Likely inborn error of metabolism

Gene: SPG7

Green List (high evidence)

Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.

Created: 8 Jan 2026, 4:01 p.m. | Last Modified: 8 Jan 2026, 4:01 p.m.

Panel Version: 8.86

PMID: 39978794 Jimoh et al., 2025
Reported 7 patients with mitochondrial dysfunction associated with ragged blue fibers in their muscle biopsies: P4 and P11C with homozygous SPG7 variant p.Leu78Ter, P32 and P46 with heterozygous p.Ala510Val, P38 with heterozygous p.Ser645Thr, P48 with heterozygous p.Val540Met, and P49 with heterozygous c.1552 + 1G>T. Authors pose that dominant / semi-dominant inheritance is likely for SPG7, as they have not found additional pathogenic AFG3L2 variants in the monoallelic cases - though the phenotype is notably milder.

PMID: 30252181 Magri et al., 2018
Proband: 25-year-old woman, presented at 5yo with severe vision impairment and signs of primary optic atrophy. At 6yo, manifested a slowly progressive motor impairment characterized by bradykinesia, internal rotation of right foot, and gait and balance instability. Mild ID, WISC-R IQ = 62 (assessed at 10yo). Compound het (digenic): de novo variant in AFG3L2 NM_006796.2:c.1402C>T, p.R468C & SPG7 variant NM_003119.3:c.(376+1_377-1)_(861+1_862-1)del, p.Glu127SerfsTer2. Mother and twin brothers carried heterozygous SPG7 deletion alone and were unaffected.
In PMID: 26539208 Charif et al., 2015, authors described the same AFG3L2 c.1402C>T mutation segregating in a family with optic atrophy and mild ID in an autosomal dominant manner - no ataxia, spasticity, or extrapyramidal involvement (AFG3L2 contribution to phenotype?).
Functional study: Yeast cells lacking the endogenous m-AAA protease exhibit a respiratory defect (OXPHOS phenotype), which is complemented by wild-type AFG3L2 (AFG3L2-WT) but not by mutant AFG3L2-R468C.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

Functional evidence: SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes (PMID: 24767997 Almontashiri et al., 2014). In 6-month-old mice, EM analysis showed the presence of swollen mitochondria in Spg7−/− spinal cord axons; Spg7−/− mice display motor impairment at 6 and 10 months of age; Spg7+/- mice were used as controls (PMID: 33045469 Sambri et al., 2020).

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.

Created: 8 Jan 2026, 2:56 p.m. | Last Modified: 8 Jan 2026, 3:59 p.m.

Panel Version: 8.86

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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

Publications

• 24466038
• 24767997
• 26539208
• 30252181
• 33045469
• 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, 12:15 p.m. | Last Modified: 18 Dec 2025, 12:15 p.m.

Panel Version: 8.83

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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: 11 Oct 2023, 12:32 p.m. | Last Modified: 11 Oct 2023, 12:32 p.m.

Panel Version: 4.51

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

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, 12:36 p.m. | Last Modified: 11 Apr 2023, 12:36 p.m.

Panel Version: 4.2

Comment on phenotypes: Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only));Spastic paraplegia 7, autosomal recessive, 607259;Disorders of mitochondrial DNA maintenance and integrity

Created: 11 Apr 2023, 9:37 a.m. | Last Modified: 11 Apr 2023, 9:37 a.m.

Panel Version: 4.2

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

Comment on mode of inheritance: See reviewer's comment. Confirmed on OMIM.

Created: 12 Feb 2016, 5:06 p.m.

Comment on list classification: Both reviewers agree this gene should be promoted from red to green.

Created: 12 Feb 2016, 5:05 p.m.

Green List (high evidence)

Green List (high evidence)

Also, some limited evidence of monoallelic pathogenicity in some cases

Created: 27 Sep 2015, 5:09 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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