CMT4A: identification of a Hispanic GDAP1 founder mutation

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are linked to autosomal recessive Charcot-Marie-Tooth disease type 4A.
• GDAP1 plays a crucial role in nerve function and myelination.

Purpose of the Study:

• To identify and characterize novel GDAP1 mutations in families with Charcot-Marie-Tooth disease.
• To investigate the clinical and neuropathological consequences of these mutations.

Main Methods:

• Genetic analysis of affected families to identify GDAP1 mutations.
• Clinical evaluation of patients, including neurological examinations and symptom onset.
• Neuropathological examination of nerve biopsies to assess myelin and axonal integrity.

Main Results:

• Four additional families with recessive GDAP1 mutations (Q163X and R120Q) were identified.
• The Q163X mutation was found in three unrelated Hispanic families, suggesting a common Spanish founder mutation.
• Both identified mutations resulted in demyelination and axonal loss, with early-onset symptoms (within the first two years of life) and involvement of cranial, sensory, and enteric nerves.
• Neuropathology revealed loss of large myelinated fibers, onion bulb formations, and focal folding of the outer myelin lamina.

Conclusions:

• Recessive GDAP1 mutations are a significant cause of early-onset Charcot-Marie-Tooth disease type 4A.
• The identified mutations lead to severe peripheral neuropathy with diverse nerve involvement.
• The findings highlight the importance of GDAP1 in maintaining peripheral nerve structure and function.