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From the Department of Neurological and Visual Sciences (Drs. Fabrizi, Ferrarini, Cavallaro, Polo, and Rizzuto), Section of Clinical Neurology, University of Verona; and Department of Neuropediatrics (Dr. Jarre), Hospital "Regina Margherita," University of Turin, Italy.
Address correspondence and reprint requests to Dr. Gian Maria Fabrizi, Section of Clinical Neurology, Department of Neurological and Visual Sciences, University of Verona, Policlinico "G.B. Rossi," P. le L.A. Scuro 10, I-37134 Verona, Italy; e-mail: fabrizi{at}borgoroma.univr.it
OBJECTIVE: To identify the molecular basis of a demyelinating Charcot–Marie–Tooth disease type 1 (CMT1) with presumed autosomal recessive inheritance.
BACKGROUND: CMT1, an inherited motor and sensory neuropathy with low nerve conduction velocities, is caused by dominantly inherited mutations in the genes of the peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ/P0), and early growth response 2 transcription factor (EGR2/Krox-20).
PATIENTS AND METHODS: Two young sisters born of clinically and electrophysiologically healthy parents had a severe CMT1 neuropathy of presumed autosomal recessive inheritance. The older sister underwent a nerve biopsy. The authors analyzed PMP22, MPZ/P0, and EGR2/Krox-20 by automated direct nucleotide sequencing. For rapid mutation detection, they determined the restriction-fragment-length polymorphisms for TaqI in the fluorescein-labeled target DNA sequence amplified by PCR.
RESULTS: Nerve biopsy disclosed a demyelinating and remyelinating neuropathy with onion bulb formations. Both sisters had a novel heterozygous G308
A transition of MPZ/P0 without any mutation of PMP22 or EGR2/Krox-20. The G308A transition was a nonconservative mutation that changed a glycine into a glutamate at the amino acid residue 74 in the extracellular domain of the mature MPZ/P0. None of 50 healthy controls had the mutation. The healthy mother had a low amount of the mutation in blood (
20%) as well as in skin, buccal epithelium, and hairs (30%). Because the healthy mother carried clones of somatic mutant cells and had transmitted the G308A transition to the affected daughters, she also harbored germline mutant cells.
CONCLUSION: In hereditary demyelinating neuropathies, somatic and germline mosaicism of dominant mutations in the myelin protein genes may mimic autosomal recessive inheritance.
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