CONGENITAL HYPOMYELINATION NEUROPATHY WITH A NOVEL MUTATION OF PMP22.

Congenital hypomyelination neuropathy (CHN) has been related with mutations of the MPZ gene that codes for P0, the major structural protein of the peripheral myelin and of EGR2/Krox20 gene that codes for a transcription factor essential for the normal development of myelinating Schwann cell. More recently, we reported the association between CHN and a Ser72Leu mutation of the peripheral myelin protein 22 (PMP22), a quantitatively minor component of the compact myelin of peripheral nerves, whose functions are still debated. Here we describe a second patient with CHN associated with a novel mutation of PMP22. The patient is the 4-year-old daughter of healthy nonconsanguineous parents and is affected with early delay of motor development. At seven years she could not walk without support; examination disclosed muscle weakness and atrophy, foot drop, pes cavus, scoliosis, areflexia, and impairment of all sensory modalities. MNCV at the median nerve was 3.6 m/s. Nerve biopsy disclosed marked loss of fibers; residual fibers were devoid of myelin or encircled by extremely thin myelin sheaths and were surrounded by basal laminae onion bulbs. Clinical follow up demonstrated no progression of the disease. Molecular analysis disclosed a novel heterozygous T-to-C transition at nucleotide 374 of PMP22, that is predicted to cause a nonconservative substitution of cysteine109 (a phylogenetically conserved residue) with arginine, in the third transmembrane domain. The duplication of PMP22 causes the common demyelinating form of Charcot-Marie-Tooth neuropathy type 1 (CMT1). Our reports indicate that missense mutations of the same protein may cause dysmyelination rather than demyelination, and prompt to investigate the function of PMP22 in myelinogenesis as well as in Schwann cell differentiation. [ABSTRACT FROM AUTHOR]