PMP22duplicaation

PMP22 duplication is a genetic alteration in which the PMP22 gene on chromosome 17p12 is present in an extra copy. This increased gene dosage commonly results in Charcot-Marie-Tooth disease type 1A (CMT1A), the most frequent form of inherited demyelinating peripheral neuropathy. The duplication typically spans about 1.5 megabases and includes PMP22 and several neighboring genes, arising through non-allelic homologous recombination.

The extra copy of PMP22 leads to overexpression of peripheral myelin protein 22, which disrupts Schwann cell function and myelin maintenance. The resulting demyelinating neuropathy slows nerve conduction and causes a length-dependent pattern of weakness and sensory loss. The condition is usually symmetric and primarily affects distal limb muscles, with common foot deformities such as pes cavus and a slowly progressive gait disturbance.

Clinically, individuals with PMP22 duplication present with progressive distal weakness and atrophy, sensory abnormalities, absent or reduced reflexes, and difficulties with walking. Onset commonly occurs in childhood or adolescence, though there is substantial clinical variability. Nerve conduction studies typically show slowed velocities consistent with a demyelinating process.

Diagnosis is confirmed by genetic testing that detects PMP22 duplication. Testing approaches include multiplex ligation-dependent probe amplification (MLPA) or array comparative genomic hybridization (array CGH). It is important to differentiate PMP22 duplication from PMP22 deletions, which cause hereditary neuropathy with liability to pressure palsies (HNPP).

Management is supportive and multidisciplinary, focusing on maintaining mobility and function. Approaches include physical and occupational therapy, orthotic devices for foot stabilization, regular foot care, and strategies to manage pain. Genetic counseling is recommended, as the condition is inherited in an autosomal dominant manner. PMP22 duplication is one of the most common genetic causes of inherited neuropathy, with Charcot-Marie-Tooth disease type 1A being its classic presentation.