Genotypic and Phenotypic Profile of Hereditary Spastic Paraplegia in Children: A Single-Centre Study from Northern...

To characterize the genotypic and phenotypic spectrum of children with genetically confirmed hereditary spastic paraplegia (HSP) at a tertiary care center in Northern India.

This prospective case series included patients with genetically confirmed (whole exome sequencing or clinical exome sequencing) HSP attending the Medical Genetics Clinic of a tertiary care center in Northern India between 2018 and 2023. Neurological and radiological assessments were also conducted.

A total of 21 patients from 16 families were included. The median (q1, q3) age of onset of symptoms was 5 (1.5, 8.5) years, and the median (q1, q3) age of diagnosis was 8 (5, 13.5) years. The most common features at diagnosis were toe walking with progressive spasticity of lower limbs. Genetic testing identified 18 variants across eight different genes, including six pathogenic variants, 10 likely pathogenic variants, and two variants of uncertain significance (VUS). Thirteen families had autosomal recessive (AR) HSP, two had autosomal dominant (AD) HSP, and one had X-linked HSP. The most frequently identified subtype was SPG35 (spastic paraplegia type 35), observed in six families, followed by SPG11 in three families and SPG52 in two families. There was one family each with SPG18B, SPG15, CSPSD (cataracts, spastic paraplegia, and speech delay), SPG4, and SPG2.

Hereditary spastic paraplegia exhibits genotypic and phenotypic heterogeneity with a predominance of AR inheritance. Five novel variants and some recurrent variants, suggesting potential founder effects, were noted. HSP should be suspected in cases with slowly progressive spasticity in lower limbs, even without a family history, which may mimic cerebral palsy.