Encephalopathy, progressive, with amyotrophy and optic atrophy

Summary

Encephalopathy, progressive, with amyotrophy and optic atrophy (MONDO:0014968) is a disease caused by TBCE (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TBCE (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 29

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy, progressive, with amyotrophy and optic atrophy
Mondo ID	MONDO:0014968
OMIM	617207
UMLS	C4310667
MedGen	934634
GARD	0027864
Is cancer (heuristic)	no

Also known as: encephalopathy, progressive, with amyotrophy and optic atrophy · encephalopathy, progressive, with amyotrophy and optic atrophy; PEAMO · PEAMO

Data availability: 29 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Mendelian encephalopathy › encephalopathy, progressive, with amyotrophy and optic atrophy

Related subtypes (18): encephalopathy, recurrent, of childhood, encephalopathy, axonal, with necrotizing myopathy, cardiomyopathy, and cataracts, Bonnemann-Meinecke-Reich syndrome, severe neonatal-onset encephalopathy with microcephaly, ethylmalonic encephalopathy, familial encephalopathy with neuroserpin inclusion bodies, spongiform encephalopathy with neuropsychiatric features, familial acute necrotizing encephalopathy, encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, severe neurodegenerative syndrome with lipodystrophy, encephalopathy due to defective mitochondrial and peroxisomal fission 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, encephalitis/encephalopathy, mild, with reversible myelin vacuolization, encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities, encephalopathy, porphyria-related

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

29 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 9 likely pathogenic, 5 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
225483	NM_003193.5(TBCE):c.143_144del (p.Lys48fs)	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2743364	NM_003193.5(TBCE):c.433A>T (p.Lys145Ter)	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372200	NM_003193.5(TBCE):c.924del (p.Ser308_Leu309insTer)	TBCE	Pathogenic	criteria provided, multiple submitters, no conflicts
372201	NM_003193.5(TBCE):c.464T>A (p.Ile155Asn)	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5290	NM_003193.5(TBCE):c.155_166del (p.Ser52_Gly55del)	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631595	NM_003193.5(TBCE):c.100+1G>A	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297492	NM_003193.5(TBCE):c.101-1G>C	TBCE	Likely pathogenic	criteria provided, single submitter
1333237	NM_003193.5(TBCE):c.737+1G>A	TBCE	Likely pathogenic	criteria provided, single submitter
3581407	NM_003193.5(TBCE):c.34C>T (p.Arg12Ter)	TBCE	Likely pathogenic	criteria provided, single submitter
3581420	NM_003193.5(TBCE):c.185+1G>C	TBCE	Likely pathogenic	criteria provided, single submitter
3581427	NM_003193.5(TBCE):c.561-2A>G	TBCE	Likely pathogenic	criteria provided, single submitter
3581430	NM_003193.5(TBCE):c.736del (p.Arg246fs)	TBCE	Likely pathogenic	criteria provided, single submitter
3581434	NM_003193.5(TBCE):c.1116+1G>T	TBCE	Likely pathogenic	criteria provided, single submitter
522753	NM_003193.5(TBCE):c.332T>G (p.Val111Gly)	TBCE	Likely pathogenic	criteria provided, single submitter
870974	NM_003193.5(TBCE):c.1038del (p.Glu347fs)	TBCE	Likely pathogenic	criteria provided, multiple submitters, no conflicts
282266	NM_003193.5(TBCE):c.1465C>A (p.Leu489Ile)	B3GALNT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193652	NM_003193.5(TBCE):c.847A>T (p.Ile283Phe)	TBCE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2189908	NM_003193.5(TBCE):c.371+2_371+8dup	TBCE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1333319	NM_003193.5(TBCE):c.1333CTA[1] (p.Leu446del)	B3GALNT2	Uncertain significance	criteria provided, single submitter
1806069	NM_003193.5(TBCE):c.1410_1434dup (p.Ser479fs)	B3GALNT2	Uncertain significance	criteria provided, single submitter
1030640	NM_003193.5(TBCE):c.527A>T (p.Asp176Val)	TBCE	Uncertain significance	criteria provided, single submitter
1030641	NM_003193.5(TBCE):c.529C>A (p.Gln177Lys)	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033980	NM_003193.5(TBCE):c.1189G>A (p.Gly397Ser)	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033981	NM_003193.5(TBCE):c.71G>A (p.Arg24His)	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1386786	NM_003193.5(TBCE):c.581C>T (p.Pro194Leu)	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1449541	NM_003193.5(TBCE):c.898+6T>C	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
3581423	NM_003193.5(TBCE):c.389A>G (p.Gln130Arg)	TBCE	Uncertain significance	criteria provided, single submitter
3892603	NM_003193.5(TBCE):c.1112G>A (p.Cys371Tyr)	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892605	NM_003193.5(TBCE):c.661-1147A>G	TBCE	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
TBCE	Strong	Autosomal recessive	early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBCE	Orphanet:2323	Sanjad-Sakati syndrome
TBCE	Orphanet:496756	Early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome
TBCE	Orphanet:93324	Autosomal recessive Kenny-Caffey syndrome
B3GALNT2	Orphanet:588	Muscle-eye-brain disease
B3GALNT2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
B3GALNT2	Orphanet:899	Walker-Warburg syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBCE	HGNC:11582	ENSG00000284770	Q15813	Tubulin-specific chaperone E	gencc,clinvar
B3GALNT2	HGNC:28596	ENSG00000162885	Q8NCR0	UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBCE	Tubulin-specific chaperone E	Tubulin-folding protein; involved in the second step of the tubulin folding pathway and in the regulation of tubulin heterodimer dissociation.
B3GALNT2	UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2	Beta-1,3-N-acetylgalactosaminyltransferase that synthesizes a unique carbohydrate structure, GalNAc-beta-1-3GlcNAc, on N- and O-glycans.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBCE	Other/Unknown	no		Ubiquitin-like_dom, CAP-Gly_domain, Ubiquitin-like_domsf
B3GALNT2	Enzyme (other)	yes	2.4.1.313	Glyco_trans_31

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
hindlimb stylopod muscle	1
ventricular zone	1
adrenal tissue	1
body of pancreas	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBCE	134	ubiquitous	yes	ventricular zone, hindlimb stylopod muscle, cortical plate
B3GALNT2	141	ubiquitous	marker	body of pancreas, skeletal muscle tissue, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBCE	1,068
B3GALNT2	748

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TBCE	Q15813	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
B3GALNT2	Q8NCR0	86.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DAG1 core M3 glycosylations	1	951.7×	0.006	B3GALNT2
Post-chaperonin tubulin folding pathway	1	237.9×	0.012	TBCE
Protein folding	1	129.8×	0.012	TBCE
Metabolism of proteins	2	12.4×	0.012	TBCE, B3GALNT2
O-linked glycosylation	1	72.3×	0.017	B3GALNT2
Post-translational protein modification	1	9.6×	0.101	B3GALNT2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle atrophy	1	4213.0×	0.003	TBCE
peripheral nervous system neuron axonogenesis	1	2106.5×	0.003	TBCE
post-chaperonin tubulin folding pathway	1	1404.3×	0.003	TBCE
tubulin complex assembly	1	842.6×	0.004	TBCE
developmental growth	1	366.4×	0.007	TBCE
glycoprotein biosynthetic process	1	168.5×	0.011	B3GALNT2
adult locomotory behavior	1	150.5×	0.011	TBCE
mitotic spindle organization	1	135.9×	0.011	TBCE
protein O-linked glycosylation	1	112.3×	0.012	B3GALNT2
post-embryonic development	1	102.8×	0.012	TBCE
microtubule cytoskeleton organization	1	60.6×	0.018	TBCE
protein folding	1	51.7×	0.019	TBCE

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TBCE	0	0
B3GALNT2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
B3GALNT2	2.4.1.313	protein O-mannose beta-1,3-N-acetylgalactosaminyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	B3GALNT2
E	Difficult family or no structure, no drug	1	TBCE

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)
TBCE	0	—
B3GALNT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.