Autosomal recessive spinocerebellar ataxia 7

Summary

Autosomal recessive spinocerebellar ataxia 7 (MONDO:0012235) is a disease caused by TPP1 (GenCC Strong), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: TPP1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 79
• Phenotypes (HPO): 21
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0000641	Dysmetric saccades	Frequent (30-79%)
HP:0000651	Diplopia	Frequent (30-79%)
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0000666	Horizontal nystagmus	Frequent (30-79%)
HP:0001152	Saccadic smooth pursuit	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002136	Broad-based gait	Frequent (30-79%)
HP:0002168	Scanning speech	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002495	Impaired vibratory sensation	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0002174	Postural tremor	Occasional (5-29%)
HP:0003445	EMG: neuropathic changes	Occasional (5-29%)
HP:0001250	Seizure	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spinocerebellar ataxia 7
Mondo ID	MONDO:0012235
MeSH	C563753
OMIM	609270
Orphanet	284324
DOID	DOID:0080059
UMLS	C1836474
MedGen	324520
GARD	0012232
Is cancer (heuristic)	no

Also known as: autosomal recessive spinocerebellar ataxia type 7 · childhood onset autosomal recessive slowly progressive spinocerebellar ataxia · SCAR7 · spinocerebellar ataxia autosomal recessive 7 · spinocerebellar ataxia, autosomal recessive 7 · spinocerebellar ataxia, autosomal recessive type 7

Data availability: 79 ClinVar variants · 2 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 cerebellar ataxia › autosomal recessive spinocerebellar ataxia 7

Related subtypes (28): Charlevoix-Saguenay spastic ataxia, infantile-onset autosomal recessive nonprogressive cerebellar ataxia, autosomal recessive ataxia, Beauce type, RIDDLE syndrome, autosomal recessive ataxia due to ubiquinone deficiency, autosomal recessive spinocerebellar ataxia 10, ataxia with oculomotor apraxia type 3, autosomal recessive spinocerebellar ataxia 14, autosomal recessive spinocerebellar ataxia 16, Lichtenstein-Knorr syndrome, autosomal recessive spinocerebellar ataxia 20, spinocerebellar ataxia, autosomal recessive 22, spinocerebellar ataxia, autosomal recessive 24, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, autosomal recessive congenital cerebellar ataxia, autosomal recessive metabolic cerebellar ataxia, autosomal recessive degenerative and progressive cerebellar ataxia, autosomal recessive syndromic cerebellar ataxia, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy, spinocerebellar ataxia, autosomal recessive 29, spinocerebellar ataxia, autosomal recessive 30, spinocerebellar ataxia, autosomal recessive 31, spinocerebellar ataxia, autosomal recessive 27, spinocerebellar ataxia, autosomal recessive 28, spinocerebellar ataxia, autosomal recessive 25, spinocerebellar ataxia, autosomal recessive 26, spinocerebellar ataxia, autosomal recessive 32, spinocerebellar ataxia, autosomal recessive 33

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

79 retrieved; paginated sample, class counts are floors:

19 pathogenic/likely pathogenic, 14 uncertain significance, 14 pathogenic, 13 conflicting classifications of pathogenicity, 7 benign/likely benign, 6 benign, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
188850	NM_000391.4(TPP1):c.972_979del (p.Ser324fs)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
189179	NM_000391.4(TPP1):c.1379G>A (p.Trp460Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2052460	NM_000391.4(TPP1):c.146_155del (p.Leu49fs)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207561	NM_000391.4(TPP1):c.311T>A (p.Leu104Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
207569	NM_000391.4(TPP1):c.379C>T (p.Arg127Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
207574	NM_000391.4(TPP1):c.509-1G>A	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
207581	NM_000391.4(TPP1):c.827A>T (p.Asp276Val)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
207586	NM_000391.4(TPP1):c.1015C>T (p.Arg339Trp)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2098723	NM_000391.4(TPP1):c.1490del (p.Arg497fs)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2418966	NM_000391.4(TPP1):c.337dup (p.Ser113fs)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2642	NM_000391.4(TPP1):c.1094G>A (p.Cys365Tyr)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2643	NM_000391.4(TPP1):c.622C>T (p.Arg208Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2644	NM_000391.4(TPP1):c.509-1G>C	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2645	NM_000391.4(TPP1):c.1340G>A (p.Arg447His)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2647	NM_000391.4(TPP1):c.851G>T (p.Gly284Val)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2911404	NM_000391.4(TPP1):c.496del (p.His166fs)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370212	NM_000391.4(TPP1):c.1259C>A (p.Ser420Ter)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
370214	NM_000391.4(TPP1):c.1551+1G>C	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551316	NM_000391.4(TPP1):c.1525C>T (p.Gln509Ter)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
552886	NM_000391.4(TPP1):c.1048C>T (p.Arg350Trp)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553222	NM_000391.4(TPP1):c.225A>G (p.Gln75=)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554563	NM_000391.4(TPP1):c.357dup (p.Leu120fs)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
558183	NM_000391.4(TPP1):c.1551+1G>T	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
645209	NM_000391.4(TPP1):c.325C>T (p.Gln109Ter)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
661918	NM_000391.4(TPP1):c.1678_1679del (p.Leu560fs)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68738	NM_000391.4(TPP1):c.1266G>C (p.Gln422His)	TPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
68740	NM_000391.4(TPP1):c.1417G>A (p.Gly473Arg)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68741	NM_000391.4(TPP1):c.1424C>T (p.Ser475Leu)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
859613	NM_000391.4(TPP1):c.481C>T (p.Gln161Ter)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
89086	NM_000391.4(TPP1):c.1397T>G (p.Val466Gly)	TPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 7 · 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
ACD	Strong	Autosomal recessive	autosomal recessive spinocerebellar ataxia 7	15
TPP1	Strong	Autosomal recessive	autosomal recessive spinocerebellar ataxia 7	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPP1	Orphanet:284324	Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia
TPP1	Orphanet:699751	Infantile CLN2 disease
TPP1	Orphanet:699761	Late infantile CLN2 disease
TPP1	Orphanet:699769	Juvenile CLN2 disease
ACD	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
ACD	Orphanet:397692	Hereditary isolated aplastic anemia
ACD	Orphanet:618	Familial melanoma

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
TPP1	HGNC:2073	ENSG00000166340	O14773	Tripeptidyl-peptidase 1	gencc,clinvar
ACD	HGNC:25070	ENSG00000102977	Q96AP0	Adrenocortical dysplasia protein homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPP1	Tripeptidyl-peptidase 1	Lysosomal serine protease with tripeptidyl-peptidase I activity.
ACD	Adrenocortical dysplasia protein homolog	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPP1	Protease	yes	3.4.14.9	Peptidase_S8/S53_dom, S53_propep, Sedolisin_dom
ACD	Other/Unknown	no		TPP1/Est3, ACD

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
dorsal motor nucleus of vagus nerve	1
pigmented layer of retina	1
retina	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPP1	298	ubiquitous	marker	pigmented layer of retina, retina, dorsal motor nucleus of vagus nerve
ACD	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPP1	1,739
ACD	1,044

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACD	Q96AP0	19
TPP1	O14773	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. 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
Depurination	1	815.7×	0.011	ACD
Depyrimidination	1	475.8×	0.011	ACD
Base-Excision Repair, AP Site Formation	1	439.2×	0.011	ACD
Telomere C-strand synthesis initiation	1	407.9×	0.011	ACD
Processive synthesis on the C-strand of the telomere	1	380.7×	0.011	ACD
Telomere C-strand (Lagging Strand) Synthesis	1	380.7×	0.011	ACD
Base Excision Repair	1	356.9×	0.011	ACD
Removal of the Flap Intermediate from the C-strand	1	317.2×	0.011	ACD
Extension of Telomeres	1	300.5×	0.011	ACD
Telomere Extension By Telomerase	1	228.4×	0.012	ACD
Polymerase switching on the C-strand of the telomere	1	211.5×	0.012	ACD
Telomere Maintenance	1	184.2×	0.013	ACD
Meiosis	1	142.8×	0.015	ACD
Packaging Of Telomere Ends	1	109.8×	0.015	ACD
XBP1(S) activates chaperone genes	1	107.7×	0.015	TPP1
Chromosome Maintenance	1	105.7×	0.015	ACD
Recognition and association of DNA glycosylase with site containing an affected purine	1	102.0×	0.015	ACD
Cleavage of the damaged purine	1	102.0×	0.015	ACD
Reproduction	1	95.2×	0.015	ACD
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	92.1×	0.015	ACD
Cleavage of the damaged pyrimidine	1	92.1×	0.015	ACD
Inhibition of DNA recombination at telomere	1	84.0×	0.015	ACD
DNA Damage/Telomere Stress Induced Senescence	1	81.6×	0.015	ACD
Meiotic synapsis	1	70.5×	0.017	ACD
Cellular Senescence	1	68.8×	0.017	ACD
DNA Repair	1	49.2×	0.023	ACD
Cellular responses to stress	1	18.4×	0.057	ACD
Cell Cycle	1	18.0×	0.057	ACD
Cellular responses to stimuli	1	15.7×	0.063	ACD

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
protein localization to chromosome, telomeric region	2	1532.0×	1e-05	TPP1, ACD
segmentation	1	4213.0×	0.003	ACD
regulation of establishment of protein localization to telomere	1	2808.7×	0.003	ACD
telomere assembly	1	2106.5×	0.003	ACD
protection from non-homologous end joining at telomere	1	1203.7×	0.004	ACD
establishment of protein localization to telomere	1	1053.2×	0.004	ACD
telomere capping	1	648.1×	0.005	ACD
peptide catabolic process	1	526.6×	0.005	TPP1
lysosomal protein catabolic process	1	526.6×	0.005	TPP1
urogenital system development	1	495.6×	0.005	ACD
telomere maintenance via telomerase	1	366.4×	0.006	ACD
negative regulation of telomere maintenance via telomerase	1	366.4×	0.006	ACD
bone resorption	1	290.6×	0.007	TPP1
positive regulation of telomere maintenance	1	255.3×	0.007	ACD
embryonic limb morphogenesis	1	200.6×	0.009	ACD
neuromuscular process controlling balance	1	165.2×	0.010	TPP1
lysosome organization	1	153.2×	0.010	TPP1
telomere maintenance	1	133.8×	0.011	ACD
protein catabolic process	1	118.7×	0.012	TPP1
epithelial cell differentiation	1	87.8×	0.015	TPP1
skeletal system development	1	62.9×	0.020	ACD
central nervous system development	1	57.7×	0.020	TPP1
lipid metabolic process	1	45.8×	0.025	TPP1
intracellular protein transport	1	32.4×	0.033	ACD
nervous system development	1	23.0×	0.045	TPP1
proteolysis	1	17.1×	0.058	TPP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TPP1	0	0
ACD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TPP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TPP1	3.4.14.9	tripeptidyl-peptidase I

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

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	TPP1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ACD

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TPP1	1	—
ACD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

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
NCT04098211	Not specified	ACTIVE_NOT_RECRUITING	Longitudinal Assessment of Atypical Tripeptidyl Peptidase 1 Enzyme Deficiency Patients