🏷

Classifications

Harrison's Chapter

Lysosomal Storage

🔗

Mappings

MONDO

MONDO:0009561 alpha-mannosidosis

Orphanet ORPHA:61 lists MONDO:0009561 as an exact cross-reference for alpha-mannosidosis.

📘

Definitions

1

Orphanet alpha-mannosidosis definition

An inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual deficit.

OTHER

Show evidence (2 references)

ORPHA:61 SUPPORT Other

"An inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual deficit."

Orphanet defines the core multisystem phenotype.

PMID:40276561 SUPPORT Human Clinical

"Alpha-mannosidosis (AM) is an ultrarare multisystemic disorder caused by"

Contemporary patient cohort supports the ultra-rare multisystem disease framing.

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Alpha-mannosidosis is inherited in an autosomal recessive pattern.

Autosomal recessive inheritance

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"Autosomal recessive"

Orphanet records autosomal recessive inheritance for alpha-mannosidosis.

◆

Subtypes

2

Alpha-mannosidosis, infantile form MONDO:0017732

Infantile-onset clinical subtype of alpha-mannosidosis with Orphanet exact MONDO mapping and MAN2B1 disease-causing gene association.

Show evidence (2 references)

ORPHA:309282 SUPPORT Other

"MONDO:0017732 | Exact"

Orphanet maps the infantile form to MONDO:0017732.

ORPHA:309282 SUPPORT Other

"MAN2B1 | mannosidase alpha class 2B member 1 | hgnc:6826 | Disease-causing germline mutation(s) in"

Orphanet identifies MAN2B1 as the disease-causing gene for this subtype.

Alpha-mannosidosis, adult form MONDO:0017733

Adult-onset clinical subtype of alpha-mannosidosis with Orphanet exact MONDO mapping and MAN2B1 disease-causing gene association.

Show evidence (2 references)

ORPHA:309288 SUPPORT Other

"MONDO:0017733 | Exact"

Orphanet maps the adult form to MONDO:0017733.

ORPHA:309288 SUPPORT Other

"MAN2B1 | mannosidase alpha class 2B member 1 | hgnc:6826 | Disease-causing germline mutation(s) in"

Orphanet identifies MAN2B1 as the disease-causing gene for this subtype.

⚙

Pathophysiology

5

MAN2B1 lysosomal alpha-mannosidase deficiency

Biallelic pathogenic variants in MAN2B1 reduce lysosomal alpha-mannosidase activity, impairing the lysosomal catabolism of glycoprotein-derived alpha-mannosides.

MAN2B1 link

glycoprotein catabolic process link ↓ DECREASED

alpha-mannosidase activity link ↓ DECREASED

lysosome link

Downstream

Mannose-rich oligosaccharide lysosomal storage Reduced lysosomal alpha-mannosidase blocks glycoprotein oligosaccharide degradation.

Reduced acid alpha-mannosidase activity MAN2B1 pathogenic variation is reflected diagnostically by reduced leukocyte or cellular acid alpha-mannosidase activity.

Infantile form abnormal circulating enzyme concentration or activity The infantile subtype records abnormal enzyme/coenzyme activity as the enzyme-level phenotype.

Show evidence (3 references)

ORPHA:309282 SUPPORT Other

"MAN2B1 | mannosidase alpha class 2B member 1 | hgnc:6826 | Disease-causing germline mutation(s) in"

Orphanet identifies MAN2B1 as the disease-causing gene.

PMID:18651971 SUPPORT Human Clinical

"The disorder is caused by lysosomal alpha-mannosidase deficiency."

Review directly supports deficient lysosomal alpha-mannosidase activity.

PMID:26048034 SUPPORT Human Clinical

"of lysosomal alpha-mannosidase activity."

Genotype-phenotype cohort supports MAN2B1 variants causing loss of lysosomal enzyme activity.

Mannose-rich oligosaccharide lysosomal storage

Deficient lysosomal alpha-mannosidase activity causes accumulation of mannose-rich oligosaccharides in cells, body fluids, and cerebrospinal fluid, linking the enzyme defect to multisystem storage pathology.

glycoprotein catabolic process link ↓ DECREASED

lysosome link

Downstream

Neurodevelopmental and motor impairment CNS storage and dysfunction contribute to cognitive, speech, hypotonia, and motor manifestations.

Immune deficiency and recurrent infections Systemic storage disease is associated with immunodeficiency and recurrent infections.

Skeletal and craniofacial storage manifestations Connective-tissue and skeletal involvement produces coarse facial features and skeletal dysplasia.

Increased urinary mannose-rich oligosaccharides Lysosomal storage is reflected by increased urinary excretion of mannose-rich oligosaccharides.

Oligosacchariduria in alpha-mannosidosis subtypes Orphanet subtype records capture oligosacchariduria as a frequent storage biomarker.

Hearing impairment Multisystem storage disease includes moderate-to-severe hearing impairment.

Cataract Ocular involvement in alpha-mannosidosis includes cataract.

Corneal opacity Ocular storage manifestations can include corneal opacity.

Infantile form cataract The infantile alpha-mannosidosis subtype includes cataract.

Infantile form strabismus The infantile alpha-mannosidosis subtype includes strabismus.

Infantile form hypermetropia The infantile alpha-mannosidosis subtype includes hypermetropia.

Infantile form myopia The infantile alpha-mannosidosis subtype includes myopia.

Splenomegaly Visceral storage manifestations include splenic enlargement.

Hepatomegaly Visceral storage manifestations include hepatic enlargement.

Infantile form hepatosplenomegaly The infantile subtype includes combined hepatic and splenic enlargement.

Generalized abnormality of skin Multisystem storage manifestations include generalized skin abnormalities.

Inguinal hernia Connective-tissue and visceral manifestations include inguinal hernia.

Show evidence (2 references)

PMID:36849760 SUPPORT Human Clinical

"alpha-mannosidase deficiency that leads to the accumulation"

Pediatric velmanase alfa study summarizes the storage substrate caused by enzyme deficiency.

PMID:26048034 SUPPORT Human Clinical

"CSF-oligosaccharides, higher point scores"

Patient genotype-phenotype study used CSF oligosaccharides as a storage-related biochemical measure.

Neurodevelopmental and motor impairment

Central nervous system involvement produces intellectual disability, developmental delay, impaired speech, hypotonia, ataxia, and behavioral or psychiatric manifestations.

central nervous system development link ⚠ ABNORMAL

brain link

Downstream

Intellectual disability Progressive CNS involvement impairs cognition and adaptive function.

Global developmental delay Early neurodevelopmental involvement delays acquisition of developmental milestones.

Hypotonia Motor system involvement contributes to low tone and delayed motor function.

Atypical behavior CNS involvement includes behavioral manifestations.

Hallucinations Psychiatric involvement can include hallucinations.

Increased intracranial pressure Neurologic involvement can include increased intracranial pressure.

Infantile form intellectual disability Neurodevelopmental involvement in the infantile subtype includes intellectual disability.

Infantile form hypotonia Motor involvement in the infantile subtype includes hypotonia.

Infantile form short attention span Neurodevelopmental involvement in the infantile subtype includes impaired attention.

Infantile form delayed speech and language development CNS involvement impairs speech and language development in the infantile subtype.

Ataxia in alpha-mannosidosis subtypes Motor-system involvement includes ataxia across recorded subtypes.

Infantile form mild intellectual disability The infantile subtype includes mild intellectual disability in Orphanet records.

Adult form mild intellectual disability The adult subtype includes mild intellectual disability in Orphanet records.

Infantile form motor delay Motor-system involvement in the infantile subtype delays motor milestones.

Infantile form specific learning disability Neurodevelopmental involvement in the infantile subtype includes specific learning disability.

Infantile form myopathy Motor-system involvement in the infantile subtype includes myopathy.

Asthenia in alpha-mannosidosis subtypes Motor and systemic involvement includes asthenia across recorded subtypes.

Show evidence (2 references)

PMID:18651971 SUPPORT Human Clinical

"gradual impairment of mental functions and speech,"

Review supports cognitive, speech, and psychiatric involvement.

PMID:26048034 SUPPORT Human Clinical

"Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."

Patient cohort summarizes neurologic and motor manifestations.

Immune deficiency and recurrent infections

Immune dysfunction is a core alpha-mannosidosis manifestation and is clinically expressed as recurrent infections, especially during childhood.

innate immune response link ↓ DECREASED

Downstream

Recurrent respiratory infections Immunodeficiency contributes to recurrent respiratory infections.

Chronic otitis media Recurrent infections include frequent middle-ear disease.

Infantile form otitis media Recurrent middle-ear infections are prominent in the infantile subtype.

Infantile form mixed hearing impairment Recurrent middle-ear disease can contribute to the conductive component of mixed hearing impairment in the infantile subtype.

Infantile form pneumonia Immunodeficiency predisposes to pneumonia in the infantile subtype.

Infantile form recurrent infections The infantile subtype includes recurrent infections as a core immune manifestation.

Adult form recurrent infections The adult subtype can also retain recurrent infections.

Infantile form immunodeficiency The infantile subtype includes immunodeficiency.

Infantile form recurrent gastroenteritis Immune dysfunction can include recurrent gastrointestinal infections.

Show evidence (1 reference)

PMID:18651971 SUPPORT Human Clinical

"Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life),"

Review directly supports immunodeficiency with recurrent infections.

Skeletal and craniofacial storage manifestations

Storage disease produces progressive craniofacial coarsening and skeletal abnormalities including dysostosis multiplex, scoliosis, thoracic deformity, hip abnormalities, and delayed skeletal maturation.

skeletal system development link ⚠ ABNORMAL

skeletal system link

Downstream

Coarse facial features Craniofacial storage contributes to coarse facial appearance.

Skeletal dysplasia Skeletal involvement causes dysplasia and delayed skeletal maturation.

Scoliosis Vertebral and skeletal involvement contributes to spinal curvature.

Macroglossia Craniofacial and oral storage manifestations include macroglossia.

Narrow palate Craniofacial development and storage manifestations include a narrow palate.

Gingival overgrowth Oral soft-tissue storage manifestations include gingival overgrowth.

Macrocephaly Craniofacial storage manifestations include macrocephaly.

Mandibular prognathia Craniofacial skeletal involvement can produce mandibular prognathia.

Hypertelorism Craniofacial involvement includes hypertelorism.

Prominent supraorbital ridges Craniofacial coarsening includes prominent supraorbital ridges.

Macrotia Craniofacial dysmorphism includes macrotia.

Short neck Craniofacial and skeletal involvement includes a short neck.

Widely spaced teeth Oral and craniofacial involvement includes widely spaced teeth.

Dental malocclusion Craniofacial skeletal and dental involvement includes malocclusion.

Arthritis Skeletal involvement can include arthritis.

Hip dysplasia Skeletal dysplasia includes hip involvement.

Delayed skeletal maturation Skeletal storage manifestations include delayed skeletal maturation.

Kyphosis Vertebral skeletal involvement contributes to kyphosis.

Craniofacial hyperostosis Craniofacial skeletal involvement includes hyperostosis.

Depressed nasal bridge Craniofacial coarsening includes a depressed nasal bridge.

Bowing of the long bones Skeletal dysplasia includes bowing of long bones.

Hypoplastic inferior ilia Pelvic skeletal dysplasia includes hypoplastic inferior ilia.

Open bite Craniofacial and dental involvement includes open bite.

Avascular necrosis Skeletal involvement can include avascular necrosis.

Abnormality of the helix Craniofacial dysmorphism includes abnormal helix morphology.

Synostosis of joints Skeletal involvement includes joint synostosis.

Infantile form coarse facial features The infantile subtype includes coarse facial features.

Infantile form hypertelorism The infantile subtype includes hypertelorism.

Infantile form dysostosis multiplex The infantile subtype includes dysostosis multiplex.

Infantile form facial shape deformation The infantile subtype includes facial shape deformation.

Infantile form abnormal skeletal morphology The infantile subtype includes abnormal skeletal morphology.

Show evidence (2 references)

PMID:18651971 SUPPORT Human Clinical

"skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum)"

Review supports skeletal dysplasia and spinal/thoracic involvement.

PMID:26048034 SUPPORT Human Clinical

"Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."

Cohort review supports craniofacial and musculoskeletal involvement.

✶

Histopathology

1

Lysosomal cellular storage pathology FREQUENT

Alpha-mannosidosis is a lysosomal enzyme-deficiency disorder; tissue and cellular pathology are expected to reflect lysosomal storage of mannose-rich oligosaccharides. This entry records the storage-pathology axis without asserting a PAS-positive lymphocyte finding not present in the current abstract-only reference cache.

Show evidence (1 reference)

PMID:18651971 SUPPORT Human Clinical

"The disorder is caused by lysosomal alpha-mannosidase deficiency."

The review supports alpha-mannosidosis as a lysosomal enzyme-deficiency storage disease.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

71

Cardiovascular 2

Splenomegaly VERY_FREQUENT Splenomegaly (HP:0001744)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0001744 | Splenomegaly | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Infantile form hepatosplenomegaly FREQUENT Hepatosplenomegaly (HP:0001433)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0001433 | Hepatosplenomegaly | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Digestive 2

Inguinal hernia FREQUENT Inguinal hernia (HP:0000023)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000023 | Inguinal hernia | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Hepatomegaly VERY_FREQUENT Hepatomegaly (HP:0002240)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0002240 | Hepatomegaly | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Ear 4

Hearing impairment VERY_FREQUENT Hearing impairment (HP:0000365)

Show evidence (2 references)

ORPHA:61 SUPPORT Other

"HP:0000365 | Hearing impairment | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

PMID:18651971 SUPPORT Human Clinical

"hearing impairment (moderate-to-severe sensorineural hearing loss)"

Review supports hearing impairment as a core manifestation.

Chronic otitis media FREQUENT Chronic otitis media (HP:0000389)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000389 | Chronic otitis media | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Macrotia FREQUENT Macrotia (HP:0000400)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000400 | Macrotia | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Infantile form otitis media VERY_FREQUENT Otitis media (HP:0000388)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000388 | Otitis media | Very frequent (99-80%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Eye 8

Hypertelorism FREQUENT Hypertelorism (HP:0000316)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000316 | Hypertelorism | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Cataract VERY_FREQUENT Cataract (HP:0000518)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000518 | Cataract | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Corneal opacity VERY_FREQUENT Corneal opacity (HP:0007957)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0007957 | Corneal opacity | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Infantile form hypertelorism FREQUENT Hypertelorism (HP:0000316)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000316 | Hypertelorism | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form cataract FREQUENT Cataract (HP:0000518)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000518 | Cataract | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form strabismus FREQUENT Strabismus (HP:0000486)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000486 | Strabismus | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form hypermetropia FREQUENT Hypermetropia (HP:0000540)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000540 | Hypermetropia | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form myopia FREQUENT Myopia (HP:0000545)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000545 | Myopia | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Head and Neck 6

Macroglossia VERY_FREQUENT Macroglossia (HP:0000158)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000158 | Macroglossia | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Macrocephaly OCCASIONAL Macrocephaly (HP:0000256)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000256 | Macrocephaly | Occasional (29-5%)"

Orphanet provides the disease-phenotype association and frequency band.

Coarse facial features VERY_FREQUENT Coarse facial features (HP:0000280)

Show evidence (2 references)

ORPHA:61 SUPPORT Other

"HP:0000280 | Coarse facial features | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

PMID:26048034 SUPPORT Human Clinical

"Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."

Cohort review supports facial coarsening as a clinical manifestation.

Short neck FREQUENT Short neck (HP:0000470)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000470 | Short neck | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Depressed nasal bridge VERY_FREQUENT Depressed nasal bridge (HP:0005280)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0005280 | Depressed nasal bridge | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Infantile form coarse facial features FREQUENT Coarse facial features (HP:0000280)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000280 | Coarse facial features | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Immune 5

Recurrent respiratory infections OCCASIONAL Recurrent respiratory infections (HP:0002205)

Show evidence (2 references)

ORPHA:61 SUPPORT Other

"HP:0002205 | Recurrent respiratory infections | Occasional (29-5%)"

Orphanet provides the disease-phenotype association and frequency band.

PMID:18651971 SUPPORT Human Clinical

"recurrent infections, especially in the first decade of life"

Review supports recurrent infections as a common childhood manifestation.

Infantile form pneumonia FREQUENT Pneumonia (HP:0002090)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0002090 | Pneumonia | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form recurrent infections VERY_FREQUENT Recurrent infections (HP:0002719)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0002719 | Recurrent infections | Very frequent (99-80%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Adult form recurrent infections FREQUENT Recurrent infections (HP:0002719)

Show evidence (1 reference)

ORPHA:309288 SUPPORT Other

"HP:0002719 | Recurrent infections | Frequent (79-30%)"

Orphanet provides the adult subtype phenotype association and frequency band.

Infantile form immunodeficiency VERY_FREQUENT Immunodeficiency (HP:0002721)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0002721 | Immunodeficiency | Very frequent (99-80%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Limbs 1

Bowing of the long bones FREQUENT Bowing of the long bones (HP:0006487)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0006487 | Bowing of the long bones | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Musculoskeletal 10

Hypotonia FREQUENT Hypotonia (HP:0001252)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0001252 | Hypotonia | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Arthritis OCCASIONAL Arthritis (HP:0001369)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0001369 | Arthritis | Occasional (29-5%)"

Orphanet provides the disease-phenotype association and frequency band.

Hip dysplasia FREQUENT Hip dysplasia (HP:0001385)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0001385 | Hip dysplasia | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Scoliosis FREQUENT Scoliosis (HP:0002650)

Show evidence (2 references)

ORPHA:61 SUPPORT Other

"HP:0002650 | Scoliosis | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

PMID:18651971 SUPPORT Human Clinical

"skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum)"

Review directly supports scoliosis as a skeletal manifestation.

Skeletal dysplasia VERY_FREQUENT Skeletal dysplasia (HP:0002652)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0002652 | Skeletal dysplasia | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Delayed skeletal maturation VERY_FREQUENT Delayed skeletal maturation (HP:0002750)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0002750 | Delayed skeletal maturation | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Kyphosis FREQUENT Kyphosis (HP:0002808)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0002808 | Kyphosis | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Infantile form hypotonia FREQUENT Hypotonia (HP:0001252)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0001252 | Hypotonia | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form dysostosis multiplex VERY_FREQUENT Dysostosis multiplex (HP:0000943)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000943 | Dysostosis multiplex | Very frequent (99-80%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form myopathy FREQUENT Myopathy (HP:0003198)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0003198 | Myopathy | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Nervous System 11

Atypical behavior FREQUENT Atypical behavior (HP:0000708)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000708 | Atypical behavior | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Hallucinations OCCASIONAL Hallucinations (HP:0000738)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000738 | Hallucinations | Occasional (29-5%)"

Orphanet provides the disease-phenotype association and frequency band.

Intellectual disability VERY_FREQUENT Intellectual disability (HP:0001249)

Show evidence (2 references)

ORPHA:61 SUPPORT Other

"HP:0001249 | Intellectual disability | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

PMID:26048034 SUPPORT Human Clinical

"Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."

Cohort review supports intellectual disability as a clinical manifestation.

Global developmental delay VERY_FREQUENT Global developmental delay (HP:0001263)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0001263 | Global developmental delay | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Increased intracranial pressure OCCASIONAL Increased intracranial pressure (HP:0002516)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0002516 | Increased intracranial pressure | Occasional (29-5%)"

Orphanet provides the disease-phenotype association and frequency band.

Infantile form intellectual disability VERY_FREQUENT Intellectual disability (HP:0001249)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0001249 | Intellectual disability | Very frequent (99-80%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form delayed speech and language development VERY_FREQUENT Delayed speech and language development (HP:0000750)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000750 | Delayed speech and language development | Very frequent (99-80%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Ataxia in alpha-mannosidosis subtypes FREQUENT Ataxia (HP:0001251)

Show evidence (2 references)

ORPHA:309282 SUPPORT Other

"HP:0001251 | Ataxia | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

ORPHA:309288 SUPPORT Other

"HP:0001251 | Ataxia | Frequent (79-30%)"

Orphanet provides the adult subtype phenotype association and frequency band.

Infantile form mild intellectual disability FREQUENT Mild intellectual disability (HP:0001256)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0001256 | Intellectual disability, mild | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Adult form mild intellectual disability VERY_FREQUENT Mild intellectual disability (HP:0001256)

Show evidence (1 reference)

ORPHA:309288 SUPPORT Other

"HP:0001256 | Intellectual disability, mild | Very frequent (99-80%)"

Orphanet provides the adult subtype phenotype association and frequency band.

Infantile form motor delay FREQUENT Motor delay (HP:0001270)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0001270 | Motor delay | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Other 22

Narrow palate FREQUENT Narrow palate (HP:0000189)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000189 | Narrow palate | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Gingival overgrowth FREQUENT Gingival overgrowth (HP:0000212)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000212 | Gingival overgrowth | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Mandibular prognathia OCCASIONAL Mandibular prognathia (HP:0000303)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000303 | Mandibular prognathia | Occasional (29-5%)"

Orphanet provides the disease-phenotype association and frequency band.

Prominent supraorbital ridges FREQUENT Prominent supraorbital ridges (HP:0000336)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000336 | Prominent supraorbital ridges | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Widely spaced teeth OCCASIONAL Widely spaced teeth (HP:0000687)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000687 | Widely spaced teeth | Occasional (29-5%)"

Orphanet provides the disease-phenotype association and frequency band.

Dental malocclusion OCCASIONAL Dental malocclusion (HP:0000689)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0000689 | Dental malocclusion | Occasional (29-5%)"

Orphanet provides the disease-phenotype association and frequency band.

Craniofacial hyperostosis VERY_FREQUENT Craniofacial hyperostosis (HP:0004493)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0004493 | Craniofacial hyperostosis | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Hypoplastic inferior ilia VERY_FREQUENT Hypoplastic inferior ilia (HP:0008821)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0008821 | Hypoplastic inferior ilia | Very frequent (99-80%)"

Orphanet provides the disease-phenotype association and frequency band.

Open bite FREQUENT Open bite (HP:0010807)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0010807 | Open bite | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Avascular necrosis OCCASIONAL Avascular necrosis (HP:0010885)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0010885 | Avascular necrosis | Occasional (29-5%)"

Orphanet provides the disease-phenotype association and frequency band.

Abnormality of the helix FREQUENT Abnormal helix morphology (HP:0011039)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0011039 | Abnormality of the helix | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Generalized abnormality of skin FREQUENT Generalized abnormality of skin (HP:0011354)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0011354 | Generalized abnormality of skin | Frequent (79-30%)"

Orphanet provides the disease-phenotype association and frequency band.

Synostosis of joints OCCASIONAL Synostosis of joints (HP:0100240)

Show evidence (1 reference)

ORPHA:61 SUPPORT Other

"HP:0100240 | Synostosis of joints | Occasional (29-5%)"

Orphanet provides the disease-phenotype association and frequency band.

Infantile form mixed hearing impairment FREQUENT Mixed hearing impairment (HP:0000410)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000410 | Mixed hearing impairment | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form short attention span FREQUENT Short attention span (HP:0000736)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0000736 | Short attention span | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form specific learning disability VERY_FREQUENT Specific learning disability (HP:0001328)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0001328 | Specific learning disability | Very frequent (99-80%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Oligosacchariduria in alpha-mannosidosis subtypes VERY_FREQUENT Oligosacchariduria (HP:0010471)

Show evidence (2 references)

ORPHA:309282 SUPPORT Other

"HP:0010471 | Oligosacchariduria | Very frequent (99-80%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

ORPHA:309288 SUPPORT Other

"HP:0010471 | Oligosacchariduria | Very frequent (99-80%)"

Orphanet provides the adult subtype phenotype association and frequency band.

Infantile form facial shape deformation FREQUENT Facial shape deformation (HP:0011334)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0011334 | Facial shape deformation | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form abnormal skeletal morphology VERY_FREQUENT Abnormal skeletal morphology (HP:0011842)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0011842 | Abnormality of skeletal morphology | Very frequent (99-80%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Infantile form abnormal circulating enzyme concentration or activity VERY_FREQUENT Abnormal circulating enzyme concentration or activity (HP:0012379)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

Asthenia in alpha-mannosidosis subtypes FREQUENT Asthenia (HP:0025406)

Show evidence (2 references)

ORPHA:309282 SUPPORT Other

"HP:0025406 | Asthenia | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

ORPHA:309288 SUPPORT Other

"HP:0025406 | Asthenia | Frequent (79-30%)"

Orphanet provides the adult subtype phenotype association and frequency band.

Infantile form recurrent gastroenteritis FREQUENT Recurrent gastroenteritis (HP:0031123)

Show evidence (1 reference)

ORPHA:309282 SUPPORT Other

"HP:0031123 | Recurrent gastroenteritis | Frequent (79-30%)"

Orphanet provides the infantile subtype phenotype association and frequency band.

🧬

Genetic Associations

1

Biallelic MAN2B1 pathogenic variants (Causative)

Autosomal recessive inheritance

Show evidence (3 references)

ORPHA:309282 SUPPORT Other

"MAN2B1 | mannosidase alpha class 2B member 1 | hgnc:6826 | Disease-causing germline mutation(s) in"

Orphanet identifies MAN2B1 as the disease-causing gene.

PMID:26048034 SUPPORT Human Clinical

"Complete MAN2B1 genotypes were established for all patients."

The cohort confirmed MAN2B1 genotypes in all patients studied.

CGGV:assertion_ef3b8e84-1f36-4aae-b167-b50dd074bf2b-2022-09-02T160000.000Z SUPPORT Other

ClinGen classifies the MAN2B1-alpha-mannosidosis gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

4

Velmanase alfa enzyme replacement therapy

Action: pharmacotherapy MAXO:0000058

Agent: velmanase alfa ↗

Velmanase alfa is recombinant human lysosomal alpha-mannosidase used as enzyme replacement therapy for non-neurological manifestations. Trials show sustained serum oligosaccharide clearance, immunologic improvement, and greater benefit when started in pediatric patients.

Mechanism Target:

RESTORES MAN2B1 lysosomal alpha-mannosidase deficiency — Velmanase alfa supplies recombinant lysosomal alpha-mannosidase activity.

Show evidence (1 reference)

PMID:36849760 SUPPORT Human Clinical

"Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase product"

Pediatric trial identifies velmanase alfa as recombinant human lysosomal alpha-mannosidase.

RESTORES Mannose-rich oligosaccharide lysosomal storage — Enzyme replacement lowers serum oligosaccharide storage biomarkers.

Show evidence (1 reference)

PMID:39381850 SUPPORT Human Clinical

"Overall, sustained serum oligosaccharide clearance and serum IgG"

Long-term extension data support biomarker clearance after velmanase alfa initiation.

Show evidence (2 references)

PMID:29846843 SUPPORT Human Clinical

"INTRODUCTION: This phase III, double-blind, randomised, placebo-controlled trial"

Phase III trial directly evaluates velmanase alfa in alpha-mannosidosis patients.

PMID:39381850 SUPPORT Human Clinical

"indicate continued benefits of velmanase alfa in patients with"

Long-term extension supports continued benefit and safety.

Hematopoietic stem cell transplantation

Action: hematopoietic stem cell transplantation MAXO:0000747

Allogeneic hematopoietic stem cell transplantation can normalize leukocyte enzyme activity and may stabilize cognitive function and improve hearing when performed early, but transplant candidacy and risk require specialist evaluation.

Mechanism Target:

RESTORES MAN2B1 lysosomal alpha-mannosidase deficiency — Donor-derived hematopoietic cells restore leukocyte alpha-mannosidase activity.

Show evidence (1 reference)

PMID:15126988 SUPPORT Human Clinical

"normalization of leukocyte enzyme activity after HCT."

Allogeneic HCT restored leukocyte alpha-mannosidase activity in the reported cohort.

Show evidence (2 references)

PMID:15126988 SUPPORT Human Clinical

"HCT can halt the progressive cognitive loss in patients with"

HCT cohort supports transplantation as a disease-modifying intervention.

PMID:15126988 SUPPORT Human Clinical

"Early diagnosis and treatment with HCT is critical for"

The study emphasizes early treatment for optimal outcomes.

Supportive care

Action: supportive care MAXO:0000950

Supportive care addresses infections, middle-ear disease, hearing loss, developmental needs, physiotherapy, orthopedic complications, and other manifestations.

Show evidence (2 references)

PMID:18651971 SUPPORT Human Clinical

"preventing complications and treating manifestations."

Review supports proactive supportive management.

PMID:18651971 SUPPORT Human Clinical

"required and use of hearing aids is invariably required."

Review supports ENT and hearing-focused supportive care.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling is appropriate because alpha-mannosidosis is autosomal recessive, and enzyme or molecular diagnosis clarifies carrier and recurrence risks for relatives.

Show evidence (1 reference)

PMID:18651971 SUPPORT Human Clinical

"of the disease and to detect carriers."

Review explicitly recommends genetic counseling.

🔬

Biochemical Markers

2

Reduced acid alpha-mannosidase activity (DECREASED)

Context: Deficient acid alpha-mannosidase activity in leukocytes or other nucleated cells is the primary diagnostic biochemical defect.

Pathograph Readouts

Readout Of MAN2B1 lysosomal alpha-mannosidase deficiency Negative Diagnostic

Reduced leukocyte or nucleated-cell acid alpha-mannosidase activity reports the primary MAN2B1 lysosomal enzyme defect.

Show evidence (2 references)

PMID:18651971 SUPPORT Human Clinical

"Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or"

Review supports leukocyte or nucleated-cell alpha-mannosidase activity as a diagnostic assay.

ORPHA:309282 SUPPORT Other

"HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"

Orphanet records abnormal enzyme/coenzyme activity as very frequent in the infantile subtype.

Increased urinary mannose-rich oligosaccharides (INCREASED)

Context: Urinary excretion of mannose-rich oligosaccharides is a suggestive storage biomarker, but it is not sufficient alone to establish the diagnosis.

Pathograph Readouts

Readout Of Mannose-rich oligosaccharide lysosomal storage Positive Diagnostic

Increased urinary mannose-rich oligosaccharide excretion reports the lysosomal oligosaccharide storage mechanism, although enzyme or molecular confirmation remains required.

Show evidence (2 references)

PMID:18651971 SUPPORT Human Clinical

"secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic."

Review supports urinary mannose-rich oligosaccharides as a supportive biochemical marker.

ORPHA:309282 SUPPORT Other

"HP:0010471 | Oligosacchariduria | Very frequent (99-80%)"

Orphanet records oligosacchariduria as very frequent in the infantile subtype.

{ }

Source YAML

click to show

name: Alpha-mannosidosis
category: Mendelian
creation_date: "2026-05-04T17:13:27Z"
updated_date: "2026-05-21T15:18:10Z"
synonyms:
- Lysosomal alpha-D-mannosidase deficiency
description: >
  Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder
  caused by biallelic MAN2B1 pathogenic variants and deficient lysosomal
  alpha-mannosidase activity. Impaired degradation of glycoprotein-derived
  mannose-rich oligosaccharides causes progressive multisystem disease with
  immune deficiency, recurrent infections, hearing impairment, intellectual
  disability, coarse facial features, skeletal dysplasia, hepatosplenomegaly,
  and ocular findings.
disease_term:
  preferred_term: alpha-mannosidosis
  term:
    id: MONDO:0009561
    label: alpha-mannosidosis
parents:
- Lysosomal Storage Disorder
- Oligosaccharidosis
classifications:
  harrisons_chapter:
  - classification_value: hereditary disease
    evidence:
    - reference: PMID:18651971
      reference_title: Alpha-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Alpha-mannosidosis is an inherited lysosomal storage disorder"
      explanation: The review supports classifying alpha-mannosidosis as an inherited disorder.
  lysosomal_storage_category:
    classification_value: glycoproteinosis
    evidence:
    - reference: PMID:18651971
      reference_title: Alpha-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic."
      explanation: Mannose-rich oligosaccharide accumulation supports the glycoproteinosis lysosomal-storage category.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009561
      label: alpha-mannosidosis
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:61
    mapping_justification: >
      Orphanet ORPHA:61 lists MONDO:0009561 as an exact cross-reference for
      alpha-mannosidosis.
external_assertions:
- name: Orphanet Alpha-mannosidosis disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:61
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=61
  description: >
    Orphanet's ORPHA:61 structured record for Alpha-mannosidosis includes the
    exact MONDO and OMIM cross-references, definition, autosomal recessive
    inheritance, epidemiology, natural-history ages of onset, and HPO phenotype
    annotations used in this entry.
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0009561 | Exact"
    explanation: Orphanet maps ORPHA:61 to the same MONDO identifier used by this entry.
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:248500 | Exact"
    explanation: Orphanet lists OMIM:248500 as an exact external cross-reference.
definitions:
- name: Orphanet alpha-mannosidosis definition
  definition_type: OTHER
  description: >
    An inherited lysosomal storage disorder characterized by immune deficiency,
    facial and skeletal abnormalities, hearing impairment, and intellectual
    deficit.
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "An inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual deficit."
    explanation: Orphanet defines the core multisystem phenotype.
  - reference: PMID:40276561
    reference_title: Disease profile in a cohort of Brazilian patients diagnosed with alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alpha-mannosidosis (AM) is an ultrarare multisystemic disorder caused by"
    explanation: Contemporary patient cohort supports the ultra-rare multisystem disease framing.
inheritance:
- name: Autosomal recessive inheritance
  description: Alpha-mannosidosis is inherited in an autosomal recessive pattern.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for alpha-mannosidosis.
has_subtypes:
- name: Infantile form
  display_name: Alpha-mannosidosis, infantile form
  subtype_term:
    preferred_term: alpha-mannosidosis, infantile form
    term:
      id: MONDO:0017732
      label: alpha-mannosidosis, infantile form
  description: >
    Infantile-onset clinical subtype of alpha-mannosidosis with Orphanet exact
    MONDO mapping and MAN2B1 disease-causing gene association.
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0017732
        label: alpha-mannosidosis, infantile form
      mapping_predicate: skos:exactMatch
      mapping_source: Orphanet ORPHA:309282
      mapping_justification: >
        Orphanet ORPHA:309282 lists MONDO:0017732 as an exact cross-reference.
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0017732 | Exact"
    explanation: Orphanet maps the infantile form to MONDO:0017732.
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAN2B1 | mannosidase alpha class 2B member 1 | hgnc:6826 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies MAN2B1 as the disease-causing gene for this subtype.
- name: Adult form
  display_name: Alpha-mannosidosis, adult form
  subtype_term:
    preferred_term: alpha-mannosidosis, adult form
    term:
      id: MONDO:0017733
      label: alpha-mannosidosis, adult form
  description: >
    Adult-onset clinical subtype of alpha-mannosidosis with Orphanet exact
    MONDO mapping and MAN2B1 disease-causing gene association.
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0017733
        label: alpha-mannosidosis, adult form
      mapping_predicate: skos:exactMatch
      mapping_source: Orphanet ORPHA:309288
      mapping_justification: >
        Orphanet ORPHA:309288 lists MONDO:0017733 as an exact cross-reference.
  evidence:
  - reference: ORPHA:309288
    reference_title: "Alpha-mannosidosis, adult form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0017733 | Exact"
    explanation: Orphanet maps the adult form to MONDO:0017733.
  - reference: ORPHA:309288
    reference_title: "Alpha-mannosidosis, adult form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAN2B1 | mannosidase alpha class 2B member 1 | hgnc:6826 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies MAN2B1 as the disease-causing gene for this subtype.
prevalence:
- population: Worldwide
  percentage: Unknown
  notes: >
    Alpha-mannosidosis is ultra-rare. Orphanet records regional prevalence-at-birth
    and point-prevalence estimates ranging from less than 1 per 1,000,000 to
    1-9 per 1,000,000, depending on country and prevalence measure.
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Europe | Point prevalence | PMID:2005"
    explanation: Orphanet records a European point-prevalence band for alpha-mannosidosis.
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Sweden | Prevalence at birth | PMID:25274184"
    explanation: Orphanet records a Swedish prevalence-at-birth estimate below 1 per 1,000,000.
progression:
- phase: Childhood-onset progressive multisystem disease
  age_range: Infancy to childhood, with occasional neonatal presentation and adult-onset subtype
  notes: >
    Children may appear normal at birth but develop progressive immune,
    neurodevelopmental, hearing, skeletal, and motor manifestations. Severity
    varies across a continuum, with many patients surviving into adulthood but
    developing progressive disability.
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: Orphanet records childhood onset for alpha-mannosidosis.
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infancy onset for alpha-mannosidosis.
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The children are often born apparently normal, and their condition worsens"
    explanation: Review supports progressive postnatal disease evolution.
pathophysiology:
- name: MAN2B1 lysosomal alpha-mannosidase deficiency
  description: >
    Biallelic pathogenic variants in MAN2B1 reduce lysosomal alpha-mannosidase
    activity, impairing the lysosomal catabolism of glycoprotein-derived
    alpha-mannosides.
  genes:
  - preferred_term: MAN2B1
    term:
      id: hgnc:6826
      label: MAN2B1
  molecular_functions:
  - preferred_term: alpha-mannosidase activity
    modifier: DECREASED
    term:
      id: GO:0004559
      label: alpha-mannosidase activity
  biological_processes:
  - preferred_term: glycoprotein catabolic process
    modifier: DECREASED
    term:
      id: GO:0006516
      label: glycoprotein catabolic process
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAN2B1 | mannosidase alpha class 2B member 1 | hgnc:6826 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies MAN2B1 as the disease-causing gene.
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder is caused by lysosomal alpha-mannosidase deficiency."
    explanation: Review directly supports deficient lysosomal alpha-mannosidase activity.
  - reference: PMID:26048034
    reference_title: "Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of lysosomal alpha-mannosidase activity."
    explanation: Genotype-phenotype cohort supports MAN2B1 variants causing loss of lysosomal enzyme activity.
  downstream:
  - target: Mannose-rich oligosaccharide lysosomal storage
    description: Reduced lysosomal alpha-mannosidase blocks glycoprotein oligosaccharide degradation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36849760
      reference_title: "Long-term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha-mannosidosis: A phase 2, open label, multicenter study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "alpha-mannosidase deficiency that leads to the accumulation"
      explanation: >
        Pediatric clinical-trial background directly links alpha-mannosidase
        deficiency to accumulation of storage substrate.
  - target: Reduced acid alpha-mannosidase activity
    description: MAN2B1 pathogenic variation is reflected diagnostically by reduced leukocyte or cellular acid alpha-mannosidase activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18651971
      reference_title: Alpha-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or"
      explanation: >
        The review identifies reduced acid alpha-mannosidase activity as the
        diagnostic enzyme readout of the MAN2B1 lysosomal enzyme defect.
  - target: Infantile form abnormal circulating enzyme concentration or activity
    description: The infantile subtype records abnormal enzyme/coenzyme activity as the enzyme-level phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"
      explanation: >
        Orphanet records abnormal enzyme/coenzyme activity as very frequent in
        the infantile subtype.
- name: Mannose-rich oligosaccharide lysosomal storage
  description: >
    Deficient lysosomal alpha-mannosidase activity causes accumulation of
    mannose-rich oligosaccharides in cells, body fluids, and cerebrospinal
    fluid, linking the enzyme defect to multisystem storage pathology.
  biological_processes:
  - preferred_term: glycoprotein catabolic process
    modifier: DECREASED
    term:
      id: GO:0006516
      label: glycoprotein catabolic process
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: PMID:36849760
    reference_title: "Long-term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha-mannosidosis: A phase 2, open label, multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "alpha-mannosidase deficiency that leads to the accumulation"
    explanation: Pediatric velmanase alfa study summarizes the storage substrate caused by enzyme deficiency.
  - reference: PMID:26048034
    reference_title: "Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CSF-oligosaccharides, higher point scores"
    explanation: Patient genotype-phenotype study used CSF oligosaccharides as a storage-related biochemical measure.
  downstream:
  - target: Neurodevelopmental and motor impairment
    description: CNS storage and dysfunction contribute to cognitive, speech, hypotonia, and motor manifestations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26048034
      reference_title: "Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."
      explanation: >
        The patient cohort supports neurologic and motor manifestations in
        alpha-mannosidosis; specific storage-to-CNS intermediates remain
        incompletely resolved.
  - target: Immune deficiency and recurrent infections
    description: Systemic storage disease is associated with immunodeficiency and recurrent infections.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18651971
      reference_title: Alpha-mannosidosis.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life),"
      explanation: >
        The review supports recurrent infections as a core manifestation,
        partially supporting the systemic storage-to-immune branch.
  - target: Skeletal and craniofacial storage manifestations
    description: Connective-tissue and skeletal involvement produces coarse facial features and skeletal dysplasia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18651971
      reference_title: Alpha-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum)"
      explanation: >
        The review directly supports skeletal abnormalities in
        alpha-mannosidosis, linking storage disease to the skeletal branch.
  - target: Increased urinary mannose-rich oligosaccharides
    description: Lysosomal storage is reflected by increased urinary excretion of mannose-rich oligosaccharides.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18651971
      reference_title: Alpha-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic."
      explanation: >
        The review supports urinary mannose-rich oligosaccharides as a
        biochemical readout of the storage lesion.
  - target: Oligosacchariduria in alpha-mannosidosis subtypes
    description: Orphanet subtype records capture oligosacchariduria as a frequent storage biomarker.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0010471 | Oligosacchariduria | Very frequent (99-80%)"
      explanation: >
        Orphanet records oligosacchariduria as a very frequent infantile-subtype
        phenotype, supporting it as a storage biomarker.
  - target: Hearing impairment
    description: Multisystem storage disease includes moderate-to-severe hearing impairment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18651971
      reference_title: Alpha-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hearing impairment (moderate-to-severe sensorineural hearing loss)"
      explanation: This evidence supports Hearing impairment as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Cataract
    description: Ocular involvement in alpha-mannosidosis includes cataract.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000518 | Cataract | Very frequent (99-80%)
      explanation: This evidence supports Cataract as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Corneal opacity
    description: Ocular storage manifestations can include corneal opacity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0007957 | Corneal opacity | Very frequent (99-80%)
      explanation: This evidence supports Corneal opacity as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Infantile form cataract
    description: The infantile alpha-mannosidosis subtype includes cataract.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000518 | Cataract | Frequent (79-30%)
      explanation: This evidence supports Infantile form cataract as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Infantile form strabismus
    description: The infantile alpha-mannosidosis subtype includes strabismus.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000486 | Strabismus | Frequent (79-30%)
      explanation: This evidence supports Infantile form strabismus as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Infantile form hypermetropia
    description: The infantile alpha-mannosidosis subtype includes hypermetropia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000540 | Hypermetropia | Frequent (79-30%)
      explanation: This evidence supports Infantile form hypermetropia as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Infantile form myopia
    description: The infantile alpha-mannosidosis subtype includes myopia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000545 | Myopia | Frequent (79-30%)
      explanation: This evidence supports Infantile form myopia as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Splenomegaly
    description: Visceral storage manifestations include splenic enlargement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001744 | Splenomegaly | Very frequent (99-80%)
      explanation: This evidence supports Splenomegaly as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Hepatomegaly
    description: Visceral storage manifestations include hepatic enlargement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002240 | Hepatomegaly | Very frequent (99-80%)
      explanation: This evidence supports Hepatomegaly as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Infantile form hepatosplenomegaly
    description: The infantile subtype includes combined hepatic and splenic enlargement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001433 | Hepatosplenomegaly | Frequent (79-30%)
      explanation: This evidence supports Infantile form hepatosplenomegaly as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Generalized abnormality of skin
    description: Multisystem storage manifestations include generalized skin abnormalities.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0011354 | Generalized abnormality of skin | Frequent (79-30%)
      explanation: This evidence supports Generalized abnormality of skin as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
  - target: Inguinal hernia
    description: Connective-tissue and visceral manifestations include inguinal hernia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000023 | Inguinal hernia | Frequent (79-30%)
      explanation: This evidence supports Inguinal hernia as an alpha-mannosidosis manifestation; the edge remains indirect because the specific intermediates from Mannose-rich oligosaccharide lysosomal storage to this phenotype are not fully resolved.
- name: Neurodevelopmental and motor impairment
  description: >
    Central nervous system involvement produces intellectual disability,
    developmental delay, impaired speech, hypotonia, ataxia, and behavioral or
    psychiatric manifestations.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  biological_processes:
  - preferred_term: central nervous system development
    modifier: ABNORMAL
    term:
      id: GO:0007417
      label: central nervous system development
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gradual impairment of mental functions and speech,"
    explanation: Review supports cognitive, speech, and psychiatric involvement.
  - reference: PMID:26048034
    reference_title: "Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."
    explanation: Patient cohort summarizes neurologic and motor manifestations.
  downstream:
  - target: Intellectual disability
    description: Progressive CNS involvement impairs cognition and adaptive function.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26048034
      reference_title: 'Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."
      explanation: This evidence supports Intellectual disability as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Global developmental delay
    description: Early neurodevelopmental involvement delays acquisition of developmental milestones.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001263 | Global developmental delay | Very frequent (99-80%)
      explanation: This evidence supports Global developmental delay as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Hypotonia
    description: Motor system involvement contributes to low tone and delayed motor function.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001252 | Hypotonia | Frequent (79-30%)
      explanation: This evidence supports Hypotonia as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Atypical behavior
    description: CNS involvement includes behavioral manifestations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000708 | Atypical behavior | Frequent (79-30%)
      explanation: This evidence supports Atypical behavior as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Hallucinations
    description: Psychiatric involvement can include hallucinations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000738 | Hallucinations | Occasional (29-5%)
      explanation: This evidence supports Hallucinations as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Increased intracranial pressure
    description: Neurologic involvement can include increased intracranial pressure.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002516 | Increased intracranial pressure | Occasional (29-5%)
      explanation: This evidence supports Increased intracranial pressure as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Infantile form intellectual disability
    description: Neurodevelopmental involvement in the infantile subtype includes intellectual disability.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001249 | Intellectual disability | Very frequent (99-80%)
      explanation: This evidence supports Infantile form intellectual disability as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Infantile form hypotonia
    description: Motor involvement in the infantile subtype includes hypotonia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001252 | Hypotonia | Frequent (79-30%)
      explanation: This evidence supports Infantile form hypotonia as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Infantile form short attention span
    description: Neurodevelopmental involvement in the infantile subtype includes impaired attention.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000736 | Short attention span | Frequent (79-30%)
      explanation: This evidence supports Infantile form short attention span as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Infantile form delayed speech and language development
    description: CNS involvement impairs speech and language development in the infantile subtype.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000750 | Delayed speech and language development | Very frequent (99-80%)
      explanation: This evidence supports Infantile form delayed speech and language development as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Ataxia in alpha-mannosidosis subtypes
    description: Motor-system involvement includes ataxia across recorded subtypes.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001251 | Ataxia | Frequent (79-30%)
      explanation: This evidence supports Ataxia in alpha-mannosidosis subtypes as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Infantile form mild intellectual disability
    description: The infantile subtype includes mild intellectual disability in Orphanet records.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001256 | Intellectual disability, mild | Frequent (79-30%)
      explanation: This evidence supports Infantile form mild intellectual disability as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Adult form mild intellectual disability
    description: The adult subtype includes mild intellectual disability in Orphanet records.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309288
      reference_title: Alpha-mannosidosis, adult form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001256 | Intellectual disability, mild | Very frequent (99-80%)
      explanation: This evidence supports Adult form mild intellectual disability as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Infantile form motor delay
    description: Motor-system involvement in the infantile subtype delays motor milestones.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001270 | Motor delay | Frequent (79-30%)
      explanation: This evidence supports Infantile form motor delay as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Infantile form specific learning disability
    description: Neurodevelopmental involvement in the infantile subtype includes specific learning disability.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001328 | Specific learning disability | Very frequent (99-80%)
      explanation: This evidence supports Infantile form specific learning disability as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Infantile form myopathy
    description: Motor-system involvement in the infantile subtype includes myopathy.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0003198 | Myopathy | Frequent (79-30%)
      explanation: This evidence supports Infantile form myopathy as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
  - target: Asthenia in alpha-mannosidosis subtypes
    description: Motor and systemic involvement includes asthenia across recorded subtypes.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0025406 | Asthenia | Frequent (79-30%)
      explanation: This evidence supports Asthenia in alpha-mannosidosis subtypes as an alpha-mannosidosis manifestation represented under the Neurodevelopmental and motor impairment branch.
- name: Immune deficiency and recurrent infections
  description: >
    Immune dysfunction is a core alpha-mannosidosis manifestation and is
    clinically expressed as recurrent infections, especially during childhood.
  biological_processes:
  - preferred_term: innate immune response
    modifier: DECREASED
    term:
      id: GO:0045087
      label: innate immune response
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life),"
    explanation: Review directly supports immunodeficiency with recurrent infections.
  downstream:
  - target: Recurrent respiratory infections
    description: Immunodeficiency contributes to recurrent respiratory infections.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18651971
      reference_title: Alpha-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life),"
      explanation: This evidence supports Recurrent respiratory infections as an alpha-mannosidosis manifestation represented under the Immune deficiency and recurrent infections branch.
  - target: Chronic otitis media
    description: Recurrent infections include frequent middle-ear disease.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000389 | Chronic otitis media | Frequent (79-30%)
      explanation: This evidence supports Chronic otitis media as an alpha-mannosidosis manifestation represented under the Immune deficiency and recurrent infections branch.
  - target: Infantile form otitis media
    description: Recurrent middle-ear infections are prominent in the infantile subtype.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000388 | Otitis media | Very frequent (99-80%)
      explanation: This evidence supports Infantile form otitis media as an alpha-mannosidosis manifestation represented under the Immune deficiency and recurrent infections branch.
  - target: Infantile form mixed hearing impairment
    description: Recurrent middle-ear disease can contribute to the conductive component of mixed hearing impairment in the infantile subtype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000410 | Mixed hearing impairment | Frequent (79-30%)
      explanation: This evidence supports Infantile form mixed hearing impairment as an alpha-mannosidosis manifestation; the edge is indirect because the Immune deficiency and recurrent infections branch uses recurrent middle-ear disease as an intermediate.
  - target: Infantile form pneumonia
    description: Immunodeficiency predisposes to pneumonia in the infantile subtype.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002090 | Pneumonia | Frequent (79-30%)
      explanation: This evidence supports Infantile form pneumonia as an alpha-mannosidosis manifestation represented under the Immune deficiency and recurrent infections branch.
  - target: Infantile form recurrent infections
    description: The infantile subtype includes recurrent infections as a core immune manifestation.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002719 | Recurrent infections | Very frequent (99-80%)
      explanation: This evidence supports Infantile form recurrent infections as an alpha-mannosidosis manifestation represented under the Immune deficiency and recurrent infections branch.
  - target: Adult form recurrent infections
    description: The adult subtype can also retain recurrent infections.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309288
      reference_title: Alpha-mannosidosis, adult form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002719 | Recurrent infections | Frequent (79-30%)
      explanation: This evidence supports Adult form recurrent infections as an alpha-mannosidosis manifestation represented under the Immune deficiency and recurrent infections branch.
  - target: Infantile form immunodeficiency
    description: The infantile subtype includes immunodeficiency.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002721 | Immunodeficiency | Very frequent (99-80%)
      explanation: This evidence supports Infantile form immunodeficiency as an alpha-mannosidosis manifestation represented under the Immune deficiency and recurrent infections branch.
  - target: Infantile form recurrent gastroenteritis
    description: Immune dysfunction can include recurrent gastrointestinal infections.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0031123 | Recurrent gastroenteritis | Frequent (79-30%)
      explanation: This evidence supports Infantile form recurrent gastroenteritis as an alpha-mannosidosis manifestation represented under the Immune deficiency and recurrent infections branch.
- name: Skeletal and craniofacial storage manifestations
  description: >
    Storage disease produces progressive craniofacial coarsening and skeletal
    abnormalities including dysostosis multiplex, scoliosis, thoracic deformity,
    hip abnormalities, and delayed skeletal maturation.
  locations:
  - preferred_term: skeletal system
    term:
      id: UBERON:0001434
      label: skeletal system
  biological_processes:
  - preferred_term: skeletal system development
    modifier: ABNORMAL
    term:
      id: GO:0001501
      label: skeletal system development
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum)"
    explanation: Review supports skeletal dysplasia and spinal/thoracic involvement.
  - reference: PMID:26048034
    reference_title: "Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."
    explanation: Cohort review supports craniofacial and musculoskeletal involvement.
  downstream:
  - target: Coarse facial features
    description: Craniofacial storage contributes to coarse facial appearance.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26048034
      reference_title: 'Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."
      explanation: This evidence supports Coarse facial features as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Skeletal dysplasia
    description: Skeletal involvement causes dysplasia and delayed skeletal maturation.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002652 | Skeletal dysplasia | Very frequent (99-80%)
      explanation: This evidence supports Skeletal dysplasia as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Scoliosis
    description: Vertebral and skeletal involvement contributes to spinal curvature.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18651971
      reference_title: Alpha-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum)"
      explanation: This evidence supports Scoliosis as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Macroglossia
    description: Craniofacial and oral storage manifestations include macroglossia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000158 | Macroglossia | Very frequent (99-80%)
      explanation: This evidence supports Macroglossia as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Narrow palate
    description: Craniofacial development and storage manifestations include a narrow palate.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000189 | Narrow palate | Frequent (79-30%)
      explanation: This evidence supports Narrow palate as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Gingival overgrowth
    description: Oral soft-tissue storage manifestations include gingival overgrowth.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000212 | Gingival overgrowth | Frequent (79-30%)
      explanation: This evidence supports Gingival overgrowth as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Macrocephaly
    description: Craniofacial storage manifestations include macrocephaly.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000256 | Macrocephaly | Occasional (29-5%)
      explanation: This evidence supports Macrocephaly as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Mandibular prognathia
    description: Craniofacial skeletal involvement can produce mandibular prognathia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000303 | Mandibular prognathia | Occasional (29-5%)
      explanation: This evidence supports Mandibular prognathia as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Hypertelorism
    description: Craniofacial involvement includes hypertelorism.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000316 | Hypertelorism | Frequent (79-30%)
      explanation: This evidence supports Hypertelorism as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Prominent supraorbital ridges
    description: Craniofacial coarsening includes prominent supraorbital ridges.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000336 | Prominent supraorbital ridges | Frequent (79-30%)
      explanation: This evidence supports Prominent supraorbital ridges as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Macrotia
    description: Craniofacial dysmorphism includes macrotia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000400 | Macrotia | Frequent (79-30%)
      explanation: This evidence supports Macrotia as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Short neck
    description: Craniofacial and skeletal involvement includes a short neck.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000470 | Short neck | Frequent (79-30%)
      explanation: This evidence supports Short neck as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Widely spaced teeth
    description: Oral and craniofacial involvement includes widely spaced teeth.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000687 | Widely spaced teeth | Occasional (29-5%)
      explanation: This evidence supports Widely spaced teeth as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Dental malocclusion
    description: Craniofacial skeletal and dental involvement includes malocclusion.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000689 | Dental malocclusion | Occasional (29-5%)
      explanation: This evidence supports Dental malocclusion as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Arthritis
    description: Skeletal involvement can include arthritis.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001369 | Arthritis | Occasional (29-5%)
      explanation: This evidence supports Arthritis as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Hip dysplasia
    description: Skeletal dysplasia includes hip involvement.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001385 | Hip dysplasia | Frequent (79-30%)
      explanation: This evidence supports Hip dysplasia as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Delayed skeletal maturation
    description: Skeletal storage manifestations include delayed skeletal maturation.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002750 | Delayed skeletal maturation | Very frequent (99-80%)
      explanation: This evidence supports Delayed skeletal maturation as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Kyphosis
    description: Vertebral skeletal involvement contributes to kyphosis.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002808 | Kyphosis | Frequent (79-30%)
      explanation: This evidence supports Kyphosis as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Craniofacial hyperostosis
    description: Craniofacial skeletal involvement includes hyperostosis.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0004493 | Craniofacial hyperostosis | Very frequent (99-80%)
      explanation: This evidence supports Craniofacial hyperostosis as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Depressed nasal bridge
    description: Craniofacial coarsening includes a depressed nasal bridge.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0005280 | Depressed nasal bridge | Very frequent (99-80%)
      explanation: This evidence supports Depressed nasal bridge as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Bowing of the long bones
    description: Skeletal dysplasia includes bowing of long bones.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0006487 | Bowing of the long bones | Frequent (79-30%)
      explanation: This evidence supports Bowing of the long bones as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Hypoplastic inferior ilia
    description: Pelvic skeletal dysplasia includes hypoplastic inferior ilia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0008821 | Hypoplastic inferior ilia | Very frequent (99-80%)
      explanation: This evidence supports Hypoplastic inferior ilia as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Open bite
    description: Craniofacial and dental involvement includes open bite.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0010807 | Open bite | Frequent (79-30%)
      explanation: This evidence supports Open bite as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Avascular necrosis
    description: Skeletal involvement can include avascular necrosis.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0010885 | Avascular necrosis | Occasional (29-5%)
      explanation: This evidence supports Avascular necrosis as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Abnormality of the helix
    description: Craniofacial dysmorphism includes abnormal helix morphology.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0011039 | Abnormality of the helix | Frequent (79-30%)
      explanation: This evidence supports Abnormality of the helix as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Synostosis of joints
    description: Skeletal involvement includes joint synostosis.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:61
      reference_title: Alpha-mannosidosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0100240 | Synostosis of joints | Occasional (29-5%)
      explanation: This evidence supports Synostosis of joints as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Infantile form coarse facial features
    description: The infantile subtype includes coarse facial features.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000280 | Coarse facial features | Frequent (79-30%)
      explanation: This evidence supports Infantile form coarse facial features as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Infantile form hypertelorism
    description: The infantile subtype includes hypertelorism.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000316 | Hypertelorism | Frequent (79-30%)
      explanation: This evidence supports Infantile form hypertelorism as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Infantile form dysostosis multiplex
    description: The infantile subtype includes dysostosis multiplex.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000943 | Dysostosis multiplex | Very frequent (99-80%)
      explanation: This evidence supports Infantile form dysostosis multiplex as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Infantile form facial shape deformation
    description: The infantile subtype includes facial shape deformation.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0011334 | Facial shape deformation | Frequent (79-30%)
      explanation: This evidence supports Infantile form facial shape deformation as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
  - target: Infantile form abnormal skeletal morphology
    description: The infantile subtype includes abnormal skeletal morphology.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:309282
      reference_title: Alpha-mannosidosis, infantile form (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0011842 | Abnormality of skeletal morphology | Very frequent (99-80%)
      explanation: This evidence supports Infantile form abnormal skeletal morphology as an alpha-mannosidosis manifestation represented under the Skeletal and craniofacial storage manifestations branch.
histopathology:
- name: Lysosomal cellular storage pathology
  description: >
    Alpha-mannosidosis is a lysosomal enzyme-deficiency disorder; tissue and
    cellular pathology are expected to reflect lysosomal storage of
    mannose-rich oligosaccharides. This entry records the storage-pathology
    axis without asserting a PAS-positive lymphocyte finding not present in the
    current abstract-only reference cache.
  frequency: FREQUENT
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder is caused by lysosomal alpha-mannosidase deficiency."
    explanation: The review supports alpha-mannosidosis as a lysosomal enzyme-deficiency storage disease.
biochemical:
- name: Reduced acid alpha-mannosidase activity
  presence: DECREASED
  context: >
    Deficient acid alpha-mannosidase activity in leukocytes or other nucleated
    cells is the primary diagnostic biochemical defect.
  readouts:
  - target: MAN2B1 lysosomal alpha-mannosidase deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Reduced leukocyte or nucleated-cell acid alpha-mannosidase activity
      reports the primary MAN2B1 lysosomal enzyme defect.
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or"
    explanation: Review supports leukocyte or nucleated-cell alpha-mannosidase activity as a diagnostic assay.
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"
    explanation: Orphanet records abnormal enzyme/coenzyme activity as very frequent in the infantile subtype.
- name: Increased urinary mannose-rich oligosaccharides
  presence: INCREASED
  context: >
    Urinary excretion of mannose-rich oligosaccharides is a suggestive storage
    biomarker, but it is not sufficient alone to establish the diagnosis.
  readouts:
  - target: Mannose-rich oligosaccharide lysosomal storage
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased urinary mannose-rich oligosaccharide excretion reports the
      lysosomal oligosaccharide storage mechanism, although enzyme or molecular
      confirmation remains required.
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic."
    explanation: Review supports urinary mannose-rich oligosaccharides as a supportive biochemical marker.
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010471 | Oligosacchariduria | Very frequent (99-80%)"
    explanation: Orphanet records oligosacchariduria as very frequent in the infantile subtype.
genetic:
- name: Biallelic MAN2B1 pathogenic variants
  gene_term:
    preferred_term: MAN2B1
    term:
      id: hgnc:6826
      label: MAN2B1
  association: Causative
  relationship_type: CAUSATIVE
  features: >
    Alpha-mannosidosis is caused by biallelic pathogenic variants in MAN2B1,
    encoding lysosomal alpha-mannosidase. Variant effects that prevent mutant
    MAN2B1 localization to lysosomes correlate with lower cognitive and motor
    scores and higher oligosaccharide storage burden.
  inheritance:
  - name: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAN2B1 | mannosidase alpha class 2B member 1 | hgnc:6826 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies MAN2B1 as the disease-causing gene.
  - reference: PMID:26048034
    reference_title: "Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete MAN2B1 genotypes were established for all patients."
    explanation: The cohort confirmed MAN2B1 genotypes in all patients studied.
  - reference: CGGV:assertion_ef3b8e84-1f36-4aae-b167-b50dd074bf2b-2022-09-02T160000.000Z
    reference_title: "MAN2B1 / alpha-mannosidosis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAN2B1 | HGNC:6826 | alpha-mannosidosis | MONDO:0009561 | AR | Definitive"
    explanation: ClinGen classifies the MAN2B1-alpha-mannosidosis gene-disease relationship as definitive with autosomal recessive inheritance.
phenotypes:
- name: Inguinal hernia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000023 | Inguinal hernia | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Macroglossia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Macroglossia
    term:
      id: HP:0000158
      label: Macroglossia
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000158 | Macroglossia | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Narrow palate
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Narrow palate
    term:
      id: HP:0000189
      label: Narrow palate
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000189 | Narrow palate | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Gingival overgrowth
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gingival overgrowth
    term:
      id: HP:0000212
      label: Gingival overgrowth
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000212 | Gingival overgrowth | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Macrocephaly
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000256 | Macrocephaly | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Coarse facial features
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000280 | Coarse facial features | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:26048034
    reference_title: "Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."
    explanation: Cohort review supports facial coarsening as a clinical manifestation.
- name: Mandibular prognathia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Mandibular prognathia
    term:
      id: HP:0000303
      label: Mandibular prognathia
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000303 | Mandibular prognathia | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Hypertelorism
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000316 | Hypertelorism | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Prominent supraorbital ridges
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Prominent supraorbital ridges
    term:
      id: HP:0000336
      label: Prominent supraorbital ridges
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000336 | Prominent supraorbital ridges | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Hearing impairment
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000365 | Hearing impairment | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hearing impairment (moderate-to-severe sensorineural hearing loss)"
    explanation: Review supports hearing impairment as a core manifestation.
- name: Chronic otitis media
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chronic otitis media
    term:
      id: HP:0000389
      label: Chronic otitis media
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000389 | Chronic otitis media | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Macrotia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Macrotia
    term:
      id: HP:0000400
      label: Macrotia
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000400 | Macrotia | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Short neck
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000470 | Short neck | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Cataract
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000518 | Cataract | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Widely spaced teeth
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Widely spaced teeth
    term:
      id: HP:0000687
      label: Widely spaced teeth
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000687 | Widely spaced teeth | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Dental malocclusion
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dental malocclusion
    term:
      id: HP:0000689
      label: Dental malocclusion
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000689 | Dental malocclusion | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Atypical behavior
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000708 | Atypical behavior | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Hallucinations
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hallucinations
    term:
      id: HP:0000738
      label: Hallucinations
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000738 | Hallucinations | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Intellectual disability
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:26048034
    reference_title: "Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities."
    explanation: Cohort review supports intellectual disability as a clinical manifestation.
- name: Hypotonia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001252 | Hypotonia | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Global developmental delay
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001263 | Global developmental delay | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Arthritis
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001369 | Arthritis | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Hip dysplasia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hip dysplasia
    term:
      id: HP:0001385
      label: Hip dysplasia
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001385 | Hip dysplasia | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Splenomegaly
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001744 | Splenomegaly | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Recurrent respiratory infections
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002205 | Recurrent respiratory infections | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent infections, especially in the first decade of life"
    explanation: Review supports recurrent infections as a common childhood manifestation.
- name: Hepatomegaly
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002240 | Hepatomegaly | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Increased intracranial pressure
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Increased intracranial pressure
    term:
      id: HP:0002516
      label: Increased intracranial pressure
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002516 | Increased intracranial pressure | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Scoliosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002650 | Scoliosis | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum)"
    explanation: Review directly supports scoliosis as a skeletal manifestation.
- name: Skeletal dysplasia
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Skeletal dysplasia
    term:
      id: HP:0002652
      label: Skeletal dysplasia
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002652 | Skeletal dysplasia | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Delayed skeletal maturation
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed skeletal maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002750 | Delayed skeletal maturation | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Kyphosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002808 | Kyphosis | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Craniofacial hyperostosis
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Craniofacial hyperostosis
    term:
      id: HP:0004493
      label: Craniofacial hyperostosis
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004493 | Craniofacial hyperostosis | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Depressed nasal bridge
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005280 | Depressed nasal bridge | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Bowing of the long bones
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006487 | Bowing of the long bones | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Corneal opacity
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007957 | Corneal opacity | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Hypoplastic inferior ilia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypoplastic inferior ilia
    term:
      id: HP:0008821
      label: Hypoplastic inferior ilia
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008821 | Hypoplastic inferior ilia | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Open bite
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Open bite
    term:
      id: HP:0010807
      label: Open bite
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010807 | Open bite | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Avascular necrosis
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Avascular necrosis
    term:
      id: HP:0010885
      label: Avascular necrosis
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010885 | Avascular necrosis | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Abnormality of the helix
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of the helix
    term:
      id: HP:0011039
      label: Abnormal helix morphology
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011039 | Abnormality of the helix | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Generalized abnormality of skin
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Generalized abnormality of skin
    term:
      id: HP:0011354
      label: Generalized abnormality of skin
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011354 | Generalized abnormality of skin | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Synostosis of joints
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Synostosis of joints
    term:
      id: HP:0100240
      label: Synostosis of joints
  evidence:
  - reference: ORPHA:61
    reference_title: "Alpha-mannosidosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100240 | Synostosis of joints | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- name: Infantile form coarse facial features
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000280 | Coarse facial features | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form hypertelorism
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000316 | Hypertelorism | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form cataract
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000518 | Cataract | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form intellectual disability
  subtype: Infantile form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Very frequent (99-80%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form hypotonia
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001252 | Hypotonia | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form otitis media
  subtype: Infantile form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Otitis media
    term:
      id: HP:0000388
      label: Otitis media
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000388 | Otitis media | Very frequent (99-80%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form mixed hearing impairment
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Mixed hearing impairment
    term:
      id: HP:0000410
      label: Mixed hearing impairment
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000410 | Mixed hearing impairment | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form strabismus
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000486 | Strabismus | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form hypermetropia
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000540 | Hypermetropia | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form myopia
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000545 | Myopia | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form short attention span
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short attention span
    term:
      id: HP:0000736
      label: Short attention span
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000736 | Short attention span | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form delayed speech and language development
  subtype: Infantile form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000750 | Delayed speech and language development | Very frequent (99-80%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form dysostosis multiplex
  subtype: Infantile form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dysostosis multiplex
    term:
      id: HP:0000943
      label: Dysostosis multiplex
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000943 | Dysostosis multiplex | Very frequent (99-80%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Ataxia in alpha-mannosidosis subtypes
  subtypes:
  - Infantile form
  - Adult form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001251 | Ataxia | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
  - reference: ORPHA:309288
    reference_title: "Alpha-mannosidosis, adult form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001251 | Ataxia | Frequent (79-30%)"
    explanation: Orphanet provides the adult subtype phenotype association and frequency band.
- name: Infantile form mild intellectual disability
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001256 | Intellectual disability, mild | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Adult form mild intellectual disability
  subtype: Adult form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: ORPHA:309288
    reference_title: "Alpha-mannosidosis, adult form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001256 | Intellectual disability, mild | Very frequent (99-80%)"
    explanation: Orphanet provides the adult subtype phenotype association and frequency band.
- name: Infantile form motor delay
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001270 | Motor delay | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form specific learning disability
  subtype: Infantile form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001328 | Specific learning disability | Very frequent (99-80%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form hepatosplenomegaly
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001433 | Hepatosplenomegaly | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form pneumonia
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002090 | Pneumonia | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form recurrent infections
  subtype: Infantile form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002719 | Recurrent infections | Very frequent (99-80%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Adult form recurrent infections
  subtype: Adult form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: ORPHA:309288
    reference_title: "Alpha-mannosidosis, adult form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002719 | Recurrent infections | Frequent (79-30%)"
    explanation: Orphanet provides the adult subtype phenotype association and frequency band.
- name: Infantile form immunodeficiency
  subtype: Infantile form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Immunodeficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002721 | Immunodeficiency | Very frequent (99-80%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form myopathy
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003198 | Myopathy | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Oligosacchariduria in alpha-mannosidosis subtypes
  subtypes:
  - Infantile form
  - Adult form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Oligosacchariduria
    term:
      id: HP:0010471
      label: Oligosacchariduria
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010471 | Oligosacchariduria | Very frequent (99-80%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
  - reference: ORPHA:309288
    reference_title: "Alpha-mannosidosis, adult form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010471 | Oligosacchariduria | Very frequent (99-80%)"
    explanation: Orphanet provides the adult subtype phenotype association and frequency band.
- name: Infantile form facial shape deformation
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Facial shape deformation
    term:
      id: HP:0011334
      label: Facial shape deformation
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011334 | Facial shape deformation | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form abnormal skeletal morphology
  subtype: Infantile form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal skeletal morphology
    term:
      id: HP:0011842
      label: Abnormal skeletal morphology
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011842 | Abnormality of skeletal morphology | Very frequent (99-80%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Infantile form abnormal circulating enzyme concentration or activity
  subtype: Infantile form
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal circulating enzyme concentration or activity
    term:
      id: HP:0012379
      label: Abnormal circulating enzyme concentration or activity
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
- name: Asthenia in alpha-mannosidosis subtypes
  subtypes:
  - Infantile form
  - Adult form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Asthenia
    term:
      id: HP:0025406
      label: Asthenia
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025406 | Asthenia | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
  - reference: ORPHA:309288
    reference_title: "Alpha-mannosidosis, adult form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025406 | Asthenia | Frequent (79-30%)"
    explanation: Orphanet provides the adult subtype phenotype association and frequency band.
- name: Infantile form recurrent gastroenteritis
  subtype: Infantile form
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent gastroenteritis
    term:
      id: HP:0031123
      label: Recurrent gastroenteritis
  evidence:
  - reference: ORPHA:309282
    reference_title: "Alpha-mannosidosis, infantile form (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031123 | Recurrent gastroenteritis | Frequent (79-30%)"
    explanation: Orphanet provides the infantile subtype phenotype association and frequency band.
diagnosis:
- name: Acid alpha-mannosidase enzyme activity assay
  description: >
    Diagnosis is established by measuring deficient acid alpha-mannosidase
    activity in leukocytes or other nucleated cells.
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or"
    explanation: Review supports enzymatic testing as the core diagnostic method.
- name: MAN2B1 molecular genetic testing
  description: >
    Molecular testing confirms biallelic pathogenic MAN2B1 variants and supports
    carrier testing and prenatal or family-based risk assessment.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can be confirmed by genetic testing."
    explanation: Review supports molecular confirmation after enzyme testing.
- name: Urinary mannose-rich oligosaccharide screening
  description: >
    Increased urinary mannose-rich oligosaccharides support clinical suspicion
    but are not diagnostic without enzyme or molecular confirmation.
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic."
    explanation: Review distinguishes screening utility from diagnostic confirmation.
treatments:
- name: Velmanase alfa enzyme replacement therapy
  description: >
    Velmanase alfa is recombinant human lysosomal alpha-mannosidase used as
    enzyme replacement therapy for non-neurological manifestations. Trials show
    sustained serum oligosaccharide clearance, immunologic improvement, and
    greater benefit when started in pediatric patients.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: velmanase alfa
      term:
        id: NCIT:C152849
        label: Velmanase Alfa
  target_mechanisms:
  - target: MAN2B1 lysosomal alpha-mannosidase deficiency
    treatment_effect: RESTORES
    description: Velmanase alfa supplies recombinant lysosomal alpha-mannosidase activity.
    evidence:
    - reference: PMID:36849760
      reference_title: "Long-term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha-mannosidosis: A phase 2, open label, multicenter study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase product"
      explanation: Pediatric trial identifies velmanase alfa as recombinant human lysosomal alpha-mannosidase.
  - target: Mannose-rich oligosaccharide lysosomal storage
    treatment_effect: RESTORES
    description: Enzyme replacement lowers serum oligosaccharide storage biomarkers.
    evidence:
    - reference: PMID:39381850
      reference_title: Extended long-term efficacy and safety of velmanase alfa treatment up to 12 years in patients with alpha-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall, sustained serum oligosaccharide clearance and serum IgG"
      explanation: Long-term extension data support biomarker clearance after velmanase alfa initiation.
  evidence:
  - reference: PMID:29846843
    reference_title: "Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "INTRODUCTION: This phase III, double-blind, randomised, placebo-controlled trial"
    explanation: Phase III trial directly evaluates velmanase alfa in alpha-mannosidosis patients.
  - reference: PMID:39381850
    reference_title: Extended long-term efficacy and safety of velmanase alfa treatment up to 12 years in patients with alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "indicate continued benefits of velmanase alfa in patients with"
    explanation: Long-term extension supports continued benefit and safety.
- name: Hematopoietic stem cell transplantation
  description: >
    Allogeneic hematopoietic stem cell transplantation can normalize leukocyte
    enzyme activity and may stabilize cognitive function and improve hearing
    when performed early, but transplant candidacy and risk require specialist
    evaluation.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  target_mechanisms:
  - target: MAN2B1 lysosomal alpha-mannosidase deficiency
    treatment_effect: RESTORES
    description: Donor-derived hematopoietic cells restore leukocyte alpha-mannosidase activity.
    evidence:
    - reference: PMID:15126988
      reference_title: Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "normalization of leukocyte enzyme activity after HCT."
      explanation: Allogeneic HCT restored leukocyte alpha-mannosidase activity in the reported cohort.
  evidence:
  - reference: PMID:15126988
    reference_title: Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HCT can halt the progressive cognitive loss in patients with"
    explanation: HCT cohort supports transplantation as a disease-modifying intervention.
  - reference: PMID:15126988
    reference_title: Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early diagnosis and treatment with HCT is critical for"
    explanation: The study emphasizes early treatment for optimal outcomes.
- name: Supportive care
  description: >
    Supportive care addresses infections, middle-ear disease, hearing loss,
    developmental needs, physiotherapy, orthopedic complications, and other
    manifestations.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "preventing complications and treating manifestations."
    explanation: Review supports proactive supportive management.
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "required and use of hearing aids is invariably required."
    explanation: Review supports ENT and hearing-focused supportive care.
- name: Genetic counseling
  description: >
    Genetic counseling is appropriate because alpha-mannosidosis is autosomal
    recessive, and enzyme or molecular diagnosis clarifies carrier and recurrence
    risks for relatives.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:18651971
    reference_title: Alpha-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of the disease and to detect carriers."
    explanation: Review explicitly recommends genetic counseling.
references:
- reference: ORPHA:61
  title: Alpha-mannosidosis
  found_in:
  - Alpha_Mannosidosis-deep-research-fallback.md
- reference: ORPHA:309282
  title: Alpha-mannosidosis, infantile form
  found_in:
  - Alpha_Mannosidosis-deep-research-fallback.md
- reference: ORPHA:309288
  title: Alpha-mannosidosis, adult form
  found_in:
  - Alpha_Mannosidosis-deep-research-fallback.md
- reference: PMID:15126988
  title: Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation.
  found_in:
  - Alpha_Mannosidosis-deep-research-fallback.md
- reference: PMID:18651971
  title: Alpha-mannosidosis.
  found_in:
  - Alpha_Mannosidosis-deep-research-fallback.md
- reference: PMID:26048034
  title: "Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation."
  found_in:
  - Alpha_Mannosidosis-deep-research-fallback.md
- reference: PMID:29846843
  title: "Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial."
  found_in:
  - Alpha_Mannosidosis-deep-research-fallback.md
- reference: PMID:36849760
  title: "Long-term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha-mannosidosis: A phase 2, open label, multicenter study."
  found_in:
  - Alpha_Mannosidosis-deep-research-fallback.md
- reference: PMID:39381850
  title: Extended long-term efficacy and safety of velmanase alfa treatment up to 12 years in patients with alpha-mannosidosis.
  found_in:
  - Alpha_Mannosidosis-deep-research-fallback.md
- reference: PMID:40276561
  title: Disease profile in a cohort of Brazilian patients diagnosed with alpha-mannosidosis.
  found_in:
  - Alpha_Mannosidosis-deep-research-fallback.md

📚

References & Deep Research

References

10

ORPHA:61

Alpha-mannosidosis

No top-level findings curated for this source.

ORPHA:309282

Alpha-mannosidosis, infantile form

No top-level findings curated for this source.

ORPHA:309288

Alpha-mannosidosis, adult form

No top-level findings curated for this source.

PMID:15126988

Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation.

No top-level findings curated for this source.

PMID:18651971

Alpha-mannosidosis.

No top-level findings curated for this source.

PMID:26048034

Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation.

No top-level findings curated for this source.

PMID:29846843

Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial.

No top-level findings curated for this source.

PMID:36849760

Long-term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha-mannosidosis: A phase 2, open label, multicenter study.

No top-level findings curated for this source.

PMID:39381850

Extended long-term efficacy and safety of velmanase alfa treatment up to 12 years in patients with alpha-mannosidosis.

No top-level findings curated for this source.

PMID:40276561

Disease profile in a cohort of Brazilian patients diagnosed with alpha-mannosidosis.

No top-level findings curated for this source.

Deep Research

1

Alpha-mannosidosis Deep Research Fallback ▸

Alpha-mannosidosis Deep Research Fallback

Provider Attempts

Falcon: just research-disorder falcon Alpha_Mannosidosis started at this worktree and produced no output for several minutes; the provider process was terminated to avoid a silent deep-research wait.
OpenAI: just research-disorder openai Alpha_Mannosidosis was attempted after Falcon and also produced no output during two bounded wait intervals; the provider process was terminated.

Evidence Scope

The YAML curation integrates deterministic Orphanet structured records and fetched PubMed abstracts:

ORPHA:61 provides the direct disease mapping to MONDO:0009561, OMIM:248500, the definition, autosomal recessive inheritance, natural-history onset terms, prevalence rows, and the complete disease-level HPO phenotype table.
ORPHA:309282 and ORPHA:309288 provide infantile and adult subtype mappings to MONDO:0017732 and MONDO:0017733 plus MAN2B1 disease-causing gene rows.
PMID:18651971 supports the clinical definition, progressive course, MAN2B1/lysosomal alpha-mannosidase disease mechanism, enzyme and urinary-oligosaccharide diagnostic approach, supportive care, and genetic counseling.
PMID:26048034 supports the MAN2B1 genotype relationship, loss of lysosomal alpha-mannosidase activity, CSF oligosaccharide burden, and neurodevelopmental/motor/craniofacial phenotype links.
PMID:15126988 supports allogeneic hematopoietic stem cell transplantation as a disease-modifying treatment that normalizes leukocyte enzyme activity and can stabilize progressive cognitive loss.
PMID:29846843, PMID:36849760, and PMID:39381850 support velmanase alfa enzyme replacement therapy, including recombinant enzyme identity, clinical trial use, serum oligosaccharide clearance, immunologic effects, and long-term benefit.
PMID:40276561 supports the contemporary cohort framing of alpha-mannosidosis as an ultrarare multisystemic disorder caused by alpha-mannosidase deficiency.

Integration Notes

The curated YAML represents the canonical mechanism as MAN2B1-related lysosomal alpha-mannosidase deficiency leading to mannose-rich oligosaccharide lysosomal storage, with downstream neurodevelopmental, immune/infectious, skeletal, craniofacial, auditory, ocular, and visceral phenotypes. All ORPHA:61 disease-level phenotypes are included with exact Orphanet snippets and frequency bands. Frequent and very frequent phenotype rows from the ORPHA:309282 infantile and ORPHA:309288 adult subtype records are included as subtype-specific phenotype assertions. Treatment sections are limited to evidence-backed velmanase alfa enzyme replacement, hematopoietic stem cell transplantation, supportive care, and genetic counseling.

Alpha-mannosidosis

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Classifications

Mappings

Definitions

Inheritance

Subtypes

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Source YAML

References & Deep Research

References

Deep Research

Alpha-mannosidosis Deep Research Fallback

Provider Attempts

Evidence Scope

Integration Notes