Spasticity-ataxia-gait anomalies syndrome

Summary

Spasticity-ataxia-gait anomalies syndrome (MONDO:0014803) is a disease caused by GLRX5 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GLRX5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 6
• Phenotypes (HPO): 25
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	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:0002191	Progressive spasticity	Very frequent (80-99%)
HP:0008288	Nonketotic hyperglycinemia	Very frequent (80-99%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000736	Short attention span	Frequent (30-79%)
HP:0001264	Spastic diplegia	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002415	Leukodystrophy	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0002928	Decreased activity of the pyruvate dehydrogenase complex	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0008945	Loss of ability to walk in early childhood	Frequent (30-79%)
HP:0100561	Spinal cord lesion	Frequent (30-79%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0002151	Increased circulating lactate concentration	Excluded (0%)
HP:0100543	Cognitive impairment	Excluded (0%)
HP:0001712	Left ventricular hypertrophy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spasticity-ataxia-gait anomalies syndrome
Mondo ID	MONDO:0014803
OMIM	616859
Orphanet	401866
UMLS	C4225178
MedGen	905660
GARD	0012681
Is cancer (heuristic)	no

Also known as: childhood-onset spasticity with variant non-ketotic hyperglycinemia · SPAHGC · spasticity, childhood-onset, with hyperglycinemia

Data availability: 6 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › atactic disorder › hereditary ataxia › spastic ataxia › spasticity-ataxia-gait anomalies syndrome

Related subtypes (5): spastic ataxia 2, autosomal dominant spastic ataxia, autosomal recessive spastic ataxia, spastic ataxia 9, autosomal recessive, spastic ataxia 10, autosomal recessive

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

6 retrieved; paginated sample, class counts are floors:

2 pathogenic, 2 likely pathogenic, 1 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1252035	NM_016417.3(GLRX5):c.197A>C (p.Gln66Pro)	GLRX5	Pathogenic	no assertion criteria provided
224513	NM_016417.3(GLRX5):c.86_93dup (p.Ala32fs)	GLRX5	Pathogenic	no assertion criteria provided
224512	NM_016417.3(GLRX5):c.148AAG[1] (p.Lys51del)	GLRX5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4056445	NM_016417.3(GLRX5):c.367G>C (p.Asp123His)	GLRX5	Likely pathogenic	criteria provided, single submitter
4691653	NM_016417.3(GLRX5):c.98_116dup (p.Gly40fs)	GLRX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805825	NM_016417.3(GLRX5):c.115G>A (p.Gly39Ser)	GLRX5	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
GLRX5	Strong	Autosomal recessive	spasticity-ataxia-gait anomalies syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLRX5	Orphanet:255132	Adult-onset autosomal recessive sideroblastic anemia
GLRX5	Orphanet:401866	Childhood-onset spasticity with hyperglycinemia

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
GLRX5	HGNC:20134	ENSG00000182512	Q86SX6	Glutaredoxin-related protein 5, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLRX5	Glutaredoxin-related protein 5, mitochondrial	Monothiol glutaredoxin involved in mitochondrial iron-sulfur (Fe/S) cluster transfer.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLRX5	Other/Unknown	no		Glutaredoxin, Monothiol_GRX-rel, GRX_PICOT-like

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
diaphragm	1
trabecular bone tissue	1
triceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLRX5	287	ubiquitous	marker	trabecular bone tissue, diaphragm, triceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLRX5	1,460

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLRX5	Q86SX6	2

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
Mitochondrial iron-sulfur cluster biogenesis	1	815.7×	0.001	GLRX5

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
[2Fe-2S] cluster assembly	1	1404.3×	0.004	GLRX5
iron-sulfur cluster assembly	1	601.9×	0.005	GLRX5
cell redox homeostasis	1	343.9×	0.005	GLRX5
hemopoiesis	1	267.5×	0.005	GLRX5
intracellular iron ion homeostasis	1	244.2×	0.005	GLRX5
protein maturation	1	163.6×	0.006	GLRX5

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
GLRX5	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	GLRX5

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)
GLRX5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford