Charcot-Marie-Tooth disease type 4G

Summary

Charcot-Marie-Tooth disease type 4G (MONDO:0011534) is a disease caused by HK1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: 1-5 / 10 000 (Czech Republic) [Orphanet-validated]
• Causal gene: HK1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 22
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	10	Czech Republic	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0001760	Abnormal foot morphology	Very frequent (80-99%)
HP:0002495	Impaired vibratory sensation	Very frequent (80-99%)
HP:0002936	Distal sensory impairment	Very frequent (80-99%)
HP:0003409	Distal sensory impairment of all modalities	Very frequent (80-99%)
HP:0003431	Decreased motor nerve conduction velocity	Very frequent (80-99%)
HP:0003477	Peripheral axonal neuropathy	Very frequent (80-99%)
HP:0007108	Demyelinating peripheral neuropathy	Very frequent (80-99%)
HP:0007230	Decreased distal sensory nerve action potential	Very frequent (80-99%)
HP:0009053	Distal lower limb muscle weakness	Very frequent (80-99%)
HP:0011096	Peripheral demyelination	Very frequent (80-99%)
HP:0012078	Motor conduction block	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0010830	Impaired tactile sensation	Frequent (30-79%)
HP:0001155	Abnormality of the hand	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0007210	Lower limb amyotrophy	Frequent (30-79%)
HP:0008959	Distal upper limb muscle weakness	Frequent (30-79%)
HP:0009129	Upper limb amyotrophy	Frequent (30-79%)
HP:0002141	Gait imbalance	Occasional (5-29%)
HP:0002505	Loss of ambulation	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0007328	Impaired pain sensation	Occasional (5-29%)
HP:0008081	Pes valgus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4G
Mondo ID	MONDO:0011534
MeSH	C535813
OMIM	605285
Orphanet	99953
DOID	DOID:0110196
ICD-11	995395080
SNOMED CT	715799004
UMLS	C1854449
MedGen	343122
GARD	0010132
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease type 4 caused by mutation in HK1 · CMT4G · hereditary motor and sensory neuropathy, Russe type · HK1 Charcot-Marie-Tooth disease type 4 · HMSNR · neuropathy, hereditary motor and sensory, Russe type

Data availability: 22 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › motor peripheral neuropathy › Charcot-Marie-Tooth disease type 4G

Related subtypes (8): motor nerve neuritis, glossopharyngeal motor neuropathy, Charcot-Marie-Tooth disease type 5, neuropathy, hereditary motor and sensory, type 6A, hereditary motor and sensory neuropathy, Okinawa type, Charcot-Marie-Tooth disease axonal type 2C, neuropathy, hereditary motor and sensory, type 6B, peripheral motor neuropathy, childhood-onset, biotin-responsive

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

22 retrieved; paginated sample, class counts are floors:

6 benign, 5 uncertain significance, 4 likely pathogenic, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172759	NM_001358263.1(HK1):c.19C>T (p.Arg7Ter)	HK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372693	NM_000188.3(HK1):c.1370C>T (p.Thr457Met)	HK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4057299	NM_001358263.1(HK1):c.2T>C (p.Met1Thr)	HK1	Likely pathogenic	criteria provided, single submitter
4845902	NM_000188.3(HK1):c.1114C>T (p.Gln372Ter)	HK1	Likely pathogenic	criteria provided, single submitter
599646	NM_000188.3(HK1):c.1252A>G (p.Lys418Glu)	HK1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
802580	NM_001358263.1(HK1):c.1A>G (p.Met1Val)	HK1	Likely pathogenic	criteria provided, single submitter
1709823	NM_000188.3(HK1):c.271C>T (p.Arg91Ter)	HK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40213	NM_001358263.1(HK1):c.-270G>C	HK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014924	NM_000188.3(HK1):c.1720-3C>T	HK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030654	NM_000188.3(HK1):c.1871dup (p.Ala625fs)	HK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
587450	NM_001358263.1(HK1):c.4G>A (p.Gly2Arg)	HK1	Uncertain significance	criteria provided, single submitter
971751	NM_000188.3(HK1):c.1550G>A (p.Arg517Gln)	HK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
994250	NM_000188.3(HK1):c.949G>A (p.Gly317Ser)	HK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1285347	NM_001358263.1(HK1):c.75+23T>C	HK1	Benign	criteria provided, multiple submitters, no conflicts
1285348	NM_000188.3(HK1):c.1839+31G>A	HK1	Benign	criteria provided, multiple submitters, no conflicts
1285349	NM_000188.3(HK1):c.2219+27T>C	HK1	Benign	criteria provided, multiple submitters, no conflicts
255483	NM_000188.3(HK1):c.1443G>A (p.Lys481=)	HK1	Benign	criteria provided, multiple submitters, no conflicts
439787	NM_000188.3(HK1):c.78C>G (p.Leu26=)	HK1	Benign	criteria provided, multiple submitters, no conflicts
776515	NM_000188.3(HK1):c.1031+6T>C	HK1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
994062	NM_001358263.1(HK1):c.75+5174A>G	HK1	Benign	criteria provided, multiple submitters, no conflicts
994196	NM_001358263.1(HK1):c.53T>C (p.Leu18Pro)	HK1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
208363	NM_001358263.1(HK1):c.-290G>C	HK1	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 35 · 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
HK1	Strong	Autosomal recessive	Charcot-Marie-Tooth disease type 4G	16
KCNA4	Strong	Autosomal recessive	Charcot-Marie-Tooth disease type 4G	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HK1	Orphanet:90031	Non-spherocytic hemolytic anemia due to hexokinase deficiency
HK1	Orphanet:99953	Charcot-Marie-Tooth disease type 4G

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
HK1	HGNC:4922	ENSG00000156515	P19367	Hexokinase-1	gencc,clinvar
KCNA4	HGNC:6222	ENSG00000182255	P22459	Potassium voltage-gated channel subfamily A member 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HK1	Hexokinase-1	Catalyzes the phosphorylation of various hexoses, such as D-glucose, D-glucosamine, D-fructose, D-mannose and 2-deoxy-D-glucose, to hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, D-fructose 6-phosphate, D-mannose 6-p…
KCNA4	Potassium voltage-gated channel subfamily A member 4	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes.

Protein-family classification

Druggable: 2 · 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
Ion channel	1	55.8×	0.036
Kinase	1	13.9×	0.071

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HK1	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
KCNA4	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar vermis	1
pharyngeal mucosa	1
pons	1
adrenal tissue	1
nucleus accumbens	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HK1	291	ubiquitous	marker	cerebellar vermis, pharyngeal mucosa, pons
KCNA4	142	broad	marker	adrenal tissue, nucleus accumbens, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNA4	2,311
HK1	2,298

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HK1	P19367	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNA4	P22459	70.48

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
Defective HK1 causes hexokinase deficiency (HK deficiency)	1	5710.0×	0.001	HK1
Synthesis of GDP-mannose	1	951.7×	0.003	HK1
Glycolysis	1	142.8×	0.012	HK1
Voltage gated Potassium channels	1	121.5×	0.012	KCNA4
Potassium Channels	1	67.2×	0.018	KCNA4
Neuronal System	1	22.1×	0.045	KCNA4

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
obsolete GDP-mannose biosynthetic process from mannose	1	2808.7×	0.003	HK1
GDP-mannose biosynthetic process	1	1404.3×	0.003	HK1
obsolete establishment of protein localization to mitochondrion	1	1404.3×	0.003	HK1
maintenance of protein location in mitochondrion	1	1404.3×	0.003	HK1
mannose metabolic process	1	1053.2×	0.003	HK1
carbohydrate phosphorylation	1	1053.2×	0.003	HK1
glucose 6-phosphate metabolic process	1	648.1×	0.004	HK1
fructose 6-phosphate metabolic process	1	561.7×	0.004	HK1
positive regulation of cytokine production involved in immune response	1	495.6×	0.004	HK1
canonical glycolysis	1	351.1×	0.006	HK1
intracellular glucose homeostasis	1	290.6×	0.006	HK1
glycolytic process	1	191.5×	0.009	HK1
action potential	1	179.3×	0.009	KCNA4
positive regulation of interleukin-1 beta production	1	129.6×	0.010	HK1
glucose metabolic process	1	127.7×	0.010	HK1
potassium ion transport	1	95.8×	0.013	KCNA4
potassium ion transmembrane transport	1	68.0×	0.017	KCNA4
protein homooligomerization	1	61.1×	0.018	KCNA4
inflammatory response	1	18.9×	0.055	HK1
innate immune response	1	16.8×	0.059	HK1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
HK1	1	3
KCNA4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EBSELEN	3	HK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KCNA4	30	Binding:26, ADMET:2, Toxicity:1, Functional:1
HK1	12	Binding:9, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HK1	2.7.1.1	hexokinase

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

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	HK1

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	HK1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	KCNA4
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)
KCNA4	30	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.