As the molecular basis of the inherited polyneuropathies has been elucidated, it has become clear that diverse mutations and molecular defects can give rise to the same clinical phenotype. From a neurobiologic perspective, it is intriguing that both Dejerine-Sottas and Roussy-Lévy syndromes are linked to a recessively inherited loss of the myelin protein P0, and that the salient clinical features of this disorder are manifestations of defective nerve myelination. However, it has also become apparent that nearly identical clinical syndromes are associated with mutations in the genes for PMP22 and for the Schwann cell DNA-binding protein EGR2. Moreover, while some mutations in the P0 gene cause infantile onset neuropathies with the Dejerine-Sottas and Roussy-Lévy phenotypes, other mutations in the same gene cause adult onset neuropathies. Although the early-onset cases show marked slowing of nerve conduction, the adult ones have conduction velocities that are typically above 35 m/s. The infancy-onset cases reveal major disruptions of folding of compact myelin, whereas in the adult-onset cases subtle alterations in the myelin protein PO lead to a slow, predominantly axonal degeneration in adult life. Many other insights into the genetic and structural alterations of this vast category of disease have been revealed and can be appreciated from reading subspecialty texts on the subject, including the chapters by Amato and Russell and the monograph by Klein, Duan, and Shy, and the study by Saporta and coworkers, which are recommended.
Inherited Polyneuropathies of Predominantly Sensory Type
Common to the diseases comprising this group are insensitivity to pain, lancinating pains, and ulcers of the feet and hands, leading to osteomyelitis, osteolysis, stress fractures, and recurrent episodes of cellulitis. Because similar symptoms and signs occur in syringomyelia, leprosy, and tabes dorsalis, there is considerable uncertainty in older writings on this subject as to whether the reported cases were examples of one of these diseases or of hereditary neuropathy. According to Dyck and Lambert (1975), it was Leplat in 1846, who first described plantar ulcers (mal perforant du pied).
The characteristic features of this group of polyneuropathies are an autosomal dominant mode of inheritance and onset of symptoms in the second decade or later. Characteristically this begins with subtle loss of sensation for painful stimuli in the feet (e.g., inability to feel the hot sand or hot water in a tub). As the disease evolves, there is involvement of the feet with calluses of the soles and, later, episodes of blistering, ulceration, and lymphangitis followed by osteomyelitis and osteolysis, shooting pains, distal sensory loss with greater affection of pain and thermal sensation than of touch and pressure, loss of sweating, diminution or absence of tendon reflexes, and only slight loss of muscle power. Over time, loss of pain sensation in the fingers leads to fingertip ulcerations, osteomyelitis, and amputations.