in an individual diagnosed with alpha-mannosidosis, the evaluations summarized in
Alpha-Mannosidosis: Recommended Evaluations Following Initial Diagnosis
To incl immunologic testing such as anti-nuclear antibodies & anti-double-stranded-DNA antibodies
Consider referral to rheumatologist.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assess for asthenia
Consider head CT to assess size of ventricles & shape/size of cerebellum, particularly if signs/symptoms of hydrocephalus are present.
Assess for signs/symptoms of ataxia & gait abnormalities.
Gross motor & fine motor skills
Muscle pain, joint aches, reduced range of motion, & bone pain
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Ultrasound is often done, although abdominal MRI may be more informative to calculate organ volumes.
Although organomegaly typically does not cause clinical symptoms, this finding can be used as a clinical marker to assess treatment response.
To assess for aortic or mitral stenosis/regurgitation &/or cardiomyopathy
Consider referral to cardiologist.
Community or
Social work involvement for parental support
Home nursing referral
Based on
ADL = activities of daily living; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SLE = systemic lupus erythematosus
Such as change in social, domestic, or school- or work-related activities or in ability to walk distances
Including headache, increasing gait ataxia, nausea, and/or papilledema
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for alpha-mannosidosis.
Velmanase alfa (Lamzede
Alpha-Mannosidosis: Targeted Treatment
Improvement in both biochemical & functional parameters have been reported.
Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis.
ERT = enzyme replacement therapy
For individuals who weigh less than 49 kg, IV infusion is typically given over a minimum of 60 minutes; for those who weigh 50 kg or more, infusion rate is typically 25 mL/hour.
The key points are:
In a study by
Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [
While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [
The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [
HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable.
Note: Most affected individuals are clinically normal at birth. Since alpha-mannosidosis can be treated with ERT or HSCT, there is a pressing need for newborn screening to identify affected individuals early, before the onset of severe irreversible pathology [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Alpha-Mannosidosis: Treatment of Manifestations
Early antibiotics for bacterial infections
Bacterial & viral infections must be treated w/vigilance.
This typically includes consideration of a ventriculocaval shunt.
Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity.
Hydrotherapy helps to avoid strain on joints.
Special shoes may help w/ankle & foot support.
Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard.
Standard treatment per gastroenterologist &/or endocrinologist
Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis.
Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices).
More complex findings (e.g., retinal dystrophy) may require further input from subspecialists.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
OT = occupational therapy; PT = physical therapy
Regular cardiopulmonary evaluations and a careful airway evaluation prior to any surgical intervention under general anesthesia is recommended.
Authors, personal observations
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [
Consultation with a developmental pediatrician may be helpful in guiding parents/caregivers through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about confusion, delusions, hallucinations, anxiety, and depression can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Alpha-Mannosidosis: Recommended Surveillance
Assess for new manifestations such ataxia & gait abnormalities.
Evaluate for asthenia
Every 6-12 mos in childhood
Annually in adults
Consider DXA bone densitometry scan
Radiographs of hips/spine may be indicated.
Monitoring for diarrhea
Assessment of liver & spleen size through physical exam
3MSCT = three-minute stair climb test; 6MWT = six-minute walk test; BMI = body mass index; DXA = dual-energy x-ray absorptiometry; ERT = enzyme replacement therapy; ESR = erythrocyte sedimentation rate; HSCT = hematopoietic stem cell transplant; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
It is unclear how many of the medical complications will improve or resolve with targeted ERT/HSCT.
In those over age two years; in those younger than age two years, assessment of weight for length may be more appropriate.
For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [
Such as change in social, domestic, or school- or work-related activities or in ability to walk distances
Including headache, increasing gait ataxia, nausea, and/or papilledema
Consider plain radiographs of the head, knees (AP view), spine (lateral view), and any symptomatic sites.
Typically done after age four years
Testing of all at-risk sibs of any age (including prenatal diagnosis) is warranted to allow for early diagnosis and targeted treatment of alpha-mannosidosis (see
Molecular genetic testing if the pathogenic variants in the family are known;
Assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known.
See
Search
Because of the limited number of affected individuals with psychiatric symptoms, no conclusion about the benefit of various psychotropic drugs can be made at this time. However, to date, 5-15 mg of olanzapine at bedtime has been used in several affected individuals with some success [D Malm, personal observations].
• To incl immunologic testing such as anti-nuclear antibodies & anti-double-stranded-DNA antibodies
• Consider referral to rheumatologist.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assess for asthenia
• Consider head CT to assess size of ventricles & shape/size of cerebellum, particularly if signs/symptoms of hydrocephalus are present.
• Assess for signs/symptoms of ataxia & gait abnormalities.
• Gross motor & fine motor skills
• Muscle pain, joint aches, reduced range of motion, & bone pain
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Ultrasound is often done, although abdominal MRI may be more informative to calculate organ volumes.
• Although organomegaly typically does not cause clinical symptoms, this finding can be used as a clinical marker to assess treatment response.
• To assess for aortic or mitral stenosis/regurgitation &/or cardiomyopathy
• Consider referral to cardiologist.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Improvement in both biochemical & functional parameters have been reported.
• Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis.
• In a study by
• Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [
• While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [
• The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [
• HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable.
• Early antibiotics for bacterial infections
• Bacterial & viral infections must be treated w/vigilance.
• This typically includes consideration of a ventriculocaval shunt.
• Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity.
• Hydrotherapy helps to avoid strain on joints.
• Special shoes may help w/ankle & foot support.
• Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard.
• Standard treatment per gastroenterologist &/or endocrinologist
• Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
• Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis.
• Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices).
• More complex findings (e.g., retinal dystrophy) may require further input from subspecialists.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [
• Assess for new manifestations such ataxia & gait abnormalities.
• Evaluate for asthenia
• Every 6-12 mos in childhood
• Annually in adults
• Consider DXA bone densitometry scan
• Radiographs of hips/spine may be indicated.
• Monitoring for diarrhea
• Assessment of liver & spleen size through physical exam
• Molecular genetic testing if the pathogenic variants in the family are known;
• Assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with alpha-mannosidosis, the evaluations summarized in
Alpha-Mannosidosis: Recommended Evaluations Following Initial Diagnosis
To incl immunologic testing such as anti-nuclear antibodies & anti-double-stranded-DNA antibodies
Consider referral to rheumatologist.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assess for asthenia
Consider head CT to assess size of ventricles & shape/size of cerebellum, particularly if signs/symptoms of hydrocephalus are present.
Assess for signs/symptoms of ataxia & gait abnormalities.
Gross motor & fine motor skills
Muscle pain, joint aches, reduced range of motion, & bone pain
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Ultrasound is often done, although abdominal MRI may be more informative to calculate organ volumes.
Although organomegaly typically does not cause clinical symptoms, this finding can be used as a clinical marker to assess treatment response.
To assess for aortic or mitral stenosis/regurgitation &/or cardiomyopathy
Consider referral to cardiologist.
Community or
Social work involvement for parental support
Home nursing referral
Based on
ADL = activities of daily living; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SLE = systemic lupus erythematosus
Such as change in social, domestic, or school- or work-related activities or in ability to walk distances
Including headache, increasing gait ataxia, nausea, and/or papilledema
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl immunologic testing such as anti-nuclear antibodies & anti-double-stranded-DNA antibodies
• Consider referral to rheumatologist.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assess for asthenia
• Consider head CT to assess size of ventricles & shape/size of cerebellum, particularly if signs/symptoms of hydrocephalus are present.
• Assess for signs/symptoms of ataxia & gait abnormalities.
• Gross motor & fine motor skills
• Muscle pain, joint aches, reduced range of motion, & bone pain
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Ultrasound is often done, although abdominal MRI may be more informative to calculate organ volumes.
• Although organomegaly typically does not cause clinical symptoms, this finding can be used as a clinical marker to assess treatment response.
• To assess for aortic or mitral stenosis/regurgitation &/or cardiomyopathy
• Consider referral to cardiologist.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for alpha-mannosidosis.
Velmanase alfa (Lamzede
Alpha-Mannosidosis: Targeted Treatment
Improvement in both biochemical & functional parameters have been reported.
Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis.
ERT = enzyme replacement therapy
For individuals who weigh less than 49 kg, IV infusion is typically given over a minimum of 60 minutes; for those who weigh 50 kg or more, infusion rate is typically 25 mL/hour.
The key points are:
In a study by
Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [
While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [
The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [
HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable.
Note: Most affected individuals are clinically normal at birth. Since alpha-mannosidosis can be treated with ERT or HSCT, there is a pressing need for newborn screening to identify affected individuals early, before the onset of severe irreversible pathology [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Alpha-Mannosidosis: Treatment of Manifestations
Early antibiotics for bacterial infections
Bacterial & viral infections must be treated w/vigilance.
This typically includes consideration of a ventriculocaval shunt.
Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity.
Hydrotherapy helps to avoid strain on joints.
Special shoes may help w/ankle & foot support.
Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard.
Standard treatment per gastroenterologist &/or endocrinologist
Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis.
Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices).
More complex findings (e.g., retinal dystrophy) may require further input from subspecialists.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
OT = occupational therapy; PT = physical therapy
Regular cardiopulmonary evaluations and a careful airway evaluation prior to any surgical intervention under general anesthesia is recommended.
Authors, personal observations
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [
Consultation with a developmental pediatrician may be helpful in guiding parents/caregivers through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about confusion, delusions, hallucinations, anxiety, and depression can be addressed by a pediatric psychiatrist.
• Improvement in both biochemical & functional parameters have been reported.
• Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis.
• In a study by
• Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [
• While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [
• The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [
• HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable.
• Early antibiotics for bacterial infections
• Bacterial & viral infections must be treated w/vigilance.
• This typically includes consideration of a ventriculocaval shunt.
• Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity.
• Hydrotherapy helps to avoid strain on joints.
• Special shoes may help w/ankle & foot support.
• Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard.
• Standard treatment per gastroenterologist &/or endocrinologist
• Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
• Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis.
• Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices).
• More complex findings (e.g., retinal dystrophy) may require further input from subspecialists.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [
## Targeted Therapies
Velmanase alfa (Lamzede
Alpha-Mannosidosis: Targeted Treatment
Improvement in both biochemical & functional parameters have been reported.
Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis.
ERT = enzyme replacement therapy
For individuals who weigh less than 49 kg, IV infusion is typically given over a minimum of 60 minutes; for those who weigh 50 kg or more, infusion rate is typically 25 mL/hour.
The key points are:
In a study by
Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [
While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [
The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [
HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable.
Note: Most affected individuals are clinically normal at birth. Since alpha-mannosidosis can be treated with ERT or HSCT, there is a pressing need for newborn screening to identify affected individuals early, before the onset of severe irreversible pathology [
• Improvement in both biochemical & functional parameters have been reported.
• Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis.
• In a study by
• Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [
• While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [
• The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [
• HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Alpha-Mannosidosis: Treatment of Manifestations
Early antibiotics for bacterial infections
Bacterial & viral infections must be treated w/vigilance.
This typically includes consideration of a ventriculocaval shunt.
Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity.
Hydrotherapy helps to avoid strain on joints.
Special shoes may help w/ankle & foot support.
Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard.
Standard treatment per gastroenterologist &/or endocrinologist
Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis.
Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices).
More complex findings (e.g., retinal dystrophy) may require further input from subspecialists.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
OT = occupational therapy; PT = physical therapy
Regular cardiopulmonary evaluations and a careful airway evaluation prior to any surgical intervention under general anesthesia is recommended.
Authors, personal observations
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [
Consultation with a developmental pediatrician may be helpful in guiding parents/caregivers through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about confusion, delusions, hallucinations, anxiety, and depression can be addressed by a pediatric psychiatrist.
• Early antibiotics for bacterial infections
• Bacterial & viral infections must be treated w/vigilance.
• This typically includes consideration of a ventriculocaval shunt.
• Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity.
• Hydrotherapy helps to avoid strain on joints.
• Special shoes may help w/ankle & foot support.
• Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard.
• Standard treatment per gastroenterologist &/or endocrinologist
• Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
• Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis.
• Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices).
• More complex findings (e.g., retinal dystrophy) may require further input from subspecialists.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [
##
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
##
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [
##
Consultation with a developmental pediatrician may be helpful in guiding parents/caregivers through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about confusion, delusions, hallucinations, anxiety, and depression can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Alpha-Mannosidosis: Recommended Surveillance
Assess for new manifestations such ataxia & gait abnormalities.
Evaluate for asthenia
Every 6-12 mos in childhood
Annually in adults
Consider DXA bone densitometry scan
Radiographs of hips/spine may be indicated.
Monitoring for diarrhea
Assessment of liver & spleen size through physical exam
3MSCT = three-minute stair climb test; 6MWT = six-minute walk test; BMI = body mass index; DXA = dual-energy x-ray absorptiometry; ERT = enzyme replacement therapy; ESR = erythrocyte sedimentation rate; HSCT = hematopoietic stem cell transplant; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
It is unclear how many of the medical complications will improve or resolve with targeted ERT/HSCT.
In those over age two years; in those younger than age two years, assessment of weight for length may be more appropriate.
For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [
Such as change in social, domestic, or school- or work-related activities or in ability to walk distances
Including headache, increasing gait ataxia, nausea, and/or papilledema
Consider plain radiographs of the head, knees (AP view), spine (lateral view), and any symptomatic sites.
Typically done after age four years
• Assess for new manifestations such ataxia & gait abnormalities.
• Evaluate for asthenia
• Every 6-12 mos in childhood
• Annually in adults
• Consider DXA bone densitometry scan
• Radiographs of hips/spine may be indicated.
• Monitoring for diarrhea
• Assessment of liver & spleen size through physical exam
## Evaluation of Relatives at Risk
Testing of all at-risk sibs of any age (including prenatal diagnosis) is warranted to allow for early diagnosis and targeted treatment of alpha-mannosidosis (see
Molecular genetic testing if the pathogenic variants in the family are known;
Assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known.
## Therapies Under Investigation
Search
## Other
Because of the limited number of affected individuals with psychiatric symptoms, no conclusion about the benefit of various psychotropic drugs can be made at this time. However, to date, 5-15 mg of olanzapine at bedtime has been used in several affected individuals with some success [D Malm, personal observations].
## Genetic Counseling
Alpha-mannosidosis is inherited in an autosomal recessive manner.
The parents of an affected individual are presumed to be heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Affected sibs (with identical pathogenic variants) may present with different phenotypes [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
It is appropriate to offer molecular genetic testing of
Note: Given the wide variability in phenotype and lack of genotype-phenotype correlation, severity of disease cannot be predicted based on the results of molecular genetic or biochemical testing.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Affected sibs (with identical pathogenic variants) may present with different phenotypes [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• It is appropriate to offer molecular genetic testing of
## Mode of Inheritance
Alpha-mannosidosis is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Affected sibs (with identical pathogenic variants) may present with different phenotypes [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are presumed to be heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Affected sibs (with identical pathogenic variants) may present with different phenotypes [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
It is appropriate to offer molecular genetic testing of
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• It is appropriate to offer molecular genetic testing of
## Prenatal Testing and Preimplantation Genetic Testing
Note: Given the wide variability in phenotype and lack of genotype-phenotype correlation, severity of disease cannot be predicted based on the results of molecular genetic or biochemical testing.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
Alpha-Mannosidosis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Alpha-Mannosidosis (
Alpha-mannosidosis belongs to a group of disorders called glycoproteinoses, which are caused by lack of one of the many enzymes required for the sequential degradation of asparagine-linked oligosaccharides from glycoproteins in the lysosomes. During normal turnover and catabolism, glycoproteins are digested by proteinases and glycosidases within the lysosomes. These enzymes degrade glycoproteins into fragments small enough to be excreted or transported to the cytosol for reuse. Lack of any one of these enzymes, including alpha-mannosidase, will compromise the degradation pathway as a whole, resulting in accumulation of oligosaccharides or glycopeptides in the lysosomes. Accumulation of storage material is thought to impair lysosomal function and thereby harm cellular functions such as vesicle maturation, endocytosis, exocytosis, and calcium homeostasis [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Alpha-mannosidosis belongs to a group of disorders called glycoproteinoses, which are caused by lack of one of the many enzymes required for the sequential degradation of asparagine-linked oligosaccharides from glycoproteins in the lysosomes. During normal turnover and catabolism, glycoproteins are digested by proteinases and glycosidases within the lysosomes. These enzymes degrade glycoproteins into fragments small enough to be excreted or transported to the cytosol for reuse. Lack of any one of these enzymes, including alpha-mannosidase, will compromise the degradation pathway as a whole, resulting in accumulation of oligosaccharides or glycopeptides in the lysosomes. Accumulation of storage material is thought to impair lysosomal function and thereby harm cellular functions such as vesicle maturation, endocytosis, exocytosis, and calcium homeostasis [
Variants listed in the table have been provided by the authors.
## Chapter Notes
Can Ficicioglu, MD, PhD (2024-present)Dag Malm, MD, PhD; Tromsø Center of Internal Medicine (2001-2024)Øivind Nilssen, PhD; University of Tromsø (2001-2024)Karolina M Stepien, MD, PhD (2024-present)
13 June 2024 (ma) Comprehensive update posted live
21 February 2019 (sw) Comprehensive update posted live
3 May 2012 (me) Comprehensive update posted live
26 August 2008 (cg) Comprehensive update posted live
25 January 2006 (me) Comprehensive update posted live
3 December 2003 (me) Comprehensive update posted live
11 October 2001 (me) Review posted live
April 2001 (dm) Original submission
• 13 June 2024 (ma) Comprehensive update posted live
• 21 February 2019 (sw) Comprehensive update posted live
• 3 May 2012 (me) Comprehensive update posted live
• 26 August 2008 (cg) Comprehensive update posted live
• 25 January 2006 (me) Comprehensive update posted live
• 3 December 2003 (me) Comprehensive update posted live
• 11 October 2001 (me) Review posted live
• April 2001 (dm) Original submission
## Author History
Can Ficicioglu, MD, PhD (2024-present)Dag Malm, MD, PhD; Tromsø Center of Internal Medicine (2001-2024)Øivind Nilssen, PhD; University of Tromsø (2001-2024)Karolina M Stepien, MD, PhD (2024-present)
## Revision History
13 June 2024 (ma) Comprehensive update posted live
21 February 2019 (sw) Comprehensive update posted live
3 May 2012 (me) Comprehensive update posted live
26 August 2008 (cg) Comprehensive update posted live
25 January 2006 (me) Comprehensive update posted live
3 December 2003 (me) Comprehensive update posted live
11 October 2001 (me) Review posted live
April 2001 (dm) Original submission
• 13 June 2024 (ma) Comprehensive update posted live
• 21 February 2019 (sw) Comprehensive update posted live
• 3 May 2012 (me) Comprehensive update posted live
• 26 August 2008 (cg) Comprehensive update posted live
• 25 January 2006 (me) Comprehensive update posted live
• 3 December 2003 (me) Comprehensive update posted live
• 11 October 2001 (me) Review posted live
• April 2001 (dm) Original submission
## Key Sections in This
## References
Guffon N, Tylki-Szymanska A, Borgwardt L, Lund AM, Gil-Campos M, Parini R, Hennermann JB. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Mol Genet Metab. 2019;126:470-4. [
Nilssen Ø, Stensland HM, Malm D. Clinical utility gene card for: α-mannosidosis. Eur J Hum Genet. 2011;19. [
• Guffon N, Tylki-Szymanska A, Borgwardt L, Lund AM, Gil-Campos M, Parini R, Hennermann JB. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Mol Genet Metab. 2019;126:470-4. [
• Nilssen Ø, Stensland HM, Malm D. Clinical utility gene card for: α-mannosidosis. Eur J Hum Genet. 2011;19. [
## Published Guidelines / Consensus Statements
Guffon N, Tylki-Szymanska A, Borgwardt L, Lund AM, Gil-Campos M, Parini R, Hennermann JB. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Mol Genet Metab. 2019;126:470-4. [
Nilssen Ø, Stensland HM, Malm D. Clinical utility gene card for: α-mannosidosis. Eur J Hum Genet. 2011;19. [
• Guffon N, Tylki-Szymanska A, Borgwardt L, Lund AM, Gil-Campos M, Parini R, Hennermann JB. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Mol Genet Metab. 2019;126:470-4. [
• Nilssen Ø, Stensland HM, Malm D. Clinical utility gene card for: α-mannosidosis. Eur J Hum Genet. 2011;19. [
## Literature Cited
|
[] |
11/10/2001
|
13/6/2024
|
18/7/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
a-thal
|
a-thal
| ["Hemoglobin Bart Hydrops Fetalis (Hb Bart) Syndrome","Hemoglobin H (HbH) Disease","a-Thalassemia Tr(...TRUNCATED) |
Alpha-Thalassemia
|
Hannah Tamary, Orly Dgany
| "Summary Alpha-thalassemia (α-thalassemia) has two clinically significant forms: hemoglobin Bart hy(...TRUNCATED) | "For synonyms and outdated names see\n\nIn descending order of severity\n\n## Diagnosis\n\nAlpha-tha(...TRUNCATED) |
[] |
1/11/2005
|
1/10/2020
|
23/5/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
aadc-def
|
aadc-def
| ["AADC Deficiency","AADC Deficiency","Aromatic-L-amino-acid decarboxylase","DDC","Aromatic L-Amino A(...TRUNCATED) |
Aromatic L-Amino Acid Decarboxylase Deficiency
|
Nenad Blau, Toni S Pearson, Manju A Kurian, Sarah H Elsea
| "Summary Individuals with aromatic L-amino acid decarboxylase (AADC) deficiency typically have compl(...TRUNCATED) | "## Diagnosis\n\nConsensus clinical diagnostic criteria for aromatic L-amino acid decarboxylase (AAD(...TRUNCATED) |
[] |
12/10/2023
|
23/1/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
aars2-dis
|
aars2-dis
| ["AARS2-Related Infant-Onset Cardiomyopathy","AARS2-Related Neurodegeneration With or Without Leukoe(...TRUNCATED) |
Tomasz Chmiela, Zbigniew K Wszolek
|
Summary The diagnosis of In In
| "Infantile-onset cardiomyopathy\n\nNeurodegeneration with or without leukoencephalopathy\n\nFor othe(...TRUNCATED) |
[] |
31/10/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
ab-lipo-p
|
ab-lipo-p
| ["Bassen-Kornzweig Syndrome","Bassen-Kornzweig Syndrome","Microsomal triglyceride transfer protein l(...TRUNCATED) |
Abetalipoproteinemia
|
John R Burnett, Amanda J Hooper, Robert A Hegele
| "Summary Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiti(...TRUNCATED) | "## Diagnosis\n\nNo formal clinical diagnostic criteria for abetalipoproteinemia have been published(...TRUNCATED) | ["S Bishara, S Merin, M Cooper, E Azizi, G Delpre, RJ Deckelbaum. Combined vitamin A and E therapy p(...TRUNCATED) |
25/10/2018
|
19/5/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
abs
|
abs
| ["POR Deficiency","PORD","POR Deficiency","PORD","Antley-Bixler Syndrome","Congenital Adrenal Hyperp(...TRUNCATED) |
Cytochrome P450 Oxidoreductase Deficiency
|
Jan Idkowiak, Deborah Cragun, Robert J Hopkin, Wiebke Arlt
| "Summary Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a br(...TRUNCATED) | "Antley-Bixler syndrome\n\nCongenital adrenal hyperplasia due to apparent combined CYP17A1 and CYP21(...TRUNCATED) | ["M Adachi, K Tachibana, Y Asakura, T Yamamoto, K Hanaki, A Oka. Compound heterozygous mutations of (...TRUNCATED) |
8/9/2005
|
3/8/2017
|
2/11/2015
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
accpn
|
accpn
| ["Agenesis of Corpus Callosum with Peripheral Neuropathy (ACCPN)","Andermann Syndrome","Agenesis of (...TRUNCATED) |
Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum
|
Claudie Gauvreau, Jean-Denis Brisson, Nicolas Dupré
| "Summary Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a (...TRUNCATED) | "## Diagnosis\n\nConsensus diagnostic criteria for hereditary motor and sensory neuropathy with agen(...TRUNCATED) |
[] |
2/2/2006
|
17/9/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
achm
|
achm
| ["Complete Achromatopsia (Rod Monochromatism, Total Color Blindness)","Incomplete Achromatopsia","Co(...TRUNCATED) |
Achromatopsia
|
Susanne Kohl, Herbert Jägle, Bernd Wissinger, Ditta Zobor
| "Summary Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sens(...TRUNCATED) | "Complete achromatopsia (rod monochromatism, total color blindness)\n\nIncomplete achromatopsia\n\nF(...TRUNCATED) |
[] |
24/6/2004
|
20/9/2018
|
25/2/2016
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
achon1b
|
achon1b
| ["ACG1B, SLC26A2-Related Achondrogenesis","ACG1B","SLC26A2-Related Achondrogenesis","Sulfate transpo(...TRUNCATED) |
Achondrogenesis Type 1B
|
Sheila Unger, Andrea Superti-Furga
| "Summary Clinical features of achondrogenesis type 1B (ACG1B) include extremely short limbs with sho(...TRUNCATED) | "## Diagnosis\n\nAchondrogenesis type 1B (ACG1B) is a perinatal-lethal disorder with death occurring(...TRUNCATED) |
[] |
30/8/2002
|
9/6/2022
|
16/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
achondroplasia
|
achondroplasia
| ["FGFR3-Related Achondroplasia","FGFR3-Related Achondroplasia","Fibroblast growth factor receptor 3"(...TRUNCATED) |
Achondroplasia
|
Janet M Legare
| "Summary Achondroplasia is the most common cause of disproportionate short stature. Affected individ(...TRUNCATED) | "## Diagnosis\n\nBoth the clinical and radiologic features of achondroplasia have been well defined (...TRUNCATED) | ["MC Ain, JA Browne. Spinal arthrodesis with instrumentation for thoracolumbar kyphosis in pediatric(...TRUNCATED) |
12/10/1998
|
6/8/2020
|
11/5/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
End of preview. Expand
in Data Studio
GeneReviews Dataset Extraction
This project extracts text and metadata from GeneReviews® chapters downloaded from NCBI Bookshelf and creates a structured dataset in Hugging Face format.
Overview
GeneReviews® is an international point-of-care resource for clinicians, providing clinically relevant and medically actionable information for inherited conditions. This project processes the XML files from the GeneReviews database and creates a structured dataset suitable for machine learning and research applications.
📈 Dataset Statistics:
- Total Records: 929 GeneReviews chapters
- Average Abstract Length: 899.6 characters
- Average Content Length: 56,377.9 characters
- Total References: 13,683 references across all chapters
- Average References per Chapter: 14.7
- Chapters with >100 references: 12 chapters
- Total Keywords: 9,616
- Unique Keywords: 6,824
Source Information
- Source: GeneReviews® on NCBI Bookshelf
- Publisher: University of Washington, Seattle
- ISSN: 2372-0697
- Content Type: Clinical reviews of genetic conditions
- License: Open access for noncommercial research purposes
Dataset Structure
Each record in the dataset contains the following fields:
| Field | Type | Description |
|---|---|---|
id |
string | Unique chapter identifier |
ch_id |
string | Chapter ID (as you renamed it) |
title |
string | Chapter title |
authors |
string | Comma-separated author names |
journal |
string | "GeneReviews®" |
abstract |
string | Chapter abstract/summary only |
content |
string | Chapter body content only (excluding abstract) |
references |
array | Array of reference citations |
keywords |
array | Keywords and terms |
source_url |
string | Link to GeneReviews resource |
publication_types |
array | ["Review", "Clinical Review"] |
created_date |
string | Creation date |
updated_date |
string | Last update date |
revised_date |
string | Revision date |
Files
extract_genereviews.py: Main extraction scriptload_genereviews_dataset.py: Script to load and demonstrate the datasetrequirements.txt: Python dependenciesgenereviews_dataset/: Hugging Face dataset directorygenereviews_dataset.json: JSON version of the dataset
Installation
- Install the required dependencies:
pip install -r requirements.txt
Usage
from datasets import load_from_disk
# Load the dataset
dataset = load_from_disk("genereviews_dataset")
# Access by chapter
record = dataset[0]
chapter_id = record['ch_id']
# Access separated content
abstract = record['abstract'] # Only the abstract
content = record['content'] # Only the body content
references = record['references'] # Array of reference citations
Search for Specific Conditions
# Search for cystic fibrosis
cf_records = dataset.filter(lambda x: "cystic fibrosis" in x['title'].lower())
# Search for cancer-related content
cancer_records = dataset.filter(lambda x: "cancer" in x['content'].lower())
Analyze Publication Dates
# Find recently updated chapters
recent_updates = dataset.filter(lambda x: "2024" in x['updated_date'])
Extract Keywords
# Get all unique keywords
all_keywords = set()
for record in dataset:
all_keywords.update(record['keywords'])
Citation
When using this dataset, please cite:
GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.
Available from: https://www.ncbi.nlm.nih.gov/books/NBK1116/
License
This dataset is derived from GeneReviews®, which is owned by the University of Washington. Permission is granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that proper attribution is given.
- Downloads last month
- 111