Hereditary spastic paraparesis (HSP) is a progressive neurodegenerative disorder, characterized by progressive lower limb weakness and spasticity. Multiple genes are associated with both the pure and complicated HSP types. Our study is aimed at seeking for novel genetic basis of HSP in a family with two affected siblings. Genetic analysis using whole exome sequencing was conducted in a family quartet with two female siblings, who presented with complicated HSP featuring slowly progressive paraparesis, mild-moderate intellectual disability, normal head circumference (HC), and normal magnetic resonance imaging (MRI). A homozygous pathogenic variant was identified in both siblings in the VPS53 gene (c.2084A>G: c.2084A>G, p.Gln695Arg). This gene acts as a component of the Golgi-associated retrograde protein (GARP) complex that is involved, among others, in intracellular cholesterol transport and sphingolipid homeostasis in lysosomes and was previously associated with progressive cerebello-cerebral atrophy (PCCA) type 2. This is the first description of the VPS53 gene as a cause of autosomal recessive complicated HSP. Lysosomal dysfunction as a result of impaired cholesterol trafficking can explain the neurodegenerative processes responsible for the HSP. Our finding expands the phenotype of VPS53-related disease and warrants the addition of VPS53 analysis to the genetic investigation in patients with autosomal recessive HSP. The exact role of GARP complex in neurodegenerative processes should be further elucidated.
Keywords: Hereditary spastic paraparesis; Hereditary spastic paraplegia; PCCA type 2; VPS53.