Disorders In Depth
Recessively inherited, demyelinating neuropathies are called CMT4 (Parman et al., 2004; Vallat et al., 2005). All cause a severe neuropathy; many patients ultimately require wheelchairs. CMT4A/GDAP1 mutations and CMT4C/SH3TC2 mutations appear to be the most common. CMT4F has more sensory involvement than the others; CMT4B1, CMT4B2, and CMT4C have distinctive pathological findings. Except for periaxin, many other cell types express the genes associated with CMT4; myelinating Schwann cells express all of the genes associated with CMT4, so that demyelination is cell autonomous.
CMT4A (OMIM 214400)
Recessive mutations in GDAP1 cause CMT4A. GDAP1 is a protein that is localized to the outer membrane of mitochondria, and is required for normal fission (Niemann et al., 2005).
Although some recessive GDAP1 mutations cause milder phenotypes, individuals with CMT4A have an early onset (typically by age 2), progressive neuropathy that results in severe proximal and distal weakness, and may cause inability to walk and vocal cord paresis (Bouhouche et al., 2007). Sensory nerve responses are absent, and motor nerve responses show variable degrees of slowing. Biopsies show a marked loss of myelinated axons, and occasional rudimentary onion bulbs. Other GDAP1 mutations cause dominant axonal CMT (CMT2K) or recessive axonal neuropathy (AR-CMT2C/CMT2B3). Because definite evidence that recessive GDAP1 mutations cause a demyelinating neuropathy is lacking, CMT4A may be a misnomer.
CMT4B-1 (OMIM 601382) and CMT4B-2 (OMIM 604563)
Recessive mutations in MTMR2 and MTMR13 cause CMT4B-1 and CMT4B-2, respectively (Prevatali et al., 2007). MTMR2 and MTMR13 form a tetramer in which MTMR2 requires the “dead” phosphatase MTMR13 to dephosphorylate the 3’ phosphate of PI(3)P and PI(3,5)P2, which tag vesicles and organelles to coordinate membrane traffic and homeostasis. The MTMR2 and MTMR13 mutants associated with CTM4B do not function, and mice with homozygous targeted genetic alterations of Mtmr2 or Mtmr13 confirm that loss of function causes demyelination. The ablation of Mtmr2 in Schwann cells alone is sufficient to cause demyelination, but it remains to be determined why this occurs.
For CMT4B1, the clinical onset was between 2 and 3 years, with difficulty walking. Distal weakness and sensory loss worsens to the point that patient stop ambulating independently by their 20s. Facial, bulbar, and diaphragmatic involvement often develop. Early in the disease, sensory responses are absent or reduced, and median motor nerve conductions are slowed, 15-20 m/s. Nerve biopsies show a loss of myelinated axons, and an outfolding of the myelin sheaths is a prominent feature in all but one of the reported cases of CMT4B1.
For CMT4B2, the clinical onset occurs by age 10, with difficulty walking. Distal weakness and sensory loss worsens to the point that patients stop ambulating independently between 10-43 years. Early in the disease, sensory responses are absent or reduced, and median motor nerve conductions are slowed, 16-21 m/s. Nerve biopsies show reduced numbers of myelinated axons, and an outfolding of the myelin sheaths. Early-onset glaucoma and hearing loss are additional features in some families.
CMT4C (OMIM 601596)
Recessive mutations in SH3TC2 cause CMT4C. SH3TC2 is an effector of Rab11, which regulates recycling endosomes. SH3TC2 mutants do not interact with Rab11, resulting in reduced endosomal recycling, which thus appears to be required for normal myelination (Roberts et al., 2010). Why myelinating Schwann cells are selectively affected, whereas SH3TC2 is widely expressed, remains unexplained.
The clinical onset is typically in childhood, but onset in the 30s has been reported. The degree of weakness is similarly variable, and slow progression is the usual course. Some patients become wheelchair-dependent. Scoliois is a frequent feature of CMT4C, and various cranial neuropathies have been noted in some patients. Sensory responses are absent and motor nerve conduction velocities in the arms range from 14-34 m/s with reduced amplitudes. Nerve biopsies show reduced numbers of myelinated axons, onion bulbs (that may mostly be comprised of basal lamina) and a peculiar ensheathment of unmyelinated axons.
CMT4D (OMIM 601455)
Recessive mutations in NDRG1 cause CMT4D. NDRG1 belongs to the superfamily of a/b hydrolases, but the crucial catalytic residues are not present. Myelinating Schwann cells, but not neurons, express NDRG1 (Berger et al., 2004), but its function in myelinating Schwann cells is unknown.
CMT4D has mainly been found in the Roma (Kalaydjieva et al., 1998); a founder effect causes a common mutation. It clinical presents as a gait disorder between 2-10 years, followed by difficulty using the hands, with commensurate atrophy. Sensation is reduced in distal extremities. Impaired hearing is common, and scoliosis is often noted. Motor conductions are ~10 m/s, and sensory responses are absent. Biopsies show reduced numbers of myelinated axons and prominent onion bulbs.
CMT4E (OMIM 605253)
Recessive mutations in EGR2 cause CMT4E. EGR2 encodes a transcription factor, EGR2/Krox20, which, along with another transcription factor, Sox10, increases the expression of many myelin-related genes. A single kindred has been found to date, in which three siblings have a severe demyelinating neuropathy (diagnosed as congenital hypomyelinating neuropathy) caused by a homozygous Ile268Asn mutation (Warner et al., 1998). The affected children were floppy at birth and had delayed motor milestones. Motor amplitudes were extremely low or absent, and conduction velocity was 3 m/s. A biopsy revealed markedly reduced numbers of myelinated axons. Mice that are homozygous for the Ile268Asn mutation also fail to myelinate, presumably because this EGR2 mutants fails to interact with a Nab2, a transcriptional co-activator (Baloh et al., 2009).
CMT4F (OMIM 145900)
Recessive mutations in PRX cause CMT4F. PRX encodes periaxin, a cytoplasmic protein that is expressed exclusively in myelinating Schwann cells. Along with DRP2, periaxin appears to be part of a complex that interacts with the dystroglycan complex. Prx-null mice have disrupted cytoplasmic channels on the outside of the myelin sheath (called Cajal bands); this may slow intracellular transport and result in abnormally short myelin internodes (and consequently, slowed conduction; (Court et al., 2004), but how this leads to demyelination remains to be shown.
Most affected individuals have delayed motor development, with distal leg weakness and atrophy developing by age 10 and hand weakness by age 15, followed by continued slow progression. In addition, patients may have a sensory ataxia and distal paresthesias. Sensory and motor responses are often absent; when the motor response is present, conduction velocity is extremely slowed (2-3 m/s). Nerve biopsies show a severe depletion of myelinated axons, as well as onion bulbs. Some milder cases (homozygous for either a Arg715stop or a Arg1070stop mutation) have also been reported: affected patients also have an early onset gait disorder, but slower progression, preserved motor responses in the arms, and faster motor conduction velocities (10-20 m/s). The milder effects of these mutations may owe to the preservation of the short isoform of peraxin; mutations that cause the more severe phenotype affect both the short and the long isoforms.
CMT4G (OMIM 605285)
CMT4G is the name given to CMT-Russe in OMIM. It is an autosomal recessive neuropathy that is mostly found in the Roma. It has been mapped to 10q23.2. Weakness in the distal legs is noted between 8-16 years, progressing with age to nearly complete paralysis of the legs accompanied by foot deformities. Hand weakness begins in the early 20s, and also progresses with age. Sensory nerve responses are absent and median motor conduction velocities average 33 m/s, without prolonged distal latencies. Sensory nerve biopsies show loss of large myelinated axons, and remarkable numbers of clusters of regenerated axons (Thomas et al., 2001). CMT4G appears to be misclassified: it has more features of a primary axonal neuropathy than a primary demyelinating neuropathy.
CMT4H (OMIM 609311)
Recessive mutations in FGD4 cause CMT4H (Delague et al., 2007; Stendel et al., 2007). FGD4 encodes Frabin, a widely expressed guanine nucleotide exchange factor (GEF) for Cdc42, one of the small rhoGTPases (including Rac1 and RhoA) that regulate cellular morphogenesis, including myelination. Because the GTP-bound form of Cdc42 is active, loss of Frabin function is predicted to decrease Cdc42 activity. The milder demyelination seen in CMT4H than in Cdc42-null nerves (in mice) suggests Cdc42 has other GEFs. Further support for the role of RhoGTPases in myelination is the identification of a mutation in another GEF, ARHGEF10, in an autosomal dominant, asymptomatic syndrome of slowed NCVs and modestly thinner myelin sheaths (Verhoeven et al., 2003).
Patients were clinically affected in the first decade, even as infants, with severe distal weakness and sensory loss. Progression is slow. Severe scoliosis may be present. Sensory responses are absent, and motor responses in the arms show marked slowing (<13 m/s). Biopsies show severe loss of myelinated axons, and myelin outfoldings that are reminescent of those seen in CMT4B1 and CTM4B2.
CMT4J (OMIM 611228)
Recessive mutations in FIG4 cause CMT4J (Chow et al., 2007). FIG4 encodes a PI(3,5)P2 5’ phosphatase. Like MTMR2/13, FIG4 is a phosphatase, but it forms a complex with Vac14 and Fab1 kinase that ultimately activates PI(3,5)P2 production. Thus, loss of FIG4 or Vac14 function produces less, not more, PIP2 in yeast and vertebrate cells – the opposite of what is expected in CMT4B1 and CMT4B2. In addition to its distinct clinical phenotype, it is suspected that neuronal abnormalities contribute to the clinical phenotype. Fig4-deficient and Vac14-null mice have a widespread neuronopathy (including sensory and motor neurons) with characteristic intracellular vacuoles. Nevertheless, there is compelling evidence of demyelination in some patients with compound heterozygous FIG4 mutations that produce partial loss of function in yeast, and in mice with homozygous Fig4 mutations, but the contribution of the demyelination to the clinical picture is unclear.
At least some cases of CMT4J are clinically distinctive from CMT, with abrupt declines of strength, and an electrophysiological appearance of a motor neuronopathy. Sensory symptoms are absent and signs are minimal (Zhang et al., 2008). In keeping with this motor predominant picture, other FIG4 mutations cause motor neuron disease (Chow et al., 2009).
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