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OBJECTIVE: To identify the causative gene for primary lateral sclerosis (PLS)-mimicking hereditary spastic paraplegia (HSP).
BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by progressive leg spasticity. Although HSP occasionally affects arms and bulbar regions in severe cases, spasticity due to HSP is usually observed in a length-dependent manner and predominantly in legs. SPG10 is one of autosomal dominant HSPs originally described as early-onset pure HSP and has been reported exclusively from Europe.
DESIGN/METHODS: The proband is a 66 year-old woman manifesting spastic dysarthria and mild gait disturbance for 6 years with the absence of ataxia, whose physical and electrophysiological findings were suggestive of primary lateral sclerosis (PLS). Exome sequencing was conducted in the proband, and the identified mutation was screened in eight family members by Sanger sequencing. Clinical information of family members was evaluated in terms of age at onset, presence of walking disturbance, dysarthria, distribution of spasticity, sensory impairment, ataxia, urinary dysfunction, Barthel index and Spastic Paraplegia Rating Scale.
RESULTS: Genetic study showed a novel missense mutation in KIF5A, c.484C>T (p.Arg162Trp), which is predicted to be pathological based on the results of bioinformatic analysis. Six family members were proven to be carrying the mutation, among which there were two (33[percnt]) cases manifesting spastic dysarthria and leg spasticity, two (33[percnt]) cases with subtle pyramidal signs in legs and two (33[percnt]) asymptomatic cases (78 and 85 years old) lacking any signs of spasticity.
CONCLUSIONS: To our knowledge, this is the first report describing SPG10-HSP outside Europe, which suggests KIF5A mutation is a shared genetic etiology for HSP over ethnicities. Distinctive phenotype observed in our family includes later symptom onset and bulbar involvement despite relatively mild leg spasticity. Given that our family showed incomplete penetrance and dysarthria, SPG10-HSP should be cautiously differentiated from PLS. Disclosure: Dr. Kaji has nothing to disclose. Dr. Miyamoto has nothing to disclose. Dr. Osaki has nothing to disclose. Dr. Nodera has nothing to disclose. Dr. Kawarai has nothing to disclose. Dr. Izumi has nothing to disclose. Dr. Kaji has received research support from GlaxoSmithKline and Eisai Inc.
Mutations in TFG gene have been demonstrated in hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) and hereditary spastic paraplegia (HSP). A broad spectrum of TFG pathology is suspected in motor neuron diseases including amyotrophic lateral sclerosis (ALS). We performed mutation screening of TFG gene in ALS cases and evaluated the biological functions of mutant TFG by expression experiment in cultured cells. Two missense mutations associated with sporadic ALS were discovered. Mislocalization of ALS-related proteins, including TDP-43 and optineurin, was demonstrated. These results indicate that mistrafficking of ALS-related proteins by mutant TFG might be a biological cascade leading to motor neuron death.
We identified two polymorphisms out of all coding regions of the dopamine transporter gene. One existed in exon 9 (1215A/G) and another in exon 15 (1898T/C). The 1215G was significantly less frequent among patients with Parkinson's disease than the controls. Although the polymorphism caused no amino acid substitution, we concluded that it was associated with decreasing the susceptibility to Parkinson's disease through mechanisms other than the protein function of dopamine transporter.
