Disorders In Depth
Charcot-Marie-Tooth disease - Advanced Description of Diseases
HNPP and CMT1
Prior to the discovery of their common genetic origin, a relationship between Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and CMT1A had not been suspected because they are so clinically distinct. Deletion and duplication of PMP22 cause HNPP and CMT1A, respectively (Shy et al., 2005). Two homologous DNA sequences flanking the PMP22 gene are the molecular basis for its deletion/duplication: their high degree of homology promotes unequal crossing over during meiosis, which simultaneously generates both a deleted and a duplicated PMP22 allele. Although de novo mutations occur, most patients inherit their deletion or duplication. PMP22 encodes peripheral myelin protein 22 kDa (PMP22), an intrinsic membrane protein of unknown function, and a component of compact myelin. Decreased and increased levels of PMP22 are thought to cause demyelination in HNPP and CMT1A, respectively.
HNPP (OMIM 162500)
HNPP is a dominantly inherited disease, probably at least as common as CMT1A, but many patients are unaware that they have a neuropathy unless they develop an episodic mononeuropathy, usually at one of the typical sites of nerve compression (Pareyson et al., 1996). In order of frequency, these are the peroneal nerve at the fibular head, the ulnar nerve at the elbow, the brachial plexus, the radial nerve at the spiral groove, and the median nerve at the wrist (Li et al., 2002). Other nerves may be affected, and atypical presentations have been described. Over half of the patients recover completely, usually within days to months, but deficits may persist. During the acute episodes of pressure palsies, electrophysiological studies may show conduction block.
In addition to focal changes at common sites of nerve entrapment, genetically affected individuals develop a mild, chronic, sensory and motor polyneuropathy. Sensory velocities are diffusely slowed, most distinctly in the upper extremities. Motor nerve conduction velocities are minimally slowed, but distal motor latencies are consistently prolonged, especially at sites prone to entrapment. Biopsies of unpalsied nerves show focal thickenings (tomacula) caused by folding of the myelin sheath, as well as segmental demyelination and remyelination.
Although deletion of PMP22 is by far the commonest cause of HNPP, other PMP22 mutations that also result in complete loss of function produce the same clinical picture.
CMT1A (OMIM 118220)
CMT1A is a dominantly inherited disease. The clinical onset is often said to occur in the first or second decade (Birouk et al., 1997; Thomas et al., 1997), but neuropathy can be detected clinically by age 5, and nerve conduction velocities are abnormally slowed even earlier. Affected patients have weakness, atrophy, and sensory loss in the distal legs followed by the distal arms; foot deformities and areflexia are variably present. There is considerable variability in the degree of neurological deficits within families, and even between identical twins, indicating that other factors modulate disease severity. Serial examinations of sensory and motor function worsen gradually (Shy et al., 2008). Atypical presentations are reported, including cranial nerve involvement, proximal weakness, diaphragmatic weakness, calf hypertrophy, and cramps.
Sensory responses are typically absent. Forearm motor conduction velocities are abnormally slowed, from 5-35 m/s; most average around 20 m/s. The lack of conduction block or temporal dispersion, and the high correlation between the conduction velocities in different motor nerves, are hallmarks. Velocities are slow in children, even before the clinical onset of disease. In individual patients, the motor nerve conduction velocities remain constant over many years, whereas the motor amplitudes decrease, albeit slowly. Nerve biopsies evolve during the disease: demyelination is more prevalent in children, and "hypomyelinated" axons (remyelinated axons with myelin sheaths that are inappropriately thin for the axonal caliber) become relatively more numerous with age (Gabreëls-Festen et al., 1992). Biopsies also show age-related loss of myelinated axons; disability correlates with axonal loss (Krajewski et al., 2000).
Although duplication of PMP22 is by far the commonest cause of CMT1A, a few PMP22 mutations produce a similar clinical picture (that has been referred to as CMT1E). Most missense PMP22 mutations, however, produce more severe neuropathy than CMT1A – CMT3/Déjérine-Sottas neuropathy (see below).
CMT1B (OMIM 118200)
Dominant mutations in MPZ cause CMT1B (Shy et al., 2004). MPZ encodes P0, the major protein of peripheral nerve myelin. P0 is an IgG-like adhesion molecule with a single intramolecular disulfide bond. P0 forms tetramers, which interact to form the molecular glue of compact myelin (Arroyo and Scherer, 2000).
More than 100 different MPZ mutations have been identified (Shy et al., 2004). A few mutations likely cause haplotype insufficiency from a simple loss-of-function; these are associated with an exceptionally mild phenotype. For most mutations, the clinical phenotype can be related to the degree of dys/demyelination as judged by conduction slowing and nerve biopsies – ranging from Congenital Hypomyelinating Neuropathy, to typical CMT1, to the exceptionally mild phenotypes noted above. In addition to causing loss of function, these mutations cause an abnormal gain of function; possibilities include a dominant-negative effect on the normal protein and an unfolded protein response (Pennuto et al., 2008). Mutations that result in unpaired cysteines are prone to cause a severe phenotype. About 25 mutations, however, have a peculiar clinical presentation – sometimes termed CMT2I, CMT2J, or CMT2-P0 (see below); the cellular basis of this phenotype remains to be determined. Most MPZ mutations causes an early onset, demyelinating neuropathy (that could often be labeled CMT3/Déjérine-Sottas neuropathy, although some patient have a favorable clinical course) or a late-onset phenotype (described below); few patients have a CMT1-like phenotype.
CMT1C (OMIM 601098)
Dominant mutations in LITAF cause CMT1C (Street et al., 2003). LITAF has been found to have several functional roles; how dominant LITAF mutations cause demyelination is unknown.
The clinical onset varies from 6-30 years. Affected patients have weakness and sensory loss in a distal distribution. Motor nerve conductions are slowed (16-33 m/s) and nerve biopsies show remyelinated axons.
CMT1D (OMIM 607687)
Dominant mutations in EGR2 cause CMT1D. EGR2 encodes a transcription factor, EGR2/Krox20, which, along with Sox10, increases the expression of many myelin-related genes (Svaren and Meijer, 2008). Dominant Krox20 mutants probably cause demyelinating neuropathy because they reduce the activity of wildtype Krox20 on myelin gene expression.
EGR2 mutations are rare, and most cause a severe, demyelinating neuropathy - Déjérine-Sottas Neuropathy or Congenital Hypomyelinating Neuropathy. A few mutations, however, are associated with a milder/CMT1 phenotype. Affected individuals have weakness and sensory loss in their distal extremities; these findings worsen with age.
CMT1E (OMIM 118300)
OMIM considers CMT1E to be CMT1 and deafness, caused by a subset of dominant PMP22 mutations, to be a distinct entity. Dr. Thomas Bird (see GeneTests website), has offered a more reasonable definition - that CMT1E is caused by a subset of PMP22 mutations (besides the more common PMP22 duplication) that result in a similar clinical picture to CMT1A.
CMT1F (OMIM 607734)
OMIM considers CMT1F to be CMT1 caused by autosomal dominant NEFL mutations. As discussed below (see CMT2E), this subset of NEFL mutations cause a severe, early-onset neuropathy with demyelinating features that are likely the result of a severe axonal pathology.
CMT1X (OMIM 302800)
CMT1X is so-named because it was linked to the X chromosome. Because female carriers are often affected, it is considered to be an X-linked dominant trait (Kleopa and Scherer, 2006). Mutations in GJB1, the gene that encodes connexin32 (Cx32), cause CMT1X; hundreds of different mutations have been identified. Cx32 forms gap junctions, which are channels on apposed cell membranes that permit the diffusion of ions and small molecules. Cx32 is localized to incisures and paranodal loops of myelinating Schwann cells, and likely forms gap junctions between adjacent layers of the myelin sheath. The loss of these gap junctions is thought to lead to demyelination and axonal loss - the chief pathological findings in humans and mice with GJB1/Gjb1 mutations.
For affected males, the clinical onset is between 5 and 20 years of age. The initial symptoms include difficulty running and frequently sprained ankles, progressing to involve the gastrocnemius and soleus muscles to the point where assistive devices are required for ambulation. Weakness, atrophy, and sensory loss also develop in the hands, particularly in thenar muscles. These clinical manifestations are the result of a chronic, length-dependent axonal loss, and are nearly indistinguishable from those seen in patients with CMT1A or CMT1B. However, muscle atrophy, particularly of intrinsic hand muscles, positive sensory phenomena, and sensory loss may be more prominent in CMT1X patients. Forearm median or ulnar motor velocities are typicall in the range of 30-40 m/s ( “intermediate”); sensory responses are typically absent except in young children.
Affected women usually have a later onset than men, after the end of second decade, and a milder version of the same phenotype at every age, because only a fraction of their myelinating Schwann cells express the mutant GJB1 allele owing to the randomness of X-inactivation. Women may even be asymptomatic, and a few kindreds have been reported to have “recessive” CMT1X. Even in these kindreds, however, at least some obligate carriers have electrophysiological evidence of peripheral neuropathy.
Many GJB1 mutations appear to be associated with electrophysiological, clinical, and/or MRI findings of CNS involvement. Subclinical involvement is common: many patients have delayed brainstem auditory evoked responses (BAER), and central visual and motor pathways may also be affected. Because these electrophysiological findings have not been found in patients with a deleted GJB1 gene, they may represent a gain of function. Clinical manifestations (spasticity, extensor plantar responses, and hyperactive reflexes) have been reported in patients with the some mutations; the degree of these findings may be masked by the peripheral neuropathy. More striking CNS findings have been reported in individual patients with duplication of amino acids 55-61 (cerebellar ataxia and dysarthria) or the Val63Ile mutation (mental retardation), but the relationship of these abnormalities to GJB1 mutations is unproven. Acute, transient encephalopathy associated with MRI changes suggesting CNS myelin dysfunction have been described; the acute deficits appear to have been triggered by travel to high altitudes, fever, or stenous physical activity (Taylor et al., 2003).
References
Arroyo EJ, Scherer SS (2000) On the molecular architecture of myelinated fibers. Histochem Cell Biol 113:1-18.
Birouk N, Gouider R, Le Guern E, Gugenheim M, Tardieu S, Maisonobe T, Le Forestier N, Agid Y, Brice A, Bouche P (1997) Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication - Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases. Brain 120:813-823.
Gabreëls-Festen AAWM, Joosten EMG, Gabreels FJM, Jennekens FGI, Kempen TWJ (1992) Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN Type-I). J Neurol Sci 107:145-154.
Kleopa KA, Scherer SS (2006) Molecular Genetics of X-linked Charcot-Marie-Tooth Disease. NeuroMolec Med 8:107-122.
Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, Kamholz J, Shy ME (2000) Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease. Brain 123:1516-1527.
Li J, Krajewski K, Shy ME, Lewis RA (2002) Hereditary neuropathy with liability to pressure palsy - The electrophysiology fits the name. Neurology 58:1769-1773.
Pareyson D, Scaioli V, Taroni F, Botti S, Lorenzetti D, Solari A, Ciano C, Sghirlanzoni A (1996) Phenotypic heterogeneity in hereditary neuropathy with liability to pressure palsies associated with chromosome 17p11.2-12 deletion. Neurology 46:1133-1137.
Pennuto M, Tinelli E, Malaguti MC, Del carro U, D'Antonio M, Ron D, Quattrini A, Feltri M-L, Wrabetz L (2008) Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in Charcot-Marie-Tooth 1B mice. Neuron 57:393-405.
Shy ME, Lupski JR, Chance PF, Klein CJ, Dyck PJ (2005) Hereditary motor and sensory neuropathies: an overview of clinical, genetic, electrophysiologic, and pathologic features. In: Peripheral Neuropathy, 4th Edition (Dyck PJ, Thomas PK, eds), pp 1623-1658. Philadelphia: Saunders.
Shy ME, Chen L, Swan ER, Taube R, Krajewski KM, Herrmann D, Lewis RA, McDermott MP (2008) Neuropathy progression in Charcot-Marie-Tooth disease type 1A. Neurology 70:378-383.
Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, Shy RR, Balsamo J, Lilien J, Garbern JY, Kamholz J (2004) Phenotypic clustering in MPZ mutations. Brain 127:371-384.
Street VA, Bennett CL, Goldy JD, Shirk AJ, Kleopa KA, Tempel BL, Lipe HP, Scherer SS, Bird TD, Chance PF (2003) Mutations of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. Neurology 60:22-26.
Svaren J, Meijer D (2008) The molecular machinery of myelin gene transcription in Schwann cells. Glia 56:1541-1551.
Taylor RA, Simon EM, Marks HG, Scherer SS (2003) The CNS phenotype of X-linked Charcot-Marie-Tooth disease - More than a peripheral problem. Neurology 61:1475-1478.
Thomas PK, Marques W, Davis MB, Sweeney MG, King RHM, Bradley JL, Muddle JR, Tyson J, Malcolm S, Harding AE (1997) The phenotypic manifestations of chromosome 17p11.2 duplication. Brain 120:465-478.
