Charcot-Marie-Tooth disease X-linked recessive 5

Summary

Charcot-Marie-Tooth disease X-linked recessive 5 (MONDO:0010699) is a disease caused by PRPS1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PRPS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 21
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0000763	Sensory neuropathy	Very frequent (80-99%)
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001761	Pes cavus	Very frequent (80-99%)
HP:0003712	Skeletal muscle hypertrophy	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0040129	Abnormal nerve conduction velocity	Very frequent (80-99%)
HP:0007328	Impaired pain sensation	Frequent (30-79%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001262	Excessive daytime somnolence	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002385	Paraparesis	Occasional (5-29%)
HP:0002463	Language impairment	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease X-linked recessive 5
Mondo ID	MONDO:0010699
OMIM	311070
Orphanet	99014
DOID	DOID:0110210
SNOMED CT	763460007
UMLS	C1839566
MedGen	374254
GARD	0000114
NORD	1677
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease X-linked recessive type 5 · Charcot-Marie-Tooth disease, X-linked recessive, 5 · Charcot-Marie-Tooth disease, X-linked recessive, 5, X-linked recessive · Charcot-Marie-Tooth disease, X-linked recessive, type 5 · Charcot-Marie-Tooth neuropathy X type 5 · Charcot-Marie-Tooth neuropathy, X-linked recessive, 5 · CMT5X · CMTX5 · familial opticoacoustic nerve degeneration and polyneuropathy · optic atrophy, polyneuropathy, and deafness · optic atrophy, sensorineural hearing loss and polyneuropathy · Rosenberg Chutorian Syndrome · Rosenberg-Chutorian syndrome · X-linked Charcot-Marie-Tooth disease type 5

Data availability: 21 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › Charcot-Marie-Tooth disease type X › Charcot-Marie-Tooth disease X-linked recessive 5

Related subtypes (5): Charcot-Marie-Tooth disease X-linked dominant 6, Charcot-Marie-Tooth disease X-linked dominant 1, Charcot-Marie-Tooth disease X-linked recessive 2, Charcot-Marie-Tooth disease X-linked recessive 3, Charcot-Marie-Tooth disease X-linked recessive 4

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

21 retrieved; paginated sample, class counts are floors:

6 benign/likely benign, 5 uncertain significance, 4 pathogenic, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
100767	NM_002764.4(PRPS1):c.362C>G (p.Ala121Gly)	PRPS1	Pathogenic	no assertion criteria provided
140572	NM_002764.4(PRPS1):c.343A>G (p.Met115Val)	PRPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140573	NM_002764.4(PRPS1):c.925G>T (p.Val309Phe)	PRPS1	Pathogenic	criteria provided, single submitter
223101	NM_002764.4(PRPS1):c.46T>C (p.Ser16Pro)	PRPS1	Pathogenic	no assertion criteria provided
9934	NM_002764.4(PRPS1):c.129A>C (p.Glu43Asp)	PRPS1	Pathogenic	no assertion criteria provided
1710220	NM_002764.4(PRPS1):c.826C>T (p.Pro276Ser)	PRPS1	Likely pathogenic	no assertion criteria provided
245728	NM_002764.4(PRPS1):c.319A>G (p.Ile107Val)	PRPS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
9935	NM_002764.4(PRPS1):c.344T>C (p.Met115Thr)	PRPS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1477376	NM_002764.4(PRPS1):c.383A>T (p.Asp128Val)	PRPS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2170185	NM_002764.4(PRPS1):c.531-15C>A	PRPS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1057937	NM_002764.4(PRPS1):c.611G>A (p.Arg204His)	PRPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1320158	NM_002764.4(PRPS1):c.641G>A (p.Arg214Gln)	PRPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1356780	NM_002764.4(PRPS1):c.334G>A (p.Val112Ile)	PRPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3597843	NM_002764.4(PRPS1):c.306+5G>T	PRPS1	Uncertain significance	criteria provided, single submitter
3597844	NM_002764.4(PRPS1):c.913A>G (p.Asn305Asp)	PRPS1	Uncertain significance	criteria provided, single submitter
1228702	NM_002764.4(PRPS1):c.705-11T>C	PRPS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
21323	NM_002764.4(PRPS1):c.447G>A (p.Pro149=)	PRPS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
382624	NM_002764.4(PRPS1):c.288G>A (p.Arg96=)	PRPS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
422624	NM_002764.4(PRPS1):c.123-16dup	PRPS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
508528	NM_002764.4(PRPS1):c.573G>A (p.Leu191=)	PRPS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
94083	NM_002764.4(PRPS1):c.477C>T (p.Ile159=)	PRPS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · 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
PRPS1	Definitive	X-linked	hearing loss, X-linked 1	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRPS1	Orphanet:1187	Lethal ataxia with deafness and optic atrophy
PRPS1	Orphanet:411536	Mild phosphoribosylpyrophosphate synthetase superactivity
PRPS1	Orphanet:411543	Severe phosphoribosylpyrophosphate synthetase superactivity
PRPS1	Orphanet:423479	X-linked intellectual disability-limb spasticity-retinal dystrophy-arginine vasopressin deficiency
PRPS1	Orphanet:90625	Rare X-linked non-syndromic sensorineural deafness type DFN
PRPS1	Orphanet:99014	X-linked Charcot-Marie-Tooth disease type 5

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRPS1	HGNC:9462	ENSG00000147224	P60891	Ribose-phosphate pyrophosphokinase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRPS1	Ribose-phosphate pyrophosphokinase 1	Catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) that is essential for nucleotide synthesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRPS1	Kinase	yes	2.7.6.1	PRTase_dom, PRib_PP_synth_CS, Rib-P_diPkinase

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	1
sural nerve	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRPS1	291	ubiquitous	marker	islet of Langerhans, ventricular zone, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRPS1	881

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRPS1	P60891	27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
5-Phosphoribose 1-diphosphate biosynthesis	1	3806.7×	3e-04	PRPS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hypoxanthine biosynthetic process	1	16852.0×	3e-04	PRPS1
pyrimidine nucleotide biosynthetic process	1	8426.0×	3e-04	PRPS1
urate biosynthetic process	1	8426.0×	3e-04	PRPS1
ribonucleoside monophosphate biosynthetic process	1	4213.0×	5e-04	PRPS1
5-phosphoribose 1-diphosphate biosynthetic process	1	3370.4×	5e-04	PRPS1
purine nucleobase metabolic process	1	2407.4×	6e-04	PRPS1
purine nucleotide biosynthetic process	1	1296.3×	9e-04	PRPS1
nervous system development	1	45.9×	0.022	PRPS1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRPS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRPS1	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRPS1	2.7.6.1	ribose-phosphate diphosphokinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	PRPS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRPS1	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.