Peer-reviewed article
Serine palmitoyltransferase (SPT) inhibition in SPTSSA-related complex hereditary spastic paraplegia.
Yi Gong, Robert Thompson, Ashley M Glover, Kenneth Gable, Sita D Gupta et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This is a biomedical research paper about a rare genetic disorder (hereditary spastic paraplegia) caused by mutations in the SPTSSA gene. The study uses mouse models and one case study to show how blocking an enzyme called serine palmitoyltransferase can reduce symptoms of this neurological disorder. While the research involves one child patient, the focus is on molecular mechanisms and disease pathology rather than child well-being outcomes.
Key points
- SPTSSA mutations impair feedback regulation of SPT enzyme, leading to excess sphingolipid accumulation
- Elevated sphingolipids peak during postnatal myelination and damage oligodendrocytes and neurons
- SPT inhibition with myriocin prevented disease symptoms in mouse models
- One child treated with D-Cycloserine (SPT inhibitor) showed reduced spasticity and decreased biomarker levels
- Dietary L-serine worsened disease progression in mutant mice
Limitations
This is primarily a mechanistic research paper with only one clinical case report, not a systematic evaluation of treatment effectiveness in children. The study does not assess broader child well-being outcomes such as quality of life, development, or school participation.
Abstract
Defective feedback inhibition of serine palmitoyltransferase (SPT) caused by pathogenic SPTSSA variants underlies childhood-onset complex hereditary spastic paraplegia, yet the developmental timing and therapeutic reversibility of sphingolipid dysregulation remain unclear. We generated a knock-in mouse carrying the disease-associated SptssaT51I variant and show that heterozygous animals exhibit preserved intrinsic SPT activity but impaired ORMDL-mediated regulation, leading to sustained elevation of bioactive sphingolipid intermediates that peak during postnatal myelination. Although gross myelin formation was initially maintained, excess sphingolipid flux rendered oligodendrocytes and neurons selectively vulnerable. Dietary L-serine, which augments SPT substrate availability, amplified sphingolipid accumulation in mutant but not wild-type mice, unmasking progressive spasticity, axonal injury, myelin ultrastructural defects, and, when administered during early postnatal development, severe pulmonary pathology likely responsible for lethality. Pharmacologic SPT inhibition with myriocin normalized sphingolipid synthesis, prevented serine-induced lethality, and reversed neurological and metabolic abnormalities. Translating these findings, treatment of a child with SPTSSA-T51I-associated complex hereditary spastic paraplegia using the FDA approved SPT inhibitor D-Cycloserine resulted in sustained improvement in spasticity, reduced baclofen requirement, and decreased plasma levels of neurofilament light chain (NFL). These data define dysregulated sphingolipid biosynthesis as a developmentally and metabolically sensitive driver of neurodegeneration and suggest SPT inhibition as a mechanistically grounded therapeutic strategy.