Charcot-Marie-Tooth disease type 1A

Francisco de Assis Aquino Gondim MD MSc PhD (Dr. Gondim of Universidade Federal Ceará & Unichristus, Fortaleza, Brazil, received honorariums from Pfizer for consulting work.)
Florian P Thomas MD MA PhD MS (Dr. Thomas, Chair, Department of Neurology, Seton Hall-Hackensack Meridian School of Medicine, has no relevant financial relationships to disclose.)
Louis H Weimer MD, editor. (Dr. Weimer of Columbia University has received consulting fees from Roche.)
Originally released September 10, 1999; last updated March 10, 2017; expires March 10, 2020

This article includes discussion of Charcot-Marie-Tooth disease type 1A; CMT, type 1A; CMT1A; hereditary motor and sensory neuropathy 1A; and hereditary motor and sensory neuropathy type 1A. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

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.

Key points

 

• Charcot-Marie-Tooth disease type 1A is the single most common subtype of Charcot-Marie-Tooth disease.

 

• It has an autosomal dominant inheritance pattern.

 

• It is caused by mutations in the peripheral myelin protein 22 gene.

 

• It is usually characterized by childhood onset and slowly progressive peripheral nerve manifestations with distal dominant weakness, sensory loss, and limb deformities (pes cavus).

 

• Demyelinating changes by neurophysiological and histological criteria are characteristic.

 

• Findings of improvement with ascorbic acid in transgenic mice have, so far, not been confirmed in humans.

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 (Charcot 1886; Tooth 1886). Several earlier descriptions had been published, including a 6-generation pedigree (Eichhorst 1873) and a clinicopathological study (Friedreich 1873). The heterogeneous nature of the condition was soon recognized; thus, Déjerine and Sottas (Déjerine and Sottas 1893) in Charcot's group described infancy onset cases that were more severe, and Roussy and Levy (Roussy and Levy 1926) described cases associated with tremor that have since been defined genetically (Auer-Grumbach et al 1998; Plante-Bordeneuve et al 1999). Different forms of inheritance were later recognized (Allan 1939); 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 (Harding and Thomas 1980a; Harding 1995).

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) (Dyck and Lambert 1968; Thomas and Calne 1974; Buchthal and Behse 1977). 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 (Harding and Thomas 1980a; Harding and Thomas 1980b). 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 (Harding and Thomas 1980b; Kaku et al 1993). 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 (De Jonghe et al 1997). 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 (Lewis and Sumner 1982; Kaku et al 1993). 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 (Bird et al 1982) and chromosome 17 (Raeymaekers et al 1989; Vance et al 1989; Middleton-Price et al 1990). 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 (Lupski et al 1991; Raeymaekers et al 1991). Some 70% of Charcot-Marie-Tooth disease type 1 cases and 90% of Charcot-Marie-Tooth disease type 1A result from this duplication (Brice et al 1992; Hallam et al 1992; Wise et al 1993; Patel and Lupski 1994). 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 (Suter et al 1992a; Suter et al 1992b) as well as in some families with a Charcot-Marie-Tooth type 1 phenotype (Valentijn et al 1992; Roa et al 1993; Nelis et al 1994). Moreover, transgenic mice and rats that overexpress PMP22 develop neuropathies resembling Charcot-Marie-Tooth type 1 (Huxley et al 1996; Magyar et al 1996; Sereda et al 1996); 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 (Fernandez-Torre et al 2001; Stankiewicz et al 2001).

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 (Lebo et al 1991), were found to be associated with mutations in the myelin protein zero gene (Hayasaka et al 1993; Kulkens et al 1993; Su et al 1993). 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 (Bergoffen et al 1993), 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 (Warner et al 1998). Deletion of PMP22 gene locus was associated with hereditary neuropathy with liability to pressure palsies and several other phenotypes (Chance et al 1993; Thomas and Oliveira 2001). 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 (Chance et al 1993). 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 (Harding 1995; Nelis et al 1996; Warner et al 1996; De Jonghe et al 1997; Reilly 1998; Warner et al 1998; Thomas and Gondim 2001).

Image: Peripheral myelin protein 22 structure

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) (Kalaydjieva et al 2000), the gene for the phosphatase myotubularin-related protein-2 (MTMR2) on chromosome 11q22 for autosomal recessive CMT4B1 (Bolino et al 2000), 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 (Baxter et al 2002; Cuesta et al 2002). In addition, there are several cytoskeletal associated genes, the neurofilament light subtype (NEFL) gene on chromosome 8p21 for CMT2E (Mersiyanova et al 2000), the KIF1B gene involved in axonal organelle transport on chromosome 1p36-35 for CMT2A (Zhao et al 2001), 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 (Boerkoel et al 2001), and the gene for a serine palmitoyltransferase subunit on chromosome 9q22 for hereditary sensory neuropathy type 1 (HSN1) (Bejaoui et al 2001; Dawkins et al 2001). A demyelinating neuropathy also results in some Pelizaeus-Merzbacher patients from absent proteolipid protein expression (Garbern et al 1997; Garbern et al 1999). Mutations in the cytoskeletal protein gigaxonin have been linked to giant axonal neuropathy (Bomont et al 2000). A locus for autosomal dominant CMT2F was found on chromosome 7q11-q21 (Ismailov et al 2001).

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 (Kennerson et al 2001), 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 (Malandrini et al 2001; Verhoeven et al 2001). A recessively inherited severe form of Charcot-Marie-Tooth disease with intermediate conduction velocities has been linked to chromosome 10q23 (Rogers et al 2000). Intermediate conduction velocities also occur with myelin protein zero and neurofilament light subtype gene mutations (De Jonghe et al 1997; De Jonghe et al 1999; De Jonghe et al 2001).

Overall, some 30 genetic loci and 10 genes are known at present for the different forms of Charcot-Marie-Tooth disease.

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