SPTSSA – Hereditary Spastic Paraplegia

The association between SPTSSA and hereditary spastic paraplegia is supported by converging genetic and functional data, with evidence derived from three unrelated children presenting with a complex form of the disease (PMID:36718090). Exome sequencing in these individuals identified two distinct variants in SPTSSA, lending weight to the gene‑disease association.

Genetic evidence is underscored by the identification of the variant c.152C>T (p.Thr51Ile), found in one of the reported cases. This variant, together with a second mutation (c.171_172del (p.Gln58fs)), was observed in cases exhibiting progressive motor disturbance often coupled with variable sensorineural hearing loss and language/cognitive dysfunction (PMID:36718090).

The reported variant c.152C>T (p.Thr51Ile) follows the canonical coding change format and is representative of the mutational spectrum in SPTSSA with pathogenic relevance. Its presence, along with the frameshift variant, supports a deleterious effect on the enzyme complex regulating sphingolipid synthesis.

The observed inheritance pattern is consistent with autosomal recessive transmission, accounting for the presence of compound heterozygous mutations that compromise normal protein function. Although explicit segregation analysis is limited, the clustering of affected individuals within independent families bolsters the genetic causality of these variants.

Functional studies have elucidated the mechanism of pathogenesis, where SPTSSA mutations impair the negative regulation of serine palmitoyltransferase by ORMDL proteins. Biochemical assays in human embryonic kidney cells and patient fibroblasts, together with rescue experiments in Drosophila models, demonstrated that dysregulated sphingolipid synthesis underlies the disease phenotype (PMID:36718090).

The convergence of genetic and experimental findings indicates that the pathogenic variants in SPTSSA lead to excessive sphingolipid synthesis, adversely affecting early brain development and neural function. This integrated evidence supports a strong gene‑disease relationship and reinforces the clinical utility of SPTSSA testing in patients with complex hereditary spastic paraplegia.

Key Take‑home: SPTSSA mutation analysis should be considered in the diagnostic workup of hereditary spastic paraplegia given its strong association with disrupted sphingolipid homeostasis and resultant neurological dysfunction.

References

• Brain : a journal of neurology • 2023 • SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia PMID:36718090

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