Hereditary ataxia with onset in adulthood

Gene: SPG7

Green List (high evidence)

BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).

Created: 6 Jan 2026, 4:33 p.m. | Last Modified: 6 Jan 2026, 4:33 p.m.

Panel Version: 8.15

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 7, autosomal recessive, OMIM:607259; hereditary spastic paraplegia 7, MONDO:0011803

Publications

• 22964162
• 23065789
• 24727571
• 26506339
• 31068484
• 31854126
• 32548275
• 33598982
• 33774748
• 34405107
• 39978794

Green List (high evidence)

Request mode of inheritance changed to biallelic only.
In Sheffield we do not report single hits in SPG7 due to limited evidence of a monoallelic association for SPG7. We have performed a case control study using local data in Sheffield and determined no association for the common p.(Ala510Val) variant as a single hit for the disease.
Evidence in the literature is extremely limited for a monoallelic MOI, and we suggest these have been reported erroneously due to the high frequency of p.(Ala510Val) in the population.
MOI in OMIM was recently changed from AD/AR to AR only.

Created: 18 Dec 2025, 12:17 p.m. | Last Modified: 18 Dec 2025, 12:17 p.m.

Panel Version: 8.15

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Variants in this GENE are reported as part of current diagnostic practice

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 10 Oct 2023, 4:24 p.m. | Last Modified: 10 Oct 2023, 4:24 p.m.

Panel Version: 4.24

Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. Numerous biallelic SPG7 variants have been reported (PMIDs: 9635427; 16534102; 17646629; 18200586, 20186691; 22571692) and at least five monoallelic SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (PMIDs: 18200586; 22571692). For this reason, the mode of inheritance for this gene should be BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form) autosomal or pseudoautosomal.

Created: 11 Apr 2023, 1:03 p.m. | Last Modified: 11 Apr 2023, 1:03 p.m.

Panel Version: 4.8

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Green List (high evidence)

On Ox and Sheffield panels. Probably on HSP panel as well but important on both as overlap in ataxic and spastic features. Often requested by PG.

Created: 27 Apr 2019, 7:39 p.m.

I don't know

Review and rating submitted by James Polke (Neurogenetics Laboratory, Institute of Neurology, London) on behalf of London North GLH for GMS Neurology specialist test group

Created: 27 Apr 2019, 8:55 p.m.

Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group.

Created: 15 Apr 2019, 10:21 a.m.

Green List (high evidence)

Pretty much the single most common cause of recessive ataxia in adult cases - almost all cases at least compound heterozygous for p.Ala510Val (common variant in British Isles). Although AD variants have been suggested I do not feel there is compelling enough evidence to report heterozygous variants at this stage

Created: 15 Apr 2019, 10:06 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autosomal recessive spastic paraplegia 7, 607259

Variants in this GENE are reported as part of current diagnostic practice