CMT Type 2: Causes and Symptoms
compiled by CMTA Scientific Advisory Board Member Steven Scherer, MD, PhD, from the University of Pennsylvania.
CMT2 patients show little if any slowing in their nerve conductions, and biopsies show the loss of myelinated axons but little segmental demyelination/remyelination. Whereas the original descriptions of CMT2 identified patients affected at an older than typical CMT1 patients, the mutations that cause these late onset cases have proven difficult to identify. Rather, MFN2 mutations, the commonest cause of CMT2 identified to date, cause an axonal neuropathy that mainly has an onset in childhood. All other types of CMT2 are rare; many more genetic causes remain to be discovered.
CMT2A1 (OMIM 118210)
A dominant mutation in KIF1B, the gene encoding kinesin1B a and b isoforms, has been identified in one (CMT2A1) kindred (Zhao et al., 2001). Kinesin1B is a molecular motor for orthograde axonal transport. Because mice that are heterozygous for a loss-of-function mutation develop neuropathy, and the mutation identified in this family causes loss-of-function, haplotype insufficiency is the likely basis of neuropathy.
The age of clinical onset ranged from 3 to 15 years. Weakness was confined to the lower legs, affecting the anterior/peroneal and posterior/tibial groups. The clinical electrophysiology on one 11-year-old boy showed an absent sural response, and length-dependent, chronic denervation. A sural nerve biopsy showed decreased numbers of myelinated axons.
CMT2A2 (OMIM 609260)
Dominant mutations in Mitofusin 2 (MFN2)cause CMT2A2. Mitofusin 2 is localized in the outer membrane of mitochondria and is required for their normal fusion (Chen et al., 2003). This affects their function, as mitochondria isolated from cultured fibroblasts of CMT2A2 patients generate ATP less efficiently than those from normals.
Most MFN2 mutations have been identified in individuals with a severe axonal neuropathy, with an onset in childhood (Verhoeven et al., 2006). These patients have more proximal weakness and atrophy than patients with CMT1, suggesting the term Severe Early Onset Axonal Neuropathy (Nicholson et al., 2008). Many patients with early onset become wheelchair-dependent. MFN2 mutations have also been found in CMT2 patients with an onset in young adults, and penetrance may be variable even within a family. A few patients have optic neuropathies, myelopathy, and even cerebral dysfunction. Sensory and motor amplitudes are reduced or absent, and motor conduction velocities are normal or slowed to 37 m/s. Biopsies show loss of large myelinated axons and clusters of regenerated axons.
CMT2B (OMIM 600882)
Dominant mutations in RAB7 cause CMT2B. RAB7 is associated with late endosomes, including those that mediate retrograde axonal transport of growth factors. The mutations that cause CMT2 alter structure of the binding pocket for GDP and GTP binding, thereby increasing their on and off rates of binding; this could affect retrograde axonal transport (McCray et al., 2010).
Affected patients have length-dependent weakness and severe sensory loss, distal ulcerations in the feet are common, often leading to toe amputations. Electrophysiological studies and nerve biopsies provide evidence of axonal loss that is length- and time-dependent. Thus, CMT2B shares a similar clinical picture with HSAN1, although spontaneous pain is not a feature of CMT2B (Auer-Grumbach, 2008).
CMT2C (OMIM 606071)
Some dominant mutations in TRPV4 cause CMT2C; these are distinct from other dominant mutations that cause developmental abnormalities in bone (OMIM 113500, 184252, 156530). TRPV4 is a cation channel that is found in many cell types, including axons. The dominant TRPV4 mutants may generate an abnormal channel that injures axons, thereby causing an axonal neuropathy (Landoure´ et al., 2010).
Patients are variably affected (Zimon et al., 2010). The most severely affected patients have severe proximal and distal weakness, including involvement of the vocal cords, even arthrogryposis and scoliosis. Sensory abnormalities are mild by comparison.
CMT2D (OMIM 601472)
Dominant mutations in Glycyl-tRNA Synthase (GARS) cause CMT2D. GARS encodes the enzyme that couples glycine to its tRNA. There is only one GARS gene, and it is expressed in every cell type and is presumed to be required for cellular function. How GARS mutations cause an axonal neuropathy is unknown.
Patients with CMT2D have a motor greater than sensory neuropathy, to the point that some cases (even belonging to the same family) have been considered have HMN V (Sivakumar et al., 2005). In the few reported cases, the onset varies from childhood to adolescence. The distinguishing feature of CMT2D is that the weakness of the intrinsic hand muscles is out of proportion to that in the distal legs, but this does not hold in cases with onset in childhood (James et al., 2006).
CMT2E (OMIM 162280)
Dominant mutations in NEFL cause CMT2E. NEFL encodes the smallest of the three subunits that comprise neurofilaments, which are the predominant cytoskeletal element in axons.
The age of onset and clinic phenotype vary considerably (Jordanova et al., 2003). In a large Russian kindred, clinical manifestations become apparent in the 2nd or 3rd decades, followed by slow progression, with mildly reduced or normal median motor conduction velocities (38-52 m/s). Other mutations cause an early onset (even a Déjérine-Sottas-like phenotype), and motor conductions can be slowed well into the demyelinating range; these patients have been referred to as CMT1F, but this is not a classic demyelinating neuropathy as nerve biopsies do not show abundant remyelinated axons. Rather, biopsies show loss of large myelinated axons, and the biopsies from the patients who have “demyelinating” mutations show abnormally enlarged axons containing disorganized groups of neurofilaments.
CMT2F (OMIM 606595)
Dominant mutations in HSPB1 have been reported to cause CMT2F; other mutations produce a more purely motor phenotype, HMN IIb (see below). HSPB1 encodes heat shock protein 27 kDa (HSP27), which is one of several small chaparone proteins with diverse cellular functions. HSP27 directly interacts with HSP22, which is affected in CMT2L (and HMN IIa).
The clinical onset of weakness ranges from the second to the fourth decade, followed by the development of prominent weakness in the distal muscles of the legs then arms.