Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

Summary

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (MONDO:0008842) is a disease caused by APTX (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: APTX (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 91
• Phenotypes (HPO): 5

Clinical features

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0000707	Abnormality of the nervous system	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0010747	Medial flaring of the eyebrow	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
Mondo ID	MONDO:0008842
MeSH	C538013
OMIM	208920
Orphanet	1168
DOID	DOID:0050754
UMLS	C1859598
MedGen	395301
GARD	0009283
Is cancer (heuristic)	no

Also known as: AOA1 · APTX oculomotor apraxia or related oculomotor disease · ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia · EAOH · early-onset ataxia with oculomotor apraxia and hypoalbuminemia · early-onset cerebellar ataxia with hypoalbuminemia · EOCA-HA · oculomotor apraxia or related oculomotor disease caused by mutation in APTX

Data availability: 91 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › ataxia-telangiectasia-like disorder › ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

Related subtypes (2): ataxia-telangiectasia-like disorder 2, ataxia-telangiectasia-like disorder 1

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

91 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 14 pathogenic, 13 benign/likely benign, 13 conflicting classifications of pathogenicity, 8 benign, 8 likely pathogenic, 6 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027441	NM_001195248.2(APTX):c.544-1G>C	APTX	Pathogenic	criteria provided, single submitter
1323370	NM_001195248.2(APTX):c.596del (p.Arg199fs)	APTX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333290	NM_001195248.2(APTX):c.388C>T (p.Gln130Ter)	APTX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334465	NM_001195248.2(APTX):c.587dup (p.Ala198fs)	APTX	Pathogenic	criteria provided, single submitter
1706448	NM_001195248.2(APTX):c.638del (p.Leu213fs)	APTX	Pathogenic	criteria provided, single submitter
420789	NM_001195248.2(APTX):c.124C>T (p.Arg42Ter)	APTX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
426093	NM_001195248.2(APTX):c.697A>T (p.Lys233Ter)	APTX	Pathogenic	no assertion criteria provided
434253	NM_001195248.2(APTX):c.875-2A>G	APTX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4425	NM_001195248.2(APTX):c.689dup (p.Glu232fs)	APTX	Pathogenic	criteria provided, single submitter
4426	NM_001195248.2(APTX):c.617C>T (p.Pro206Leu)	APTX	Pathogenic	no assertion criteria provided
4427	NM_001195248.2(APTX):c.841del (p.Ser281fs)	APTX	Pathogenic	criteria provided, single submitter
4428	NM_001195248.2(APTX):c.788T>G (p.Val263Gly)	APTX	Pathogenic	no assertion criteria provided
4429	NM_001195248.2(APTX):c.602A>G (p.His201Arg)	APTX	Pathogenic	no assertion criteria provided
4430	NM_001195248.2(APTX):c.875-1G>A	APTX	Pathogenic	no assertion criteria provided
4431	NM_001195248.2(APTX):c.837G>A (p.Trp279Ter)	APTX	Pathogenic	criteria provided, multiple submitters, no conflicts
4432	NC_000009.12:g.(?32973498)(33001604_?)del	APTX	Pathogenic	no assertion criteria provided
634641	NM_001195248.2(APTX):c.484-1G>T	APTX	Pathogenic	criteria provided, single submitter
635168	NM_001195248.2(APTX):c.776del (p.Val259fs)	APTX	Pathogenic	criteria provided, multiple submitters, no conflicts
930027	NM_001195248.2(APTX):c.46C>T (p.Arg16Ter)	APTX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159788	NM_007254.4(PNKP):c.1295_1298+6del	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501668	NM_001195248.2(APTX):c.729del (p.Lys243fs)	APTX	Likely pathogenic	criteria provided, single submitter
3065435	NM_001195248.2(APTX):c.484-1G>C	APTX	Likely pathogenic	criteria provided, single submitter
3775216	NM_001195248.2(APTX):c.874+1del	APTX	Likely pathogenic	criteria provided, single submitter
3896779	NM_001195248.2(APTX):c.603T>A (p.His201Gln)	APTX	Likely pathogenic	criteria provided, single submitter
4433	NM_001195248.2(APTX):c.668T>C (p.Leu223Pro)	APTX	Likely pathogenic	criteria provided, single submitter
4532125	NM_001195248.2(APTX):c.601C>T (p.His201Tyr)	APTX	Likely pathogenic	criteria provided, single submitter
994780	NM_001195248.2(APTX):c.593C>T (p.Ala198Val)	APTX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
977926	NM_015046.7(SETX):c.1856_1863del (p.Ser618_Tyr619insTer)	SETX	Likely pathogenic	criteria provided, single submitter
136416	NM_001195248.2(APTX):c.971A>T (p.Gln324Leu)	APTX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214122	NM_001195248.2(APTX):c.742T>A (p.Leu248Met)	APTX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
APTX	Definitive	Autosomal recessive	ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APTX	Orphanet:1168	Ataxia-oculomotor apraxia type 1
SETX	Orphanet:357043	Amyotrophic lateral sclerosis type 4
SETX	Orphanet:64753	Spinocerebellar ataxia with axonal neuropathy type 2
PNKP	Orphanet:101101	Charcot-Marie-Tooth disease type 2B2
PNKP	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
PNKP	Orphanet:459033	Ataxia-oculomotor apraxia type 4

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APTX	HGNC:15984	ENSG00000137074	Q7Z2E3	Aprataxin	gencc,clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
PNKP	HGNC:9154	ENSG00000039650	Q96T60	Bifunctional polynucleotide phosphatase/kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APTX	Aprataxin	DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair and base excision repair.
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
PNKP	Bifunctional polynucleotide phosphatase/kinase	Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Phosphatase	1	28.0×	0.106
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APTX	Transcription factor	no	3.1.11.7	SMAD_FHA_dom_sf, HIT-like, Znf_C2H2_type
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
PNKP	Phosphatase	yes	2.7.1.78	HAD-SF_hydro_IIIA, PNKP, Polynucleotide_phosphatase

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	1
islet of Langerhans	1
primordial germ cell in gonad	1
calcaneal tendon	1
left testis	1
right testis	1
granulocyte	1
right adrenal gland cortex	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APTX	278	ubiquitous	marker	colonic epithelium, islet of Langerhans, primordial germ cell in gonad
SETX	281	ubiquitous	marker	right testis, calcaneal tendon, left testis
PNKP	259	ubiquitous	marker	right uterine tube, granulocyte, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SETX	3,127
PNKP	2,445
APTX	2,077

Intra-cohort edges

A	B	Sources
APTX	SETX	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APTX	Q7Z2E3	11
PNKP	Q96T60	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SETX	Q7Z333	52.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 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
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	1	1631.4×	6e-04	PNKP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 termination of DNA-templated transcription	1	5617.3×	0.005	SETX
positive regulation of termination of RNA polymerase II transcription, poly(A)-coupled	1	1872.4×	0.008	SETX
positive regulation of DNA-templated transcription initiation	1	624.1×	0.009	SETX
DNA-templated transcription termination	1	510.7×	0.009	SETX
single strand break repair	1	468.1×	0.009	APTX
termination of RNA polymerase II transcription	1	432.1×	0.009	SETX
response to radiation	1	401.2×	0.009	PNKP
base-excision repair, gap-filling	1	374.5×	0.009	PNKP
positive regulation of RNA splicing	1	351.1×	0.009	SETX
positive regulation of double-strand break repair via nonhomologous end joining	1	330.4×	0.009	PNKP
mRNA splice site recognition	1	267.5×	0.010	SETX
DNA-templated DNA replication	1	187.2×	0.013	PNKP
positive regulation of telomere maintenance	1	170.2×	0.014	PNKP
double-strand break repair via nonhomologous end joining	1	140.4×	0.015	PNKP
nucleotide-excision repair	1	127.7×	0.016	PNKP
DNA recombination	1	112.3×	0.017	SETX
circadian rhythm	1	81.4×	0.021	SETX
cellular response to hydrogen peroxide	1	78.0×	0.021	SETX
RNA processing	1	73.0×	0.022	SETX
double-strand break repair	1	67.7×	0.022	SETX
cellular response to oxidative stress	1	51.5×	0.028	SETX
positive regulation of neuron projection development	1	45.7×	0.030	SETX
response to oxidative stress	1	43.5×	0.030	PNKP
regulation of protein stability	1	41.9×	0.030	APTX
DNA repair	1	21.3×	0.056	PNKP
DNA damage response	1	17.8×	0.064	SETX
nervous system development	1	15.3×	0.071	SETX
spermatogenesis	1	11.7×	0.089	SETX
cell differentiation	1	9.7×	0.103	SETX
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	SETX

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APTX	0	0
SETX	0	0
PNKP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PNKP	8	Binding:8
APTX	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
APTX	3.1.11.7, 3.6.1.70, 3.6.1.71, 3.6.1.72	adenosine-5’-diphospho-5’-[DNA] diphosphatase, guanosine-5’-diphospho-5’-[DNA] diphosphatase, adenosine-5’-diphospho-5’-[DNA] diphosphatase, DNA-3’-diphospho-5’-guanosine diphosphatase
PNKP	2.7.1.78, 3.1.3.32	polynucleotide 5’-hydroxyl-kinase, polynucleotide 3’-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	PNKP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	APTX, SETX

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APTX	1	—
SETX	0	—
PNKP	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.