ClinVar

Description

In this patient the sequence variant c.698T>A could be detected in heterozygous state in the KIF5A gene. The KIF5A gene codes for the protein kinesin heavy chain isoform 5A, which belongs to the kinesin family. Mutations in the KIF5A gene cause the clinical picture of autosomal dominant spastic paraplegia type 10 (MIM # 604187) (Reid et al. 2002). To date, more than 60 mutations in the KIF5A gene have been described as causative, including approximately 50 missense mutations (HMGD Professional 2019.1). Spastic paraplegia type 10 is an autosomal dominant neurological disease with variable phenotype and variable clinical onset of symptoms. Clinical manifestations include spasticity of the lower and upper extremities, hyperreflexia, muscle weakness, muscle cramps and gait disorders. Some patients show mainly axonal sensomotoric peripheral neuropathy with distal sensory impairment and distal muscular atrophy (Liu et al, 2014). In rare cases, additional neurological features have been described in patients with KIF5A mutations, such as cognitive impairment. The sequence variant c.698T>A leads to the exchange of the highly conserved amino acid leucine to glutamic acid at position 233. This exchange is classified as pathogenic by several prediction programs. The variant has not been described in ExAC or gnomAD so far. The mutation is located in the switch region II of the motor domain of the protein. Missense mutations of the adjacent amino acids have already been described as the cause of type 10 spastic paraplegia (Crimella et al, 2011). Assuming that the genotype fits well with the patient's phenotype, we classify the variant as probably pathogenic (class IV) according to the current state of knowledge. A further indication for the pathogenicity of the variant would be the co-segregation within the family.