What is the genetic inheritance pattern of Charcot-Marie-Tooth (CMT) disease?

Genetic Inheritance Pattern of Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease is inherited primarily in an autosomal dominant pattern, which is the most common mode of transmission, though X-linked and autosomal recessive patterns also occur. 1, 2, 3

Primary Inheritance Patterns

Autosomal Dominant Inheritance (Most Common)

• Autosomal dominant inheritance accounts for the majority of CMT cases, particularly CMT1 (demyelinating) and CMT2 (axonal) subtypes 1, 2, 4
• CMT1A, caused by PMP22 gene duplication, represents approximately 70% of CMT1 cases and follows autosomal dominant inheritance 1, 2
• Each affected individual has a 50% chance of transmitting the mutation to offspring 1
• Approximately 22.7% to 30% of CMT cases result from de novo mutations, meaning affected individuals may have no family history 2, 5

X-Linked Inheritance

• X-linked CMT (CMTX) is caused by mutations in the Cx32/GJB1 gene and accounts for approximately 12% of all CMT cases 1, 2, 3
• Males are typically more severely affected than carrier females 1
• CMTX can present with either demyelinating or axonal phenotypes on electrodiagnostic studies 1
• The pedigree pattern shows no male-to-male transmission, which distinguishes it from autosomal dominant inheritance 1

Autosomal Recessive Inheritance (Less Common)

• Autosomal recessive forms are less frequent but include severe early-onset variants 3, 4, 6
• Both parents must be carriers, with a 25% recurrence risk for each pregnancy 6
• These forms often present with more severe phenotypes, such as Déjérine-Sottas syndrome (HMSN-III) 6

Genotype-Specific Inheritance Patterns

CMT1 (Demyelinating Forms)

• CMT1A (PMP22 duplication): Autosomal dominant - accounts for 70% of CMT1 cases and 76-90% of sporadic CMT1 cases 1, 2
• MPZ mutations: Autosomal dominant - account for approximately 5% of CMT cases 1
• PMP22 point mutations: Autosomal dominant - account for approximately 2.5% of CMT cases 1
• EGR2 and LITAF mutations: Autosomal dominant - rare causes 1

CMT2 (Axonal Forms)

• MFN2 mutations: Autosomal dominant - account for approximately 33% of CMT2 cases 1, 2
• Other CMT2-associated genes (RAB7, GARS, NEFL, HSPB1): Predominantly autosomal dominant 1

CMTX (X-Linked Forms)

• Cx32/GJB1 mutations: X-linked dominant - account for 12% of all CMT cases 1, 2, 3

Clinical Implications for Genetic Counseling

Family History Assessment

• Obtain a three-generation pedigree focusing on symptoms of peripheral neuropathy, foot deformities, and gait abnormalities 2
• Look for patterns suggesting autosomal dominant (affected individuals in multiple generations, male-to-male transmission possible) versus X-linked (no male-to-male transmission, affected males more severe than carrier females) 1

Sporadic Cases

• Even without family history, genetic testing is warranted as 22.7-30% of mutations are de novo 2, 5
• CMT1A duplication accounts for 76-90% of sporadic CMT1 cases 1

Recurrence Risk Counseling

• For autosomal dominant forms: 50% risk to each offspring of an affected individual 1
• For X-linked forms: 50% of male offspring of carrier females will be affected; 50% of female offspring will be carriers 1
• For autosomal recessive forms: 25% recurrence risk if both parents are carriers 6

Common Pitfalls in Understanding Inheritance

• Assuming no genetic cause when family history is negative - up to 30% of cases are de novo mutations 2, 5
• Missing X-linked inheritance when pedigree is uninformative - lack of male-to-male transmission may not be apparent in small families 1
• Overlooking variable expressivity in autosomal dominant forms - some carriers may have minimal symptoms, leading to apparent "skipped generations" 1
• Failing to recognize that the same gene can cause different phenotypes - for example, MPZ mutations can cause severe early-onset disease or mild late-onset disease depending on the specific mutation 5