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The PHE64LEU Variant Of TTR Is Associated With A Late-Onset Form Of Familial Amyloidotic Polyneuropathy Dominated By Motor Involvement

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Autosomal dominant Familial Amyloidotic polyneuropathy (FAP) is caused by mutations of transthyretin (TTR). The prototype is the “Portoguese” Val30Met variant characterized by a length dependent sensory-motor and autonomic neuropathy with onset in the third-fourth decade; it affects mostly the unmyelinated and small myelinated nerve fibers with deposits of TTR-amyloid in the endo- and epineurium. Sensory or autonomic neuropathy is the first manifestation. Carpal tunnel syndrome (CTS), cardiac, renal, and ocular involvement may occur variably leading to phenotypic heterogeneity. In two unrelated Italian pedigrees originating from Apulia and Sicily we identified the Phe64Leu variant. In both pedigrees, the disorder manifested in the sixth-seventh decade with weakness of hand/leg muscles and dysesthesias in the extremities; generalized weakness and atrophy were prevalent in the distal muscles and became rapidly disabling; fasciculations were prominent, affecting also the tongue in one case with dysarthria and dysphagia. Late symptoms/signs included weight loss, impairment of thermal, pain and position sense, intractable diarrhea and vomiting. Initial diagnoses had been various: CTS, Charcot-Marie-Tooth disease, Chronic Inflammatory Demyelinating Polyneuropathy. In the two probands a nerve biopsy disclosed severe loss of myelinated fibers with scattered distribution, few Wallerian degenerations and diffuse loss of unmyelinated fibers, without evidence of amyloid deposition. Phe64Leu had been reported in two other pedigrees of Italian origin associated with a similar clinical and pathological phenotype (Ferlini A et al., Clin Genet 1996); that raises the possibility of a “founder effect.” Analysis of informative polymorphisms at nucleotide positions 2422, 2537, 5610 and 5708 of the TTR gene disclosed in the identified pedigrees a common haplotype associated with Phe64Leu (haplotype II), suggesting that the mutation might actually have occurred once and then spread in different geographical areas.
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Document Type: Abstract

Affiliations: Department of Neurological and Visual Sciences, Section of Clinical Neurology, University of Verona, Italy.

Publication date: March 1, 2001

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