Neuronopathy, distal hereditary motor, autosomal recessive 8

Summary

Neuronopathy, distal hereditary motor, autosomal recessive 8 (MONDO:0030055) is a disease caused by SORD (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SORD (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, autosomal recessive 8
Mondo ID	MONDO:0030055
OMIM	618912
Orphanet	700508
DOID	DOID:0081427
UMLS	C5394466
MedGen	1714781
GARD	0025518
Is cancer (heuristic)	no

Also known as: sorbitol dehydrogenase deficiency · sorbitol dehydrogenase deficiency with peripheral neuropathy · SORDD

Data availability: 21 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 › autosomal genetic disease › autosomal recessive disease › neuronopathy, distal hereditary motor, autosomal recessive › neuronopathy, distal hereditary motor, autosomal recessive 8

Related subtypes (11): autosomal recessive distal spinal muscular atrophy 1, autosomal recessive distal spinal muscular atrophy 2, neuronopathy, distal hereditary motor, autosomal recessive 3, neuronopathy, distal hereditary motor, autosomal recessive 4, neuronopathy, distal hereditary motor, autosomal recessive 5, neuronopathy, distal hereditary motor, autosomal recessive 7, early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome, spinal muscular atrophy, distal, autosomal recessive, 6, neuronopathy, distal hereditary motor, autosomal recessive 9, neuronopathy, distal hereditary motor, autosomal recessive 10, neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity

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:

8 uncertain significance, 3 pathogenic/likely pathogenic, 3 benign, 3 conflicting classifications of pathogenicity, 2 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012846	NM_003104.6(SORD):c.458C>A (p.Ala153Asp)	SORD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2443690	NM_003104.6(SORD):c.776C>T (p.Ala259Val)	SORD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2443692	NM_003104.6(SORD):c.851T>C (p.Leu284Pro)	SORD	Pathogenic	no assertion criteria provided
929257	NM_003104.6(SORD):c.895C>T (p.Arg299Ter)	SORD	Pathogenic	no assertion criteria provided
929258	NM_003104.6(SORD):c.757del (p.Ala253fs)	SORD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805124	NM_003104.6(SORD):c.73_88del (p.Tyr25fs)	SORD	Likely pathogenic	criteria provided, single submitter
3024137	NM_003104.6(SORD):c.361G>C (p.Ala121Pro)	SORD	Likely pathogenic	no assertion criteria provided
1275801	NM_003104.6(SORD):c.328C>T (p.Arg110Ter)	SORD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1698070	NM_003104.6(SORD):c.1021G>T (p.Gly341Ter)	SORD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2664713	NM_003104.6(SORD):c.553G>A (p.Gly185Arg)	SORD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1298619	NM_003104.6(SORD):c.935C>T (p.Ala312Val)	SORD	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709111	NM_003104.6(SORD):c.787-3C>G	SORD	Uncertain significance	criteria provided, single submitter
1709947	NM_003104.6(SORD):c.306TGA[1] (p.Asp103del)	SORD	Uncertain significance	criteria provided, single submitter
2436239	NM_003104.6(SORD):c.287C>T (p.Pro96Leu)	SORD	Uncertain significance	criteria provided, single submitter
2443691	NM_003104.6(SORD):c.731C>T (p.Pro244Leu)	SORD	Uncertain significance	criteria provided, single submitter
2664964	NM_003104.6(SORD):c.50C>T (p.Pro17Leu)	SORD	Uncertain significance	criteria provided, multiple submitters, no conflicts
3897016	NM_003104.6(SORD):c.1048T>G (p.Cys350Gly)	SORD	Uncertain significance	criteria provided, single submitter
4076193	NM_003104.6(SORD):c.778G>C (p.Gly260Arg)	SORD	Uncertain significance	criteria provided, multiple submitters, no conflicts
1229011	NM_003104.6(SORD):c.806A>C (p.Asn269Thr)	SORD	Benign	criteria provided, multiple submitters, no conflicts
1261613	NM_003104.6(SORD):c.908+11C>T	SORD	Benign	criteria provided, multiple submitters, no conflicts
1280097	NM_003104.6(SORD):c.266-35C>T	SORD	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 1 · 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
SORD	Strong	Autosomal recessive	neuronopathy, distal hereditary motor, autosomal recessive 8	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SORD	Orphanet:700508	Distal muscle weakness-foot deformity-elevated sorbitol level-hereditary motor neuropathy

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
SORD	HGNC:11184	ENSG00000140263	Q00796	Sorbitol dehydrogenase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SORD	Sorbitol dehydrogenase	Polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SORD	Enzyme (other)	yes	1.1.1.14	ADH_Zn_CS, GroES-like_sf, ADH-like_C

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
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SORD	199	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SORD	3,915

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SORD	Q00796	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Fructose biosynthesis	1	2855.0×	5e-04	SORD
Formation of xylulose-5-phosphate	1	1903.3×	5e-04	SORD

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
D-sorbitol catabolic process	1	8426.0×	3e-04	SORD
xylitol catabolic process	1	8426.0×	3e-04	SORD
xylitol metabolic process	1	8426.0×	3e-04	SORD
fructose biosynthetic process	1	4213.0×	4e-04	SORD
obsolete D-glucuronate catabolic process to D-xylulose 5-phosphate	1	2808.7×	5e-04	SORD
glucose metabolic process	1	255.3×	0.005	SORD
flagellated sperm motility	1	117.0×	0.009	SORD

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
SORD	EPALRESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SORD	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EPALRESTAT	4	SORD
QUERCETIN	3	SORD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SORD	17	Binding:16, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SORD	1.1.1.14	L-iditol 2-dehydrogenase

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

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)
EPALRESTAT	4	SORD
QUERCETIN	3	SORD

Druggability pyramid

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

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

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.