Objectives : This paper presents the first report of amyotrophic lateral sclerosis (ALS) kindred due to the KIF5A p.Arg1007Lys, a splice-altering variant. Methods : An index case was a 54-year-old male who developed progressive gait difficulty and imbalance followed by mild parkinsonism, spasticity, neuropathy, ataxia, and cognitive impairment with predominant subcortical frontal involvement. Brain MRI showed marked bilateral parietal lobes atrophy. Electromyography demonstrated chronic diffuse neurogenic changes. Due to the positive history of similar symptoms in his father and the diagnosis of ALS in 10 other family members, extensive genetic testing was pursued. Results : Genetic screening for GRN, C9orf72, TARDBP, SOD1, FUS, MAPT mutations, and hereditary ataxia panel, was unremarkable. Whole-exome sequencing revealed c.3020G > A (p.Arg1007Lys) mutation in the KIF5A gene, later confirmed in two affected relatives. Discussion : Similar to previous reports on KIF5A -related ALS, our index case, had a mild disease course with prolonged survival. However, as the rate of progression and survival time differed even among the same family members, other factors were probably at play. Additionally, our index case and his father displayed features overlapping ALS, spastic paraplegia, Charcot-Marie-Tooth disease type 2, and frontotemporal dementia. Therefore, we suggest considering KIF5A mutations in the differential diagnosis, particularly in the presence of overlapping features of spasticity, neuropathy, cerebellar ataxia, and dementia.
Keyphrases
- amyotrophic lateral sclerosis
- case report
- cognitive impairment
- spinal cord injury
- early onset
- cerebral palsy
- botulinum toxin
- upper limb
- genome wide
- white matter
- working memory
- multiple sclerosis
- copy number
- magnetic resonance imaging
- functional connectivity
- mild cognitive impairment
- free survival
- resting state
- emergency department
- single cell
- computed tomography
- low grade
- gene expression
- drug induced
- magnetic resonance
- children with cerebral palsy
- adverse drug
- blood brain barrier