Extended Phenotypic Spectrum of KIF5A Mutations: From Spastic Paraplegia to Axonal Neuropathy

Overview

Journal Neurology

Specialty Neurology

Date 2014 Jul 11

PMID 25008398

Citations 57

Authors

Yo-Tsen Liu

Matilde Laura

Joshua Hersheson

Alejandro Horga

Zane Jaunmuktane

Sebastian Brandner

Alan Pittman

Deborah Hughes

James M Polke

Mary G Sweeney

Christos Proukakis

John C Janssen

Michaela Auer-Grumbach

Stephan Zuchner

Kevin G Shields

Mary M Reilly

Henry Houlden

Affiliations

Soon will be listed here.

Abstract

Objective: To establish the phenotypic spectrum of KIF5A mutations and to investigate whether KIF5A mutations cause axonal neuropathy associated with hereditary spastic paraplegia (HSP) or typical Charcot-Marie-Tooth disease type 2 (CMT2).

Methods: KIF5A sequencing of the motor-domain coding exons was performed in 186 patients with the clinical diagnosis of HSP and in 215 patients with typical CMT2. Another 66 patients with HSP or CMT2 with pyramidal signs were sequenced for all exons of KIF5A by targeted resequencing. One additional patient was genetically diagnosed by whole-exome sequencing.

Results: Five KIF5A mutations were identified in 6 unrelated patients: R204W and D232N were novel mutations; R204Q, R280C, and R280H have been previously reported. Three patients had CMT2 as the predominant and presenting phenotype; 2 of them also had pyramidal signs. The other 3 patients presented with HSP but also had significant axonal neuropathy or other additional features.

Conclusion: This is currently the largest study investigating KIF5A mutations. By combining next-generation sequencing and conventional sequencing, we confirm that KIF5A mutations can cause variable phenotypes ranging from HSP to CMT2. The identification of mutations in CMT2 broadens the phenotypic spectrum and underlines the importance of KIF5A mutations, which involve degeneration of both the central and peripheral nervous systems and should be tested in HSP and CMT2.

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