A review of genetic counseling for Charcot Marie Tooth disease (CMT).

Charcot Marie Tooth disease (CMT) encompasses the inherited peripheral neuropathies. While four genes have been found to cause over 90 % of genetically identifiable causes of CMT (PMP22, GJB1, MPZ, MFN2), at least 51 genes and loci have been found to cause CMT when mutated, creating difficulties for clinicians to find a genetic subtype for families. Here, the classic features of CMT as well as characteristic features of the most common subtypes of CMT are described, as well as methods for narrowing down the possible subtypes.

Charcot-Marie-Tooth neuropathies: diagnosis and management.

Charcot-Marie-Tooth (CMT) disease is caused by mutations in several genes expressed in myelinating Schwann cells and the axons they ensheathe. Typical patients present with distally accentuated motor weakness, muscle wasting, and sensory loss leading to significant and progressive clinical morbidity and impaired quality of life. The wealth of recent information regarding genotype-phenotype correlations, recognition of disease heterogeneity, and newly characterized animal models provide exciting insights into the molecular disease-related pathogenetic and pathophysiologic mechanisms.

Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5).

We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss.

Stoichiometric alteration of PMP22 protein determines the phenotype of hereditary neuropathy with liability to pressure palsies.

Background: Hereditary neuropathy with liability to pressure palsies (HNPP) is caused by a 1.4-megabase deletion at chromosome 17p11.2, which bears the PMP22 gene and other genes.

Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration.

Mutations in the major peripheral nervous system (PNS) myelin protein, myelin protein zero (MPZ), cause Charcot-Marie-Tooth Disease type 1B (CMT1B), typically thought of as a demyelinating peripheral neuropathy. Certain MPZ mutations, however, cause adult onset neuropathy with minimal demyelination but pronounced axonal degeneration. Mechanism(s) for this phenotype are unknown.

T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy.

Objective: To determine the clinical consequences of the PMP22 point mutation, T118M, which has been previously considered to either cause an autosomal recessive form of Charcot-Marie-Tooth (CMT) disease or be a benign polymorphism.

Methods: We analyzed patients from five separate kindreds and characterized their peripheral nerve function by clinical and electrophysiological methods.

Results: All heterozygous patients had clinical and/or electrophysiological features of a neuropathy similar to hereditary neuropathy with liability to pressure palsies (HNPPs).

Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.

Objective: Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has remained elusive.

Methods: Here, we describe six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients.

SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies characterized by progressive weakness and atrophy of distal limb muscles. Recently, SIMPLE/LITAF was shown to be responsible for an autosomal dominant demyelinating form of CMT linked to 16p (CMT1C). Although two transcripts encoding different proteins (SIMPLE and LITAF) have been reported from the same gene, we could not confirm the existence of LITAF.

Genetic testing in neuromuscular disease.

With the completion of the human genome, the availability of genetic testing is becoming widespread at a rapid pace. Testing for rare neurologic conditions often is possible. With the availability of this testing, it becomes necessary for the physician to be able to determine the potential benefits of testing and when and what testing is warranted.

Loss-of-function phenotype of hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) provides a human model to investigate the role of PMP22 in myelinated peripheral nerve, since the disease is caused by a deletion of one of the two PMP22 alleles. To systematically characterize the phenotype of HNPP, we prospectively evaluated the clinical features and electrophysiological findings in 17 genetically confirmed patients, 7 men and 10 women, ranging in age from 9 to 66 years (mean, 41 +/- 13). Fifteen symptomatic patients presented with episodes of transient focal weakness or sensory loss that were usually related to particular activities causing nerve compression, including stretching or minor repetitive focal trauma.

Phenotypic clustering in MPZ mutations.

Myelin protein zero (MPZ) is a member of the immunoglobulin gene superfamily with single extracellular, transmembrane and cytoplasmic domains. Homotypic interactions between extracellular domains of MPZ adhere adjacent myelin wraps to each other. MPZ is also necessary for myelin compaction since mice which lack MPZ develop severe dysmyelinating neuropathies in which compaction is dramatically disrupted.

Motor unit number estimate of distal and proximal muscles in Charcot-Marie-Tooth disease.

In order to determine the utility of motor unit number estimation (MUNE) in assessing axonal loss in chronic inherited neuropathies, we determined MUNEs in 54 patients with Charcot-Marie-Tooth (CMT) disease (29 patients with CMT-1A, 13 with CMT-X, and 12 with CMT-2) by using spike-triggered averaging (STA) of the ulnar-innervated abductor digiti minimi/hypothenar muscles (ADM) and the musculo-cutaneous innervated biceps/brachialis (BB) muscles. MUNEs were analyzed in relationship to the corresponding compound muscle action potential (CMAP) amplitudes as well as to clinical strength. Proximal muscles, which appeared strong clinically, had evidence of chronic denervation/reinnervation, although to a lesser extent than weak distal hand muscles, supporting the concept that axonal loss in CMT occurs in a length-dependent fashion.

Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy.

Proteolipid protein (PLP1) and its alternatively spliced isoform, DM20, are the major myelin proteins in the CNS, but are also expressed in the PNS. The proteins have an identical sequence except for 35 amino acids in PLP1 (the PLP1-specific domain) not present in DM20. Mutations of PLP1/DM20 cause Pelizaeus-Merzbacher Disease (PMD), a leukodystrophy, and in some instances, a peripheral neuropathy.

Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease.

X-linked Charcot-Marie-Tooth disease (CMTX) is a hereditary demyelinating neuropathy caused by mutations in the connexin 32 (Cx32) gene. Cx32 is widely expressed in brain and peripheral nerve, yet clinical manifestations of CMTX mainly arise from peripheral neuropathy. We have evaluated two male patients with CMTX who on separate occasions developed transient ataxia, dysarthria, and weakness within 3 days of returning from ski trips at altitudes above 8,000 feet.

Hereditary neuropathy with liability to pressure palsy: the electrophysiology fits the name.

Background: Studies of patients with hereditary neuropathy with liability to pressure palsies (HNPP) have shown accentuated distal slowing along with nonuniform conduction abnormalities at segments liable to compression, suggesting a distal myelinopathy as an underlying pathophysiological mechanism.

Methods: We evaluated 12 patients with HNPP by standard nerve conduction studies and by conduction to more proximal muscles in the arm and leg. Three CMT1A patients and six healthy subjects also were evaluated as controls.

Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N-myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N-myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT-causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22.