A Novel Mutation in Motor Domain of KIF5A Associated With an HSP/Axonal Neuropathy Phenotype Fabrizio Rinaldi, MD,* Maria T. Bassi, MD,† Alice Todeschini, MD,* Silvia Rota, MD,* Alessia Arnoldi, MD,† Alessandro Padovani, MD, PhD,* and Massimiliano Filosto, MD, PhD* Abstract SPG10 is an autosomal dominant hereditary spastic paraplegia (HSP) caused by mutations in the gene KIF5A encoding the heavy chain of kinesin, a motor protein implied in motility functions within cells. Most of the KIF5A mutations are clustered in 2 areas of motor domain of the protein, the switch regions I and II, that are necessary for microtubules interac- tion. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity rang- ing from pure HSP to isolated peripheral nerve involvement (Charcot–Marie–Tooth phenotype) or complicated HSP phenotypes. We here describe a patient presenting with progressive walking diffi- culties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological exam- ination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies dis- closed axonal damage of peripheral nerves at lower limbs. We identified the novel variant c.967C.T in the KIF5A gene resulting in the R323W change, which is located at the C-terminus of the motor domain of the KIF5A protein, just upstream the linker region but out of the switch regions. Our findings confirm that the “mixed” central–peripheral involvement is the most frequent clinical picture related to KIF5A motor domain mutations and that motor domain “in toto,” even outside of the switch regions, is a hot spot for pathogenic mutations. We stress the concept that detection of a peripheral axonal neuropathy in an autosomal dominant HSP patient should be regarded as an important diagnostic tool and should guide clinicians to seek, first of all, KIF5A mutations. Key Words: hereditary spastic paraplegias, HSP, KI- F5A, SPG10, axonal neuropathy ( J Clin Neuromusc Dis 2015;16:153–158) INTRODUCTION Hereditary spastic paraplegias (HSP) are genetically determinate disorders characterized by a wide clinical and genetic heterogeneity. Clinically, HSP syndromes are classified in “uncomplicated HSP,” which present with lower extremity weakness and spasticity (some- times accompanied by urinary urgency and mild sensory disturbance including minor vibra- tion loss) and “complicated HSP,” in which spastic paraplegia is associated with additional neurologic or systemic abnormalities, including cognitive impairment, epilepsy, extrapyramidal signs, cerebellar ataxia, sensory system involve- ment, neuropathy, ophthalmological dysfunc- tions, and corpus callosum/cerebellar atrophy on magnetic resonance imaging. 1–3 HSPs can be inherited as autosomal dominant (AD-HSP), recessive, or X-linked traits and correspond to a growing range of mutated loci and genes (SPG1–48). 4 Autosomal dominant transmission is observed in 70%–80% of the cases in Euro- pean countries. 5 Mutations in SPAST (SPG4) and ATL1 (SPG3A) account for 50%–60% of all AD-HSP cases. 6 SPG10 is an AD-HSP caused by mutations in the gene encoding the kinesin heavy chain KIF5A involved in anterograde axonal trans- port. 6 KIF5A mutation frequency has been esti- mated in 8.8% in the Italian HSP population. 7 The age at onset ranges from childhood to the third decade, and patients can have either pure or complicated forms. 7–9 Rare cases of KIF5A- associated Charcot–Marie–Tooth 2 (CMT2)-like neuropathy were also described. 7,10,11 Here, we report molecular and clinical findings in a patient affected with an HSP/axonal Journal of CLINICAL NEUROMUSCULAR DISEASE Volume 16, Number 3 March 2015 From the *Section for Neuromuscular Diseases and Neuropathies, Clinical Neurology, University Hospital “Spedali Civili,” Brescia, Italy; and †Laboratory of Molecular Biology, Scientific Institute IRCCS Eugenio Medea, Lecco, Italy. Supported by the Italian Ministry of Health funds, under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases, the RC2013-2014, and the 5XMILLE funds to M. T. Bassi. The authors report no conflicts of interest. Reprints: Massimiliano Filosto, MD, PhD, Clinical Neurology, University Hospital “Spedali Civili,” Pz.le Spedali Civili 1, Brescia 25100, Italy (e-mail: massimiliano.filosto@unibs.it). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Case Review 153 Copyright © 201 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 5