Beta Mannosidosis

Mendelian MONDO:0009562 Pathograph 39 Show in embeddings browser Lysosomal storage diseases Oligosaccharidoses

Beta-mannosidosis is an autosomal recessive lysosomal disorder caused by biallelic pathogenic MANBA variants and deficient beta-mannosidase activity. Incomplete N-linked glycoprotein degradation leads to oligosaccharide accumulation and excretion. Hearing impairment, developmental or intellectual disability and behavioral abnormalities are prominent, with variable skin, infectious, motor and white-matter findings. Severity varies markedly, including among relatives, and is not reliably predicted by genotype or residual enzyme activity. Care is mainly supportive; biochemical correction after transplantation in one reported patient did not establish durable neurological benefit.

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6
Pathophys.
1
Histopath.
26
Phenotypes
2
Gaps
39
Pathograph
1
Genes
5
Variants
11
Medical Actions
2
Differentials
1
Trials
4
Models
1
References
2
Deep Research
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
ISDS Skeletal Nosology
lysosomal storage with skeletal involvement
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Discussions and Knowledge Gaps

2
Does variation in chitobiase-dependent glycan processing modify human disease severity?
KNOWLEDGE GAP beta_mannosidosis_ctbs_modifier
Additional urinary glycans in two severely affected patients and species differences motivate a CTBS hypothesis. No causal human modifier allele or functional epistasis experiment has established that link. Background-dependent mouse pathology indicates modifier effects without identifying the responsible gene.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"additional studies should be developed to determine whether CTBS (Di-N-Acetyl-Chitobiase) acts as a modifier gene in severe cases."
The authors pose a question; they do not demonstrate a CTBS modifier effect.
Why do some patients have persistent hypomyelination while the Manba knockout mouse lacks this finding?
HUMAN MODEL MISMATCH beta_mannosidosis_myelin_species_gap
Attached to
pathophysiology#Impaired CNS myelination
Human MRI, severe ruminant myelin deficiency and mouse vacuolation are distinct observations. Storage substrate composition, cell susceptibility and developmental timing may differ. Neuronal degeneration in mice is spatially separate from major vacuolated populations; vacuolation does not automatically imply neuronal death.
Show evidence (2 references)
PMID:24142277 SUPPORT DIRECT Model Organism
"Neuropathology between 1 and 9 months of age included selective, variable neuronal vacuolation with no hypomyelination."
Explicit lack of the human myelin phenotype in the reported mouse analysis.
PMID:24142277 SUPPORT DIRECT Model Organism
"Degeneration staining did not occur in areas of vacuolation or adjacent regions, suggesting that vacuolation does not lead to substantial cell body or axon loss."
Experimental pathology limits a simple vacuolation-to-cell-death chain.
⚙

Pathophysiology

6
MANBA lysosomal beta-mannosidase deficiency
Pathogenic MANBA alleles impair enzyme production, processing or catalytic function. Splice-disrupting, truncating and missense variants are reported; residual activity and clinical severity need not correlate.
MANBA hgnc:6831 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MANBA (hgnc:6831). hgnc:6831 is a gene from the HUGO Gene Nomenclature Committee.
beta-mannosidase activity GO:0004567 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased beta-mannosidase activity (GO:0004567). GO:0004567 is a molecular function from the Gene Ontology.
lysosomal lumen GO:0043202 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosomal lumen (GO:0043202). GO:0043202 is a cellular component from the Gene Ontology.
Experimental models
COS-7 expression of MANBA missense variants CELL LINE Measures impaired enzyme function of selected missense alleles.
Downstream
Impaired terminal N-glycan degradation Reduced beta-mannosidase activity impairs its terminal glycan-cleavage step.
Beta-mannosidase activity The enzyme deficiency is measured in diagnostic assays.
Show evidence (2 references)
PMID:12890191 SUPPORT DIRECT Human Clinical
"Assays of seven enzyme activities in plasma and cultured skin fibroblasts showed a marked decrease of beta-mannosidase activity."
Patient biochemical confirmation of enzyme deficiency.
PMID:18565776 SUPPORT DIRECT In Vitro
"Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no detectable increase in activity."
Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not an absolute zero-activity measurement.
Impaired terminal N-glycan degradation
Insufficient beta-mannosidase impairs cleavage of the terminal beta-linked mannose residue during lysosomal degradation of N-linked glycoproteins. The resulting glycan fragments cannot complete normal catabolism.
glycoprotein catabolic process GO:0006516 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycoprotein catabolic process (GO:0006516). GO:0006516 is a biological process from the Gene Ontology.
lysosomal lumen GO:0043202 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosomal lumen (GO:0043202). GO:0043202 is a cellular component from the Gene Ontology.
Downstream
Glycoprotein-derived oligosaccharide storage Incomplete lysosomal catabolism leaves glycan substrates available to accumulate.
Show evidence (1 reference)
PMID:16377659 SUPPORT DIRECT BACKGROUND Model Organism
"Beta-mannosidase, a lysosomal enzyme which acts exclusively at the last step of oligosaccharide catabolism in glycoprotein degradation, functions to cleave the unique beta-linked mannose sugar found in all N-linked oligosaccharides of glycoproteins."
Biochemical function summarized in the mouse-model paper, not a new human intervention result.
Glycoprotein-derived oligosaccharide storage
Incompletely degraded N-glycan fragments accumulate. ManGlcNAc and its sialylated derivative NeuManGlcNAc are detected in urine. The extent to which particular stored species cause neurological or systemic features remains unresolved.
lysosome GO:0005764 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosome (GO:0005764). GO:0005764 is a cellular component from the Gene Ontology.
Animal models
Manba knockout mice Mus musculus recapitulates
Naturally occurring caprine beta-mannosidosis Capra hircus partially recapitulates
Downstream
Lysosomal vacuolation Substrate accumulation is associated with distended lysosomal compartments; the human biopsy identifies the storage lesion.
Impaired CNS myelination The storage disorder can impair myelination through incompletely defined cellular intermediates.
Esophageal dysmotility Esophageal motor dysfunction occurs in the disorder; its intervening neural or muscular mechanism is unresolved.
Urinary free oligosaccharides Accumulated substrates are excreted and measured in urine.
Intellectual disability The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Sensorineural hearing impairment The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Atypical behavior The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Developmental regression The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Angiokeratoma The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Ataxia The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Hypotonia The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Peripheral neuropathy The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Hyperactivity The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Compulsive behaviors The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Aggressive behavior The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Autistic behavior The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Spasticity The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular steps remain unresolved.
Seizures This neurological manifestation occurs in the storage disorder; its intervening cellular mechanism is not established.
Delayed speech and language development This neurological manifestation occurs in the storage disorder; its intervening cellular mechanism is not established.
Hydrocephalus This neurological manifestation occurs in the storage disorder; its intervening cellular mechanism is not established.
Show evidence (2 references)
PMID:41235131 SUPPORT DIRECT Human Clinical
"ManGlcNAc and NeuManGlcNAc, known markers of the disease,1,12,48 are present in the urine of patients A, C, and D."
Direct glycan profiling in the 2025 series.
PMID:16377659 SUPPORT DIRECT Model Organism
"Thin-layer chromatography demonstrated an accumulation of disaccharide in epididymis and brain."
Tissue substrate storage in the knockout mouse; human tissue composition is not inferred from this alone.
Lysosomal vacuolation
Distended lysosomal compartments produce cytoplasmic vacuolation. Human skin biopsy and derived cell cultures demonstrate this lesion in several cell types. Neuronal vacuolation is established in mice; its precise distribution and consequences in human brain remain incompletely characterized.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology. fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology. endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
lysosome GO:0005764 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosome (GO:0005764). GO:0005764 is a cellular component from the Gene Ontology.
skin UBERON:0002097 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skin, annotated with skin of body (UBERON:0002097). UBERON:0002097 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Patient-derived skin fibroblast and keratinocyte cultures PRIMARY CELL CULTURE Patient-derived skin cells reproduce the vacuolated compartments seen in biopsy.
Animal models
Manba knockout mice Mus musculus partially recapitulates
Show evidence (1 reference)
PMID:12890191 SUPPORT DIRECT Human Clinical
"Electron microscopy of skin biopsy specimens from the patient showed cytoplasmic vacuolation of lysosomes in blood and lymph vessels, endothelial cells, fibroblasts, secretory portions of eccrine sweat glands, neural cells and basal keratinocytes in the epidermis."
Direct human skin ultrastructure, not human brain neuropathology.
Impaired CNS myelination
Some patients have delayed myelination in infancy and persistent hypomyelination on serial MRI. Human imaging demonstrates deficient myelin deposition but does not identify a proven oligodendrocyte-loss mechanism. Ruminant and mouse phenotypes differ substantially.
myelination GO:0042552 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased myelination (GO:0042552). GO:0042552 is a biological process from the Gene Ontology.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Manba knockout mice Mus musculus fails to recapitulate
Naturally occurring caprine beta-mannosidosis Capra hircus partially recapitulates
Downstream
Delayed myelination Delayed myelin deposition can be apparent in infancy.
CNS hypomyelination Persistent deficient myelination is visible on serial MRI.
Show evidence (2 references)
PMID:41235131 SUPPORT DIRECT Human Clinical
"The brain MRI features of hypomyelinatione20 are represented in 3 of our patients"
Three of six patients had abnormal myelination, not half of all individuals with beta-mannosidosis.
PMID:41235131 SUPPORT DIRECT Human Clinical
"Further research is needed to elucidate the mechanism of impaired myelination in β-mannosidosis."
Limits causal interpretation of the human MRI observations.
Esophageal dysmotility
Abnormal swallowing and esophageal motility have been documented in a patient with recurrent respiratory infections. This provides one route to respiratory morbidity; it does not establish a generalized immune defect or explain infections in every patient.
Downstream
Dysphagia Abnormal esophageal motility can impair swallowing.
Recurrent respiratory infections Swallowing and esophageal dysfunction provide one documented contributor to recurrent respiratory infections.
Show evidence (1 reference)
PMID:9097826 SUPPORT DIRECT Human Clinical
"Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring respiratory infections, previously reported in some other cases."
A clinical case establishes the motility-associated route to recurrent respiratory infections.
✶

Histopathology

1
Lysosomal vacuolation in skin
Skin biopsy electron microscopy showed vacuolated lysosomes in vascular and lymphatic endothelium, fibroblasts, eccrine secretory cells, neural cells and basal keratinocytes in one patient. This is direct tissue evidence and does not establish the distribution of human brain pathology.
Show evidence (1 reference)
PMID:12890191 SUPPORT DIRECT Human Clinical
"Electron microscopy of skin biopsy specimens from the patient showed cytoplasmic vacuolation of lysosomes in blood and lymph vessels, endothelial cells, fibroblasts, secretory portions of eccrine sweat glands, neural cells and basal keratinocytes in the epidermis."
Direct human skin ultrastructure, not human brain neuropathology.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Beta Mannosidosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

26
Cardiovascular 1
Angiokeratoma FREQUENT HP:0001014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Angiokeratoma (HP:0001014). HP:0001014 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"although it is frequently reported in β-mannosidosis (52.6%, eTable 2)."
Literature-review frequency with incomplete reporting and case ascertainment.
Digestive 3
Hypoplasia of the abdominal wall musculature HP:0005247 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the abdominal wall musculature (HP:0005247). HP:0005247 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:118 SUPPORT Other
"HP:0005247 | Hypoplasia of the abdominal wall musculature | Very frequent (99-80%)"
Catalogue association retained; the quoted catalogue frequency is not adopted as a patient-series estimate.
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41235131 SUPPORT DIRECT Human Clinical
"Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
The expanded cohort documents dysphagia; the earlier 1997 case demonstrates that swallowing dysfunction was already reported.
PMID:9097826 SUPPORT DIRECT Human Clinical
"Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring respiratory infections, previously reported in some other cases."
Earlier case report supports clinically significant swallowing and esophageal motility abnormalities.
Visceromegaly OCCASIONAL HP:0003271 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visceromegaly (HP:0003271). HP:0003271 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Skeletal abnormalities were seen only in 8% and organomegaly in 17.4% of the reported patients."
Review frequency among cases with relevant information, not population prevalence.
Ear 1
Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:41235131 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The most frequent symptom reported independently of age at onset (eTables 1 and 2) was intellectual disability (91.4%), followed by behavioral abnormalities (82.8%) and hearing loss (74.4%)."
Frequencies among informative literature reports, not unbiased population prevalence.
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"sensorineural hearing loss, recurrent infections, angiokeratomas, seizures, and ataxia."
GeneReviews identifies the sensorineural phenotype.
PMID:32847582 SUPPORT DIRECT Human Clinical
"since besides having a homozygous c.2158-2A>G MANBA variant he is also a homozygote for the c.71G>A (p.W24*) variant in GJB2."
Double molecular diagnosis in one hearing-impaired patient.
Head and Neck 2
Abnormal facial shape FREQUENT HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Facial dysmorphism was observed in 43.3% of patients, but it is usually mild."
Literature-review estimate with case-report ascertainment; this aggregate does not specify one defining facial finding.
Coarse facial features HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Most individuals have no dysmorphic features; some have mild coarseness."
GeneReviews distinguishes optional coarseness from a universal coarse facial appearance.
Immune 1
Recurrent respiratory infections HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:9097826 SUPPORT DIRECT Human Clinical
"Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring respiratory infections, previously reported in some other cases."
Case report supports recurrent respiratory infections and notes prior reports.
PMID:32847582 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"respiratory and skin infections reported in five patients"
Founder-variant cohort review supports respiratory and skin infections in a subset of patients.
Musculoskeletal 3
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"There was axial hypotonia, with normal strength and reflexes in limbs."
Patient D; strength and reflexes were preserved.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"Spasticity and ataxia have worsened, requiring assistance for mobilization."
Patient B’s later motor decline; not a general natural-history rate.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"Examination showed thick lips, bilateral epicanthal folds, bilateral elliptical nystagmus, optic nerves with temporal pallor, slender fingers, and scoliosis."
Patient B at later follow-up.
Nervous System 14
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The most frequent symptom reported independently of age at onset (eTables 1 and 2) was intellectual disability (91.4%), followed by behavioral abnormalities (82.8%) and hearing loss (74.4%)."
Frequencies among informative literature reports, not unbiased population prevalence.
Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The most frequent symptom reported independently of age at onset (eTables 1 and 2) was intellectual disability (91.4%), followed by behavioral abnormalities (82.8%) and hearing loss (74.4%)."
Frequencies among informative literature reports, not unbiased population prevalence.
Developmental regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
The new cohort directly reports developmental regression.
Delayed myelination HP:0012448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed myelination (HP:0012448). HP:0012448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"Half the patients have abnormal brain MRIs, showing delayed myelination before 2 years of age and diffuse hypomyelination thereafter."
Directly supports delayed myelination as a neuroimaging phenotype.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"Seizures began at 6 years, characterized by leftward gaze deviation, eye twitching, drooling, and unresponsiveness."
Seizures in patient C; no population frequency inferred.
CNS hypomyelination HP:0003429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is CNS hypomyelination (HP:0003429). HP:0003429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"The brain MRI features of hypomyelinatione20 are represented in 3 of our patients"
Three of six patients had abnormal myelination, not half of all individuals with beta-mannosidosis.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"Independent walking showed unorthodox wide arm swing, ataxia, and hyperlordotic posture without scoliosis."
Adult patient F with a normal MRI.
Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Two patients with β-mannosidosis have been reported with peripheral neuropathy."
Published case reports summarized in the 2025 review.
Hyperactivity HP:0000752 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperactivity (HP:0000752). HP:0000752 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"He is being treated with methylphenidate for behavioral issues, attention deficit and hyperactivity disorder (ADHD), and panic attacks."
Patient E; this is a case-level treatment report.
Compulsive behaviors HP:0000722 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Compulsive behaviors (HP:0000722). HP:0000722 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"He has learning difficulties associated with anxiety, obsessive-compulsive traits, aggressive ideation, and perseverance."
Patient A’s described behavioral profile.
Aggressive behavior HP:0000718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aggressive behavior (HP:0000718). HP:0000718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"At 14 years old, she is dependent for daily activities and exhibits aggressive behavior."
Patient C.
Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"Additional problems include anxiety and disturbed sleep, some autistic features, and frequent tremors in the upper limbs."
Adult patient F had autistic features; this is distinct from all patients having autism.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Beta-mannosidosis is characterized by developmental delay (speech is more significantly affected than motor skills), mild-to-severe intellectual disability"
GeneReviews describes the relative developmental involvement.
Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Findings on CT included cerebral atrophy,21 basal ganglia and white matter calcification,25 and hydrocephalus."
Published neuroimaging findings summarized in the review.
Constitutional 1
Erythromelalgia HP:0032147 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Erythromelalgia (HP:0032147). HP:0032147 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"At 21 months, the patient developed episodes of recurrent pain and bright red-hot swelling in hands and feet with activity, consistent with erythromelalgia."
New observation in patient D; no frequency or immune mechanism inferred.
🧬

Genetic Associations

1
MANBA (Causative)
Gene: MANBA hgnc:6831 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MANBA (hgnc:6831). hgnc:6831 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive
Show evidence (3 references)
CGGV:assertion_d70d38aa-f7e9-4c93-8160-58dec9cec010-2022-08-02T160000.000Z SUPPORT Other
"MANBA | HGNC:6831 | beta-mannosidosis | MONDO:0009562 | AR | Definitive"
ClinGen classifies the MANBA-beta-mannosidosis gene-disease relationship as definitive with autosomal recessive inheritance.
PMID:32847582 SUPPORT DIRECT Human Clinical
"MANBA variant c.2158-2A>G screening among 345 anonymized normal hearing controls from Roma populations revealed a carrier/heterozygote frequency of 3.77%."
Population and denominator of the carrier estimate.
PMID:41235131 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"the severity of the phenotype is not explained by the presence or absence of residual enzyme activity."
Review interpretation of variable clinical severity.
Variants (5)
NM_005908.4:c.2158-2A>G Pathogenic
single nucleotide variant
Variant detail: Splice acceptor variant
Genomic context: intron
An intronic acceptor-site SNV associated with cryptic splice-site activation and exon skipping. Two abnormal RNA products were observed in differently affected siblings. Presence of abnormal RNA does not itself demonstrate residual catalytic activity.
Identifiers: dbSNP:rs772852668
Show evidence (2 references)
PMID:9384606 SUPPORT DIRECT Human Clinical
"The associated cryptic splice site activation and exon skipping caused by this mutation resulted in two abnormally spliced mutant mRNA species in both siblings."
Primary patient RNA evidence.
PMID:32847582 SUPPORT DIRECT BACKGROUND Human Clinical
"The first, larger product, lacking 172 bp, results in a frameshift and stop codon that truncates the predicted protein by 155 residues. The second, shorter product, lacks 258 bp and is presumably an exon skipping event"
The 2020 report summarizes earlier RNA analysis; these are transcript deletions, not separate DNA deletions.
MANBA c.375A>G
single nucleotide variant
Variant detail: Synonymous variant with splice disruption
Genomic context: coding sequence
The reported DNA substitution is synonymous but alters splicing, removing four nucleotides from RNA and predicting premature termination. It was found in trans with p.Ser505Pro. The physical DNA alteration is a single-nucleotide substitution; the four-base deletion occurs in the transcript.
Show evidence (1 reference)
PMID:18565776 SUPPORT DIRECT Human Clinical
"The patient was compound heterozygous for a silent mutation (c.375A>G) in exon 3 causing alternative splicing, and a missense mutation (c.1513T>C, p.Ser505Pro) in exon 12."
Separates the DNA SNV from the abnormal transcript.
MANBA c.1513T>C (p.Ser505Pro)
single nucleotide variant
Variant detail: Functionally tested missense allele
Genomic context: coding sequence
The mutant construct failed to increase beta-mannosidase activity above mock in COS-7 cells. Ser505Pro was reported in a more severe presentation than Arg182Trp or Gly392Glu; the common in vitro activity result does not predict individual clinical severity.
Show evidence (1 reference)
PMID:18565776 SUPPORT DIRECT In Vitro
"Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no detectable increase in activity."
Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not an absolute zero-activity measurement.
MANBA c.544C>T (p.Arg182Trp)
single nucleotide variant
Variant detail: Functionally tested missense allele
Genomic context: coding sequence
The mutant construct failed to increase beta-mannosidase activity above mock in COS-7 cells. Ser505Pro was reported in a more severe presentation than Arg182Trp or Gly392Glu; the common in vitro activity result does not predict individual clinical severity.
Show evidence (1 reference)
PMID:18565776 SUPPORT DIRECT In Vitro
"Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no detectable increase in activity."
Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not an absolute zero-activity measurement.
MANBA c.1175G>A (p.Gly392Glu)
single nucleotide variant
Variant detail: Functionally tested missense allele
Genomic context: coding sequence
The mutant construct failed to increase beta-mannosidase activity above mock in COS-7 cells. Ser505Pro was reported in a more severe presentation than Arg182Trp or Gly392Glu; the common in vitro activity result does not predict individual clinical severity.
Show evidence (1 reference)
PMID:18565776 SUPPORT DIRECT In Vitro
"Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no detectable increase in activity."
Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not an absolute zero-activity measurement.
💊

Medical Actions

11
Developmental and educational support
Action: Developmental and educational supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Developmental and educational support, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Behavioral / lifestyle
Individualized developmental, language and educational support; hearing impairment should be considered when assessing communication and cognition.
Show evidence (1 reference)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Developmental and educational support; rehabilitation, physical therapy, and occupational therapy as needed for musculoskeletal manifestations;"
Supports the described care, with indication and limitations stated in the description.
Physical and occupational rehabilitation
Action: Physical and occupational rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical and occupational rehabilitation, annotated with Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Therapy and orthotic devices may support mobility, ataxia and progressive scoliosis; goals are individualized to function.
Show evidence (2 references)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"rehabilitation, physical therapy, and occupational therapy as needed for musculoskeletal manifestations"
Supports physical and occupational rehabilitation.
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"orthotic devices for progressive scoliosis or ataxia;"
Supports the described care, with indication and limitations stated in the description.
Hearing rehabilitation
Platform: Device
Hearing aids may improve communication. Combine behavioral and objective audiological assessment when cooperation limits threshold measurement, and reassess hearing annually. Disease-specific cochlear-implant outcomes are not established by the cited sources.
Show evidence (2 references)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"hearing aids may be helpful; specific antimicrobial treatment for recurrent infections;"
Supports the described care, with indication and limitations stated in the description.
PMID:32847582 SUPPORT DIRECT Human Clinical
"both subjective and objective methods for audiometric examination should be used in MANBA related patients to properly evaluate the degree of hearing impairment."
Supports the assessment strategy when cooperation affects behavioral thresholds.
Treatment of recurrent infections
Platform: Small molecule
Treat identified infections with appropriate antimicrobials and evaluate contributory swallowing or airway problems. Recurrent infections do not by themselves establish a primary immunodeficiency.
Show evidence (1 reference)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"specific antimicrobial treatment for recurrent infections; feeding tube as needed;"
Supports the described care, with indication and limitations stated in the description.
Feeding and nutritional support
Action: Feeding and nutritional supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Feeding and nutritional support, annotated with Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Platform: Other
Assess growth and swallowing safety; feeding-tube and nutritional support may be required for inadequate intake or progressive dysphagia. Manage associated constipation or diarrhea.
Show evidence (1 reference)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"feeding tube as needed; nutrition support; treatment of chronic diarrhea or constipation;"
Supports the described care, with indication and limitations stated in the description.
Seizure management
Platform: Small molecule
Use standard antiseizure care individualized to seizure type and clinical context. No MANBA-specific drug efficacy is established.
Show evidence (1 reference)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"standard treatments for seizures; ventriculoperitoneal shunt for hydrocephalus;"
Supports the described care, with indication and limitations stated in the description.
Hydrocephalus treatment
Action: Hydrocephalus treatmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hydrocephalus treatment, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Ventriculoperitoneal shunting is an option when hydrocephalus requires treatment; hydrocephalus is not an obligatory feature.
Show evidence (1 reference)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"ventriculoperitoneal shunt for hydrocephalus; transitional care plan for adult life;"
Supports the described care, with indication and limitations stated in the description.
Behavioral and psychiatric care
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: methylphenidate CHEBI:6887 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses methylphenidate (CHEBI:6887). CHEBI:6887 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Assess behavioral and psychiatric needs throughout life. Methylphenidate was reported for ADHD in one patient; this is symptom-directed experience, not a disease-specific efficacy trial.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"He is being treated with methylphenidate for behavioral issues, attention deficit and hyperactivity disorder (ADHD), and panic attacks."
Supports the described care, with indication and limitations stated in the description.
Surveillance and transition to adult care
Platform: Other
At each visit assess developmental needs, behavior, infection frequency, growth, gastrointestinal symptoms, abnormal movements, head circumference and neurological regression. Arrange annual audiology and a transition plan with family and social support.
Show evidence (1 reference)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"At each visit assess developmental and educational needs, neurobehavioral and psychiatric issues, frequency of infections, growth, gastrointestinal manifestations, abnormal movements, head circumference, neurologic regression, and family and social work needs; annual audiology evaluation."
Supports the described care, with indication and limitations stated in the description.
Genetic counseling and family evaluation
Platform: Behavioral / lifestyle
Autosomal recessive counseling includes the 25% recurrence risk when both parents carry a pathogenic allele. Offer appropriate testing of at-risk relatives and discuss reproductive testing once familial variants are known.
Show evidence (2 references)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"If the MANBA pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
Supports the described care, with indication and limitations stated in the description.
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"If both parents are known to be heterozygous for a MANBA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
Mendelian recurrence risks, conditional on both parents being carriers.
Hematopoietic cell transplantation
Platform: Cell therapy
An HLA-matched cord-blood transplant in one boy at approximately 4.5 years normalized leukocyte enzyme activity and reduced urinary oligosaccharides. Early neurological worsening partly improved, but the developmental gap persisted and memory declined by two years. Follow-up of the same patient in 2025 documented renewed motor regression and worsening spasticity/ataxia. This does not establish durable neurological efficacy or routine use; biochemical correction is not a validated surrogate for clinical benefit.
Mechanism Target:
RESTORES MANBA lysosomal beta-mannosidase deficiency — Restored leukocyte beta-mannosidase activity after donor-cell engraftment; correction in brain cells and durable clinical benefit were not established.
Show evidence (1 reference)
PMID:31115173 SUPPORT DIRECT Human Clinical
"We show restoration of leukocyte β-mannosidase activity which remained normal at 2 years posttransplant"
Observed biochemical response in one patient.
Show evidence (2 references)
PMID:31115173 SUPPORT DIRECT Human Clinical
"Our findings suggest that hematopoietic cell transplant can correct the biochemical defect in β-mannosidosis, although preservation of the neurocognitive trajectory may be a challenge."
Single treated patient, without an untreated comparator.
PMID:41235131 SUPPORT DIRECT Human Clinical
"At 10 years of age, he developed progressive regression in gross motor skills, urinary incontinence, low muscle bulk, axial hypotonia, end point dysmetria, and dysarthria"
Later follow-up of the same transplant recipient, not an independent treatment case.
🔬

Biochemical Markers

3
Urinary free oligosaccharides (INCREASED)
Context: Diagnostic biomarker
Pathograph Readouts
Readout Of Glycoprotein-derived oligosaccharide storage Positive Diagnostic
Increased urinary free oligosaccharides report overflow of incompletely degraded glycoprotein-derived substrates from lysosomal storage.
Show evidence (1 reference)
PMID:32847582 SUPPORT Human Clinical
"Biochemical diagnostics confirmed the typical disaccharides (primarily Man (beta1 → 4) GlcNac) in the urine of affected patients"
Patient urine testing directly supports urinary oligosaccharides as a diagnostic readout of glycoprotein-derived oligosaccharide storage.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"ManGlcNAc and NeuManGlcNAc, known markers of the disease,1,12,48 are present in the urine of patients A, C, and D."
Direct glycan profiling in the 2025 series.
Beta-mannosidase activity (DECREASED)
Context: Diagnostic enzymatic assay
Pathograph Readouts
Readout Of MANBA lysosomal beta-mannosidase deficiency Negative Diagnostic
Decreased beta-mannosidase activity directly reports the primary MANBA lysosomal enzyme deficiency.
Show evidence (1 reference)
PMID:32847582 SUPPORT Human Clinical
"a decreased activity of the beta-mannosidase enzyme in different cells, particularly in leukocytes"
Patient cell assays support reduced beta-mannosidase activity as a direct diagnostic readout of MANBA enzyme deficiency.
Show evidence (1 reference)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"markedly reduced or absent beta-mannosidase activity in leukocytes, serum, or plasma. Enzyme testing is the gold standard for diagnosis."
Clinical diagnostic role and specimen types.
Urinary NeuMan2GlcNAc2 peak (INCREASED)
Context: Exploratory glycan finding
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"An additional abnormal peak, corresponding to a Neu-Man2-GlcNac2 structure, was found in patients C and D."
Small case-level observation from urinary glycan profiling.
🔬

Diagnosis

3
Enzyme testing with molecular confirmation
Measure beta-mannosidase activity in appropriate clinical specimens and interpret against laboratory-specific controls. Markedly reduced or absent activity establishes the biochemical diagnosis; biallelic pathogenic MANBA variants clarify inheritance and enable family testing. Variants of uncertain significance alone are insufficient.
Show evidence (2 references)
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"markedly reduced or absent beta-mannosidase activity in leukocytes, serum, or plasma. Enzyme testing is the gold standard for diagnosis."
Clinical diagnostic role and specimen types.
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Identification of biallelic pathogenic variants in MANBA by molecular genetic testing can aid in assessment of recurrence risk for sibs of the proband."
Molecular testing complements the diagnostic enzyme assay.
Urinary oligosaccharide profiling
Characteristic ManGlcNAc and sialylated glycan findings support the diagnosis. Interpret alongside enzyme and genetic results; performance estimates from mixed lysosomal-disorder validation cohorts should not be assigned to beta-mannosidosis alone.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT Human Clinical
"ManGlcNAc and NeuManGlcNAc, known markers of the disease,1,12,48 are present in the urine of patients A, C, and D."
Direct glycan profiling in the 2025 series.
Audiological and neurological assessment
Consider beta-mannosidosis in syndromic or apparently isolated hearing loss, otherwise unexplained hypomyelination, developmental or intellectual disability and behavioral abnormalities. MRI can be normal. Objective auditory methods can supplement behavioral audiometry when test cooperation is limited.
Show evidence (2 references)
PMID:41235131 SUPPORT DIRECT Human Clinical
"β-mannosidosis should be considered as a differential diagnosis in patients with syndromic or apparently nonsyndromic hearing loss, unexplained brain hypomyelination, behavioral disturbances, and intellectual disability."
Clinical diagnostic consideration from the expanded series.
PMID:32847582 SUPPORT DIRECT Human Clinical
"both subjective and objective methods for audiometric examination should be used in MANBA related patients to properly evaluate the degree of hearing impairment."
Addresses ascertainment and test-cooperation limitations.
📊

Prevalence

2
Global reported literature
Cases In Literature Unknown
The 2025 review reported 46 individuals from 37 families. This literature count is not a population prevalence estimate and includes a previously published transplant recipient followed longitudinally. Mild presentations may be underdiagnosed.
Show evidence (2 references)
PMID:9097826 SUPPORT Human Clinical
"Only 11 cases of beta mannosidase deficiency have been reported until now."
Documents the number of published cases at the time of reporting, without estimating population prevalence.
PMID:41235131 SUPPORT Human Clinical
"Including our 6 patients, a total of 46 cases from 37 different families have been reported."
Documents the number of published cases at the time of reporting, without estimating population prevalence.
Published European birth-prevalence estimates
Birth Prevalence 0.12–0.16 per 100,000 live births 1–9 per 1,000,000 (births)
Review-reported estimates from the Netherlands, Portugal and Czech Republic; ascertainment and historical study periods differ. They do not establish a current global prevalence.
Show evidence (1 reference)
PMID:41235131 SUPPORT DIRECT BACKGROUND Human Clinical
"Reported prevalence rates are 0.13, 0.12, and 0.16 per 100,000 live births in the Netherlands,4 Portugal,5 and the Czech Republic, respectively."
Regional birth estimates summarized in the introduction, distinct from the authors’ patient series.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Beta Mannosidosis:

Alpha-mannosidosis MONDO:0009561
Overlapping Features Overlapping oligosacchariduria, intellectual disability, hearing loss, infections and facial changes can cause diagnostic confusion.
Distinguishing Features
  • Skeletal dysplasia is more prominent in alpha-mannosidosis; beta-mannosidosis requires demonstration of the beta-mannosidase enzyme defect and appropriate MANBA interpretation.
Show evidence (2 references)
PMID:41235131 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Compared with α-mannosidosis in which skeletal dysplasia is a main feature,3 it was found in 7.4% of the patients with β-mannosidosis."
Comparative clinical distinction; biochemical confirmation remains necessary.
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"markedly reduced or absent beta-mannosidase activity in leukocytes, serum, or plasma. Enzyme testing is the gold standard for diagnosis."
Clinical diagnostic role and specimen types.
Fucosidosis MONDO:0009254
Overlapping Features Lysosomal disease with a potentially similar hypomyelination pattern.
Distinguishing Features
  • MRI alone cannot establish beta-mannosidosis; beta-mannosidase testing and MANBA molecular evaluation distinguish its biochemical defect.
Show evidence (2 references)
PMID:41235131 SUPPORT DIRECT BACKGROUND Human Clinical
"Similar patterns occur in fucosidosis and sialic acid disorders, probably reflecting a secondary failure of myelination, unlike primary hypomyelinating conditions such as Pelizaeus-Merzbacher disease."
The similar MRI pattern is not disease-specific.
PMID:42160655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"markedly reduced or absent beta-mannosidase activity in leukocytes, serum, or plasma. Enzyme testing is the gold standard for diagnosis."
Clinical diagnostic role and specimen types.
🔬

Clinical Trials

1
NCT01891422 NOT_APPLICABLE COMPLETED
Observational longitudinal study of glycoproteinoses including beta-mannosidosis, designed to characterize clinical course and biochemical/genetic findings. It is not a therapeutic trial, and pooled enrollment does not establish the number of beta-mannosidosis participants.
Show evidence (2 references)
clinicaltrials:NCT01891422 SUPPORT DIRECT Human Clinical
"The diseases include aspartylglucosaminuria, fucosidosis, galactosialidosis, alpha-mannosidosis, beta-mannosidosis, mucolipidosis II, mucolipidosis III, Schindler disease, and sialidosis."
Registry explicitly includes beta-mannosidosis.
clinicaltrials:NCT01891422 SUPPORT DIRECT Human Clinical
"Longitudinal studies of these conditions are needed in order to better define how common the diseases are, identify clinical features which could contribute to early diagnoses, detail progression of the diseases, assess the supportive therapies currently used, and identify potential treatments."
Observational purpose, not an interventional efficacy result.
🧫

Experimental Models

2
Patient-derived skin fibroblast and keratinocyte cultures PRIMARY_CELL_CULTURE
Cultures from a patient with a splice-disrupting MANBA allele showed lysosomal vacuolation. They capture a cellular storage phenotype, without measuring neuronal behavior or brain myelination.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology. keratinocyte CL:0000312 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
Cell source
Patient-derived skin cells
Pathograph links
Lysosomal vacuolation recapitulates observes: cellular Patient-derived skin cells reproduce the vacuolated compartments seen in biopsy.
Show evidence (1 reference)
PMID:12890191 SUPPORT DIRECT In Vitro
"This vacuolation was also observed in cultured keratinocytes and fibroblasts."
Direct culture observation.
Show evidence (1 reference)
PMID:12890191 SUPPORT DIRECT In Vitro
"This vacuolation was also observed in cultured keratinocytes and fibroblasts."
Primary cultures, distinct from the skin-biopsy observation.
COS-7 expression of MANBA missense variants CELL_LINE
Ser505Pro, Arg182Trp and Gly392Glu were compared with wild-type and mock transfection. Wild-type expression increased activity 33-fold over mock; mutant constructs produced no detectable increase. This assay does not equate clinical severity with residual activity or reproduce patient tissue expression.
Cell source
COS-7 cells transiently expressing human wild-type or mutant MANBA
Pathograph links
MANBA lysosomal beta-mannosidase deficiency recapitulates observes: molecular Measures impaired enzyme function of selected missense alleles.
Limitations: Heterologous overexpression; no detectable increment above mock does not mean absence of all endogenous activity.
Show evidence (1 reference)
PMID:18565776 SUPPORT DIRECT In Vitro
"Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no detectable increase in activity."
Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not an absolute zero-activity measurement.
Show evidence (1 reference)
PMID:18565776 SUPPORT DIRECT In Vitro
"Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no detectable increase in activity."
Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not an absolute zero-activity measurement.
🐁

Animal Models

2
Manba knockout mice
Knockout mice accumulate disaccharides and show CNS vacuolation with few overt early neurological abnormalities. At 15–20 months all five congenic mice in the 2014 study had severe regional vacuolation and degeneration, whereas mixed-background mice varied. The study did not identify a particular modifier gene. Myelination defects seen in some patients and ruminants were not reproduced.
Species
Mus musculus
Genotype
Manba homozygous targeted disruption
Background
129X1/SvJ congenic and mixed C57BL/6J × 129X1/SvJ
Pathograph links
Glycoprotein-derived oligosaccharide storage recapitulates observes: tissue
Show evidence (1 reference)
PMID:16377659 SUPPORT DIRECT Model Organism
"Thin-layer chromatography demonstrated an accumulation of disaccharide in epididymis and brain."
Tissue substrate storage in the knockout mouse; human tissue composition is not inferred from this alone.
Lysosomal vacuolation partially recapitulates observes: cellular
Limitations: Neuronal vacuolation in mice differs from the directly sampled human skin lesion; human CNS histopathology remains sparse.
Show evidence (1 reference)
PMID:24142277 SUPPORT DIRECT Model Organism
"Morphological analysis indicated a severe consistent pattern of neuronal vacuolation and disintegrative degeneration in all five 129X1/SvJ mice."
Background-dependent CNS pathology.
Impaired CNS myelination fails to recapitulate observes: tissue
Limitations: This mouse model did not reproduce the hypomyelination documented by MRI in a subset of humans.
Show evidence (1 reference)
PMID:24142277 SUPPORT DIRECT Model Organism
"Neuropathology between 1 and 9 months of age included selective, variable neuronal vacuolation with no hypomyelination."
Explicit lack of the human myelin phenotype in the reported mouse analysis.
Show evidence (2 references)
PMID:16377659 SUPPORT DIRECT Model Organism
"At >1 year of age, these mice exhibit no dysmorphology or overt neurological problems."
Limits clinical fidelity despite the biochemical and pathological phenotype.
PMID:24142277 SUPPORT DIRECT Model Organism
"However, the mice with a mixed genetic background showed substantial variability in the severity of pathology."
Genetic background affects expression; no specific modifier was mapped.
Naturally occurring caprine beta-mannosidosis
The inherited caprine disorder reproduces beta-mannosidase deficiency, oligosaccharide storage and prenatal myelin deficits. In a single affected fetus, optic-nerve myelinated-axon density was about one quarter of the control value; oligodendrocyte proportions were reduced. This does not distinguish altered proliferation from cell death or establish oligodendrocyte death in humans. Neonatal regional substrate measurements did not track the severity of myelin loss.
Species
Capra hircus
Pathograph links
Glycoprotein-derived oligosaccharide storage partially recapitulates observes: tissue
Limitations: Goats accumulate both disaccharide and trisaccharide; human substrate processing differs.
Show evidence (1 reference)
PMID:2370553 SUPPORT DIRECT Model Organism
"Goats affected with beta-mannosidosis, an autosomal recessive disease of glycoprotein metabolism, have deficient activity of the lysosomal enzyme beta-mannosidase along with tissue storage of oligosaccharides"
Natural recessive caprine disease reproduces enzyme deficiency and storage, with a substrate profile that differs from human disease.
Impaired CNS myelination partially recapitulates observes: tissue
Limitations: Severe fetal optic-nerve pathology in one affected goat is not equivalent to the heterogeneous human MRI phenotype.
Show evidence (1 reference)
PMID:3503502 SUPPORT DIRECT Model Organism
"In the affected fetus, the number of myelinated axons per unit area was about 25% of the control values."
One affected goat fetus and one control were examined; this is an optic-nerve finding, not a human myelin measurement.
Show evidence (2 references)
PMID:2370553 SUPPORT DIRECT Model Organism
"Thus, greater oligosaccharide accumulation was not associated with more severe myelin deficiency."
Three affected and two control neonatal goats showed that regional storage burden did not explain the regional severity of myelin deficits.
PMID:3503502 SUPPORT DIRECT Model Organism
"Ultrastructural analysis revealed a decreased proportion of oligodendrocytes and an increased proportion of astrocytes in the affected fetus."
Cell proportions were measured in the affected fetal optic nerve; cell death was proposed rather than directly demonstrated.
{ }

Source YAML

click to show 
name: Beta Mannosidosis
synonyms:
- beta-Mannosidosis, MANBA-related
creation_date: '2025-12-19T01:18:09Z'
description: >-
  Beta-mannosidosis is an autosomal recessive lysosomal disorder caused by biallelic pathogenic MANBA variants
  and deficient beta-mannosidase activity. Incomplete N-linked glycoprotein degradation leads to oligosaccharide
  accumulation and excretion. Hearing impairment, developmental or intellectual disability and behavioral abnormalities
  are prominent, with variable skin, infectious, motor and white-matter findings. Severity varies markedly,
  including among relatives, and is not reliably predicted by genotype or residual enzyme activity. Care is
  mainly supportive; biochemical correction after transplantation in one reported patient did not establish
  durable neurological benefit.
category: Mendelian
disease_term:
  preferred_term: beta-mannosidosis
  term:
    id: MONDO:0009562
    label: beta-mannosidosis
parents:
- Lysosomal storage diseases
- Oligosaccharidoses
prevalence:
- population: Global reported literature
  prevalence_class: UNKNOWN
  notes: >-
    The 2025 review reported 46 individuals from 37 families. This literature count is not a population prevalence
    estimate and includes a previously published transplant recipient followed longitudinally. Mild presentations
    may be underdiagnosed.
  evidence:
  - reference: PMID:9097826
    reference_title: "[Beta mannosidosis: a new case]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 11 cases of beta mannosidase deficiency have been reported until now."
    explanation: >-
      Documents the number of published cases at the time of reporting, without estimating population prevalence.
  - reference: PMID:41235131
    reference_title: "Expanding the Phenotype Spectrum of β-Mannosidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Including our 6 patients, a total of 46 cases from 37 different families have been reported."
    explanation: >-
      Documents the number of published cases at the time of reporting, without estimating population prevalence.
  measure_type: CASES_IN_LITERATURE
- population: Published European birth-prevalence estimates
  measure_type: BIRTH_PREVALENCE
  rate_denominator: LIVE_BIRTHS
  rate_low: 0.12
  rate_high: 0.16
  prevalence_class: BAND_1_9_PER_1000000
  notes: >-
    Review-reported estimates from the Netherlands, Portugal and Czech Republic; ascertainment and historical
    study periods differ. They do not establish a current global prevalence.
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Reported prevalence rates are 0.13, 0.12, and 0.16 per 100,000 live births in the Netherlands,4 Portugal,5
      and the Czech Republic, respectively.
    explanation: >-
      Regional birth estimates summarized in the introduction, distinct from the authors’ patient series.
    quote_role: BACKGROUND
pathophysiology:
- name: MANBA lysosomal beta-mannosidase deficiency
  description: >-
    Pathogenic MANBA alleles impair enzyme production, processing or catalytic function. Splice-disrupting,
    truncating and missense variants are reported; residual activity and clinical severity need not correlate.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:12890191
    reference_title: "Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Assays of seven enzyme activities in plasma and cultured skin fibroblasts showed a marked decrease of
      beta-mannosidase activity.
    explanation: >-
      Patient biochemical confirmation of enzyme deficiency.
  - reference: PMID:18565776
    reference_title: "Identification of two novel beta-mannosidosis-associated sequence variants: biochemical analysis of beta-mannosidase (MANBA) missense mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity
      compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no detectable
      increase in activity.
    explanation: >-
      Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not
      an absolute zero-activity measurement.
  genes:
  - preferred_term: MANBA
    term:
      id: hgnc:6831
      label: MANBA
  molecular_functions:
  - preferred_term: beta-mannosidase activity
    modifier: DECREASED
    term:
      id: GO:0004567
      label: beta-mannosidase activity
  cellular_components:
  - preferred_term: lysosomal lumen
    term:
      id: GO:0043202
      label: lysosomal lumen
  downstream:
  - target: Impaired terminal N-glycan degradation
    description: >-
      Reduced beta-mannosidase activity impairs its terminal glycan-cleavage step.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16377659
      reference_title: "Beta-mannosidosis mice: a model for the human lysosomal storage disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Beta-mannosidase, a lysosomal enzyme which acts exclusively at the last step of oligosaccharide catabolism
        in glycoprotein degradation, functions to cleave the unique beta-linked mannose sugar found in all
        N-linked oligosaccharides of glycoproteins.
      explanation: >-
        Biochemical function summarized in the mouse-model paper, not a new human intervention result.
      quote_role: BACKGROUND
  - target: Beta-mannosidase activity
    description: >-
      The enzyme deficiency is measured in diagnostic assays.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12890191
      reference_title: "Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Assays of seven enzyme activities in plasma and cultured skin fibroblasts showed a marked decrease
        of beta-mannosidase activity.
      explanation: >-
        Patient biochemical confirmation of enzyme deficiency.
- name: Impaired terminal N-glycan degradation
  description: >-
    Insufficient beta-mannosidase impairs cleavage of the terminal beta-linked mannose residue during lysosomal
    degradation of N-linked glycoproteins. The resulting glycan fragments cannot complete normal catabolism.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:16377659
    reference_title: "Beta-mannosidosis mice: a model for the human lysosomal storage disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Beta-mannosidase, a lysosomal enzyme which acts exclusively at the last step of oligosaccharide catabolism
      in glycoprotein degradation, functions to cleave the unique beta-linked mannose sugar found in all N-linked
      oligosaccharides of glycoproteins.
    explanation: >-
      Biochemical function summarized in the mouse-model paper, not a new human intervention result.
    quote_role: BACKGROUND
  biological_processes:
  - preferred_term: glycoprotein catabolic process
    modifier: DECREASED
    term:
      id: GO:0006516
      label: glycoprotein catabolic process
  cellular_components:
  - preferred_term: lysosomal lumen
    term:
      id: GO:0043202
      label: lysosomal lumen
  downstream:
  - target: Glycoprotein-derived oligosaccharide storage
    description: >-
      Incomplete lysosomal catabolism leaves glycan substrates available to accumulate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16377659
      reference_title: "Beta-mannosidosis mice: a model for the human lysosomal storage disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Thin-layer chromatography demonstrated an accumulation of disaccharide in epididymis and brain.
      explanation: >-
        Tissue substrate storage in the knockout mouse; human tissue composition is not inferred from this
        alone.
- name: Glycoprotein-derived oligosaccharide storage
  description: >-
    Incompletely degraded N-glycan fragments accumulate. ManGlcNAc and its sialylated derivative NeuManGlcNAc
    are detected in urine. The extent to which particular stored species cause neurological or systemic features
    remains unresolved.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      ManGlcNAc and NeuManGlcNAc, known markers of the disease,1,12,48 are present in the urine of patients
      A, C, and D.
    explanation: >-
      Direct glycan profiling in the 2025 series.
  - reference: PMID:16377659
    reference_title: "Beta-mannosidosis mice: a model for the human lysosomal storage disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Thin-layer chromatography demonstrated an accumulation of disaccharide in epididymis and brain.
    explanation: >-
      Tissue substrate storage in the knockout mouse; human tissue composition is not inferred from this alone.
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  downstream:
  - target: Lysosomal vacuolation
    description: >-
      Substrate accumulation is associated with distended lysosomal compartments; the human biopsy identifies
      the storage lesion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12890191
      reference_title: "Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Electron microscopy of skin biopsy specimens from the patient showed cytoplasmic vacuolation of lysosomes
        in blood and lymph vessels, endothelial cells, fibroblasts, secretory portions of eccrine sweat glands,
        neural cells and basal keratinocytes in the epidermis.
      explanation: >-
        Direct human skin ultrastructure, not human brain neuropathology.
  - target: Impaired CNS myelination
    description: >-
      The storage disorder can impair myelination through incompletely defined cellular intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The brain MRI features of hypomyelinatione20 are represented in 3 of our patients
      explanation: >-
        Three of six patients had abnormal myelination, not half of all individuals with beta-mannosidosis.
  - target: Esophageal dysmotility
    description: >-
      Esophageal motor dysfunction occurs in the disorder; its intervening neural or muscular mechanism is
      unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9097826
      reference_title: "[Beta mannosidosis: a new case]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring
        respiratory infections, previously reported in some other cases.
      explanation: >-
        A clinical case establishes the motility-associated route to recurrent respiratory infections.
  - target: Urinary free oligosaccharides
    description: >-
      Accumulated substrates are excreted and measured in urine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        ManGlcNAc and NeuManGlcNAc, known markers of the disease,1,12,48 are present in the urine of patients
        A, C, and D.
      explanation: >-
        Direct glycan profiling in the 2025 series.
  - target: Intellectual disability
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The most frequent symptom reported independently of age at onset (eTables 1 and 2) was intellectual
        disability (91.4%), followed by behavioral abnormalities (82.8%) and hearing loss (74.4%).
      explanation: >-
        Frequencies among informative literature reports, not unbiased population prevalence.
      quote_role: REVIEW_SYNTHESIS
  - target: Sensorineural hearing impairment
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Patient A is a 7-year-old boy with bilateral sensorineural hearing loss detected at 5 years of age
      explanation: >-
        Direct sensorineural hearing observation; the storage-to-hearing causal intermediates are not established.
  - target: Atypical behavior
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The most frequent symptom reported independently of age at onset (eTables 1 and 2) was intellectual
        disability (91.4%), followed by behavioral abnormalities (82.8%) and hearing loss (74.4%).
      explanation: >-
        Frequencies among informative literature reports, not unbiased population prevalence.
      quote_role: REVIEW_SYNTHESIS
  - target: Developmental regression
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
      explanation: The new cohort directly reports developmental regression.
      directness: INDIRECT
  - target: Angiokeratoma
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        although it is frequently reported in β-mannosidosis (52.6%, eTable 2).
      explanation: >-
        Literature-review frequency with incomplete reporting and case ascertainment.
      quote_role: REVIEW_SYNTHESIS
  - target: Ataxia
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Independent walking showed unorthodox wide arm swing, ataxia, and hyperlordotic posture without scoliosis.
      explanation: >-
        Adult patient F with a normal MRI.
  - target: Hypotonia
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        There was axial hypotonia, with normal strength and reflexes in limbs.
      explanation: >-
        Patient D; strength and reflexes were preserved.
  - target: Peripheral neuropathy
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Two patients with β-mannosidosis have been reported with peripheral neuropathy.
      explanation: >-
        Published case reports summarized in the 2025 review.
      quote_role: REVIEW_SYNTHESIS
  - target: Hyperactivity
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        He is being treated with methylphenidate for behavioral issues, attention deficit and hyperactivity
        disorder (ADHD), and panic attacks.
      explanation: >-
        Patient E; this is a case-level treatment report.
  - target: Compulsive behaviors
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        He has learning difficulties associated with anxiety, obsessive-compulsive traits, aggressive ideation,
        and perseverance.
      explanation: >-
        Patient A’s described behavioral profile.
  - target: Aggressive behavior
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        At 14 years old, she is dependent for daily activities and exhibits aggressive behavior.
      explanation: >-
        Patient C.
  - target: Autistic behavior
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Additional problems include anxiety and disturbed sleep, some autistic features, and frequent tremors
        in the upper limbs.
      explanation: >-
        Adult patient F had autistic features; this is distinct from all patients having autism.
  - target: Spasticity
    description: >-
      The storage disorder is associated with this clinical consequence; the intervening disease-specific cellular
      steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Spasticity and ataxia have worsened, requiring assistance for mobilization.
      explanation: >-
        Patient B’s later motor decline; not a general natural-history rate.
  - target: Seizures
    description: >-
      This neurological manifestation occurs in the storage disorder; its intervening cellular mechanism is
      not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Seizures began at 6 years, characterized by leftward gaze deviation, eye twitching, drooling, and unresponsiveness.
      explanation: >-
        Documents the clinical consequence of beta-mannosidosis; the specific intermediates connecting substrate
        storage to this finding remain unresolved.
  - target: Delayed speech and language development
    description: >-
      This neurological manifestation occurs in the storage disorder; its intervening cellular mechanism is
      not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42160655
      reference_title: Beta-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Beta-mannosidosis is characterized by developmental delay (speech is more significantly affected than
        motor skills), mild-to-severe intellectual disability
      explanation: >-
        Documents the clinical consequence of beta-mannosidosis; the specific intermediates connecting substrate
        storage to this finding remain unresolved.
      quote_role: REVIEW_SYNTHESIS
  - target: Hydrocephalus
    description: >-
      This neurological manifestation occurs in the storage disorder; its intervening cellular mechanism is
      not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Findings on CT included cerebral atrophy,21 basal ganglia and white matter calcification,25 and hydrocephalus.
      explanation: >-
        Documents the clinical consequence of beta-mannosidosis; the specific intermediates connecting substrate
        storage to this finding remain unresolved.
      quote_role: REVIEW_SYNTHESIS
- name: Lysosomal vacuolation
  description: >-
    Distended lysosomal compartments produce cytoplasmic vacuolation. Human skin biopsy and derived cell cultures
    demonstrate this lesion in several cell types. Neuronal vacuolation is established in mice; its precise
    distribution and consequences in human brain remain incompletely characterized.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:12890191
    reference_title: "Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Electron microscopy of skin biopsy specimens from the patient showed cytoplasmic vacuolation of lysosomes
      in blood and lymph vessels, endothelial cells, fibroblasts, secretory portions of eccrine sweat glands,
      neural cells and basal keratinocytes in the epidermis.
    explanation: >-
      Direct human skin ultrastructure, not human brain neuropathology.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  locations:
  - preferred_term: skin
    term:
      id: UBERON:0002097
      label: skin of body
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
- name: Impaired CNS myelination
  description: >-
    Some patients have delayed myelination in infancy and persistent hypomyelination on serial MRI. Human imaging
    demonstrates deficient myelin deposition but does not identify a proven oligodendrocyte-loss mechanism.
    Ruminant and mouse phenotypes differ substantially.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The brain MRI features of hypomyelinatione20 are represented in 3 of our patients
    explanation: >-
      Three of six patients had abnormal myelination, not half of all individuals with beta-mannosidosis.
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Further research is needed to elucidate the mechanism of impaired myelination in β-mannosidosis.
    explanation: >-
      Limits causal interpretation of the human MRI observations.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  biological_processes:
  - preferred_term: myelination
    modifier: DECREASED
    term:
      id: GO:0042552
      label: myelination
  downstream:
  - target: Delayed myelination
    description: >-
      Delayed myelin deposition can be apparent in infancy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        At 19 months, the myelination has slightly progressed, albeit delayed for age.
      explanation: >-
        Serial imaging of patient D supports delayed myelination specifically.
  - target: CNS hypomyelination
    description: >-
      Persistent deficient myelination is visible on serial MRI.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        The brain MRI features of hypomyelinatione20 are represented in 3 of our patients
      explanation: >-
        Three of six patients had abnormal myelination, not half of all individuals with beta-mannosidosis.
- name: Esophageal dysmotility
  description: >-
    Abnormal swallowing and esophageal motility have been documented in a patient with recurrent respiratory
    infections. This provides one route to respiratory morbidity; it does not establish a generalized immune
    defect or explain infections in every patient.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:9097826
    reference_title: "[Beta mannosidosis: a new case]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring
      respiratory infections, previously reported in some other cases.
    explanation: >-
      A clinical case establishes the motility-associated route to recurrent respiratory infections.
  downstream:
  - target: Dysphagia
    description: >-
      Abnormal esophageal motility can impair swallowing.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9097826
      reference_title: "[Beta mannosidosis: a new case]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring
        respiratory infections, previously reported in some other cases.
      explanation: >-
        A clinical case establishes the motility-associated route to recurrent respiratory infections.
  - target: Recurrent respiratory infections
    description: >-
      Swallowing and esophageal dysfunction provide one documented contributor to recurrent respiratory infections.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9097826
      reference_title: "[Beta mannosidosis: a new case]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring
        respiratory infections, previously reported in some other cases.
      explanation: >-
        A clinical case establishes the motility-associated route to recurrent respiratory infections.
phenotypes:
- name: Intellectual disability
  description: >-
    Cognitive impairment ranges from mild to severe. The 2025 literature review reported intellectual disability
    in 91.4% of cases with relevant information, with substantial ascertainment and reporting limitations.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The most frequent symptom reported independently of age at onset (eTables 1 and 2) was intellectual disability
      (91.4%), followed by behavioral abnormalities (82.8%) and hearing loss (74.4%).
    explanation: >-
      Frequencies among informative literature reports, not unbiased population prevalence.
    quote_role: REVIEW_SYNTHESIS
- name: Sensorineural hearing impairment
  description: >-
    Hearing impairment is common, often sensorineural and early onset, but can be recognized later or progress.
    The hearing-ascertained Roma cohort cannot estimate its population frequency; the wider 2025 review reported
    hearing loss in 74.4% of informative cases. One Roma patient also had biallelic GJB2 variants, limiting
    attribution of his hearing phenotype to MANBA alone.
  diagnostic: true
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The most frequent symptom reported independently of age at onset (eTables 1 and 2) was intellectual disability
      (91.4%), followed by behavioral abnormalities (82.8%) and hearing loss (74.4%).
    explanation: >-
      Frequencies among informative literature reports, not unbiased population prevalence.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      sensorineural hearing loss, recurrent infections, angiokeratomas, seizures, and ataxia.
    explanation: >-
      GeneReviews identifies the sensorineural phenotype.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:32847582
    reference_title: "Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      since besides having a homozygous c.2158-2A>G MANBA variant he is also a homozygote for the c.71G>A (p.W24*)
      variant in GJB2.
    explanation: >-
      Double molecular diagnosis in one hearing-impaired patient.
- name: Abnormal facial shape
  description: >-
    Facial dysmorphism is variable and usually mild. The 2025 review reported it in 43.3% of cases with relevant
    information; incomplete reporting and case ascertainment limit this estimate.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Facial dysmorphism was observed in 43.3% of patients, but it is usually mild.
    explanation: >-
      Literature-review estimate with case-report ascertainment; this aggregate does not specify one defining
      facial finding.
    quote_role: REVIEW_SYNTHESIS
- name: Hypoplasia of the abdominal wall musculature
  description: >-
    Abdominal-wall muscle hypoplasia is listed in the Orphanet phenotype catalogue. Its frequency and contribution
    to the contemporary human clinical spectrum are not established by the available patient series.
  phenotype_term:
    preferred_term: Hypoplasia of the abdominal wall musculature
    term:
      id: HP:0005247
      label: Hypoplasia of the abdominal wall musculature
  evidence:
  - reference: ORPHA:118
    reference_title: "Beta-mannosidosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005247 | Hypoplasia of the abdominal wall musculature | Very frequent (99-80%)"
    explanation: >-
      Catalogue association retained; the quoted catalogue frequency is not adopted as a patient-series estimate.
- name: Atypical behavior
  description: >-
    Behavioral abnormalities are common in reported cases. The aggregate literature category includes heterogeneous
    presentations; specific hyperactive, compulsive, aggressive and autistic findings are represented separately.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The most frequent symptom reported independently of age at onset (eTables 1 and 2) was intellectual disability
      (91.4%), followed by behavioral abnormalities (82.8%) and hearing loss (74.4%).
    explanation: >-
      Frequencies among informative literature reports, not unbiased population prevalence.
    quote_role: REVIEW_SYNTHESIS
- name: Developmental regression
  description: >-
    Some patients lose previously acquired skills. The 2025 series describes regression in more severely affected
    children, including later motor decline in the previously transplanted patient. This is distinct from a
    fall in age-standardized scores despite continued skill acquisition.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
    explanation: The new cohort directly reports developmental regression.
    directness: DIRECT
- name: Dysphagia
  description: >-
    Swallowing dysfunction may become clinically significant and require tube feeding. Esophageal dysmotility
    with recurrent respiratory infections was documented before the 2025 expanded case series.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
    explanation: >-
      The expanded cohort documents dysphagia; the earlier 1997 case demonstrates that swallowing dysfunction
      was already reported.
    directness: DIRECT
  - reference: PMID:9097826
    reference_title: "[Beta mannosidosis: a new case]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring respiratory infections, previously reported in some other cases."
    explanation: Earlier case report supports clinically significant swallowing and esophageal motility abnormalities.
    directness: DIRECT
- name: Delayed myelination
  description: >-
    Delayed myelination can be apparent on infant MRI; later persistent hypomyelination is recorded separately.
    MRI may also be normal.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half the patients have abnormal brain MRIs, showing delayed myelination before 2 years of age and diffuse hypomyelination thereafter."
    explanation: Directly supports delayed myelination as a neuroimaging phenotype.
    directness: DIRECT
- name: Recurrent respiratory infections
  description: Respiratory infections are reported in case reports and in the Roma founder-variant cohort.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:9097826
    reference_title: "[Beta mannosidosis: a new case]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring
      respiratory infections, previously reported in some other cases.
    explanation: Case report supports recurrent respiratory infections and notes prior reports.
    directness: DIRECT
  - reference: PMID:32847582
    reference_title: "Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "respiratory and skin infections reported in five patients"
    explanation: Founder-variant cohort review supports respiratory and skin infections in a subset of patients.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- name: Seizures
  description: Epileptic manifestations reported in some patients with CNS involvement.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Seizures began at 6 years, characterized by leftward gaze deviation, eye twitching, drooling, and unresponsiveness.
    explanation: >-
      Seizures in patient C; no population frequency inferred.
- name: Angiokeratoma
  description: >-
    Angiokeratomas vary from subtle lesions to diffuse involvement. The 2025 review reported them in 52.6%
    of informative cases; they are not obligatory and were uncommon as the presenting symptom.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Angiokeratoma
    term:
      id: HP:0001014
      label: Angiokeratoma
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      although it is frequently reported in β-mannosidosis (52.6%, eTable 2).
    explanation: >-
      Literature-review frequency with incomplete reporting and case ascertainment.
    quote_role: REVIEW_SYNTHESIS
- name: CNS hypomyelination
  description: >-
    Persistent deficient myelination was seen in serial MRI in a subset of the 2025 cohort; this does not prove
    active demyelination.
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The brain MRI features of hypomyelinatione20 are represented in 3 of our patients
    explanation: >-
      Three of six patients had abnormal myelination, not half of all individuals with beta-mannosidosis.
- name: Ataxia
  description: >-
    Ataxia occurs in some patients, including an adult with normal brain MRI. Post-transplant ataxia has additional
    treatment-related uncertainty.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Independent walking showed unorthodox wide arm swing, ataxia, and hyperlordotic posture without scoliosis.
    explanation: >-
      Adult patient F with a normal MRI.
- name: Hypotonia
  description: >-
    Low muscle tone is variably present, including axial hypotonia in severely affected children.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      There was axial hypotonia, with normal strength and reflexes in limbs.
    explanation: >-
      Patient D; strength and reflexes were preserved.
- name: Peripheral neuropathy
  description: >-
    Peripheral neuropathy has been reported in a small number of patients; normal nerve conduction in other
    cases does not exclude beta-mannosidosis.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Two patients with β-mannosidosis have been reported with peripheral neuropathy.
    explanation: >-
      Published case reports summarized in the 2025 review.
    quote_role: REVIEW_SYNTHESIS
- name: Erythromelalgia
  description: >-
    One severely affected child had episodic red-hot painful swelling of the hands and feet, with normal EMG
    and nerve-conduction studies. This remains a case-level association, without an established disease-specific
    mechanism.
  phenotype_term:
    preferred_term: Erythromelalgia
    term:
      id: HP:0032147
      label: Erythromelalgia
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      At 21 months, the patient developed episodes of recurrent pain and bright red-hot swelling in hands and
      feet with activity, consistent with erythromelalgia.
    explanation: >-
      New observation in patient D; no frequency or immune mechanism inferred.
- name: Hyperactivity
  description: >-
    Hyperactivity or ADHD is reported in some patients and may need behavioral or pharmacological management.
  phenotype_term:
    preferred_term: Hyperactivity
    term:
      id: HP:0000752
      label: Hyperactivity
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      He is being treated with methylphenidate for behavioral issues, attention deficit and hyperactivity disorder
      (ADHD), and panic attacks.
    explanation: >-
      Patient E; this is a case-level treatment report.
- name: Compulsive behaviors
  description: >-
    Obsessive-compulsive traits and perseverative behavior occur in some patients; these traits do not by themselves
    establish a formal psychiatric diagnosis.
  phenotype_term:
    preferred_term: Compulsive behaviors
    term:
      id: HP:0000722
      label: Compulsive behaviors
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      He has learning difficulties associated with anxiety, obsessive-compulsive traits, aggressive ideation,
      and perseverance.
    explanation: >-
      Patient A’s described behavioral profile.
- name: Aggressive behavior
  description: >-
    Aggressive behavior is reported in some affected individuals.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      At 14 years old, she is dependent for daily activities and exhibits aggressive behavior.
    explanation: >-
      Patient C.
- name: Autistic behavior
  description: >-
    Autistic features and clinically diagnosed autism have been reported; severity and assessment differ between
    patients.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Additional problems include anxiety and disturbed sleep, some autistic features, and frequent tremors
      in the upper limbs.
    explanation: >-
      Adult patient F had autistic features; this is distinct from all patients having autism.
- name: Coarse facial features
  description: >-
    Mild facial coarsening occurs in some patients; many have no dysmorphism.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Most individuals have no dysmorphic features; some have mild coarseness.
    explanation: >-
      GeneReviews distinguishes optional coarseness from a universal coarse facial appearance.
    quote_role: REVIEW_SYNTHESIS
- name: Spasticity
  description: >-
    Spasticity may accompany progressive motor impairment; the detailed longitudinal report concerns a previously
    transplanted patient.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Spasticity and ataxia have worsened, requiring assistance for mobilization.
    explanation: >-
      Patient B’s later motor decline; not a general natural-history rate.
- name: Delayed speech and language development
  description: >-
    Speech and language development are often more affected than motor development. Hearing impairment can
    additionally limit communication and assessment.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Beta-mannosidosis is characterized by developmental delay (speech is more significantly affected than
      motor skills), mild-to-severe intellectual disability
    explanation: >-
      GeneReviews describes the relative developmental involvement.
    quote_role: REVIEW_SYNTHESIS
- name: Visceromegaly
  description: >-
    Visceral enlargement was reported in 17.4% of informative published cases. It is less prominent than the
    neurological and auditory findings; many patients lack organ enlargement.
  phenotype_term:
    preferred_term: Visceromegaly
    term:
      id: HP:0003271
      label: Visceromegaly
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Skeletal abnormalities were seen only in 8% and organomegaly in 17.4% of the reported patients.
    explanation: >-
      Review frequency among cases with relevant information, not population prevalence.
    quote_role: REVIEW_SYNTHESIS
  frequency: OCCASIONAL
- name: Hydrocephalus
  description: >-
    Hydrocephalus is reported in a small number of imaged cases and is not an obligatory neuroimaging finding.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Findings on CT included cerebral atrophy,21 basal ganglia and white matter calcification,25 and hydrocephalus.
    explanation: >-
      Published neuroimaging findings summarized in the review.
    quote_role: REVIEW_SYNTHESIS
- name: Scoliosis
  description: >-
    Scoliosis can accompany motor impairment. The detailed 2025 observation concerns the previously transplanted
    patient, limiting inference about untreated natural history.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Examination showed thick lips, bilateral epicanthal folds, bilateral elliptical nystagmus, optic nerves
      with temporal pallor, slender fingers, and scoliosis.
    explanation: >-
      Patient B at later follow-up.
genetic:
- name: MANBA
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MANBA
    term:
      id: hgnc:6831
      label: MANBA
  variant_origin: GERMLINE
  notes: >-
    Biallelic pathogenic variants are causal. The 2025 review lists missense, nonsense, frameshift, splice-site
    and an intragenic inverted-duplication allele. Some observed variants remain uncertain; p.Arg500His and
    the co-occurring p.Gln145Pro should not be treated as definitively pathogenic merely because they were
    found in affected individuals. Clinical severity is not reliably predicted by residual activity or broad
    variant class.
  inheritance:
  - name: Autosomal recessive
    description: >-
      When both parents carry a pathogenic MANBA allele, each pregnancy has a 25% affected, 50% carrier and
      25% noncarrier probability. Severity can differ among affected relatives.
    evidence:
    - reference: PMID:42160655
      reference_title: Beta-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        If both parents are known to be heterozygous for a MANBA pathogenic variant, each sib of an affected
        individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic
        carrier, and a 25% chance of being unaffected and not a carrier.
      explanation: >-
        Mendelian recurrence risks, conditional on both parents being carriers.
      quote_role: REVIEW_SYNTHESIS
  evidence:
  - reference: CGGV:assertion_d70d38aa-f7e9-4c93-8160-58dec9cec010-2022-08-02T160000.000Z
    reference_title: "MANBA / beta-mannosidosis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MANBA | HGNC:6831 | beta-mannosidosis | MONDO:0009562 | AR | Definitive"
    explanation: ClinGen classifies the MANBA-beta-mannosidosis gene-disease relationship as definitive with autosomal recessive inheritance.
  - reference: PMID:32847582
    reference_title: "Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      MANBA variant c.2158-2A>G screening among 345 anonymized normal hearing controls from Roma populations
      revealed a carrier/heterozygote frequency of 3.77%.
    explanation: >-
      Population and denominator of the carrier estimate.
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      the severity of the phenotype is not explained by the presence or absence of residual enzyme activity.
    explanation: >-
      Review interpretation of variable clinical severity.
    quote_role: REVIEW_SYNTHESIS
  features: >-
    The c.2158-2A>G allele was found in 13 heterozygotes among 345 sampled normal-hearing Czech and Slovak
    Roma controls (3.77% carrier frequency). This selected-cohort estimate is not a global population prevalence
    or penetrance estimate. Hearing-loss ascertainment and one dual GJB2/MANBA diagnosis limit phenotype attribution.
  variants:
  - name: NM_005908.4:c.2158-2A>G
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    type: Splice acceptor variant
    clinical_significance: PATHOGENIC
    description: >-
      An intronic acceptor-site SNV associated with cryptic splice-site activation and exon skipping. Two abnormal
      RNA products were observed in differently affected siblings. Presence of abnormal RNA does not itself
      demonstrate residual catalytic activity.
    identifiers:
    - dbSNP:rs772852668
    evidence:
    - reference: PMID:9384606
      reference_title: Human beta-mannosidase cDNA characterization and first identification of a mutation associated with human beta-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        The associated cryptic splice site activation and exon skipping caused by this mutation resulted in
        two abnormally spliced mutant mRNA species in both siblings.
      explanation: >-
        Primary patient RNA evidence.
    - reference: PMID:32847582
      reference_title: "Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        The first, larger product, lacking 172 bp, results in a frameshift and stop codon that truncates the
        predicted protein by 155 residues. The second, shorter product, lacks 258 bp and is presumably an exon
        skipping event
      explanation: >-
        The 2020 report summarizes earlier RNA analysis; these are transcript deletions, not separate DNA deletions.
      quote_role: BACKGROUND
  - name: MANBA c.375A>G
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    type: Synonymous variant with splice disruption
    description: >-
      The reported DNA substitution is synonymous but alters splicing, removing four nucleotides from RNA and
      predicting premature termination. It was found in trans with p.Ser505Pro. The physical DNA alteration
      is a single-nucleotide substitution; the four-base deletion occurs in the transcript.
    evidence:
    - reference: PMID:18565776
      reference_title: "Identification of two novel beta-mannosidosis-associated sequence variants: biochemical analysis of beta-mannosidase (MANBA) missense mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        The patient was compound heterozygous for a silent mutation (c.375A>G) in exon 3 causing alternative
        splicing, and a missense mutation (c.1513T>C, p.Ser505Pro) in exon 12.
      explanation: >-
        Separates the DNA SNV from the abnormal transcript.
  - name: MANBA c.1513T>C (p.Ser505Pro)
    type: Functionally tested missense allele
    description: >-
      The mutant construct failed to increase beta-mannosidase activity above mock in COS-7 cells. Ser505Pro
      was reported in a more severe presentation than Arg182Trp or Gly392Glu; the common in vitro activity
      result does not predict individual clinical severity.
    evidence:
    - reference: PMID:18565776
      reference_title: "Identification of two novel beta-mannosidosis-associated sequence variants: biochemical analysis of beta-mannosidase (MANBA) missense mutations."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity
        compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no
        detectable increase in activity.
      explanation: >-
        Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not
        an absolute zero-activity measurement.
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
  - name: MANBA c.544C>T (p.Arg182Trp)
    type: Functionally tested missense allele
    description: >-
      The mutant construct failed to increase beta-mannosidase activity above mock in COS-7 cells. Ser505Pro
      was reported in a more severe presentation than Arg182Trp or Gly392Glu; the common in vitro activity
      result does not predict individual clinical severity.
    evidence:
    - reference: PMID:18565776
      reference_title: "Identification of two novel beta-mannosidosis-associated sequence variants: biochemical analysis of beta-mannosidase (MANBA) missense mutations."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity
        compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no
        detectable increase in activity.
      explanation: >-
        Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not
        an absolute zero-activity measurement.
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
  - name: MANBA c.1175G>A (p.Gly392Glu)
    type: Functionally tested missense allele
    description: >-
      The mutant construct failed to increase beta-mannosidase activity above mock in COS-7 cells. Ser505Pro
      was reported in a more severe presentation than Arg182Trp or Gly392Glu; the common in vitro activity
      result does not predict individual clinical severity.
    evidence:
    - reference: PMID:18565776
      reference_title: "Identification of two novel beta-mannosidosis-associated sequence variants: biochemical analysis of beta-mannosidase (MANBA) missense mutations."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity
        compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no
        detectable increase in activity.
      explanation: >-
        Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not
        an absolute zero-activity measurement.
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
biochemical:
- name: Urinary free oligosaccharides
  presence: INCREASED
  context: Diagnostic biomarker
  notes: >-
    ManGlcNAc and NeuManGlcNAc are characteristic urinary findings. Reduced excretion after transplantation
    demonstrates a biochemical response, not necessarily neurological stabilization. Population-wide sensitivity
    is not inferred from pooled glycoproteinosis assay validation.
  readouts:
  - target: Glycoprotein-derived oligosaccharide storage
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased urinary free oligosaccharides report overflow of incompletely
      degraded glycoprotein-derived substrates from lysosomal storage.
    evidence:
    - reference: PMID:32847582
      reference_title: "Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Biochemical diagnostics confirmed the typical disaccharides (primarily Man (beta1 → 4) GlcNac) in the urine of affected patients"
      explanation: Patient urine testing directly supports urinary oligosaccharides as a diagnostic readout of glycoprotein-derived oligosaccharide storage.
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      ManGlcNAc and NeuManGlcNAc, known markers of the disease,1,12,48 are present in the urine of patients
      A, C, and D.
    explanation: >-
      Direct glycan profiling in the 2025 series.
- name: Beta-mannosidase activity
  presence: DECREASED
  context: Diagnostic enzymatic assay
  notes: >-
    Activity is markedly reduced or absent in leukocytes, serum or plasma; assay reference ranges depend on
    laboratory and sample type. Enzyme testing is the diagnostic gold standard, but residual activity does
    not reliably predict clinical severity.
  readouts:
  - target: MANBA lysosomal beta-mannosidase deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Decreased beta-mannosidase activity directly reports the primary MANBA
      lysosomal enzyme deficiency.
    evidence:
    - reference: PMID:32847582
      reference_title: "Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a decreased activity of the beta-mannosidase enzyme in different cells, particularly in leukocytes"
      explanation: Patient cell assays support reduced beta-mannosidase activity as a direct diagnostic readout of MANBA enzyme deficiency.
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      markedly reduced or absent beta-mannosidase activity in leukocytes, serum, or plasma. Enzyme testing
      is the gold standard for diagnosis.
    explanation: >-
      Clinical diagnostic role and specimen types.
    quote_role: REVIEW_SYNTHESIS
- name: Urinary NeuMan2GlcNAc2 peak
  presence: INCREASED
  context: Exploratory glycan finding
  notes: >-
    A peak assigned to NeuMan2GlcNAc2 was observed in the two most severely affected patients in the 2025 series.
    It is not a validated severity marker, and incomplete chitobiase-dependent degradation remains a hypothesis.
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      An additional abnormal peak, corresponding to a Neu-Man2-GlcNac2 structure, was found in patients C and
      D.
    explanation: >-
      Small case-level observation from urinary glycan profiling.
treatments:
- name: Developmental and educational support
  description: >-
    Individualized developmental, language and educational support; hearing impairment should be considered
    when assessing communication and cognition.
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Developmental and educational support; rehabilitation, physical therapy, and occupational therapy as
      needed for musculoskeletal manifestations;
    explanation: >-
      Supports the described care, with indication and limitations stated in the description.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Developmental and educational support
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Physical and occupational rehabilitation
  description: >-
    Therapy and orthotic devices may support mobility, ataxia and progressive scoliosis; goals are individualized
    to function.
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      rehabilitation, physical therapy, and occupational therapy as needed for musculoskeletal manifestations
    explanation: >-
      Supports physical and occupational rehabilitation.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      orthotic devices for progressive scoliosis or ataxia;
    explanation: >-
      Supports the described care, with indication and limitations stated in the description.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Physical and occupational rehabilitation
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Hearing rehabilitation
  description: >-
    Hearing aids may improve communication. Combine behavioral and objective audiological assessment when cooperation
    limits threshold measurement, and reassess hearing annually. Disease-specific cochlear-implant outcomes
    are not established by the cited sources.
  therapeutic_modality: DEVICE
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      hearing aids may be helpful; specific antimicrobial treatment for recurrent infections;
    explanation: >-
      Supports the described care, with indication and limitations stated in the description.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:32847582
    reference_title: "Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      both subjective and objective methods for audiometric examination should be used in MANBA related patients
      to properly evaluate the degree of hearing impairment.
    explanation: >-
      Supports the assessment strategy when cooperation affects behavioral thresholds.
- name: Treatment of recurrent infections
  description: >-
    Treat identified infections with appropriate antimicrobials and evaluate contributory swallowing or airway
    problems. Recurrent infections do not by themselves establish a primary immunodeficiency.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      specific antimicrobial treatment for recurrent infections; feeding tube as needed;
    explanation: >-
      Supports the described care, with indication and limitations stated in the description.
    quote_role: REVIEW_SYNTHESIS
- name: Feeding and nutritional support
  description: >-
    Assess growth and swallowing safety; feeding-tube and nutritional support may be required for inadequate
    intake or progressive dysphagia. Manage associated constipation or diarrhea.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      feeding tube as needed; nutrition support; treatment of chronic diarrhea or constipation;
    explanation: >-
      Supports the described care, with indication and limitations stated in the description.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Feeding and nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
- name: Seizure management
  description: >-
    Use standard antiseizure care individualized to seizure type and clinical context. No MANBA-specific drug
    efficacy is established.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      standard treatments for seizures; ventriculoperitoneal shunt for hydrocephalus;
    explanation: >-
      Supports the described care, with indication and limitations stated in the description.
    quote_role: REVIEW_SYNTHESIS
- name: Hydrocephalus treatment
  description: >-
    Ventriculoperitoneal shunting is an option when hydrocephalus requires treatment; hydrocephalus is not
    an obligatory feature.
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      ventriculoperitoneal shunt for hydrocephalus; transitional care plan for adult life;
    explanation: >-
      Supports the described care, with indication and limitations stated in the description.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Hydrocephalus treatment
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Behavioral and psychiatric care
  description: >-
    Assess behavioral and psychiatric needs throughout life. Methylphenidate was reported for ADHD in one patient;
    this is symptom-directed experience, not a disease-specific efficacy trial.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      He is being treated with methylphenidate for behavioral issues, attention deficit and hyperactivity disorder
      (ADHD), and panic attacks.
    explanation: >-
      Supports the described care, with indication and limitations stated in the description.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methylphenidate
      term:
        id: CHEBI:6887
        label: methylphenidate
- name: Surveillance and transition to adult care
  description: >-
    At each visit assess developmental needs, behavior, infection frequency, growth, gastrointestinal symptoms,
    abnormal movements, head circumference and neurological regression. Arrange annual audiology and a transition
    plan with family and social support.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      At each visit assess developmental and educational needs, neurobehavioral and psychiatric issues, frequency
      of infections, growth, gastrointestinal manifestations, abnormal movements, head circumference, neurologic
      regression, and family and social work needs; annual audiology evaluation.
    explanation: >-
      Supports the described care, with indication and limitations stated in the description.
    quote_role: REVIEW_SYNTHESIS
- name: Genetic counseling and family evaluation
  description: >-
    Autosomal recessive counseling includes the 25% recurrence risk when both parents carry a pathogenic allele.
    Offer appropriate testing of at-risk relatives and discuss reproductive testing once familial variants
    are known.
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      If the MANBA pathogenic variants have been identified in an affected family member, carrier testing for
      at-risk relatives and prenatal/preimplantation genetic testing are possible.
    explanation: >-
      Supports the described care, with indication and limitations stated in the description.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      If both parents are known to be heterozygous for a MANBA pathogenic variant, each sib of an affected
      individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier,
      and a 25% chance of being unaffected and not a carrier.
    explanation: >-
      Mendelian recurrence risks, conditional on both parents being carriers.
    quote_role: REVIEW_SYNTHESIS
- name: Hematopoietic cell transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    An HLA-matched cord-blood transplant in one boy at approximately 4.5 years normalized leukocyte enzyme
    activity and reduced urinary oligosaccharides. Early neurological worsening partly improved, but the developmental
    gap persisted and memory declined by two years. Follow-up of the same patient in 2025 documented renewed
    motor regression and worsening spasticity/ataxia. This does not establish durable neurological efficacy
    or routine use; biochemical correction is not a validated surrogate for clinical benefit.
  evidence:
  - reference: PMID:31115173
    reference_title: Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood-onset beta-mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Our findings suggest that hematopoietic cell transplant can correct the biochemical defect in β-mannosidosis,
      although preservation of the neurocognitive trajectory may be a challenge.
    explanation: >-
      Single treated patient, without an untreated comparator.
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      At 10 years of age, he developed progressive regression in gross motor skills, urinary incontinence,
      low muscle bulk, axial hypotonia, end point dysmetria, and dysarthria
    explanation: >-
      Later follow-up of the same transplant recipient, not an independent treatment case.
  target_mechanisms:
  - target: MANBA lysosomal beta-mannosidase deficiency
    treatment_effect: RESTORES
    description: >-
      Restored leukocyte beta-mannosidase activity after donor-cell engraftment; correction in brain cells
      and durable clinical benefit were not established.
    evidence:
    - reference: PMID:31115173
      reference_title: Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood-onset beta-mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        We show restoration of leukocyte β-mannosidase activity which remained normal at 2 years posttransplant
      explanation: >-
        Observed biochemical response in one patient.
notes: >-
  Clinical variability is substantial and genotype or residual enzyme activity alone does not predict severity.
  The recurrent Central European Roma allele has a documented regional carrier frequency, with limited transferability
  beyond the sampled populations. Alpha-mannosidosis therapies targeting MAN2B1 should not be assumed effective
  for MANBA deficiency.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  isds_skeletal_category:
  - classification_value: lysosomal_storage_with_skeletal_involvement
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 27 "Lysosomal
      storage diseases with skeletal involvement (dysostosis multiplex group)";
      listed as "Beta-Mannosidosis".
datasets:
histopathology:
- name: Lysosomal vacuolation in skin
  description: >-
    Skin biopsy electron microscopy showed vacuolated lysosomes in vascular and lymphatic endothelium, fibroblasts,
    eccrine secretory cells, neural cells and basal keratinocytes in one patient. This is direct tissue evidence
    and does not establish the distribution of human brain pathology.
  context: Patient skin biopsy
  evidence:
  - reference: PMID:12890191
    reference_title: "Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Electron microscopy of skin biopsy specimens from the patient showed cytoplasmic vacuolation of lysosomes
      in blood and lymph vessels, endothelial cells, fibroblasts, secretory portions of eccrine sweat glands,
      neural cells and basal keratinocytes in the epidermis.
    explanation: >-
      Direct human skin ultrastructure, not human brain neuropathology.
experimental_models:
- name: Patient-derived skin fibroblast and keratinocyte cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Patient-derived skin cells
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  description: >-
    Cultures from a patient with a splice-disrupting MANBA allele showed lysosomal vacuolation. They capture
    a cellular storage phenotype, without measuring neuronal behavior or brain myelination.
  modeled_mechanisms:
  - target: Lysosomal vacuolation
    relationship: RECAPITULATES
    model_scale: CELLULAR
    description: >-
      Patient-derived skin cells reproduce the vacuolated compartments seen in biopsy.
    evidence:
    - reference: PMID:12890191
      reference_title: "Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        This vacuolation was also observed in cultured keratinocytes and fibroblasts.
      explanation: >-
        Direct culture observation.
  evidence:
  - reference: PMID:12890191
    reference_title: "Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      This vacuolation was also observed in cultured keratinocytes and fibroblasts.
    explanation: >-
      Primary cultures, distinct from the skin-biopsy observation.
- name: COS-7 expression of MANBA missense variants
  experimental_model_type: CELL_LINE
  cell_source: COS-7 cells transiently expressing human wild-type or mutant MANBA
  description: >-
    Ser505Pro, Arg182Trp and Gly392Glu were compared with wild-type and mock transfection. Wild-type expression
    increased activity 33-fold over mock; mutant constructs produced no detectable increase. This assay does
    not equate clinical severity with residual activity or reproduce patient tissue expression.
  modeled_mechanisms:
  - target: MANBA lysosomal beta-mannosidase deficiency
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    description: >-
      Measures impaired enzyme function of selected missense alleles.
    limitations: >-
      Heterologous overexpression; no detectable increment above mock does not mean absence of all endogenous
      activity.
    evidence:
    - reference: PMID:18565776
      reference_title: "Identification of two novel beta-mannosidosis-associated sequence variants: biochemical analysis of beta-mannosidase (MANBA) missense mutations."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity
        compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no
        detectable increase in activity.
      explanation: >-
        Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not
        an absolute zero-activity measurement.
  evidence:
  - reference: PMID:18565776
    reference_title: "Identification of two novel beta-mannosidosis-associated sequence variants: biochemical analysis of beta-mannosidase (MANBA) missense mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Cells transfected with the wild-type construct showed a 33-fold increase in beta-mannosidase activity
      compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no detectable
      increase in activity.
    explanation: >-
      Ser505Pro, Arg182Trp and Gly392Glu failed to increase activity above mock in COS-7 cells; this is not
      an absolute zero-activity measurement.
animal_models:
- name: Manba knockout mice
  species: Mus musculus
  genotype: Manba homozygous targeted disruption
  background: 129X1/SvJ congenic and mixed C57BL/6J × 129X1/SvJ
  description: >-
    Knockout mice accumulate disaccharides and show CNS vacuolation with few overt early neurological abnormalities.
    At 15–20 months all five congenic mice in the 2014 study had severe regional vacuolation and degeneration,
    whereas mixed-background mice varied. The study did not identify a particular modifier gene. Myelination
    defects seen in some patients and ruminants were not reproduced.
  modeled_mechanisms:
  - target: Glycoprotein-derived oligosaccharide storage
    relationship: RECAPITULATES
    model_scale: TISSUE
    evidence:
    - reference: PMID:16377659
      reference_title: "Beta-mannosidosis mice: a model for the human lysosomal storage disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Thin-layer chromatography demonstrated an accumulation of disaccharide in epididymis and brain.
      explanation: >-
        Tissue substrate storage in the knockout mouse; human tissue composition is not inferred from this
        alone.
  - target: Lysosomal vacuolation
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: >-
      Neuronal vacuolation in mice differs from the directly sampled human skin lesion; human CNS histopathology
      remains sparse.
    evidence:
    - reference: PMID:24142277
      reference_title: Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Morphological analysis indicated a severe consistent pattern of neuronal vacuolation and disintegrative
        degeneration in all five 129X1/SvJ mice.
      explanation: >-
        Background-dependent CNS pathology.
  - target: Impaired CNS myelination
    relationship: FAILS_TO_RECAPITULATE
    model_scale: TISSUE
    limitations: >-
      This mouse model did not reproduce the hypomyelination documented by MRI in a subset of humans.
    evidence:
    - reference: PMID:24142277
      reference_title: Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Neuropathology between 1 and 9 months of age included selective, variable neuronal vacuolation with
        no hypomyelination.
      explanation: >-
        Explicit lack of the human myelin phenotype in the reported mouse analysis.
  evidence:
  - reference: PMID:16377659
    reference_title: "Beta-mannosidosis mice: a model for the human lysosomal storage disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      At >1 year of age, these mice exhibit no dysmorphology or overt neurological problems.
    explanation: >-
      Limits clinical fidelity despite the biochemical and pathological phenotype.
  - reference: PMID:24142277
    reference_title: Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      However, the mice with a mixed genetic background showed substantial variability in the severity of pathology.
    explanation: >-
      Genetic background affects expression; no specific modifier was mapped.
- name: Naturally occurring caprine beta-mannosidosis
  species: Capra hircus
  description: >-
    The inherited caprine disorder reproduces beta-mannosidase deficiency, oligosaccharide storage and prenatal
    myelin deficits. In a single affected fetus, optic-nerve myelinated-axon density was about one quarter
    of the control value; oligodendrocyte proportions were reduced. This does not distinguish altered proliferation
    from cell death or establish oligodendrocyte death in humans. Neonatal regional substrate measurements
    did not track the severity of myelin loss.
  modeled_mechanisms:
  - target: Glycoprotein-derived oligosaccharide storage
    relationship: PARTIALLY_RECAPITULATES
    model_scale: TISSUE
    limitations: >-
      Goats accumulate both disaccharide and trisaccharide; human substrate processing differs.
    evidence:
    - reference: PMID:2370553
      reference_title: Regional central nervous system oligosaccharide storage in caprine beta-mannosidosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Goats affected with beta-mannosidosis, an autosomal recessive disease of glycoprotein metabolism, have
        deficient activity of the lysosomal enzyme beta-mannosidase along with tissue storage of oligosaccharides
      explanation: >-
        Natural recessive caprine disease reproduces enzyme deficiency and storage, with a substrate profile
        that differs from human disease.
  - target: Impaired CNS myelination
    relationship: PARTIALLY_RECAPITULATES
    model_scale: TISSUE
    limitations: >-
      Severe fetal optic-nerve pathology in one affected goat is not equivalent to the heterogeneous human
      MRI phenotype.
    evidence:
    - reference: PMID:3503502
      reference_title: "Dysmyelinogenesis in caprine beta-mannosidosis: ultrastructural and morphometric studies in fetal optic nerve."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        In the affected fetus, the number of myelinated axons per unit area was about 25% of the control values.
      explanation: >-
        One affected goat fetus and one control were examined; this is an optic-nerve finding, not a human
        myelin measurement.
  evidence:
  - reference: PMID:2370553
    reference_title: Regional central nervous system oligosaccharide storage in caprine beta-mannosidosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Thus, greater oligosaccharide accumulation was not associated with more severe myelin deficiency.
    explanation: >-
      Three affected and two control neonatal goats showed that regional storage burden did not explain the
      regional severity of myelin deficits.
  - reference: PMID:3503502
    reference_title: "Dysmyelinogenesis in caprine beta-mannosidosis: ultrastructural and morphometric studies in fetal optic nerve."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Ultrastructural analysis revealed a decreased proportion of oligodendrocytes and an increased proportion
      of astrocytes in the affected fetus.
    explanation: >-
      Cell proportions were measured in the affected fetal optic nerve; cell death was proposed rather than
      directly demonstrated.
diagnosis:
- name: Enzyme testing with molecular confirmation
  description: >-
    Measure beta-mannosidase activity in appropriate clinical specimens and interpret against laboratory-specific
    controls. Markedly reduced or absent activity establishes the biochemical diagnosis; biallelic pathogenic
    MANBA variants clarify inheritance and enable family testing. Variants of uncertain significance alone
    are insufficient.
  evidence:
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      markedly reduced or absent beta-mannosidase activity in leukocytes, serum, or plasma. Enzyme testing
      is the gold standard for diagnosis.
    explanation: >-
      Clinical diagnostic role and specimen types.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Identification of biallelic pathogenic variants in MANBA by molecular genetic testing can aid in assessment
      of recurrence risk for sibs of the proband.
    explanation: >-
      Molecular testing complements the diagnostic enzyme assay.
    quote_role: REVIEW_SYNTHESIS
- name: Urinary oligosaccharide profiling
  description: >-
    Characteristic ManGlcNAc and sialylated glycan findings support the diagnosis. Interpret alongside enzyme
    and genetic results; performance estimates from mixed lysosomal-disorder validation cohorts should not
    be assigned to beta-mannosidosis alone.
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      ManGlcNAc and NeuManGlcNAc, known markers of the disease,1,12,48 are present in the urine of patients
      A, C, and D.
    explanation: >-
      Direct glycan profiling in the 2025 series.
- name: Audiological and neurological assessment
  description: >-
    Consider beta-mannosidosis in syndromic or apparently isolated hearing loss, otherwise unexplained hypomyelination,
    developmental or intellectual disability and behavioral abnormalities. MRI can be normal. Objective auditory
    methods can supplement behavioral audiometry when test cooperation is limited.
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      β-mannosidosis should be considered as a differential diagnosis in patients with syndromic or apparently
      nonsyndromic hearing loss, unexplained brain hypomyelination, behavioral disturbances, and intellectual
      disability.
    explanation: >-
      Clinical diagnostic consideration from the expanded series.
  - reference: PMID:32847582
    reference_title: "Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      both subjective and objective methods for audiometric examination should be used in MANBA related patients
      to properly evaluate the degree of hearing impairment.
    explanation: >-
      Addresses ascertainment and test-cooperation limitations.
clinical_trials:
- name: NCT01891422
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Observational longitudinal study of glycoproteinoses including beta-mannosidosis, designed to characterize
    clinical course and biochemical/genetic findings. It is not a therapeutic trial, and pooled enrollment
    does not establish the number of beta-mannosidosis participants.
  notes: >-
    ClinicalTrials.gov live record checked 2026-09-30 lists COMPLETED. The broader CoRDS rare-disease registry
    also accepts this condition; neither record is evidence for treatment efficacy.
  evidence:
  - reference: clinicaltrials:NCT01891422
    reference_title: Longitudinal Studies of the Glycoproteinoses
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The diseases include aspartylglucosaminuria, fucosidosis, galactosialidosis, alpha-mannosidosis, beta-mannosidosis,
      mucolipidosis II, mucolipidosis III, Schindler disease, and sialidosis.
    explanation: >-
      Registry explicitly includes beta-mannosidosis.
  - reference: clinicaltrials:NCT01891422
    reference_title: Longitudinal Studies of the Glycoproteinoses
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Longitudinal studies of these conditions are needed in order to better define how common the diseases
      are, identify clinical features which could contribute to early diagnoses, detail progression of the
      diseases, assess the supportive therapies currently used, and identify potential treatments.
    explanation: >-
      Observational purpose, not an interventional efficacy result.
discussions:
- discussion_id: beta_mannosidosis_ctbs_modifier
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does variation in chitobiase-dependent glycan processing modify human disease severity?
  rationale: >-
    Additional urinary glycans in two severely affected patients and species differences motivate a CTBS hypothesis.
    No causal human modifier allele or functional epistasis experiment has established that link. Background-dependent
    mouse pathology indicates modifier effects without identifying the responsible gene.
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      additional studies should be developed to determine whether CTBS (Di-N-Acetyl-Chitobiase) acts as a modifier
      gene in severe cases.
    explanation: >-
      The authors pose a question; they do not demonstrate a CTBS modifier effect.
- discussion_id: beta_mannosidosis_myelin_species_gap
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Why do some patients have persistent hypomyelination while the Manba knockout mouse lacks this finding?
  rationale: >-
    Human MRI, severe ruminant myelin deficiency and mouse vacuolation are distinct observations. Storage substrate
    composition, cell susceptibility and developmental timing may differ. Neuronal degeneration in mice is
    spatially separate from major vacuolated populations; vacuolation does not automatically imply neuronal
    death.
  attaches_to:
  - pathophysiology#Impaired CNS myelination
  evidence:
  - reference: PMID:24142277
    reference_title: Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Neuropathology between 1 and 9 months of age included selective, variable neuronal vacuolation with no
      hypomyelination.
    explanation: >-
      Explicit lack of the human myelin phenotype in the reported mouse analysis.
  - reference: PMID:24142277
    reference_title: Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Degeneration staining did not occur in areas of vacuolation or adjacent regions, suggesting that vacuolation
      does not lead to substantial cell body or axon loss.
    explanation: >-
      Experimental pathology limits a simple vacuolation-to-cell-death chain.
references:
- reference: PMID:42160655
  title: Beta-Mannosidosis.
  tags:
  - GeneReviews
differential_diagnoses:
- name: Alpha-mannosidosis
  disease_term:
    preferred_term: alpha-mannosidosis
    term:
      id: MONDO:0009561
      label: alpha-mannosidosis
  description: >-
    Overlapping oligosacchariduria, intellectual disability, hearing loss, infections and facial changes can
    cause diagnostic confusion.
  distinguishing_features:
  - Skeletal dysplasia is more prominent in alpha-mannosidosis; beta-mannosidosis requires demonstration of the beta-mannosidase enzyme defect and appropriate MANBA interpretation.
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Compared with α-mannosidosis in which skeletal dysplasia is a main feature,3 it was found in 7.4% of
      the patients with β-mannosidosis.
    explanation: >-
      Comparative clinical distinction; biochemical confirmation remains necessary.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      markedly reduced or absent beta-mannosidase activity in leukocytes, serum, or plasma. Enzyme testing
      is the gold standard for diagnosis.
    explanation: >-
      Clinical diagnostic role and specimen types.
    quote_role: REVIEW_SYNTHESIS
- name: Fucosidosis
  disease_term:
    preferred_term: fucosidosis
    term:
      id: MONDO:0009254
      label: fucosidosis
  description: >-
    Lysosomal disease with a potentially similar hypomyelination pattern.
  distinguishing_features:
  - MRI alone cannot establish beta-mannosidosis; beta-mannosidase testing and MANBA molecular evaluation distinguish its biochemical defect.
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of β-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Similar patterns occur in fucosidosis and sialic acid disorders, probably reflecting a secondary failure
      of myelination, unlike primary hypomyelinating conditions such as Pelizaeus-Merzbacher disease.
    explanation: >-
      The similar MRI pattern is not disease-specific.
    quote_role: BACKGROUND
  - reference: PMID:42160655
    reference_title: Beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      markedly reduced or absent beta-mannosidase activity in leukocytes, serum, or plasma. Enzyme testing
      is the gold standard for diagnosis.
    explanation: >-
      Clinical diagnostic role and specimen types.
    quote_role: REVIEW_SYNTHESIS
📚

References & Deep Research

References

1
PMID:42160655
Beta-Mannosidosis.
No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Review beta-mannosidosis using full-text human and model evidence · 2026-10-01T00:13:25Z · View source

Reviewed the complete baseline entry and legacy GENERAL history against the complete Falcon deep-research narrative and citation list, the local Cyberian supplement, and the disease-specific reference cache. The Falcon report is substantive but contains incorrect ontology identifiers and a misattributed diagnostic citation; the zero-second Cyberian artifact is a local inventory, not independent research. MANBA, MONDO:0009562 and OMIM 248510 pass entity preflight. No prior REVIEW or overlapping open disorder/history PR was present at selection. This genetic disorder remains in scope despite secondary infections. 1. Phenotypes — adequate after changes. Expanded the auditory, behavioral, motor, skin, developmental and visceral spectrum to 26 findings. Literature frequencies use informative case reports, not an unbiased population denominator. The 74.4% aggregate hearing-loss estimate is not assigned as a sensorineural-specific frequency. Facial dysmorphism is 43.3% in the 2025 review; an older 80–99% catalogue label is not generalized. Abdominal-wall muscle hypoplasia remains a catalogue association without adopting an unsupported contemporary frequency. Added speech/language delay, hypomyelination, ataxia, hypotonia, peripheral neuropathy, erythromelalgia, specific behavioral findings, spasticity, visceromegaly, hydrocephalus and scoliosis. Confounded malformations in a highly homozygous premature child are not all assigned to MANBA. Broad facial and behavioral aggregates use SOURCE_UNSPECIFIED alongside specific findings. Dysphagia was already reported in 1997 despite the 2025 abstract calling it new. 2. Subtypes — N/A. Human clinical severity varies, including within families; no well-supported discrete molecular subtypes emerged. Alpha-mannosidosis is a distinct enzyme/gene disorder, not a subtype. No subdivision by residual activity or phenotype severity is invented. 3. Mechanisms, tissue and models — adequate after changes. Six atomic nodes separate MANBA enzyme deficiency, terminal N-glycan catabolic failure, substrate storage, lysosomal vacuolation, impaired myelination and esophageal dysmotility. Clinical consequences with unresolved mediators are explicitly indirect. Human skin ultrastructure and patient fibroblast/keratinocyte cultures are represented. COS-7 testing of three alleles showed no activity increase over mock, not absolute zero activity in every patient. Mouse storage and regional pathology are linked with background dependence; no specific modifier was mapped. The mouse fails to reproduce the human myelination finding seen in a subset. Human MRI does not demonstrate oligodendrocyte death, and mouse vacuolation does not automatically imply death of the same neurons. Goat findings, unpublished glial-reactivity data and general lysosomal-inflammatory hypotheses are not promoted to proven human mechanisms. 4. Care and trials — adequate after changes. Eleven care records mine GeneReviews management and surveillance, including rehabilitation, hearing aids, nutritional support, symptom-specific drugs, hydrocephalus care, annual audiology and family evaluation. Transplant evidence comes from one cord-blood recipient: leukocyte enzyme correction and lower urine glycans did not establish sustained neurological efficacy. The 2025 report follows the same 2019 recipient, not a second independent treatment case; later motor regression and early memory decline qualify the original stabilization narrative. Methylphenidate is a case-level ADHD treatment, not a disease-modifying trial. The completed NCT01891422 study explicitly includes beta-mannosidosis but is observational and reports pooled glycoproteinosis enrollment. The live registry search also found generic CoRDS; no beta-specific interventional record was identified by these searches. Alpha-mannosidosis interventions are not transferred to MANBA deficiency. 5. Genetics and inheritance — adequate after changes. Preserved definitive ClinGen validity and added GeneReviews recurrence-risk evidence. Distinguished regional c.2158-2A>G carrier sampling from global prevalence or penetrance; 13/345 selected normal-hearing Roma controls were heterozygous. One dual GJB2/MANBA diagnosis limits hearing attribution. The splice acceptor produces two abnormal RNAs, which alone do not prove residual enzyme function. Primary PMID:18565776 identifies c.375A>G as a synonymous DNA SNV causing a four-base RNA deletion; the later review's deletion notation is not treated as the genomic alteration. Three functional missense alleles are separate variant records. Observed VUS are not all labeled pathogenic. CTBS remains a knowledge gap, not an established human modifier. No disease-specific epigenetic or omics mechanism was supported. 6. Biomarkers and diagnosis — adequate after changes. Enzyme testing remains the diagnostic gold standard with molecular confirmation/family evaluation. ManGlcNAc and NeuManGlcNAc support urinary profiling; NeuMan2GlcNAc2 in two severely affected patients is exploratory, not a validated prognostic marker. Pooled lysosomal-assay performance is not beta-mannosidosis-specific accuracy. Audiological assessment can require objective and behavioral methods. Imaging may be normal; three of six new patients had myelination abnormalities, while the historical 40% rate concerns six of 15 imaged cases, not all published patients. Added alpha-mannosidosis and fucosidosis differentials with biochemical confirmation rather than MRI-only diagnosis. Regional birth-prevalence estimates and published-case counts are separate measures. 7. Reference consumption — adequate with stated access limits. Read complete scientific full texts and relevant tables for PMID:41235131, 32847582, 31115173 and 24142277. Read complete cached abstracts for PMID:12890191, 16377659, 9384606, 18565776, 9097826 and GeneReviews PMID:42160655. Attempted primary full texts where absent. The current GeneReviews chapter was previously untagged; its cached abstract is actively mined for clinical characteristics, diagnosis, management and counseling. Bookshelf HTML, reader/XML and PDF routes returned CAPTCHA, so those unusable cache artifacts are excluded. No full-chapter reading is claimed. The 2003 DOI remained unavailable; its PubMed abstract supports the skin findings. The 2024 mixed-lysosomal-disorder assay abstract does not identify a beta-mannosidosis validation sample and is not used for disease-specific sensitivity. All reference caches were generated/refreshed through repository fetch commands, never hand-edited. Titles were checked for disease, gene and claim relevance. 8. Overall consumption — adequate. Central disease-specific omissions were incorporated; speculative CTBS effects and cross-species myelin differences are explicit discussions. No unverified data accession, regulatory target, immunodeficiency, retinal mechanism or treatment efficacy is invented. The source's inconsistent sex totals and splice-variant percentages are not silently recalculated into new claims. Existing review-process prose is removed from disease-facing notes. Validation passes schema/live ontology checks and verifies 121 snippets and 122 titles with none skipped or unavailable; additional content/history checks and commit hooks accompany the PR.

Disorder ▸

Disorder

  • Name: Beta Mannosidosis
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 8

Key Pathophysiology Nodes

  • Beta-mannosidase deficiency
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/978-3-642-40337-8_26
  • DOI:10.1007/978-3-642-40337-8_26
  • DOI:10.1046/j.1365-2133.2003.05365.x
  • DOI:10.1093/clinchem/hvae043
  • DOI:10.1186/s13023-020-01508-3
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 11 citations 2025-12-18T13:53:45.754720

Disease Pathophysiology Research Report

Target Disease - Disease Name: Beta-mannosidosis - MONDO ID: MONDO_0009562 - Category: Mendelian

1) Core Pathophysiology: Key concepts and current understanding - Definition and cause: Beta-mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in MANBA, encoding lysosomal beta-mannosidase, a soluble hydrolase responsible for terminal removal of beta-linked mannose residues from N-linked glycoprotein-derived oligosaccharides during lysosomal degradation (clinical enzymology and mutation evidence) (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8). - Primary pathophysiologic mechanism: Loss or marked reduction of beta-mannosidase activity impairs lysosomal catabolism of glycoprotein-derived oligosaccharides, leading to intra-lysosomal storage and cellular vacuolation. Electron microscopy and histology in patient tissues/cells (skin keratinocytes, fibroblasts) demonstrate prominent lysosomal enlargement/vacuolation consistent with storage pathology (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). As Uchino et al. reported, “prominent cytoplasmic vacuoles … were confirmed by electron microscopy to be lysosomes,” with “vacuolation increased during 1 week in culture” (Jul 2003; https://doi.org/10.1046/j.1365-2133.2003.05365.x) (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Substrates that accumulate: Free oligosaccharides are detected in urine, including Man-GlcNAc (m/z ~518 Da), sialylated species (Neu5Ac-Man-GlcNAc, ~879 Da), and higher oligosaccharides (e.g., pentasaccharide ~1328.6 Da), consistent with incomplete trimming of N-glycan-derived species (Aug 2020; https://doi.org/10.1186/s13023-020-01508-3) (brozkova2020variantc.21582a>gin pages 6-8). Modern UPLC-MS/MS approaches classify and quantify these urinary oligosaccharides for glycoproteinoses (including beta-mannosidosis), supporting their role as disease biomarkers and readouts of disrupted oligosaccharide metabolism (Apr 2024; https://doi.org/10.1093/clinchem/hvae043) (uchino2003morphologicalandbiochemical pages 7-7). - Subcellular processing steps affected: The defect lies within the lysosomal phase of glycoprotein degradation (endosome–lysosome network). Morphologic evidence of lysosomal storage/vacuolation in patient cells supports organellar dysfunction and lysosome organization changes (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Downstream cellular effects: Storage triggers lysosomal enlargement and likely perturbs lysosomal–autophagic flux and cellular homeostasis; clinical evidence and reviews suggest CNS involvement with variable neurodevelopmental impact, and reviews point to potential neuroinflammatory and myelin-related consequences in some cases, though direct mechanistic dissection remains limited in humans (Jan 2022; chapter review) (lukacs2022oligosaccharidosesandsialic pages 11-12).

2) Key Molecular Players and Affected Systems - Genes/Proteins (HGNC): MANBA (HGNC:6768) encodes lysosomal beta-mannosidase; truncating and splice-site variants can severely reduce or abolish activity. Uchino et al. identified aberrant splicing due to a G→A transition at intron 7 donor, causing a 4-nt insertion, frameshift at codon 321 and early termination at codon 325, with plasma activity ~2% of normal and fibroblast activity ~10% (Jul 2003; DOI above) (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Chemical entities/metabolites (CHEBI classes): Accumulated urinary free oligosaccharides include Man-β1→4-GlcNAc disaccharide and sialylated derivatives (Neu5Ac-containing oligosaccharides), consistent with impaired glycoprotein catabolism (Aug 2020; DOI above; Apr 2024; DOI above) (brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7). - Cell types (CL): Neurons and glia (especially oligodendrocytes) are implicated due to CNS phenotypes; microglia are hypothesized mediators of secondary neuroinflammation in lysosomal storage contexts. Keratinocytes and fibroblasts show clear lysosomal vacuolation in patient samples (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, lukacs2022oligosaccharidosesandsialic pages 11-12). - Anatomical locations (UBERON): Brain (cortex, white matter) and cochlea are primary organs relating to intellectual disability, leukoencephalopathy/demyelination in some cases, and sensorineural hearing loss. Skin (epidermis/dermis) shows vacuolated cells and cutaneous lesions in some reports (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, lukacs2022oligosaccharidosesandsialic pages 11-12).

3) Dysregulated Biological Processes (candidate GO terms) - Lysosomal catabolic process; glycoprotein catabolic process; oligosaccharide metabolic process: impaired terminal trimming of β-linked mannose residues results in storage and elevated urinary free oligosaccharides (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7). - Lysosome organization/homeostasis: storage leads to lysosomal enlargement/vacuolation in multiple cell types (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Inflammatory response/neuroinflammation (proposed): reviews highlight that lysosomal storage can drive inflammatory pathways; for beta-mannosidosis, this remains a plausible but incompletely defined contributor to CNS manifestations (lukacs2022oligosaccharidosesandsialic pages 11-12).

4) Cellular Components (candidate GO terms) - Lysosome and lysosomal lumen: the site of beta-mannosidase action and storage accumulation (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8). - Endosome–lysosome system: trafficking and degradative compartments engaged in glycoprotein turnover (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7).

5) Disease Progression: Sequence of events - Initial trigger: Biallelic loss-of-function or severe hypomorphic variants in MANBA reduce lysosomal beta-mannosidase activity (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Substrate accumulation: Incompletely degraded glycoprotein-derived oligosaccharides accumulate in lysosomes, with overflow into urine as free oligosaccharides (e.g., Man-GlcNAc, Neu5Ac-Man-GlcNAc, higher oligosaccharides) (brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7). - Cellular pathology: Lysosomal vacuolation/expansion is observed in multiple cell types, reflecting storage and organellar stress (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Tissue/organ involvement: CNS involvement (variable cognitive impairment, seizures; some reports of leukoencephalopathy), and inner ear involvement (sensorineural hearing loss); skin may show vacuolated cells and angiokeratomas in some cases (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, lukacs2022oligosaccharidosesandsialic pages 11-12). - Clinical manifestation: Spectrum ranges from attenuated to more severe neurodevelopmental disease; expressivity is variable and not fully predicted by genotype or residual activity, per review evidence (lukacs2022oligosaccharidosesandsialic pages 11-12).

6) Phenotypic Manifestations and Mechanistic Links - Hearing loss: Early (often prelingual) sensorineural hearing impairment is a prominent feature in multiple cohorts, including a founder variant (c.2158-2A>G) in Roma patients; mechanistically, cochlear/neuronal storage and dysfunction are implicated, though detailed inner ear histopathology in humans remains limited (Aug 2020; DOI above) (brozkova2020variantc.21582a>gin pages 6-8). - Neurodevelopmental features: Intellectual disability and seizures occur variably; neuronal lysosomal storage and potential neuroinflammatory cascades may contribute (uchino2003morphologicalandbiochemical pages 4-7, lukacs2022oligosaccharidosesandsialic pages 11-12). - White matter involvement: Some cases show leukoencephalopathy/demyelination, implicating oligodendrocyte/axonal myelin pathology secondary to lysosomal dysfunction (review synthesis) (lukacs2022oligosaccharidosesandsialic pages 11-12). - Cutaneous findings: Angiokeratomas and epidermal cellular vacuolation have been described, consistent with storage in skin cells (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7).

7) Genotype–Phenotype and Residual Enzyme Activity Correlations - Residual activity: Reported patient enzyme activities span “undetectable up to 0.02–10.0% of control,” with marked clinical variability; carriers may show ~40% activity without disease (Uchino data; Jul 2003; DOI above) (uchino2003morphologicalandbiochemical pages 4-7). As Uchino et al. noted, a truncated enzyme yielded “plasma β‑mannosidase activity … ~2% of normal” and fibroblast activity ~10% (uchino2003morphologicalandbiochemical pages 2-4). - Genotype variability and founder effects: The c.2158‑2A>G MANBA variant is a prevalent founder allele among Czech/Slovak Roma with beta-mannosidosis and hearing loss, with a carrier frequency of 3.77% in sampled Roma controls, illustrating population-specific risk (Aug 2020; DOI above) (brozkova2020variantc.21582a>gin pages 6-8). - Correlation limitations: Reviews emphasize variable expressivity and that residual activity does not perfectly predict severity; severe CNS involvement may occur even with apparent residual activity, underscoring complex modifiers (Jan 2022; chapter review) (lukacs2022oligosaccharidosesandsialic pages 11-12).

8) Diagnostics, Biomarkers, and Current Applications - Enzymatic assay: Diagnostic measurement of beta-mannosidase activity in leukocytes, fibroblasts, or plasma is reduced or absent in affected individuals (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8). - Urinary free oligosaccharides (FOS): Distinctive patterns of Man-GlcNAc and related oligosaccharides can be detected; UPLC‑MS/MS assays now allow multiplexed detection and disease subtyping across glycoproteinoses, achieving high sensitivity/specificity in validation cohorts and showing substantial reductions of disease-specific biomarkers in treated patients (class-wide observation across LSDs, with inclusion of glycoproteinoses) (Apr 2024; https://doi.org/10.1093/clinchem/hvae043) (uchino2003morphologicalandbiochemical pages 7-7).

9) Therapeutic Implications and Developments - Monitoring: Given robust urinary oligosaccharide signatures, modern UPLC‑MS/MS provides a platform for diagnostic confirmation and potential treatment monitoring in glycoproteinoses; reductions in biomarkers after therapy have been documented in validation sets (LSDs including glycoproteinoses) (Apr 2024; DOI above) (uchino2003morphologicalandbiochemical pages 7-7). - Disease-modifying approaches: While enzyme replacement therapy and gene therapy are established in other LSDs, specific clinical efficacy data for beta-mannosidosis remain sparse in the accessible evidence here; reviews highlight the principle that lysosomal correction may ameliorate storage and downstream inflammation, but patient-level interventional outcomes for MANBA deficiency require further study (lukacs2022oligosaccharidosesandsialic pages 11-12).

10) Expert Opinions and Analysis - Clinical heterogeneity: Expert reviews emphasize that beta-mannosidosis exhibits broad phenotypic variability—even among null or severely disruptive genotypes—complicating prediction of course and underscoring the need for biochemical confirmation and longitudinal assessment (Jan 2022; chapter review) (lukacs2022oligosaccharidosesandsialic pages 11-12). - Diagnostic strategy: Combining enzyme activity assays with next-generation sequencing and urinary oligosaccharide profiling can reduce diagnostic delay and enable cascade testing in families (brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7).

11) Relevant Statistics and Data - Residual enzyme activities: Affected individuals can exhibit activities “undetectable up to 0.02–10.0% of control,” whereas an asymptomatic heterozygous mother showed ~40% activity (Jul 2003; DOI above) (uchino2003morphologicalandbiochemical pages 4-7). - Population genetics: c.2158‑2A>G MANBA carrier frequency 3.77% in Roma controls (n=345), about 925-fold higher than gnomAD frequency; founder effect with multiple affected families (Aug 2020; DOI above) (brozkova2020variantc.21582a>gin pages 6-8). - Biomarker performance: A 2024 UPLC‑MS/MS platform achieved unambiguous diagnosis across multiple LSD subtypes with 100% sensitivity/specificity in a validation set, and showed substantial biomarker reduction in treated patients (platform covers glycoproteinoses, supporting applicability to beta-mannosidosis) (Apr 2024; DOI above) (uchino2003morphologicalandbiochemical pages 7-7).

Ontology-Aligned Annotations and Evidence Table | Category | Term/ID | Ontology | Description | Evidence | URL/DOI | |---|---|---|---|---|---| | Gene | MANBA (HGNC:6768) | HGNC | Encodes lysosomal beta-mannosidase; causal gene for autosomal-recessive beta-mannosidosis | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, lukacs2022oligosaccharidosesandsialic pages 11-12) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x; Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Biological process | Lysosomal catabolic process (GO:0009056) | GO | Degradation of macromolecules in lysosomes; impaired in MANBA deficiency leading to substrate accumulation | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, lukacs2022oligosaccharidosesandsialic pages 11-12) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Biological process | Glycoprotein catabolic process (GO:0006515) | GO | Defective trimming of N- and O-linked oligosaccharides from glycoproteins due to loss of beta-mannosidase activity | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Biological process | Oligosaccharide metabolic process (GO:0009311) | GO | Accumulation and altered metabolism of free oligosaccharides derived from incomplete glycoprotein degradation | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7) | Wongkittichote 2024 DOI: 10.1093/clinchem/hvae043 | | Biological process | Lysosome organization (GO:0007040) | GO | Lysosomal enlargement/vacuolation observed in patient cells due to storage material | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Biological process | Inflammatory response (GO:0006954) | GO | Proposed downstream response (neuroinflammation) in some patients / models; mechanistic links under investigation | (lukacs2022oligosaccharidosesandsialic pages 11-12) | Lukacs & Beck 2022 DOI: 10.1007/978-3-642-40337-8_26 | | Cellular component | Lysosome (GO:0005764) | GO | Primary organelle of substrate accumulation and beta-mannosidase localization | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Cellular component | Lysosomal lumen (GO:0043202) | GO | Enzymatic activity site for soluble hydrolases including beta-mannosidase | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Cellular component | Endosome-lysosome system | — | Endocytic/lysosomal compartments involved in glycoprotein processing and accumulation | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Phenotype | Sensorineural hearing impairment (HP:0000407) | HP | Early, often prelingual hearing loss is a common and characteristic clinical feature | (brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Phenotype | Intellectual disability (HP:0001249) | HP | Variable cognitive impairment reported across patients; degree correlates imperfectly with genotype/residual activity | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, lukacs2022oligosaccharidosesandsialic pages 11-12) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Phenotype | Seizures (HP:0001250) | HP | Epileptic manifestations reported in some patients with CNS involvement | (uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Phenotype | Peripheral neuropathy (HP:0009830) | HP | Peripheral nerve involvement and neuropathic features documented in cases | (uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Phenotype | Angiokeratoma (HP:0000982) | HP | Cutaneous vascular lesions reported in some beta-mannosidosis cases | (uchino2003morphologicalandbiochemical pages 4-7, uchino2003morphologicalandbiochemical pages 7-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Cell type | Neuron (CL:0000540) | CL | Neuronal storage and dysfunction underlie cognitive, seizure, and neurodegenerative features | (uchino2003morphologicalandbiochemical pages 4-7, lukacs2022oligosaccharidosesandsialic pages 11-12) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Cell type | Oligodendrocyte (CL:0000128) | CL | Implicated in reported leukoencephalopathy/demyelination phenotypes in some patients/models | (lukacs2022oligosaccharidosesandsialic pages 11-12) | Lukacs & Beck 2022 DOI: 10.1007/978-3-642-40337-8_26 | | Cell type | Microglial cell (CL:0000129) | CL | Candidate mediator of neuroinflammation secondary to lysosomal storage (mechanistic studies limited) | (lukacs2022oligosaccharidosesandsialic pages 11-12) | Lukacs & Beck 2022 DOI: 10.1007/978-3-642-40337-8_26 | | Cell type | Keratinocyte (CL:0000312) | CL | Skin cell vacuolation described histologically in patient biopsies | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Cell type | Fibroblast (CL:0000057) | CL | Patient fibroblasts show lysosomal vacuolation in culture; used for biochemical assays | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Anatomical site | Brain (UBERON:0000955) | UBERON | Central organ affected; cognitive and seizure phenotypes originate here | (uchino2003morphologicalandbiochemical pages 4-7, lukacs2022oligosaccharidosesandsialic pages 11-12) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Anatomical site | White matter (UBERON:0002436) | UBERON | Reported leukoencephalopathy/demyelination implicates white-matter pathology | (lukacs2022oligosaccharidosesandsialic pages 11-12) | Lukacs & Beck 2022 DOI: 10.1007/978-3-642-40337-8_26 | | Anatomical site | Cochlea (UBERON:0001844) | UBERON | Site relevant to sensorineural hearing loss observed in patients | (brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Anatomical site | Skin (UBERON:0002097) | UBERON | Cutaneous manifestations (vacuolation, angiokeratoma) documented | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 7-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Chemical entity | Man-β1-4GlcNAc disaccharide (CHEBI:?) | CHEBI (pending) | Free disaccharide/oligosaccharide species identified in glycoproteinoses; reported as bioactive in other contexts and detected in patients' urine | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3; Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Chemical entity | Neu5Ac-containing oligosaccharides (Neu5Ac-) | CHEBI (Neu5Ac) | Sialylated oligosaccharide species reported among urinary peaks in some patients | (brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Chemical entity | Free urinary oligosaccharides | — | Biomarker class: accumulated oligosaccharides (e.g., Man-GlcNAc, Neu5Ac-Man-GlcNAc) detected by urinary profiling | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7) | Wongkittichote 2024 DOI: 10.1093/clinchem/hvae043; Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Biomarker / assay | Urinary free oligosaccharides by UPLC-MS/MS | Assay | Sensitive multiplexed detection and subtyping of glycoproteinoses including beta-mannosidosis; useful for diagnosis and monitoring | (uchino2003morphologicalandbiochemical pages 7-7, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8) | Wongkittichote 2024 DOI: 10.1093/clinchem/hvae043 | | Biomarker / assay | Enzyme activity assay in leukocytes (β-mannosidase) | Assay | Diagnostic enzymatic assay: leukocyte/plasma activity is reduced or absent in affected individuals | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 |

Table: Compact ontology-aligned annotation table summarizing genes, processes, components, phenotypes, cell types, tissues, chemical entities, and diagnostic biomarkers for beta-mannosidosis with evidence mappings to the gathered sources (pqac IDs) and key DOIs.

Evidence Items (key citations with URLs and dates) - Uchino Y, et al. Morphological and biochemical studies of human β‑mannosidosis: identification of a novel β‑mannosidase gene mutation. British Journal of Dermatology. Jul 2003. DOI: 10.1046/j.1365-2133.2003.05365.x. URL: https://doi.org/10.1046/j.1365-2133.2003.05365.x (pathogenic variant; residual enzyme activity; lysosomal vacuolation) (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, uchino2003morphologicalandbiochemical pages 7-7). - Brozkova DS, et al. Variant c.2158‑2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population. Orphanet J Rare Dis. Aug 2020. DOI: 10.1186/s13023-020-01508-3. URL: https://doi.org/10.1186/s13023-020-01508-3 (urinary oligosaccharide species; undetectable enzyme activity; founder variant; hearing loss) (brozkova2020variantc.21582a>gin pages 6-8). - Lukacs Z, Beck M. Oligosaccharidoses and sialic acid disorders. In: Physician’s Guide… Chapter. Jan 2022. DOI: 10.1007/978-3-642-40337-8_26. URL: https://doi.org/10.1007/978-3-642-40337-8_26 (clinical heterogeneity; genotype–phenotype considerations; possible white-matter involvement; conceptual therapeutic landscape) (lukacs2022oligosaccharidosesandsialic pages 11-12). - Wongkittichote P, et al. UPLC‑MS/MS Analysis of Urinary Oligosaccharides and Glycoamino Acids for the Diagnosis of MPS and Glycoproteinosis. Clinical Chemistry. Apr 2024. DOI: 10.1093/clinchem/hvae043. URL: https://doi.org/10.1093/clinchem/hvae043 (modern diagnostics; sensitivity/specificity; biomarker reduction after treatment, class-wide) (uchino2003morphologicalandbiochemical pages 7-7).

Notes on Scope and Gaps - While mechanistic plausibility supports roles for microglial activation and demyelination in some patients, direct human mechanistic studies in beta-mannosidosis are limited in the accessible literature. The above synthesis highlights what is established versus proposed and indicates where additional research (e.g., patient-derived neural models, advanced neuroimaging–biomarker correlations) is needed (lukacs2022oligosaccharidosesandsialic pages 11-12).

References

  1. (uchino2003morphologicalandbiochemical pages 2-4): Y. Uchino, T. Fukushige, S. Yotsumoto, T. Hashiguchi, H. Taguchi, N. Suzuki, I. Konohana, and T. Kanzaki. Morphological and biochemical studies of human β‐mannosidosis: identification of a novel β‐mannosidase gene mutation. British Journal of Dermatology, 149:23-29, Jul 2003. URL: https://doi.org/10.1046/j.1365-2133.2003.05365.x, doi:10.1046/j.1365-2133.2003.05365.x. This article has 28 citations and is from a highest quality peer-reviewed journal.

  2. (uchino2003morphologicalandbiochemical pages 4-7): Y. Uchino, T. Fukushige, S. Yotsumoto, T. Hashiguchi, H. Taguchi, N. Suzuki, I. Konohana, and T. Kanzaki. Morphological and biochemical studies of human β‐mannosidosis: identification of a novel β‐mannosidase gene mutation. British Journal of Dermatology, 149:23-29, Jul 2003. URL: https://doi.org/10.1046/j.1365-2133.2003.05365.x, doi:10.1046/j.1365-2133.2003.05365.x. This article has 28 citations and is from a highest quality peer-reviewed journal.

  3. (brozkova2020variantc.21582a>gin pages 6-8): Dana Safka Brozkova, Lukas Varga, Anna Uhrova Meszarosova, Zuzana Slobodova, Martina Skopkova, Andrea Soltysova, Andrej Ficek, Jan Jencik, Jana Lastuvkova, Daniela Gasperikova, and Pavel Seeman. Variant c.2158-2a>g in manba is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the czech and slovak roma population- evidence for a new ethnic-specific variant. Orphanet Journal of Rare Diseases, Aug 2020. URL: https://doi.org/10.1186/s13023-020-01508-3, doi:10.1186/s13023-020-01508-3. This article has 12 citations and is from a peer-reviewed journal.

  4. (lukacs2022oligosaccharidosesandsialic pages 11-12): Zoltan Lukacs and Michael Beck. Oligosaccharidoses and sialic acid disorders. Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, pages 437-448, Jan 2022. URL: https://doi.org/10.1007/978-3-642-40337-8_26, doi:10.1007/978-3-642-40337-8_26. This article has 0 citations.

  5. (uchino2003morphologicalandbiochemical pages 7-7): Y. Uchino, T. Fukushige, S. Yotsumoto, T. Hashiguchi, H. Taguchi, N. Suzuki, I. Konohana, and T. Kanzaki. Morphological and biochemical studies of human β‐mannosidosis: identification of a novel β‐mannosidase gene mutation. British Journal of Dermatology, 149:23-29, Jul 2003. URL: https://doi.org/10.1046/j.1365-2133.2003.05365.x, doi:10.1046/j.1365-2133.2003.05365.x. This article has 28 citations and is from a highest quality peer-reviewed journal.