# Expanding Hereditary Spastic Paraplegias Limits: Biallelic SPAST Variants in Cerebral Palsy Mimics

## TL;DR

This study expands the understanding of hereditary spastic paraplegias by linking biallelic SPAST gene variants to cerebral palsy-like symptoms, highlighting the need for genetic testing in such cases.

## Contribution

The study provides the first evidence of biallelic inheritance in SPAST-related disorders and expands the clinical spectrum to include early-onset encephalopathy.

## Key findings

- Biallelic SPAST variants were found in individuals with cerebral palsy-like symptoms, indicating a new inheritance pattern.
- Functional studies showed reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient-derived fibroblasts.
- The findings suggest a threshold effect of spastin levels influences phenotypic variation in SPAST-related disorders.

## Abstract

Hereditary spastic paraplegias (HSP) are rare neurodegenerative disorders marked by spasticity and lower limb weakness. The most common type, SPG4, is usually autosomal dominant and caused by SPAST gene variants, typically presenting as pure HSP. We describe five individuals from three unrelated families who meet the clinical criteria for cerebral palsy and carry biallelic SPAST variants. We aim to increase the clinical and genetic understanding of SPAST‐related disorders and explore the underlying abnormal cellular mechanisms.

We performed comprehensive phenotyping and genetic analysis. In silico and functional studies were conducted using confocal microscopy on fibroblast cultures derived from carriers of the biallelic SPAST variants, a monoallelic SPAST variant, and a healthy control.

Individuals exhibited early‐onset complex HSP with a diverse range of encephalopathy severity, spasticity, and neuronoaxonal involvement, occasionally leading to the diagnosis of cerebral palsy. Whole‐exome sequencing identified homozygous and compound heterozygous SPAST variants. Functional studies demonstrated reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient‐derived fibroblasts, supporting the pathogenicity of the variants.

We provide the first evidence of biallelic inheritance in SPAST‐related disorders, supported by functional analysis, expanding the clinical spectrum to include moderate‐to‐severe early‐onset encephalopathy. Our findings emphasize the importance of genetic diagnosis in cerebral palsy for prognosis, counseling, and personalized therapy. The identified variants reveal the genetic complexity of SPAST‐related disease and suggest a threshold effect of spastin levels in phenotypic variation. Cellular mechanisms such as mitochondrial dynamics and membrane morphology may contribute to pathogenesis and warrant further investigation.