Abstract

  1. Charcot-Marie-Tooth (CMT) (MIM 118220) polyneuropathy syndrome represents a clinically and genetically heterogeneous group of disorders of the peripheral nerve. Two major types are distinguished by measuring motor nerve conduction velocities (NCV). CMT1 is a demyelinating neuropathy characterized by symmetrically slowed motor NCV (usually <38 meters per second; NCV = nerve conduction velocities (m/s)). Microscopic sections of peripheral nerve in CMT1 patients reveal onion bulb formation. CMT2 is an axonal neuropathy associated with normal or near normal NCV with decreased amplitudes and axonal loss on nerve biopsy. CMT1, which is more common and usually autosomal dominant, generally presents in the second or third decade and is associated with slowly progressive symmetric distal muscle weakness and atrophy, gait disturbance, and absent stretch reflexes. CMT2 is autosomal dominant and usually manifests later in life. Different genetic subtypes of both CMT1 and CMT2 can be further delineated based on genetic linkage analysis and mapping to distinct loci.

  2. Hereditary neuropathy with liability to pressure palsies (HNPP) (MIM 162500) is a demyelinating neuropathy whose neuropathologic hallmark is sausage-like thickening of myelin sheaths (tomacula). Electrophysiological findings include mildly slowed NCV and conduction blocks. The clinical manifestations are typically episodic, nonsymmetric palsies, that may be precipitated by trauma or compression. Multifocal neuropathies, especially entrapment neuropathies such as carpal tunnel syndrome, may be manifestations of HNPP.

  3. Dejerine-Sottas syndrome (DSS) (MIM 145900) is a clinically distinct entity that is more severe than CMT. DSS has earlier onset of clinical symptoms that include delayed motor milestones, more significant slowing of NCV, more pronounced demyelination, and more numerous onion bulbs than observed in CMT. Congenital hypomyelinating neuropathy (CHN) is distinguished from DSS by its congenital manifestation and, in some cases, by absence of myelin. Roussy-Levy syndrome (RLS) (MIM 180800) combines sensory ataxia and tremor with a CMT1 phenotype but may not represent a distinct clinical entity.

  4. Most CMT1 patients have DNA rearrangements as the molecular cause of their disease. A 1.5-Mb tandem duplication, the CMT1A duplication, accounts for approximately 70 percent of CMT1 cases. A deletion of the same 1.5-Mb region in chromosome 17p12 is found in >85 percent of patients with HNPP. The CMT1A duplication and HNPP deletion result from unequal crossing over and reciprocal homologous recombination involving a 24-kb repeat—CMT1A region-specific low-copy repeats (CMT1A-REP)—that flanks the 1.5-Mb region. A meiotic recombination hotspot occurs within CMT1A-REP. The majority of the de novo duplication and deletion events occur in meiosis of the male germ cells.

  5. The CMT1A and HNPP phenotypes result from a gene dosage effect. CMT1A is due to trisomic overexpression of the peripheral myelin protein-22 gene (PMP22) whereas HNPP results from monosomic underexpression of PMP22. In rare patients without the CMT1A duplication or HNPP deletion, PMP22 point mutations can cause disease. Null alleles or haploinsufficiency cause HNPP, while gain-of-function or dominant-negative missense amino acid substitution results in CMT1A or DSS.

  6. Mutations in myelin protein zero (MPZ), connexin 32 (Cx32) or gap junction protein β1 (GJB1), and early growth response 2 (EGR2, the human Krox-20 homologue) genes can also cause CMT1 (MPZ, Cx32, EGR2), DSS (MPZ, EGR2), or CHN (MPZ, EGR2). Mutation of Cx32 causes the X-linked form of CMT. Thus, these myelinopathies appear to represent a spectrum of related disorders resulting from myelin dysfunction. Each of these genes (PMP22 , Cx32, MPZ, and EGR2) are expressed in myelinating Schwann cells so that mutations probably exert their effects on Schwann cells and may perturb axon-glia interactions.

  7. Spontaneous murine mutants Trembler (Tr) and allelic two trembler alleles in mouse. (TrJ), as well as transgenic and knockout rodents, have been instrumental in identifying myelinopathy associated disease genes and determining the molecular, cellular, and pathophysiological consequences of mutations or altered dosage of these genes.

  8. Clinical variability is the rule in inherited neuropathies. Discordance is even noted in identical twins with the CMT1A duplication. De novo CMT1A duplication is frequently found in sporadic CMT1. DSS and RLS can also be associated with CMT1A duplication. Multifocal neuropathy, autosomal dominant carpal tunnel syndrome, and CMT1 can also be associated with the HNPP deletion. These inherited demyelinating neuropathies can be difficult to distinguish from acquired demyelinating neuropathies. Because of the clinical heterogeneity, the clinical workup of a patient with peripheral neuropathy requires molecular definition. Determining an exact molecular etiology enables a precise and secure diagnosis, provides prognostic information, allows proper genetic counseling, and makes possible the design and implementation of rational therapeutic strategies.

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