Neuropathy genetics

Abstract

Charcot-Marie-Tooth disease (CMT) is the most frequent form of hereditary neuropathy. Three genes commonly causing CMT encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). PMP22 duplication causes mainly demyelinating phenotype, known as CMT1A, with slowed motor nerve conduction velocity (MCV). Two distinctive phenotypic subgroups are present in patients with MPZ mutations: one shows preserved MCV and exclusively axonal pathological features, while the other is exclusively demyelinating. Patients with Cx32 mutations show intermediate slowing of MCV. Hereditary neuropathy with liability to pressure palsies (HNPP) usually is associated with a deletion of PMP22, which represents a reciprocal product of CMT1A. Focal thickening of the myelin sheath, known as tomacula, is a characteristic pathological feature in HNPP. Motor conduction studies show age-associated deterioration of compound muscle action potentials in nerves vulnerable to repetitive compression (median, ulnar, and peroneal nerves), but not in others such as the tibial nerve, suggesting that irreversible axonal damage occurs at entrapment sites in motor nerves in HNPP patients. Familial amyloid polyneuropathy (FAP) is also an important hereditary neuropathy. Although FAP was originally reported in endemic foci of Portugal, Japan, and Sweden, recent progress in diagnostic techniques has revealed that late-onset form of this disease is widely prevalent beyond these conventional endemic foci. Clinicians should consider the possibility of FAP in patients presenting with neuropathy of undetermined etiology to avoid misdiagnosis.