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| 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. |
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| Likely inborn error of metabolism v8.56 | GNS | Arina Puzriakova Phenotypes for gene: GNS were changed from MPS IIID, Sanfilippo D disease (Mucopolysaccharidoses); Mucopolysaccharidosis Type IIID; Mucopolysaccharidosis type IIID, 252940; Mucopolysaccharidosis Type III; Mucopolysaccharidosis, Type III to Mucopolysaccharidosis type IIID, OMIM:252940 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v1.76 | MICU1 |
Sarah Leigh Source Expert Review Green was added to MICU1. Mode of inheritance for gene MICU1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal Added phenotypes Myopathy with extrapyramidal signs 615673 for gene: MICU1 Publications for gene MICU1 were changed from to 24336167; 29721912 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| Likely inborn error of metabolism v1.47 | GNS |
Ivone Leong Source NHS GMS was added to GNS. Source London North GLH was added to GNS. |
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| Likely inborn error of metabolism v0.4 | GNS |
Ellen McDonagh gene: GNS was added gene: GNS was added to Inborn errors of metabolism. Sources: Expert Review Green Mode of inheritance for gene: GNS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GNS were set to 27604308 Phenotypes for gene: GNS were set to MPS IIID, Sanfilippo D disease (Mucopolysaccharidoses); Mucopolysaccharidosis Type IIID; Mucopolysaccharidosis type IIID, 252940; Mucopolysaccharidosis Type III; Mucopolysaccharidosis, Type III |
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