Childhood onset hereditary spastic paraplegia

Gene: SPTSSA

The mode of inheritance of this gene has been updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 20 Mar 2026, 3:37 p.m. | Last Modified: 20 Mar 2026, 3:37 p.m.

Panel Version: 8.41

Green List (high evidence)

The additional report of the de novo occurrence of (NM_138288.4):c.152C>T, p.(Thr51Ile) in a patient has been made by a NHS colleague. Therefore, there have now been three reports of this variant in unrelated cases.

Created: 19 Feb 2025, 5:34 p.m. | Last Modified: 19 Feb 2025, 5:36 p.m.

Panel Version: 7.3

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 90A, autosomal dominant, OMIM:620416; spastic paraplegia 90A, autosomal dominant, MONDO:0957308

Green List (high evidence)

Comment on mode of inheritance: There are three unrelated published patient cases and an additional patient suggested by an NHS colleague are available in support of the association of monoallelic Thr51Ile variant with Spastic paraplegia 90A, autosomal dominant (MIM #620416). However, there is only one patient reported with biallelic SPTSSA variant. There is also functional evidence available for the variant and homozygous mouse knock-out model available.

The MOI should be set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' with the current evidence.

Created: 12 Mar 2026, 2:12 p.m. | Last Modified: 16 Mar 2026, 10:43 a.m.

Panel Version: 8.37

PMID:40533086 (2026) reported a 10-year-old female patient with the same recurrent heterozygous pathogenic variant in SPTSSA (p.Thr51Ile) identified via exome sequencing and presenting with global developmental delay, inability to walk, axial hypotonia, extremity spasticity, dystonia, distal renal tubular acidosis, recurrent urinary tract infections, nephrolithiasis, neurogenic bladder, and primary polydipsia.

Created: 12 Mar 2026, 2:06 p.m. | Last Modified: 12 Mar 2026, 2:06 p.m.

Panel Version: 8.33

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 11 Mar 2026, 5:37 p.m. | Last Modified: 11 Mar 2026, 5:37 p.m.

Panel Version: 8.33

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'.

Created: 14 Oct 2023, 7:57 a.m. | Last Modified: 14 Oct 2023, 7:57 a.m.

Panel Version: 4.25

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

Created: 13 Oct 2023, 6:27 p.m. | Last Modified: 14 Oct 2023, 7:51 a.m.

Panel Version: 4.24

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spastic paraplegia 90A, autosomal dominant, OMIM:620416; ?Spastic paraplegia 90B, autosomal recessive, OMIM:620417

Publications

• 26438849
• 33662400
• 36718090
• 40533086