A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype

Fabrizio Rinaldi, Maria T. Bassi, Alice Todeschini, Silvia Rota, Alessia Arnoldi, Alessandro Padovani, Massimiliano Filosto

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 interaction. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity ranging 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 difficulties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological examination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies disclosed 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.

Original languageEnglish
Pages (from-to)153-158
Number of pages6
JournalJournal of Clinical Neuromuscular Disease
Volume16
Issue number3
DOIs
Publication statusPublished - Mar 6 2015

Fingerprint

Hereditary Spastic Paraplegia
Phenotype
Mutation
Peripheral Nerves
Lower Extremity
Neurologic Gait Disorders
Mobility Limitation
Proprioception
Kinesin
Hypesthesia
Paresthesia
Neural Conduction
Neurologic Examination
Motor Cortex
Peripheral Nervous System Diseases
Microtubules
Genes
Tooth
Extremities
Pain

Keywords

  • axonal neuropathy
  • hereditary spastic paraplegias
  • HSP
  • KIF5A
  • SPG10

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype. / Rinaldi, Fabrizio; Bassi, Maria T.; Todeschini, Alice; Rota, Silvia; Arnoldi, Alessia; Padovani, Alessandro; Filosto, Massimiliano.

In: Journal of Clinical Neuromuscular Disease, Vol. 16, No. 3, 06.03.2015, p. 153-158.

Research output: Contribution to journalArticle

Rinaldi, Fabrizio ; Bassi, Maria T. ; Todeschini, Alice ; Rota, Silvia ; Arnoldi, Alessia ; Padovani, Alessandro ; Filosto, Massimiliano. / A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype. In: Journal of Clinical Neuromuscular Disease. 2015 ; Vol. 16, No. 3. pp. 153-158.
@article{1abc8e37d48345458449175f8fe02251,
title = "A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype",
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 interaction. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity ranging 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 difficulties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological examination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies disclosed 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.",
keywords = "axonal neuropathy, hereditary spastic paraplegias, HSP, KIF5A, SPG10",
author = "Fabrizio Rinaldi and Bassi, {Maria T.} and Alice Todeschini and Silvia Rota and Alessia Arnoldi and Alessandro Padovani and Massimiliano Filosto",
year = "2015",
month = "3",
day = "6",
doi = "10.1097/CND.0000000000000063",
language = "English",
volume = "16",
pages = "153--158",
journal = "Journal of Clinical Neuromuscular Disease",
issn = "1522-0443",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype

AU - Rinaldi, Fabrizio

AU - Bassi, Maria T.

AU - Todeschini, Alice

AU - Rota, Silvia

AU - Arnoldi, Alessia

AU - Padovani, Alessandro

AU - Filosto, Massimiliano

PY - 2015/3/6

Y1 - 2015/3/6

N2 - 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 interaction. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity ranging 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 difficulties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological examination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies disclosed 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.

AB - 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 interaction. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity ranging 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 difficulties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological examination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies disclosed 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.

KW - axonal neuropathy

KW - hereditary spastic paraplegias

KW - HSP

KW - KIF5A

KW - SPG10

UR - http://www.scopus.com/inward/record.url?scp=84924126155&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924126155&partnerID=8YFLogxK

U2 - 10.1097/CND.0000000000000063

DO - 10.1097/CND.0000000000000063

M3 - Article

VL - 16

SP - 153

EP - 158

JO - Journal of Clinical Neuromuscular Disease

JF - Journal of Clinical Neuromuscular Disease

SN - 1522-0443

IS - 3

ER -