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.

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.

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.

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.