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Adult Onset Metachromatic Leukodystrophy Without Electroclinical Peripheral Nervous System Involvement
A New Mutation in the ARSA Gene
Ana M. Marcão, BSc;
Roland Wiest, MD;
Kaspar Schindler, MD, PhD;
Ulrich Wiesmann, MD;
Joachim Weis, MD;
Gerhard Schroth, MD;
Maria Clara S. Miranda, PhD;
Matthias Sturzenegger, MD;
Volkmar Gieselmann, MD
Arch Neurol. 2005;62:309-313.
Background Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ARSA). Clinically, the disease is heterogeneous with respect to the age of onset, affection of peripheral and central nervous systems, and progression.
Objectives To analyze mutations in the ARSA gene of a patient with adult-onset MLD with no signs of peripheral polyneuropathy and to emphasize the clinical, neuroradiologic, neuropathologic, and genetic features of the disease.
Design Case study of a patient clinically presenting with rapidly progressive dementia and behavioral abnormalities. We report the findings of clinical evaluation and neurophysiologic and neuropathologic studies of peripheral nerves; we also performed DNA sequence analysis, transfections, metabolic labeling, and immunoprecipitation of mutant ARSA polypeptides.
Setting Genetic research and clinical unit, university hospital.
Results Genetic analysis revealed homozygosity for a novel mutation in exon 3 of ARSA (F219V). This substitution leads to a misfolded unstable enzyme with a specific activity less than 1% of normal. There were no clinical or neurophysiologic signs of peripheral nervous system dysfunction. Typical neuropathologic signs for MLD were absent from nerve biopsy specimens.
Conclusions This novel mutation is associated with progressive psychocognitive impairment without clinical or electrophysiologic signs and only minor morphologic signs of peripheral nerve affection. The F219V substitution causes reduction in enzyme activity to an extent unexpected for an adult patient with MLD.
Author Affiliations: Institute of Physiological Chemistry, University of Bonn, Bonn, Germany (Ms Marcão and Dr Gieselmann); Departments of Neurology (Drs Wiest, Schindler, and Sturzenegger), Neuroradiology (Drs Wiest and Schroth), and Pediatrics (Dr Wiesmann) and Division of Neuropathology, Institute of Pathology (Dr Weis), University of Berne, Inselspital, Berne, Switzerland; and Instituto de Genética Médica Jacinto de Magalhães, Porto, Portugal (Dr Miranda). Ms Marcão is currently with the Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. Dr Weis is now with the Institute of Neuropathology, RWTH Aachen, Aachen, Germany.
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