Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy

Summary

Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy (MONDO:0033043) is a disease caused by NKX6-2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NKX6-2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 28
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000571	Hypometric saccades	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0007704	Paroxysmal involuntary eye movements	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0002415	Leukodystrophy	Frequent (30-79%)
HP:0002599	Head titubation	Frequent (30-79%)
HP:0003429	CNS hypomyelination	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002191	Progressive spasticity	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0001007	Hirsutism	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0012534	Dysesthesia	Excluded (0%)
HP:0001249	Intellectual disability	Very rare (<1-4%)
HP:0002079	Hypoplasia of the corpus callosum	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy
Mondo ID	MONDO:0033043
OMIM	617560
Orphanet	527497
DOID	DOID:0080252
UMLS	C4479653
MedGen	1382553
GARD	0017964
Is cancer (heuristic)	no

Also known as: spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy · SPAX8

Data availability: 28 ClinVar variants · 4 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 › autosomal recessive spastic ataxia › spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy

Related subtypes (6): Charlevoix-Saguenay spastic ataxia, spastic ataxia-corneal dystrophy syndrome, spastic ataxia 3, spastic ataxia 4, spastic ataxia 5, spastic ataxia-dysarthria due to glutaminase deficiency

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

28 retrieved; paginated sample, class counts are floors:

9 pathogenic, 7 uncertain significance, 7 likely pathogenic, 3 pathogenic/likely pathogenic, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1218560	NM_177400.3(NKX6-2):c.234dup (p.Leu79fs)	NKX6-2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323367	NM_177400.3(NKX6-2):c.119del (p.Phe40fs)	NKX6-2	Pathogenic	criteria provided, single submitter
1344692	NM_177400.3(NKX6-2):c.571C>T (p.Gln191Ter)	NKX6-2	Pathogenic	no assertion criteria provided
1344694	NM_177400.3(NKX6-2):c.598C>T (p.Arg200Trp)	NKX6-2	Pathogenic	no assertion criteria provided
1700622	NM_177400.3(NKX6-2):c.516C>G (p.Tyr172Ter)	NKX6-2	Pathogenic	criteria provided, single submitter
430622	NM_177400.3(NKX6-2):c.121A>T (p.Lys41Ter)	NKX6-2	Pathogenic	criteria provided, multiple submitters, no conflicts
430623	NM_177400.3(NKX6-2):c.487C>G (p.Leu163Val)	NKX6-2	Pathogenic	criteria provided, multiple submitters, no conflicts
503871	NM_177400.3(NKX6-2):c.196del (p.Arg66fs)	NKX6-2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
627615	NM_177400.3(NKX6-2):c.565G>T (p.Glu189Ter)	NKX6-2	Pathogenic	no assertion criteria provided
627617	NM_177400.3(NKX6-2):c.599G>A (p.Arg200Gln)	NKX6-2	Pathogenic	criteria provided, single submitter
627618	NM_177400.3(NKX6-2):c.606delinsTA (p.Lys202fs)	NKX6-2	Pathogenic	no assertion criteria provided
627619	NM_177400.3(NKX6-2):c.608G>A (p.Trp203Ter)	NKX6-2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344690	NM_177400.3(NKX6-2):c.301C>A (p.Arg101Ser)	NKX6-2	Likely pathogenic	no assertion criteria provided
1344693	NM_177400.3(NKX6-2):c.592A>G (p.Asn198Asp)	NKX6-2	Likely pathogenic	no assertion criteria provided
2503419	NM_177400.3(NKX6-2):c.287_288dup (p.Ala97fs)	NKX6-2	Likely pathogenic	no assertion criteria provided
4278252	NM_177400.3(NKX6-2):c.161_162insA (p.Gly55fs)	NKX6-2	Likely pathogenic	criteria provided, single submitter
4278253	NM_177400.3(NKX6-2):c.161delinsAA (p.Leu54fs)	NKX6-2	Likely pathogenic	criteria provided, single submitter
504099	NM_177400.3(NKX6-2):c.234del (p.Leu79fs)	NKX6-2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
627616	NM_177400.3(NKX6-2):c.589C>T (p.Gln197Ter)	NKX6-2	Likely pathogenic	criteria provided, single submitter
1031744	NM_177400.3(NKX6-2):c.450C>G (p.His150Gln)	NKX6-2	Uncertain significance	criteria provided, single submitter
1031745	NM_177400.3(NKX6-2):c.59A>G (p.His20Arg)	NKX6-2	Uncertain significance	criteria provided, single submitter
1344691	NM_177400.3(NKX6-2):c.541C>G (p.Leu181Val)	NKX6-2	Uncertain significance	criteria provided, single submitter
2434373	NM_177400.3(NKX6-2):c.175G>T (p.Gly59Cys)	NKX6-2	Uncertain significance	criteria provided, single submitter
2442100	NM_177400.3(NKX6-2):c.89T>G (p.Phe30Cys)	NKX6-2	Uncertain significance	criteria provided, single submitter
2921133	NM_177400.3(NKX6-2):c.305G>T (p.Gly102Val)	NKX6-2	Uncertain significance	criteria provided, single submitter
638677	NM_177400.3(NKX6-2):c.501C>G (p.Phe167Leu)	NKX6-2	Uncertain significance	criteria provided, single submitter
1170385	NM_177400.3(NKX6-2):c.626T>C (p.Val209Ala)	NKX6-2	Benign	criteria provided, multiple submitters, no conflicts
3362620	NM_177400.3(NKX6-2):c.162C>A (p.Leu54=)	NKX6-2	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
NKX6-2	Strong	Autosomal recessive	spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX6-2	Orphanet:527497	NKX6-2-related autosomal recessive hypomyelinating leukodystrophy

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
NKX6-2	HGNC:19321	ENSG00000148826	Q9C056	Homeobox protein Nkx-6.2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NKX6-2	Homeobox protein Nkx-6.2	Transcription factor with repressor activity involved in the regulation of axon-glial interactions at myelin paranodes in oligodendrocytes.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKX6-2	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf

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
C1 segment of cervical spinal cord	1
putamen	1
substantia nigra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NKX6-2	101	tissue_specific	marker	C1 segment of cervical spinal cord, substantia nigra, putamen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NKX6-2	1,445

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NKX6-2	Q9C056	66.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
positive regulation of cell fate commitment	1	8426.0×	0.001	NKX6-2
negative regulation of cell fate commitment	1	5617.3×	0.001	NKX6-2
pancreatic A cell differentiation	1	2407.4×	0.002	NKX6-2
spinal cord motor neuron cell fate specification	1	1532.0×	0.002	NKX6-2
negative regulation of oligodendrocyte differentiation	1	1123.5×	0.002	NKX6-2
central nervous system myelination	1	991.3×	0.002	NKX6-2
regulation of myelination	1	887.0×	0.002	NKX6-2
positive regulation of oligodendrocyte differentiation	1	674.1×	0.002	NKX6-2
neuromuscular process controlling balance	1	330.4×	0.004	NKX6-2
regulation of DNA-templated transcription	1	31.6×	0.037	NKX6-2
negative regulation of DNA-templated transcription	1	31.6×	0.037	NKX6-2
cell differentiation	1	29.1×	0.037	NKX6-2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	NKX6-2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
NKX6-2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NKX6-2

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)
NKX6-2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.