PMM2-congenital disorder of glycosylation

Summary

PMM2-congenital disorder of glycosylation (MONDO:0008907) is a disease caused by PMM2 (GenCC Definitive), with 3 cohort genes and 6 clinical trials. Top therapeutic interventions include acetazolamide and epalrestat.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: PMM2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 784
• Phenotypes (HPO): 86
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000		Europe	Validated
Prevalence at birth	1-9 / 100 000	1.73	Italy	Validated

Signs & symptoms

Clinical features (HPO)

86 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Very frequent (80-99%)
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000582	Upslanted palpebral fissure	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000154	Wide mouth	Frequent (30-79%)
HP:0000219	Thin upper lip vermilion	Frequent (30-79%)
HP:0000276	Long face	Frequent (30-79%)
HP:0000278	Retrognathia	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000448	Prominent nose	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000565	Esotropia	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0001763	Pes planus	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002751	Kyphoscoliosis	Frequent (30-79%)
HP:0003186	Inverted nipples	Frequent (30-79%)
HP:0007552	Abnormal subcutaneous fat tissue distribution	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0009125	Lipodystrophy	Frequent (30-79%)
HP:0011220	Prominent forehead	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012448	Delayed myelination	Frequent (30-79%)
HP:0100807	Long fingers	Frequent (30-79%)
HP:0000044	Hypogonadotropic hypogonadism	Occasional (5-29%)
HP:0000091	Abnormal renal tubule morphology	Occasional (5-29%)
HP:0000093	Proteinuria	Occasional (5-29%)
HP:0000100	Nephrotic syndrome	Occasional (5-29%)
HP:0000377	Abnormal pinna morphology	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000510	Rod-cone dystrophy	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000842	Hyperinsulinemia	Occasional (5-29%)
HP:0000845	Elevated circulating growth hormone concentration	Occasional (5-29%)
HP:0000855	Insulin resistance	Occasional (5-29%)
HP:0000870	Increased circulating prolactin concentration	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	PMM2-congenital disorder of glycosylation
Mondo ID	MONDO:0008907
MeSH	C535739
OMIM	212065
Orphanet	79318
DOID	DOID:0080552
NCIT	C126868
SNOMED CT	459063003
UMLS	C0349653
MedGen	138111
GARD	0009826
NORD	1585
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type Ia · carbohydrate-deficient glycoprotein syndrome type 1A · carbohydrate-deficient glycoprotein syndrome type 1A (formerly) · carbohydrate-deficient glycoprotein syndrome, type Ia · CDG 1A · CDG syndrome type Ia · CDG-IA · CDG1A · congenital disorder of glycosylation type 1a · congenital disorder of glycosylation type Ia · congenital disorder of glycosylation, type Ia · phosphomannomutase 2 deficiency · PMM2-CDG · PMM2-CDG (CDG-Ia) · PMM2-congenital disorder of glycosylation

Data availability: 784 ClinVar variants · 4 GenCC gene-disease records · 22 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › congenital disorder of glycosylation › congenital disorder of glycosylation type I › PMM2-congenital disorder of glycosylation

Related subtypes (27): developmental and epileptic encephalopathy, 36, SSR4-congenital disorder of glycosylation, ALG3-congenital disorder of glycosylation, MPI-congenital disorder of glycosylation, ALG6-congenital disorder of glycosylation 1C, ALG12-congenital disorder of glycosylation, ALG2-congenital disorder of glycosylation, DPAGT1-congenital disorder of glycosylation, ALG8-congenital disorder of glycosylation, ALG1-congenital disorder of glycosylation, ALG9-congenital disorder of glycosylation, congenital disorder of glycosylation type 1E, MPDU1-congenital disorder of glycosylation, DK1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, SRD5A3-congenital disorder of glycosylation, DPM3-congenital disorder of glycosylation, ALG11-congenital disorder of glycosylation, DDOST-congenital disorder of glycosylation, PGM1-congenital disorder of glycosylation, congenital muscular dystrophy with intellectual disability and severe epilepsy, STT3A-congenital disorder of glycosylation, STT3B-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 50, congenital disorder of glycosylation, type IAA, congenital disorder of glycosylation, type ICC, SSR3-CDG

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:

213 likely benign, 159 uncertain significance, 84 likely pathogenic, 47 pathogenic, 41 pathogenic/likely pathogenic, 37 conflicting classifications of pathogenicity, 14 benign, 3 benign/likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068915	NM_000303.3(PMM2):c.385G>T (p.Val129Leu)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069079	NM_000303.3(PMM2):c.243_244del (p.Leu82fs)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
1070199	NM_000303.3(PMM2):c.72del (p.Thr25fs)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072362	NM_000303.3(PMM2):c.377_381del (p.Met126fs)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072807	NM_000303.3(PMM2):c.73dup (p.Thr25fs)	PMM2	Pathogenic	criteria provided, single submitter
1072868	NM_000303.3(PMM2):c.458_462del (p.Ile153fs)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
1073046	NM_000303.3(PMM2):c.457dup (p.Ile153fs)	PMM2	Pathogenic	criteria provided, single submitter
1073938	NM_000303.3(PMM2):c.66+1G>A	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
1074658	NC_000016.9:g.(?8895646)(8895777_?)del	PMM2	Pathogenic	criteria provided, single submitter
1075469	NM_000303.3(PMM2):c.264_265del (p.His90fs)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076104	NM_000303.3(PMM2):c.201_202del (p.Phe68fs)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333359	NM_000303.3(PMM2):c.573C>A (p.Tyr191Ter)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333592	NM_000303.3(PMM2):c.713G>C (p.Arg238Pro)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342149	NM_000303.3(PMM2):c.696del (p.Ala233fs)	PMM2	Pathogenic	no assertion criteria provided
1358766	NM_000303.3(PMM2):c.451G>T (p.Glu151Ter)	PMM2	Pathogenic	criteria provided, single submitter
1367452	NM_000303.3(PMM2):c.59del (p.Pro20fs)	PMM2	Pathogenic	criteria provided, single submitter
1393525	NM_000303.3(PMM2):c.16_22del (p.Pro6fs)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1440145	NM_000303.3(PMM2):c.523+1del	PMM2	Pathogenic	criteria provided, single submitter
1693586	NM_000303.3(PMM2):c.728T>C (p.Leu243Pro)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1693595	NM_000303.3(PMM2):c.556G>A (p.Gly186Arg)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188744	NM_000303.3(PMM2):c.24del (p.Cys9fs)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
188763	NM_000303.3(PMM2):c.470T>C (p.Phe157Ser)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188965	NM_000303.3(PMM2):c.1A>G (p.Met1Val)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189141	NM_000303.3(PMM2):c.620T>C (p.Phe207Ser)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1966607	NM_000303.3(PMM2):c.196dup (p.Tyr66fs)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
197658	NM_000303.3(PMM2):c.430T>C (p.Phe144Leu)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
197659	NM_000303.3(PMM2):c.442G>A (p.Asp148Asn)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2031800	NM_000303.3(PMM2):c.348-2A>G	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2034426	NM_000303.3(PMM2):c.255+2T>G	PMM2	Pathogenic	criteria provided, single submitter
2041195	NM_000303.3(PMM2):c.17_28del (p.Pro6_Cys9del)	PMM2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
PMM2	Definitive	Autosomal recessive	congenital disorder of glycosylation type I	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PMM2	Orphanet:79318	PMM2-CDG
ABAT	Orphanet:2066	Gamma-aminobutyric acid transaminase deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PMM2	HGNC:9115	ENSG00000140650	O15305	Phosphomannomutase 2	gencc,clinvar
ABAT	HGNC:23	ENSG00000183044	P80404	4-aminobutyrate aminotransferase, mitochondrial	clinvar
TMEM186	HGNC:24530	ENSG00000184857	Q96B77	Transmembrane protein 186	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PMM2	Phosphomannomutase 2	Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions.
ABAT	4-aminobutyrate aminotransferase, mitochondrial	Catalyzes the conversion of gamma-aminobutyrate and L-beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively.
TMEM186	Transmembrane protein 186	As part of the MCIA complex, required for efficient assembly of the mitochondrial complex I.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PMM2	Enzyme (other)	yes	5.4.2.8	PMM, HAD-SF_hydro_IIB, HAD_sf
ABAT	Enzyme (other)	yes	2.6.1.19	4NH2But_aminotransferase_euk, Aminotrans_3, PyrdxlP-dep_Trfase_major
TMEM186	Other/Unknown	no		Tmem186, TMEM70/TMEM186/TMEM223

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
calcaneal tendon	1
rectum	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
cervix squamous epithelium	1
mucosa of transverse colon	1
tongue squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PMM2	139	ubiquitous	marker	body of pancreas, calcaneal tendon, rectum
ABAT	289	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
TMEM186	278	ubiquitous	marker	cervix squamous epithelium, mucosa of transverse colon, tongue squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PMM2	2,002
ABAT	1,711
TMEM186	957

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PMM2	O15305	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABAT	P80404	93.91
TMEM186	Q96B77	60.13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective PMM2 causes PMM2-CDG	1	3806.7×	0.001	PMM2
Degradation of GABA	1	1903.3×	0.001	ABAT
Synthesis of GDP-mannose	1	634.4×	0.003	PMM2
Complex I biogenesis	1	55.2×	0.023	TMEM186
Respiratory electron transport	1	31.7×	0.031	TMEM186

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
copulation	1	2808.7×	0.002	ABAT
obsolete GABA metabolic process	1	2808.7×	0.002	ABAT
GABA catabolic process	1	2808.7×	0.002	ABAT
negative regulation of gamma-aminobutyric acid secretion	1	2808.7×	0.002	ABAT
obsolete GDP-D-mannose biosynthetic process from fructose-6-phosphate	1	2808.7×	0.002	PMM2
positive regulation of prolactin secretion	1	2808.7×	0.002	ABAT
positive regulation of aspartate secretion	1	2808.7×	0.002	ABAT
obsolete GDP-mannose biosynthetic process from mannose	1	1872.4×	0.002	PMM2
negative regulation of dopamine secretion	1	1404.3×	0.002	ABAT
positive regulation of dopamine metabolic process	1	1404.3×	0.002	ABAT
positive regulation of heat generation	1	1123.5×	0.003	ABAT
GDP-mannose biosynthetic process	1	936.2×	0.003	PMM2
positive regulation of inhibitory postsynaptic potential	1	936.2×	0.003	ABAT
mannose metabolic process	1	702.2×	0.003	PMM2
GABA biosynthetic process	1	702.2×	0.003	ABAT
positive regulation of uterine smooth muscle contraction	1	702.2×	0.003	ABAT
nervous system process	1	401.2×	0.005	ABAT
response to iron ion	1	312.1×	0.006	ABAT
exploration behavior	1	216.1×	0.007	ABAT
negative regulation of blood pressure	1	216.1×	0.007	ABAT
response to cocaine	1	193.7×	0.008	ABAT
response to nicotine	1	140.4×	0.010	ABAT
mitochondrial respiratory chain complex I assembly	1	137.0×	0.010	TMEM186
cerebellum development	1	119.5×	0.011	ABAT
glycoprotein biosynthetic process	1	112.3×	0.011	PMM2
protein N-linked glycosylation	1	87.8×	0.013	PMM2
positive regulation of insulin secretion	1	85.1×	0.013	ABAT
locomotory behavior	1	59.8×	0.018	ABAT
response to ethanol	1	48.9×	0.022	ABAT
response to hypoxia	1	31.9×	0.032	ABAT

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PMM2	1	3
ABAT	0	0
TMEM186	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EBSELEN	3	PMM2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ABAT	41	Binding:41
PMM2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PMM2	5.4.2.8	phosphomannomutase
ABAT	2.6.1.19	4-aminobutyrate-2-oxoglutarate transaminase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
EBSELEN	3	PMM2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	PMM2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ABAT
E	Difficult family or no structure, no drug	1	TMEM186

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ABAT	41	—
TMEM186	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	2
PHASE2	2
PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06892288	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study to Assess the Efficacy and Safety of Weekly Doses of GLM101 in Participants With PMM2-CDG
NCT04679389	PHASE2/PHASE3	TERMINATED	Acetazolamide Efficacy in Ataxia in PMM2-CDG
NCT04925960	PHASE3	TERMINATED	Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG
NCT06657859	PHASE2	ENROLLING_BY_INVITATION	Open-Label Extension Study to Assess GLM101 in PMM2-CDG Patients
NCT05549219	PHASE2	COMPLETED	24-Week Study to Assess the PD, Safety, Tolerability, and PK of GLM101 in Participants With PMM2-CDG
NCT03173300	Not specified	ACTIVE_NOT_RECRUITING	Natural History Study Protocol in PMM2-CDG (CDG-Ia)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ACETAZOLAMIDE	4	1
EPALRESTAT	4	1
CHEMBL3976215	0	1