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Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska commented on gene: SPG7: 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.
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska changed review comment from: 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.; to: 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.
Likely inborn error of metabolism v2.247 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450 to Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Likely inborn error of metabolism v2.135 AFG3L2 Sarah Leigh Added comment: Comment on phenotypes: Ataxia, spastic, 5, autosomal recessive, 614487;Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only));Spinocerebellar ataxia 28, 610246;Disorders of mitochondrial DNA maintenance and integrity
Likely inborn error of metabolism v2.135 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Ataxia, spastic, 5, autosomal recessive, 614487; Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Spinocerebellar ataxia 28, 610246; Disorders of mitochondrial DNA maintenance and integrity to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Likely inborn error of metabolism v1.47 AFG3L2 Ivone Leong Source NHS GMS was added to AFG3L2.
Source London North GLH was added to AFG3L2.
Likely inborn error of metabolism v0.4 AFG3L2 Ellen McDonagh Added phenotypes Ataxia, spastic, 5, autosomal recessive, 614487; Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Spinocerebellar ataxia 28, 610246; Disorders of mitochondrial DNA maintenance and integrity for gene: AFG3L2
Publications for gene AFG3L2 were changed from to 27604308
Likely inborn error of metabolism v0.4 AFG3L2 Ellen McDonagh gene: AFG3L2 was added
gene: AFG3L2 was added to Inborn errors of metabolism. Sources: Expert Review Green
Mode of inheritance for gene: AFG3L2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: AFG3L2 were set to Ataxia, spastic, 5, autosomal recessive, 614487; Spinocerebellar ataxia 28, 610246; Disorders of mitochondrial DNA maintenance and integrity