What are the types and modes of inheritance of Hereditary Sensory and Motor Neuropathy (HSMN)?

Types and Modes of Inheritance of Hereditary Sensory and Motor Neuropathy (HSMN)

Hereditary Sensory and Motor Neuropathy (HSMN), also known as Charcot-Marie-Tooth (CMT) disease, is primarily classified into demyelinating (CMT1), axonal (CMT2), and X-linked (CMTX) forms, with inheritance patterns including autosomal dominant (most common), X-linked, and autosomal recessive. 1, 2

Primary Classification Based on Pathophysiology

• Demyelinating forms (CMT1): Characterized by damage to the myelin sheath surrounding nerve fibers, resulting in slowed nerve conduction velocities (<38 m/s) on electrodiagnostic testing 1, 3
• Axonal forms (CMT2): Characterized by damage to the nerve axon itself, with relatively preserved conduction velocities but reduced amplitude on nerve conduction studies 1, 3
• Intermediate forms: Show features of both demyelinating and axonal damage 2

Inheritance Patterns

• Autosomal dominant: Most common inheritance pattern in HSMN/CMT 2, 3
• X-linked: Seen in CMTX (GJB1/Cx32 mutations) 1, 2
• Autosomal recessive: Less common, but typically presents with more severe phenotypes 4, 5

Major HSMN/CMT Subtypes and Their Genetic Causes

Demyelinating Forms (CMT1)

• CMT1A (Autosomal dominant):

  • Most common form (70% of all CMT1 cases)
  • Caused by PMP22 gene duplication on chromosome 17p11.2
  • Accounts for 76-90% of sporadic CMT1 cases 1

• CMT1B (Autosomal dominant):

  • Caused by mutations in the MPZ gene (myelin protein zero)
  • Accounts for approximately 5% of CMT cases 1, 4

• CMT1D (Autosomal dominant):

  • Results from mutations in the EGR2 gene
  • Less common, approximately 2.5% of cases 4

• AR-CMT1 (Autosomal recessive demyelinating):

  • Previously classified as CMT4
  • Includes several subtypes with various genetic causes including GDAP1, PRX, and other mutations 5

Axonal Forms (CMT2)

• CMT2A (Autosomal dominant):

  • Most common axonal form
  • Caused by MFN2 mutations
  • Accounts for approximately 33% of CMT2 cases 1

• Other CMT2 subtypes:

  • Include mutations in NEFL, HSPB1, GARS, and other genes
  • Each represents a small percentage of cases 1, 6

• AR-CMT2 (Autosomal recessive axonal):

  • Includes several subtypes with various genetic causes
  • Often presents with more severe phenotypes 5, 7

X-linked Forms (CMTX)

• CMTX1:
  • Caused by mutations in the Cx32/GJB1 gene
  • Accounts for approximately 12% of all CMT cases
  • May present with either predominantly demyelinating or axonal features
  • Males typically more severely affected than females 1, 2

Diagnostic Approach

• Electrodiagnostic studies are essential for classifying HSMN into demyelinating or axonal subtypes 1, 3

• Genetic testing should follow a tiered approach based on:

  • Electrophysiological findings (demyelinating vs. axonal)
  • Inheritance pattern (if available)
  • Family history 1

• First-tier genetic testing:

  • For demyelinating forms with autosomal dominant inheritance: PMP22 duplication (CMT1A)
  • For axonal forms: MFN2 mutations (CMT2A)
  • For possible X-linked inheritance: Cx32/GJB1 mutations (CMTX) 1, 2

• Second-tier genetic testing:

  • MPZ mutations (5% of cases)
  • PMP22 point mutations (2.5% of cases) 1

• Third-tier genetic testing:

  • Various less common mutations including EGR2, LITAF, GDAP1, RAB7, PRX, NEFL, HSPB1, and GARS 1

Common Pitfalls in Diagnosis

• Failure to perform electrodiagnostic studies, which are essential for proper classification 2, 3
• Overlooking hereditary causes in sporadic cases (30% of mutations are de novo) 1, 3
• Incomplete genetic testing (not following the tiered approach) 1, 3
• Misdiagnosis as acquired neuropathies (diabetic, toxic, or inflammatory) 2

By following a systematic approach to diagnosis that includes electrodiagnostic studies and targeted genetic testing based on inheritance patterns and clinical features, clinicians can accurately identify the specific type of HSMN affecting their patients, which is crucial for genetic counseling and potential future targeted therapies 1, 2.