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  • Updated 12.11.2023
  • Released 05.07.1999
  • Expires For CME 12.11.2026

Charcot-Marie-Tooth disease type 1B and other CMT neuropathies associated with MPZ mutations



Approximately one in 30,000 individuals in the general population suffers from Charcot-Marie-Tooth disease type 1B (CMT1B). Considering that the prevalence of Charcot-Marie-Tooth disease, in general, is one in 2500, this subtype is, thus, a relatively rare form. Although several new gene loci and genes are reported each year for novel subtypes, CMT1B remains among the best-studied forms. In this article, the authors include advances in our understanding of the clinical phenotype and the relation between particular mutations and the specific clinical and histological changes they cause.

Key points

• Charcot-Marie-Tooth disease type 1B affects about one in 30,000 individuals in the general population.

• It has an autosomal dominant inheritance pattern.

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

• It is usually characterized by childhood, 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.

Historical note and terminology

The Charcot-Marie-Tooth disease entity was recognized independently in Great Britain and France (21; 117). Several earlier descriptions had been published, including a 6-generation pedigree by Eichhorst in 1873. A more severe form of inherited neuropathy was described a few years later (27). A source of confusion was the description of a progressive childhood neuropathy associated with tremor (99), which has been defined genetically (02; 92). Different forms of inheritance were later recognized (01). Since the late 1960s, the clinical and pathological spectrum has been defined, and a classification system based on seven types of hereditary motor and sensory neuropathy has been introduced, including HMSN1 and HMSN2 (31; 44).

HMSN1 is the most common form of hereditary neuropathy, characterized by severely and uniformly slowed nerve conduction velocities and primary hypertrophic myelin pathology with prominent onion bulbs and secondary axonal changes. HMSN2, on the other hand, represents the nondemyelinating neuronal type with relatively normal nerve conduction velocities and primary axonal pathology. In the neuronal form (HMSN2), characteristically, nerves are not enlarged, weakness is often less marked, and onset is generally later, although the distinction is difficult to make in individual patients by history and exam alone. Although separating neuronal and nonneuronal forms is an important etiologic and pathogenic distinction, it is noteworthy that even in HMSN1, the clinical deficits appear to correlate better with progressive axonal degeneration than slowed nerve conduction. This is not surprising, given that demyelination disturbs axonal structure and transport. The distinction between demyelinating and nondemyelinating hereditary motor and sensory neuropathy has been called into question by a report of relatively normal nerve conduction velocities suggestive of HMSN2 in younger members of a family with a myelin protein zero mutation, whereas older relatives had severely slowed conduction consistent with HMSN1 (25). As a dividing value between both forms, some use nerve conduction velocities of 38 m/s, and others use nerve conduction velocities of 42 m/s (44; 51). Because nerve conduction velocities within and between type 1 families range from normal or near normal to severely abnormal, the diagnostic usefulness of this parameter has its limits.

The hereditary motor and sensory neuropathy and Charcot-Marie-Tooth 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 CMT2 and CMT4 with several subtypes.

In the 1980s, linkages to chromosomes 1, 17, and X were recognized for certain Charcot-Marie-Tooth pedigrees, and Charcot-Marie-Tooth was subcategorized to cover CMT1A, aka hereditary motor and sensory neuropathy 1A (70% to 80% of CMT1), CMT1B, aka hereditary motor and sensory neuropathy 1B (4% to 5% of CMT1), and CMTX (40; 118; 62) (15% of Charcot-Marie-Tooth disease). In 1991, two groups showed that CMT1A, the most common form of CMT1 disease, was associated with a 1.5 mB duplication within chromosome 17p11.2 (96). Some 90% of CMT1A cases result from this duplication (90). 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 as well as in some patients with CMT1A and CMT3 (87). Moreover, transgenic mice and rats overexpressing PMP22 develop neuropathies resembling CMT1 (106). An approximately 1.5 mB long deletion of the proximal short arm of chromosome 17 is detected in most families with hereditary neuropathy with a predisposition to pressure palsy (19), whereas about 14% to 25% of patients develop hereditary neuropathy with a predisposition to pressure palsies due to other PMP22 mutations (88). The deletion includes all markers duplicated in CMT1A. Several nondeletion mutations have been identified, such as nonsense mutations with a stop codon at G183A (Trp61stop) and G372A (Trp124stop); frameshift mutations with premature termination at 19-20delAG and 434delT or with a longer transcript at 281-282insG; splice site mutations at 78+1G>T, 179+1G>C; and missense mutations at G208A (Val30Met) in exon 3 (64). A similar condition, hereditary brachial plexus neuropathy or hereditary neuralgic amyotrophy with a predilection for the brachial plexus, is not linked to the PMP22 locus but was mapped to chromosome 17q25 (91).

The 1990s also saw the identification of other Charcot-Marie-Tooth disease genes, including myelin protein zero for CMT1B and CMT3 (46; 59; 112) and the gap junction protein connexin 32 or beta 1 on chromosome Xq13.1 for the more common CMTX1 (05), whereas the rare CMTX2 was mapped to chromosome Xq24-26 (95), and the zinc-finger domain containing transcription factor early growth response 2 gene for congenital hypomyelination neuropathy and CMT1D (122). Mutations of all of these genes have been associated with several overlapping clinical phenotypes. For instance, Dejerine-Sottas syndrome is associated with PMP22 or myelin protein zero mutations or deletions (88; 121; 26).

Several disease linkages and genes have been identified, including two 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 (52); the gene for the phosphatase myotubularin-related protein-2 (MTMR2) on chromosome 11q22 for autosomal recessive CMT4B (13); a cytoskeletal gene, the neurofilament light subtype gene on chromosome 8p21 for CMT2E (79); the periaxin gene on chromosome 19q13.1-2, which is regulated by EGR2, for recessive Dejerine-Sottas syndrome (12); the gene for a serine palmitoyltransferase subunit on chromosome 9q22 for hereditary sensory neuropathy type 1 (04; 24); and the gene involved in axonal organelle transport on chromosome 1p36-35 for CMT2A (130). A demyelinating neuropathy also results in some patients with Pelizaeus-Merzbacher from absent proteolipid protein expression. Mutations in the cytoskeletal protein gigaxonin have been linked to giant axonal neuropathy (14). A locus for autosomal dominant CMT2F was found on chromosome 7q11-q21 (49).

Loci with several candidate genes have been identified in two families with autosomal dominant Charcot-Marie-Tooth disease and conduction velocities between 24 and 54 m/s. These include one on chromosome 19p12-p13.2 (53); the other is 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 (70; 120). A recessively inherited severe form of Charcot-Marie-Tooth disease with intermediate conduction velocities is linked to chromosome 10q23 (98). Intermediate conduction velocities also occur with myelin protein zero and neurofilament light subtype gene mutations (25).

Overall, some 100 genes are known for the different forms of Charcot-Marie-Tooth disease.

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