The hereditary spastic paraplegias (HSPs) refer to a group of neurodegenerative disorders, characterized by upper motor neuron degeneration leading to progressive spasticity and weakness of the lower limbs. This group of diseases is both clinically and genetically heterogenous, with several separate loci having been mapped. SPG35 is a recently described subtype of spastic paraplegia. Clinically, SPG35 is a severe form of the paraplegia, following a progressive course, and is associated with intellectual disability. Radiologically, the disease shows features of leukodystrophy.
There are no specific treatments to prevent HSP. Management consists of symptomatic treatment and regular physical therapy to strengthen muscles.
Dick et al. (2008) studied a large consanguineous Omani family with an autosomal recessive form of HSP. The disease had a progressive course in this family and was associated with intellectual disability. In addition, two affected individuals also had seizures. Brain MRI revealed white matter abnormalities indicating leukodystrophy. Whole genome analysis identified a 20.4 Mb region of homozygozity on chromosome 16q. Two putative candidate genes in this region, Dynein, cytoplasmic 1, light intermediate chain 2 (DYNC1LI2) and vacuolar protein sorting 4 homolog A (VPS4A) were screened for mutations. However, none were found. Dick et al. (2008) stated that this was a novel form of autosomal recessive HSP and named it SPG35. Later, Dick et al. (2010) found mutations in the FA2H gene in the same family to be the underlying cause of the condition. They also detected significantly reduced function of the F2H enzyme in affected patients.