Expanding the spectrum of KIF5A mutations—case report of a large kindred with familial ALS and overlapping syndrome

Abstract

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.

Keywords:

• Amyotrophic lateral sclerosis
• spastic paraplegia
• Charcot-Marie-Tooth
• frontotemporal dementia
• KINESIN FAMILY MEMBER 5A
• DNA
• genetics

Declaration of interest

Jarosław Dulski: Stock ownership in medically-related fields: none. Intellectual property rights: none. Consultancies: none. Expert testimony: none. Advisory boards: none. Employment: Medical University of Gdansk, Copernicus PL Ltd., MJ Jarosław Dulski. Partnerships: none. Contracts: none. Honoraria: VM Media Ltd., Radosław Lipiński 90 Consulting, and Ipsen. Royalties: none. Grants: the Haworth Family Professorship in Neurodegenerative Diseases fund, Polish National Agency for Academic Exchange (BPN/WAL/2022/1/00007/U/00001). Other: none. Audrey J. Strongosky: Stock ownership in medically-related fields: none. Intellectual property rights: none. Consultancies: none. Expert testimony: none. Advisory boards: none. Employment: Mayo Clinic Florida. Partnerships: none. Contracts: none. Honoraria: none. Royalties: none. Grants: none. Other: none. Rana Hanna Al-Shaikh: Stock ownership in medically-related fields: none. Intellectual property rights: none. Consultancies: none. Expert testimony: none. Advisory boards: none. Employment: Mayo Clinic Florida. Partnerships: none. Contracts: none. Honoraria: none. Royalties: none. Grants: none. Other: none. Zbigniew K. Wszolek: Stock ownership in medically-related fields: none. Intellectual property rights: Mayo Clinic and ZKW have a financial interest in technologies entitled, “Identification of Mutations in PARK8, a Locus for Familial Parkinson’s Disease” and “Identification of a Novel LRRK2 Mutation, 6055G > A (G2019S), Linked to Autosomal Dominant Parkinsonism in Families from Several European Populations”. Those technologies have been licensed to a commercial entity, and to date, ZKW has received royalties <$1.500 through Mayo Clinic in accordance with its royalty sharing policies. Consultancies: Vigil Neuroscience, Inc. Expert testimony: none. Advisory boards: Vigil Neuroscience, Inc. Employment: Mayo Clinic Florida. Partnerships: none. Contracts: none. Honoraria: Polish Neurological Society—co-editor-in-chief of Neurologia i Neurochirurgia Polska. Royalties: none. Grants: NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson’s Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301), Neuraly, Inc. (NLY01-PD-1), and Vigil Neuroscience, Inc. (VGL101-01.001) grants. Other: none.

Data availability statement

The datasets from the current study are available from the corresponding author upon reasonable request.