Genotype-phenotype correlations of KIF5A stalk domain variants
de Boer, Eva M J; van Rheenen, Wouter; Goedee, H Stephan; Kamsteeg, Erik-Jan; Brilstra, Eva H; Veldink, Jan H; van Den Berg, Leonard H; van Es, Michael A
(2021) Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration, volume 22, issue 7-8, pp. 561 - 570
(Article)
Abstract
The kinesin family member 5A (KIF5A) motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 (CMT2), while KIF5A tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of KIF5A are relatively rare. We describe a family of
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three patients with a complex HSP phenotype and a likely pathogenic KIF5A stalk variant. More family members were reported to have walking difficulties. When reviewing the literature on KIF5A stalk variants, we found 22 other cases. The phenotypes varied with most cases having (complex) HSP/CMT2 or ALS. Symptom onset varied from childhood to adulthood and common additional symptoms for HSP are involvement of the upper limbs, sensorimotor polyneuropathy, and foot deformities. We conclude that KIF5A variants lead to a broad clinical spectrum of disease. Phenotype distribution according to variants in specific domains occurs often in the motor and tail domain but are not definite. However, variants in the stalk domain are not bound to a specific phenotype.
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Keywords: Charcot-Marie-Tooth disease 2, KIF5A, amyotrophic lateral sclerosis, hereditary spastic paraplegia, stalk domain, Neurology, Clinical Neurology
ISSN: 2167-8421
Publisher: Informa Healthcare
Note: Funding Information: MAvE received grants from the Netherlands Organization for Health Research and Development (VENI scheme), The Thierry Latran foundation and the Netherlands ALS foundation (Stichting ALS Nederland), the MND association, FIGHT-MND, and the EU Joint Programme-Neurodegenerative Disease Research (JPND), has consulted for Biogen and serves on the medical ethical review board of the UMC Utrecht. Funding Information: LHvdB reports grants from ALS Foundation Netherlands, The Netherlands Organization for Health Research and Development (VICI scheme, funded through the EU Joint Programme-Neurodegenerative Disease Research, JPND [SOPHIA, STRENGTH, ALS-CarE projects), and personal fees from Shire, Cytokinetics, and Treeway, outside the submitted work. Publisher Copyright: © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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