Novel homozygous DSTYK mutation causes late onset spastic paraparesis and cerebellar atrophy

Whole exome sequencing of a 52 years old male with progressive spastic paraparesis presenting at age 44 years, displayed a homozygous missense mutation in DSTYK (NM_015375.2, c.1840C>T, p.R614W) within an evolutionary conserved sequence of its 7^th exon (CADD Score 35). The frequency of the heterozygous mutation in gnomAD in Europeans was 0.001% while in our in-house database of 440 exomes and in other open access databases (1000 genomes, ExAC, gnomAD and NHLBI ESP exomes) the frequency was 0%. Additional 200 DNA samples of ethnically matched individuals were tested, none of which harbored the mutation. The proband, child of consanguineous parents of Jewish Moroccan ancestry, has five siblings. Only one of his siblings was homozygous for the mutation – a 43-years old sister, who had been limping for over a year. Neurological exam of both the proband and the sibling pointed to bilateral upper neuron defect. MRI findings of both siblings presented various stages of cerebellar atrophy. Notably, DSTYK mutations are known to cause SPG23, yet are also known to cause urinary system abnormalities and hypopigmentation, but none of the latter was identified. The other 4 siblings, not homozygous for the mutation, were asymptomatic.

DSTYK is abundant throughout the central nervous system, particularly in the cerebellar hemispheres, and is thought to be a mediator of cell death. Our study delineates a genotype-phenotype correlation in DSTYK mutations and highlights DSTYK mutations in the differential diagnosis of late onset spastic paraparesis and cerebellar atrophy.