What is the cause of Charcot-Marie-Tooth (CMT) disease?

Genetic Causes of Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth (CMT) disease is primarily caused by genetic mutations affecting genes responsible for peripheral nerve function, with the most common being PMP22 gene duplication (CMT1A) accounting for approximately 70% of demyelinating CMT cases. 1, 2

Classification of CMT Based on Genetic and Electrophysiological Findings

• CMT is classified into demyelinating forms (CMT1) and axonal forms (CMT2) based on electrophysiological studies, which are essential for proper diagnosis and genetic testing strategy 1, 2
• Inheritance patterns include autosomal dominant (most common), X-linked, and autosomal recessive 2, 3

Demyelinating Forms (CMT1)

• CMT1A: Caused by PMP22 gene duplication on chromosome 17p11.2-p12, accounting for 70% of CMT1 cases and 76-90% of sporadic CMT1 cases 1, 2, 4
• CMT1B: Caused by point mutations in the myelin protein zero (MPZ) gene, accounting for approximately 5% of all CMT cases 1, 5
• CMT1D: Results from mutations in the early growth response 2 (EGR2) gene, occurring in approximately 2.5% of cases 1, 5

Axonal Forms (CMT2)

• CMT2A: Most commonly caused by mutations in the mitofusin 2 (MFN2) gene, accounting for approximately 33% of axonal CMT cases 1, 2, 3
• Other less common mutations in various genes can cause CMT2 3

X-linked CMT (CMTX)

• Caused by mutations in the connexin 32 (Cx32/GJB1) gene, accounting for approximately 12% of all CMT cases 1, 2, 3
• Can present with either predominantly demyelinating or axonal phenotypes 1

Genetic Mechanisms in CMT

• Most CMT1A cases result from a gene dosage effect due to having three copies of a normal PMP22 gene rather than a mutant gene 4
• The majority of mutations in CMT genes are loss of function mutations including nonsense, frameshift, and splice site mutations 3
• Larger deletions and duplications of multiple exons have been recognized in CMT genes 3
• De novo mutations account for approximately 22.7% of CMT cases, explaining sporadic presentations 3

Molecular Pathophysiology

• PMP22, MPZ, and Cx32 genes all play important roles in myelin formation or maintenance of peripheral nerves 4
• CMT1A, CMT1B, and CMTX have been categorized as "myelinopathies" due to their effects on myelin 4
• In CMT1A, overexpression of PMP22 leads to demyelination, while underexpression (as seen in hereditary neuropathy with liability to pressure palsies) causes a different phenotype 4
• Mutations in MPZ affect the functional tetramers of myelin protein zero, with severe changes causing predominantly uncompacted myelin 3

Genetic Testing Approach

• A stepwise approach to genetic testing is recommended based on clinical presentation and electrophysiological findings 1, 2
• First-tier genetic testing should focus on PMP22 duplication for demyelinating forms, MFN2 mutations for axonal forms, and Cx32(GJB1) mutations for possible X-linked inheritance 1, 2
• When testing is restricted to patients with clinically probable CMT1, the yield of PMP22 duplication testing is 54-80% 1

Common Pitfalls in Genetic Diagnosis

• Failure to perform electrodiagnostic studies before genetic testing can lead to inappropriate test selection 2
• Overlooking hereditary causes in sporadic cases (30% of mutations are de novo) 2, 3
• Incomplete genetic testing (not following the recommended tiered approach) 2
• Misdiagnosis as acquired neuropathies (diabetic, toxic, or inflammatory) 2

The understanding of the genetic basis of CMT continues to evolve, with at least 47 hereditary neuropathy genes identified, though mutations are only found in approximately 50% of CMT cases, suggesting many genes remain to be discovered 3.