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| Childhood onset hereditary spastic paraplegia v4.26 | SPTSSA | Achchuthan Shanmugasundram Classified gene: SPTSSA as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset hereditary spastic paraplegia v4.26 | SPTSSA | Achchuthan Shanmugasundram Gene: sptssa has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset hereditary spastic paraplegia v4.25 | SPTSSA |
Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are two unrelated cases (with the same variant) in support of the association of this gene with the autosomal dominant spastic paraplegia. Although there is only one case with the autosomal recessive condition, homozygous knockout mouse model is available in support of the association. Functional evidence is also available for both homozygous and heterozygous variants. Hence, the rating should be amber and the MOI should be set to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'. |
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| Childhood onset hereditary spastic paraplegia v4.25 | SPTSSA | Achchuthan Shanmugasundram Mode of inheritance for gene: SPTSSA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset hereditary spastic paraplegia v4.24 | SPTSSA | Achchuthan Shanmugasundram edited their review of gene: SPTSSA: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset hereditary spastic paraplegia v4.24 | SPTSSA |
Achchuthan Shanmugasundram changed review comment from: Two unrelated patients were identified with the same de novo missense heterozygous variant (p.Thr51Ile) and the third patient was identified with a homozygous truncation variant (c.171_172del) in SPTSSA gene. All these patients were reported with a complex form of paediatric-onset hereditary spastic paraplegia associated with progressive motor impairment and spasticity and variable language/cognitive impact. Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in Drosophila, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA. The heterozygous p.Thr51Ile variant was shown to impact regulation more than the homozygous truncation variant, while the truncated region was previously shown to be important for ORMDL regulation. Mice model with a homozygous knockout of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration. Sources: Literature; to: Two unrelated patients were identified with the same de novo missense heterozygous variant (p.Thr51Ile) and the third patient was identified with a homozygous truncation variant (c.171_172del) in SPTSSA gene. All these patients were reported with a complex form of paediatric-onset hereditary spastic paraplegia associated with progressive motor impairment and spasticity and variable language/cognitive impact (PMID:36718090). Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in Drosophila, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA. The heterozygous p.Thr51Ile variant was shown to impact regulation more than the homozygous truncation variant, while the truncated region was previously shown to be important for ORMDL regulation (PMID:36718090). Mice model with homozygous ssSPTa null mutants are embryonic lethal (PMID:33662400). However, homozygous knockout of the functional equivalent ssSPTb had early onset ataxia and died prematurely, with evidence of axonic degeneration (PMID:26438849). This gene has already been associated with relevant phenotypes in OMIM (MIMs #620416 & #620417). Sources: Literature |
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| Childhood onset hereditary spastic paraplegia v4.24 | SPTSSA | Achchuthan Shanmugasundram edited their review of gene: SPTSSA: Changed publications to: 26438849, 33662400, 36718090 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset hereditary spastic paraplegia v4.24 | SPTSSA |
Achchuthan Shanmugasundram changed review comment from: Two unrelated patients were identified with the same heterozygous variant (p.Thr51Ile) and the third patient was identified with a homozygous variant (c.171_172del) in SPTSSA gene. All these patients were reported with a complex form of paediatric-onset hereditary spastic paraplegia associated with progressive motor impairment and spasticity and variable language/cognitive impact. Sources: Literature; to: Two unrelated patients were identified with the same de novo missense heterozygous variant (p.Thr51Ile) and the third patient was identified with a homozygous truncation variant (c.171_172del) in SPTSSA gene. All these patients were reported with a complex form of paediatric-onset hereditary spastic paraplegia associated with progressive motor impairment and spasticity and variable language/cognitive impact. Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in Drosophila, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA. The heterozygous p.Thr51Ile variant was shown to impact regulation more than the homozygous truncation variant, while the truncated region was previously shown to be important for ORMDL regulation. Mice model with a homozygous knockout of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration. Sources: Literature |
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| Childhood onset hereditary spastic paraplegia v4.24 | SPTSSA |
Achchuthan Shanmugasundram changed review comment from: Sources: Literature; to: Two unrelated patients were identified with the same heterozygous variant (p.Thr51Ile) and the third patient was identified with a homozygous variant (c.171_172del) in SPTSSA gene. All these patients were reported with a complex form of paediatric-onset hereditary spastic paraplegia associated with progressive motor impairment and spasticity and variable language/cognitive impact. Sources: Literature |
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| Childhood onset hereditary spastic paraplegia v4.24 | SPTSSA |
Achchuthan Shanmugasundram gene: SPTSSA was added gene: SPTSSA was added to Childhood onset hereditary spastic paraplegia. Sources: Literature Mode of inheritance for gene: SPTSSA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SPTSSA were set to 36718090 Phenotypes for gene: SPTSSA were set to Spastic paraplegia 90A, autosomal dominant, OMIM:620416; ?Spastic paraplegia 90B, autosomal recessive, OMIM:620417 Review for gene: SPTSSA was set to AMBER Added comment: Sources: Literature |
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