Charcot-Marie-Tooth Disease - Wiley Online Library

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1Department of Pediatrics, Zagreb University Medical School, Zagreb, Croatia .... 1p33-36. GTP-ase, axonal transport of mitochondria severe, early onset, hearing loss,. CNS and ...... clear mechanics and impaired mechanically activated gene.
REVIEW ARTICLE

doi: 10.1111/j.1469-1809.2007.00412.x

Charcot-Marie-Tooth Disease: A Clinico-genetic Confrontation 3 ¨ N. Barisic1, ∗ , K. G. Claeys2,3 , M. Sirotkovi´c-Skerlev4 , A. Lofgren , E. Nelis3 , P. De Jonghe2,3 and V. Timmerman5 1 Department of Pediatrics, Zagreb University Medical School, Zagreb, Croatia 2 Department of Neurology, University Hospital Antwerp, Antwerpen, Belgium 3 Neurogenetics Group, Department of Molecular Genetics, “VIB”, University of Antwerp, Antwerpen, Belgium 4 Department of Pathophysiology, Zagreb University Medical School, Zagreb, Croatia 5 Peripheral Neuropathy Group, Department of Molecular Genetics, “VIB”, University of Antwerp, Antwerpen, Belgium

Summary Charcot-Marie-Tooth disease (CMT) is the most common neuromuscular disorder. It represents a group of clinically and genetically heterogeneous inherited neuropathies. Here, we review the results of molecular genetic investigations and the clinical and neurophysiological features of the different CMT subtypes. The products of genes associated with CMT phenotypes are important for the neuronal structure maintenance, axonal transport, nerve signal transduction and functions related to the cellular integrity. Identifying the molecular basis of CMT and studying the relevant genes and their functions is important to understand the pathophysiological mechanisms of these neurodegenerative disorders, and the processes involved in the normal development and function of the peripheral nervous system. The results of molecular genetic investigations have impact on the appropriate diagnosis, genetic counselling and possible new therapeutic options for CMT patients. Keywords: Charcot-Marie-Tooth disease, molecular genetics, gene product function, neurophysiology, phenotype

Introduction Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy (HMSN) comprises a group of clinically and genetically heterogeneous hereditary neuropathies. CMT is the most common inherited neuromuscular disorder, with a prevalence of 17-40 per 100,000 individuals. CMT is associated with more than 30 loci and about 20 causative genes are known thus far (http://www.molgen.ua.ac.be/CMTMutations/; http://www.neuro.wustl.edu/neuromuscular/time/hmsn. html) (see Table 1). The clinical features of HMSN include progressive distal muscle weakness and atrophy, starting in the lower limbs and later on also affecting the upper

∗ Corresponding author: Nina Barisic, MD, PhD, Department of Pediatrics, Zagreb University Medical School, Address Kispaticeva 12 Zagreb, Croatia. Phone: +385-1-23-88-531. Fax: +385-24-21894. E-mail: [email protected] 416

Annals of Human Genetics (2008) 72,416–441

extremities, steppage gait, foot deformities, distal sensory loss, and decreased or absent tendon reflexes (Harding & Thomas, 1980). Hereditary neuropathies are classified as mixed motor and sensory neuropathies (HMSN) if muscle weakness is predominant with mild sensory deficits, distal hereditary motor neuropathy (HMN) if the motor deficit is dominant, and hereditary sensory neuropathy (HSN) or hereditary sensory and autonomic neuropathy (HSAN) if sensory deficits and/or autonomic dysfunctions predominate (Dyck et al., 1993). According to electrophysiological criteria, HMSN is classified into two main subgroups: demyelinating type (HMSN I or CMT1), which is a primarily demyelinating neuropathy with severely reduced motor nerve conduction velocities (MNCV 38 m/s) but decreased amplitudes (Dyck et al., 1993). Further subdivisions within those two types are based on the inheritance pattern and the results of molecular genetic investigations.  C 2008 The Authors C 2008 University College London Journal compilation 

 C

Gene

8p23

1p33-36

1p33-36 3q13-q22,

NEFL

PMP-22

connexin -31 (GJB3)

ARGHEF 10

MFN2

KIF1B RAB7

CMT1F

2008 The Authors C 2008 University College London Journal compilation 

Special forms: HNPP

Neuropathy with hearing impairment

Hypomyelinating neuropathy without clinical symptoms Dominant:Axonal CMT2A

CMT2B

1p35.1

17p11.2-12 deletion/point mutations)

8q21

16p13 10q21-22

LITAF/SIMPLE EGR2/Krox20

CMT1C CMT1D

1q22

MPZ/P0

CMT1B

17p11.2-12 (duplication/point mutations)

Locus

synaptic vesicle transport intracellular membrane traffic

GTP-ase, axonal transport of mitochondria

development of peripheral nerve myelination

ion channel formation

protein degradation transcription factor upregulation of myelin genes neurofilaments organization, axonal transport

adhesion proteins

myelination, cell growth, differentiation

Gene product function

MNCV 15–38 m/s

MNCV < 20 m/s (in patients with early onset) > 38 m/s (in patients with late onset) MNCV 16–25 m/s MNCV 9–42 m/s

MNCV< 38 m/s, median MNCV 15-30m/s, no conduction block

Electrophysiological findings

sensory loss, feet ulcerations distal motor weakness, hyperkeratosis

severe, early onset, hearing loss, CNS and pyramidal tract involvement

Normal MNCV

very low CMAPs and SNAPs normal or slightly reduced NCV

normal, or mild decreasing, episodes of painless weakness, calf conduction block at pressure hypertrophy, asymmetrical, CNS site, prolonged distal latencies demyelination, dystonia rarely, corticosteroid efficient in some patients predominantly sensory neuropathy, MNCV and SNCV mildly reduced variable disease severity, SNAPs and CMAPs mildly asymmetrical hearing loss decreased clinically asymptomatic MNCV 27–42 m/s, CMAPs and SNAPs normal

onset in early childhood, delayed motor development, severe CMT1 phenotype, similar to DSS

progressive distal muscle weakness and atrophy, mostly at lower extremities, peroneal gait, areflexia onset in first decade, variable degree of progressive distal muscle weakness typical CMT1 cranial nerve involvement progressive scoliosis

Specific clinical phenotype

Clinical and electrophysiological findings in correlation with molecular genetics and gene product function in Charcot-Marie-Tooth disease

Dominant Demyelinating CMT1A PMP-22

Disease

Table 1

Charcot-Marie-Tooth Disease

Annals of Human Genetics (2008) 72,416–441

417

418

Annals of Human Genetics (2008) 72,416–441

GARS

NEFL

HSPB1 (HSP27)

unknown

GDAP1

MPZ

CMT2D

CMT2E

CMT2F

CMT2G

CMT2H/K

CMT 2I/J

19q12-q13.2

dynamin 2

YARS

MPZ

DI-CMTB

DI-CMTC

DI-CMTD

1q22

1p34-p35

10q24.1-q25.1

12q24.3

1q22-23

8q13-21.1

12q12-13.3

7q11-q21

8p21

7p15

12q23-q24

Locus

Dominant:Intermediate DI-CMTA unknown

HSPB8/HSP22

unknown

CMT2C

CMT2L

Gene

Continued

Disease

Table 1

vesicular traffic, endocytosis protein synthesis

mitochondrial protein expressed mostly in neurons, regulation of mitochondrial dynamics

translation process, motor neuron integrity axonal transport, neurofilament organization protection of the structure of cell proteins

Gene product function

CMT phenotype of moderate severity variable and moderate severity

CMT phenotype of moderate severity normal or increased tendon reflexes neutropenia

mild sensory loss, scoliosis

deafness, Adie pupils

sensory loss, motor impairment of different severity, small hand muscles atrophy later in the course of disease slowly progressive walking difficulties, preserved knee jerks, absent triceps surae jerks mild clinical phenotype, vocal cord paralysis, slowly progressive course

sensory loss of all modalities

diaphragmal and vocal cord paresis, death small hand muscles atrophy

Specific clinical phenotype

MNCV 25-45 m/s

MNCV