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
