A large kindred with familial ALS due to the KIF5A p.Arg1007Lys mutation (P10-8.004)

Résumé fourni par la source

Objective: To present the first kindred with KIF5A p.Arg1007Lys mutation. Background: KIF5A mutations were reported in hereditary spastic paraplegia type 10 (SPG10) and sensory neuropathy type 2. In 2018, a genome-wide association study identified KIF5A p.Arg1007Lys mutation in two isolated and unrelated cases with amyotrophic lateral sclerosis (ALS). However, to date, there has been no pedigree report with this mutation. Design/Methods: We analyzed a large multigenerational kindred with multiple affected cases and a well-documented 6-year follow-up of the proband. Results: The proband presented at the age of 54 with progressive gait difficulty. In the following years, he developed motor slowness, decreased hand dexterity, sensory disturbances in the stocking-glove pattern, pyramidal signs (spasticity, hyperactive reflexes, Babinski sign), and four-limb ataxia. Neuropsychological testing showed mild cognitive impairment. Brain MRI revealed parietal atrophy, whereas cervical, thoracic, and lumbar MRI showed degenerative spinal changes. Neurophysiological studies evidenced chronic neurogenic changes. He became a wheelchair user at 60. On the follow-up at 60, he also displayed dysarthria, dysphagia, and bilateral knee and ankle clonus. The patient had a remarkable family history of similar symptoms in his father and 10 other paternal relatives. The genetic testing for mutations in ALS-associated genes was negative. Whole exome sequencing revealed c.3020 G>A (p.Arg1007Lys) mutation in the KIF5A gene. The presence of the mutation was confirmed in two other affected relatives. Conclusions: Mutations in the KIF5A should be included in the differential diagnosis of familial ALS. In particular, the presence of other symptoms from the KIF5A spectrum, including spasticity and neuropathy, should prompt testing for KIF5A mutations. Disclosure: Dr. Dulski has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for VM Media Ltd.. Dr. Dulski has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Radoslaw Lipinski 90 Consulting. Dr. Dulski has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Ipsen. Dr. Dulski has received research support from Polish Neurological Society. Dr. Dulski has received research support from Polish National Agency for Academic Exchange. Audrey Strongosky has nothing to disclose. Dr. Hanna AL-Shaikh has nothing to disclose. Dr. Wszolek has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Polish Neurological Society/Via Medica.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.