Charcot-Marie-Tooth disease type 1A (CMT1A) is the single most common subtype of Charcot-Marie-Tooth disease, with a reported prevalence of approximately 1 in 5000. Although several new gene loci and genes are reported each year for novel subtypes, CMT1A remains among the best-studied forms. Characterized typically by childhood onset and slowly progressive peripheral nerve manifestations with distal dominant weakness, sensory loss, and limb deformities, occasional atypical features, including central nervous system manifestations, must be recognized. Although demyelinating by neurophysiological and histological criteria, the disease course reflects continued axonal loss. In this updated article, the authors discuss novel genotype-phenotype correlations and outcome of treatment trials.
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• Charcot-Marie-Tooth disease type 1A is the single most common subtype of Charcot-Marie-Tooth disease.
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• It has an autosomal dominant inheritance pattern.
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• It is caused by mutations in the peripheral myelin protein 22 gene.
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• It is usually characterized by childhood onset and slowly progressive peripheral nerve manifestations with distal dominant weakness, sensory loss, and limb deformities (pes cavus).
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• Demyelinating changes by neurophysiological and histological criteria are characteristic.
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• Clinical trials of pharmacologic interventions are in progress.
Historical note and terminology
Inherited peripheral neuropathies, or Charcot-Marie-Tooth disorders, were described independently in 1886 by Charcot and Marie in France and by Tooth in England (28; 157). Several earlier descriptions had been published, including a 6-generation pedigree (44) and a clinicopathological study (52). The heterogeneous nature of the condition was soon recognized; thus, Déjerine and Sottas (33) in Charcot’s group described infancy onset cases that were more severe, and Roussy and Levy (140) described cases associated with tremor that have since been defined genetically (07; 132). Different forms of inheritance were later recognized (04); however, rather than clarifying the inherited neuropathies, these descriptions actually increased nosological confusion because of the overlapping clinical and pathologic features and the lack of precise diagnostic criteria (69; 68).
With the advent of neurophysiological testing, a stringent classification became possible. Early studies suggested that Charcot-Marie-Tooth disease patients could be divided into 2 groups: 1 group with slow nerve conduction velocities and pathological evidence of a hypertrophic demyelinating neuropathy (hereditary motor and sensory neuropathy type 1 or Charcot-Marie-Tooth disease type 1), and a second group with relatively normal velocities and axonal and neuronal degeneration (hereditary motor and sensory neuropathy type 2 or Charcot-Marie-Tooth disease type 2) (43; 154; 24). The features of Charcot-Marie-Tooth diseases type 1 and type 2 patients were outlined in 2 landmark publications detailing the genetic and clinical characteristics of over 200 patients (69; 70). Most Charcot-Marie-Tooth disease patients have an autosomal dominant inheritance pattern, weakness, and muscle wasting and sensory loss predominantly in the distal legs as well as evidence of disease within the first 2 decades of life. Although nerves are not enlarged in the neuronal form, weakness is often less marked and onset is later. The distinction is difficult to make in individual patients by history and exam alone. Charcot-Marie-Tooth disease type 1 patients had median motor nerve conduction velocities below 38 m/sec, and type 2 patients had velocities above 38 m/sec. As a dividing value between both forms, nerve conduction velocities of 38 m/sec are used by some, and nerve conduction velocities of 42 m/sec by others (70; 82). Although the separation of neuronal and nonneuronal forms is an important etiologic and pathogenic distinction, it is noteworthy that even in hereditary motor and sensory neuropathy type 1, the clinical deficits appear to correlate better with progressive axonal degeneration than with slowed nerve conduction. This is not surprising given the fact that demyelination disturbs axonal structure and transport. The distinction between demyelinating and nondemyelinating hereditary motor and sensory neuropathy was called into question by De Jonghe and colleagues. They reported relatively normal conduction velocities suggestive of hereditary motor and sensory neuropathy type 2 in younger members of a family with a myelin protein zero mutation, whereas older relatives had severely slowed conduction consistent with hereditary motor and sensory neuropathy type 1 (36). Nerve conduction velocities in Charcot-Marie-Tooth disease type 1 patients have subsequently been shown to be uniformly slowed along individual nerves and between different nerves of an individual patient, distinguishing Charcot-Marie-Tooth disease type 1 patients from those with acquired demyelinating neuropathies such as Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy (96; 82). The hereditary motor and sensory neuropathy, or Charcot-Marie-Tooth type 1, disease classification system also covers hereditary motor neuropathies and hereditary sensory neuropathies and refers to other conditions linked to specific chromosomal regions or genes such as Charcot-Marie-Tooth disease type 2 and Charcot-Marie-Tooth disease type 4 with several subtypes.
Despite clinical similarities among Charcot-Marie-Tooth type 1 patients, it was soon discovered that the group was genetically heterogeneous, as linkage studies demonstrated Charcot-Marie-Tooth type 1 loci on both chromosome 1 (17) and chromosome 17 (133; 163; 111). In 1991, 2 groups showed that Charcot-Marie-Tooth type 1A, the most common form of Charcot-Marie-Tooth type 1, was associated with a 1.5 mB duplication within chromosome 17p11.2 (101; 134). Some 70% of Charcot-Marie-Tooth disease type 1 cases and 90% of Charcot-Marie-Tooth disease type 1A result from this duplication (23; 66; 171; 129). Mutations in the peripheral myelin protein 22 kD (PMP22) gene, contained within the 1.5 kB duplication on chromosome 17, have been demonstrated to cause demyelinating neuropathies in Trembler and Trembler-J mice (148; 149) as well as in some families with a Charcot-Marie-Tooth type 1 phenotype (161; 137; 118). Moreover, transgenic mice and rats that overexpress PMP22 develop neuropathies resembling Charcot-Marie-Tooth type 1 (75; 104; 143); therefore, it is now believed that the extra PMP22 gene copy within the 1.5 mB duplication on chromosome 17 causes the majority of cases of Charcot-Marie-Tooth disease type 1A. Charcot-Marie-Tooth disease type 1A also occurs with partial or complete trisomy for the short art chromosome 17 as part of a multiorgan phenotype with developmental and growth delay, craniofacial and skeletal anomalies, and heart defects (46; 146).
The 1990s also saw the identification of other Charcot-Marie-Tooth genes: Charcot-Marie-Tooth disease type 1B and some cases of Déjerine-Sottas syndrome, known to be linked to chromosome 1 q22-q23 (94), were found to be associated with mutations in the myelin protein zero gene (72; 92; 147). Charcot-Marie-Tooth disease type X1 was found to be due to mutations in the gap junction protein beta 1/connexin 32 on chromosome Xq13.1 (15), whereas the rarer X-linked Charcot-Marie-Tooth disease type X2 was mapped to chromosome Xq24-q26. Mutations in the zinc-finger domain containing transcription factor early growth response 2 gene on chromosome 10q21.1-q22.1 were linked to Charcot-Marie-Tooth disease type 1D and congenital hypomyelinating neuropathy (170). Deletion of PMP22 gene locus was associated with hereditary neuropathy with liability to pressure palsies and several other phenotypes (27). A similar condition, hereditary brachial plexus neuropathy (or hereditary neuralgic amyotrophy with predilection for the brachial plexus), is not linked to the PMP22 locus, but was mapped to chromosome 17q25 (27). Mutations of all of these genes have been associated with several overlapping clinical phenotypes. For instance, Déjerine-Sottas syndrome is associated with PMP22, Cx32, or myelin protein zero mutations or deletions (68; 119; 169; 36; 136; 170).
Several disease linkages and genes have been identified. These include 4 signal transduction genes, the N-MYC downstream-regulated gene-1 (NDRG1) on chromosome 8q24.3 for the Lom form of autosomal recessive motor and sensory neuropathy (HMSNL or CMT4D) (83), the gene for the phosphatase myotubularin-related protein-2 (MTMR2) on chromosome 11q22 for autosomal recessive CMT4B1 (21), the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) at chromosome 1q21-q22 for hereditary sensory and autonomic neuropathy type 4 (HSN4 or HSAN4), and the ganglioside-induced differentiation-associated protein-1 (GDAP1) on chromosome 8q13-q21.1 for axonal or demyelinating CMT4A (11; 31). In addition, there are several cytoskeletal associated genes, the neurofilament light subtype (NEFL) gene on chromosome 8p21 for CMT2E (108), the KIF1B gene involved in axonal organelle transport on chromosome 1p36-35 for CMT2A (175), the periaxin gene on chromosome 19q13.1-2, regulated by EGR2 and apparently responsible for the assembly of larger protein complexes at sites of cell-cell interaction, such as the myelin-axon interface through a 90 amino acid PDZ domain for recessive DSS (20), and the gene for a serine palmitoyltransferase subunit on chromosome 9q22 for hereditary sensory neuropathy type 1 (HSN1) (13; 32). A demyelinating neuropathy also results in some Pelizaeus-Merzbacher patients from absent proteolipid protein expression (60; 59). Mutations in the cytoskeletal protein gigaxonin have been linked to giant axonal neuropathy (22). A locus for autosomal dominant CMT2F was found on chromosome 7q11-q21 (78).
Loci with several candidate genes have been identified in 2 families with autosomal dominant Charcot-Marie-Tooth disease and conduction velocities between 24 to 54 m/sec: one on chromosome 19p12-p13.2 (86), the other associated with both large fiber loss and regeneration clusters as well as onion bulbs and uncompacted enlarged myelin lamellae on chromosome 10q24.1-q25.1 (105; 166). A recessively inherited severe form of Charcot-Marie-Tooth disease with intermediate conduction velocities has been linked to chromosome 10q23 (139). Intermediate conduction velocities also occur with myelin protein zero and neurofilament light subtype gene mutations (36; 35; 34).
Overall, more than 100 genes are known at present for the different forms of Charcot-Marie-Tooth disease.