Beta-mannosidosis

Summary

Beta-mannosidosis (MONDO:0009562) is a disease caused by MANBA (GenCC Definitive), with 6 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: MANBA (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 716
• Phenotypes (HPO): 6
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.14	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.16	Czech Republic	Validated
Prevalence at birth	1-9 / 1 000 000	0.13	Netherlands	Validated
Prevalence at birth	1-9 / 1 000 000	0.12	Portugal	Validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0005247	Hypoplasia of the abdominal wall musculature	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	beta-mannosidosis
Mondo ID	MONDO:0009562
MeSH	D044905
OMIM	248510
Orphanet	118
DOID	DOID:3633
ICD-11	1578707401
NCIT	C84596
SNOMED CT	238047006
UMLS	C4048196
MedGen	888408
GARD	0000869
Is cancer (heuristic)	no

Also known as: Beta-mannosidase deficiency · beta-mannosidase deficiency · beta-mannosidosis · lysosomal beta-mannosidase deficiency · mannosidosis, beta · mannosidosis, BETA A, lysosomal · MANSB

Data availability: 716 ClinVar variants · 6 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › oligosaccharidosis › beta-mannosidosis

Related subtypes (6): aspartylglucosaminuria, fucosidosis, alpha-mannosidosis, galactosialidosis, sialidosis, alpha-N-acetylgalactosaminidase deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

316 likely benign, 158 uncertain significance, 53 pathogenic, 25 likely pathogenic, 21 benign, 10 pathogenic/likely pathogenic, 10 conflicting classifications of pathogenicity, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1456123	NC_000004.11:g.(?101947022)(104640832_?)del	CISD2	Pathogenic	criteria provided, single submitter
1028959	NM_005908.4(MANBA):c.177+2T>C	MANBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324696	NM_005908.4(MANBA):c.544C>T (p.Arg182Trp)	MANBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1369625	NM_005908.4(MANBA):c.279G>A (p.Trp93Ter)	MANBA	Pathogenic	criteria provided, single submitter
1384377	NM_005908.4(MANBA):c.1434del (p.Lys479fs)	MANBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1406698	NM_005908.4(MANBA):c.2030G>A (p.Trp677Ter)	MANBA	Pathogenic	criteria provided, single submitter
1457048	NM_005908.4(MANBA):c.1628G>A (p.Trp543Ter)	MANBA	Pathogenic	criteria provided, single submitter
1676	NM_005908.4(MANBA):c.960+1G>A	MANBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1677	NM_005908.4(MANBA):c.563_572dup (p.Asp191_Trp192insTer)	MANBA	Pathogenic	criteria provided, multiple submitters, no conflicts
1678	NM_005908.4(MANBA):c.1705-1G>A	MANBA	Pathogenic	no assertion criteria provided
1679	NM_005908.4(MANBA):c.1513T>C (p.Ser505Pro)	MANBA	Pathogenic	no assertion criteria provided
1680	NM_005908.4(MANBA):c.375A>G (p.Arg125=)	MANBA	Pathogenic	criteria provided, multiple submitters, no conflicts
1681	NM_005908.4(MANBA):c.247G>T (p.Glu83Ter)	MANBA	Pathogenic	no assertion criteria provided
1682	NM_005908.4(MANBA):c.1276C>T (p.Gln426Ter)	MANBA	Pathogenic	no assertion criteria provided
1683	NM_005908.4(MANBA):c.1454_1455del (p.Tyr485fs)	MANBA	Pathogenic	criteria provided, multiple submitters, no conflicts
1683317	NM_005908.4(MANBA):c.2175dup (p.Ser726fs)	MANBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705136	NM_005908.4(MANBA):c.1753C>T (p.Arg585Ter)	MANBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723323	NM_005908.4(MANBA):c.916del (p.Leu306fs)	MANBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1958813	NM_005908.4(MANBA):c.1153_1162del (p.Asn385fs)	MANBA	Pathogenic	criteria provided, single submitter
1978132	NM_005908.4(MANBA):c.1156_1157del (p.Thr386fs)	MANBA	Pathogenic	criteria provided, single submitter
2058638	NM_005908.4(MANBA):c.1649del (p.Arg550fs)	MANBA	Pathogenic	criteria provided, single submitter
2070212	NM_005908.4(MANBA):c.1534G>T (p.Glu512Ter)	MANBA	Pathogenic	criteria provided, single submitter
2095842	NM_005908.4(MANBA):c.2101_2102insTGTGACGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTGTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAGAATGAAAACA (p.Thr701delinsMetTer)	MANBA	Pathogenic	criteria provided, single submitter
2109699	NM_005908.4(MANBA):c.1724G>A (p.Trp575Ter)	MANBA	Pathogenic	criteria provided, single submitter
2142091	NM_005908.4(MANBA):c.63_64del (p.Ser22fs)	MANBA	Pathogenic	criteria provided, single submitter
2626857	NM_005908.4(MANBA):c.692G>A (p.Trp231Ter)	MANBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2636760	NM_005908.4(MANBA):c.1623G>A (p.Trp541Ter)	MANBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2703999	NM_005908.4(MANBA):c.1836dup (p.Arg613fs)	MANBA	Pathogenic	criteria provided, single submitter
2704638	NM_005908.4(MANBA):c.1453dup (p.Tyr485fs)	MANBA	Pathogenic	criteria provided, single submitter
2709615	NM_005908.4(MANBA):c.2102_2103insAT (p.Phe702fs)	MANBA	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MANBA	Definitive	Autosomal recessive	beta-mannosidosis	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MANBA	Orphanet:118	Beta-mannosidosis
CDH23	Orphanet:231169	Usher syndrome type 1
CDH23	Orphanet:2965	Prolactinoma
CDH23	Orphanet:314777	Familial isolated pituitary adenoma
CDH23	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CDH23	Orphanet:91347	TSH-secreting pituitary adenoma
CDH23	Orphanet:96253	Cushing disease
ADGRV1	Orphanet:231178	Usher syndrome type 2
ADGRV1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
CISD2	Orphanet:3463	Wolfram syndrome
DIAPH1	Orphanet:2573	Moyamoya disease
DIAPH1	Orphanet:477814	Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
DIAPH1	Orphanet:494444	DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome
FAH	Orphanet:882	Tyrosinemia type 1

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MANBA	HGNC:6831	ENSG00000109323	O00462	Beta-mannosidase	gencc,clinvar
CDH23	HGNC:13733	ENSG00000107736	Q9H251	Cadherin-23	clinvar
ADGRV1	HGNC:17416	ENSG00000164199	Q8WXG9	Adhesion G-protein coupled receptor V1	clinvar
CISD2	HGNC:24212	ENSG00000145354	Q8N5K1	CDGSH iron-sulfur domain-containing protein 2	clinvar
DIAPH1	HGNC:2876	ENSG00000131504	O60610	Protein diaphanous homolog 1	clinvar
FAH	HGNC:3579	ENSG00000103876	P16930	Fumarylacetoacetase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MANBA	Beta-mannosidase	Exoglycosidase that cleaves the single beta-linked mannose residue from the non-reducing end of all N-linked glycoprotein oligosaccharides.
CDH23	Cadherin-23	Cadherins are calcium-dependent cell adhesion proteins.
ADGRV1	Adhesion G-protein coupled receptor V1	G-protein coupled receptor which has an essential role in the development of hearing and vision.
CISD2	CDGSH iron-sulfur domain-containing protein 2	Regulator of autophagy that contributes to antagonize BECN1-mediated cellular autophagy at the endoplasmic reticulum.
DIAPH1	Protein diaphanous homolog 1	Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	4.9×	0.452
GPCR	1	4.0×	0.452
Enzyme (other)	1	2.0×	0.543
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MANBA	Antibody/Immunoglobulin	yes		Glyco_hydro_2_cat, Galactose-bd-like_sf, Ig-like_fold
CDH23	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
ADGRV1	GPCR	yes		GPCR_2_secretin-like, Calx_beta, EPTP
CISD2	Other/Unknown	no		FeS-contain_CDGSH-typ, FeS-contain_mitoNEET_N, MitoNEET_CISD
DIAPH1	Other/Unknown	no		Drf_DAD, FH3_dom, GTPase-bd
FAH	Enzyme (other)	yes	3.7.1.2	Fumarylacetoacetase, Fumarylacetoacetase-like_C, Fumarylacetoacetase_N

Expression context

Cohort genes with no expression data: 0.

6 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	2
right adrenal gland	2
monocyte	1
mononuclear cell	1
left ovary	1
right ovary	1
ventricular zone	1
left adrenal gland	1
right adrenal gland cortex	1
epithelial cell of pancreas	1
oviduct epithelium	1
tendon of biceps brachii	1
granulocyte	1
lower esophagus mucosa	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MANBA	246	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
CDH23	161	broad	marker	ventricular zone, left ovary, right ovary
ADGRV1	196	broad	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
CISD2	261	ubiquitous	marker	epithelial cell of pancreas, oviduct epithelium, tendon of biceps brachii
DIAPH1	291	ubiquitous	marker	granulocyte, lower esophagus mucosa, leukocyte
FAH	255	ubiquitous	marker	right lobe of liver, liver, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DIAPH1	2,316
MANBA	2,014
CISD2	1,987
FAH	1,872
ADGRV1	1,658
CDH23	1,575

Intra-cohort edges

A	B	Sources
ADGRV1	CDH23	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAH	P16930	8
CDH23	Q9H251	6
CISD2	Q8N5K1	4
DIAPH1	O60610	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MANBA	O00462	96.05
ADGRV1	Q8WXG9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 6 evidence-associated genes (5 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Lysosomal oligosaccharide catabolism	1	571.0×	0.016	MANBA
Regulation of MITF-M dependent genes involved in invasion	1	571.0×	0.016	DIAPH1
Tyrosine catabolism	1	456.8×	0.016	FAH
ERBB2 Regulates Cell Motility	1	142.8×	0.038	DIAPH1
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	73.7×	0.053	ADGRV1
Sensory processing of sound	1	61.7×	0.053	CDH23
RHOF GTPase cycle	1	51.9×	0.053	DIAPH1
Neutrophil degranulation	2	9.2×	0.053	MANBA, DIAPH1
RHOD GTPase cycle	1	40.8×	0.053	DIAPH1
Sensory processing of sound by outer hair cells of the cochlea	1	40.8×	0.053	CDH23
Sensory processing of sound by inner hair cells of the cochlea	1	32.6×	0.057	CDH23
RHOB GTPase cycle	1	30.9×	0.057	DIAPH1
RHOC GTPase cycle	1	29.3×	0.057	DIAPH1
Metabolism of carbohydrates and carbohydrate derivatives	1	24.0×	0.064	MANBA
Sensory Perception	1	19.0×	0.075	CDH23
RHO GTPases Activate Formins	1	15.5×	0.084	DIAPH1
RHOA GTPase cycle	1	14.9×	0.084	DIAPH1
Nervous system development	1	8.6×	0.136	ADGRV1
Innate Immune System	1	5.1×	0.210	MANBA
Developmental Biology	1	2.9×	0.331	ADGRV1
Immune System	1	2.6×	0.346	MANBA
Metabolism	1	2.3×	0.362	MANBA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory perception of light stimulus	2	624.1×	2e-04	CDH23, ADGRV1
sensory perception of sound	3	50.5×	5e-04	CDH23, ADGRV1, DIAPH1
photoreceptor cell maintenance	2	119.5×	0.002	CDH23, ADGRV1
homogentisate catabolic process	1	2808.7×	0.004	FAH
maintenance of animal organ identity	1	561.7×	0.011	ADGRV1
inner ear receptor cell differentiation	1	561.7×	0.011	ADGRV1
L-arginine catabolic process	1	468.1×	0.011	FAH
L-tyrosine catabolic process	1	468.1×	0.011	FAH
cellular response to histamine	1	468.1×	0.011	DIAPH1
equilibrioception	1	401.2×	0.011	CDH23
visual perception	2	26.5×	0.011	CDH23, ADGRV1
L-phenylalanine catabolic process	1	351.1×	0.012	FAH
regulation of microtubule-based process	1	312.1×	0.012	DIAPH1
oligosaccharide catabolic process	1	255.3×	0.013	MANBA
self proteolysis	1	255.3×	0.013	ADGRV1
protein localization to microtubule	1	216.1×	0.014	DIAPH1
nervous system process	1	200.6×	0.014	ADGRV1
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	187.2×	0.015	CDH23
glycoprotein catabolic process	1	175.5×	0.015	MANBA
detection of mechanical stimulus involved in sensory perception of sound	1	156.0×	0.015	ADGRV1
regulation of release of sequestered calcium ion into cytosol	1	156.0×	0.015	DIAPH1
auditory receptor cell stereocilium organization	1	140.4×	0.015	CDH23
inner ear receptor cell stereocilium organization	1	140.4×	0.015	ADGRV1
autophagy of mitochondrion	1	122.1×	0.017	CISD2
regulation of cytoskeleton organization	1	108.0×	0.018	DIAPH1
calcium-dependent cell-cell adhesion	1	80.2×	0.022	CDH23
actin filament polymerization	1	80.2×	0.022	DIAPH1
cochlea development	1	78.0×	0.022	CDH23
establishment of protein localization	1	72.0×	0.023	ADGRV1
positive regulation of bone mineralization	1	65.3×	0.024	ADGRV1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 4 of 6 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CISD2	ROSIGLITAZONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CISD2	2	4
MANBA	0	0
CDH23	0	0
ADGRV1	0	0
DIAPH1	0	0
FAH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ROSIGLITAZONE	4	CISD2
PIOGLITAZONE	4	CISD2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MANBA	13	Binding:11, Functional:2
CISD2	6	Binding:6
DIAPH1	3	Binding:3
FAH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FAH	3.7.1.2	fumarylacetoacetase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ROSIGLITAZONE	4	CISD2
PIOGLITAZONE	4	CISD2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CISD2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FAH
D	Druggable family + AlphaFold only, no drug	2	MANBA, ADGRV1
E	Difficult family or no structure, no drug	2	CDH23, DIAPH1

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MANBA	13	—
CDH23	0	—
ADGRV1	0	—
DIAPH1	3	—
FAH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01891422	Not specified	COMPLETED	Longitudinal Studies of the Glycoproteinoses