title: Adult onset metachromatic leukodystrophy without electroclinical peripheral nervous system involvement: a new mutation in the ARSA gene.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Institute of Physiological Chemistry, University of Bonn, Bonn, Germany.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Marcão
authors.forename: Roland
authors.initials: R
authors.lastname: Wiest
authors.forename: Kaspar
authors.initials: K
authors.lastname: Schindler
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wiesmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schroth
authors.forename: Maria Clara S
authors.initials: MC
authors.lastname: Miranda
authors.forename: Matthias
authors.initials: M
authors.lastname: Sturzenegger
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000235:genetics* / Q000378:metabolism; D019343:Citric Acid / Q000494:pharmacology; D006224:Cricetinae; D004252:DNA Mutational Analysis / Q000379:methods; D016521:Electrophoresis, Gel, Pulsed-Field / Q000379:methods; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005071:Evoked Potentials / Q000502:physiology; D005091:Exons / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D007966:Leukodystrophy, Metachromatic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation; D010525:Peripheral Nerves / Q000473:pathology / Q000503:physiopathology*; D010649:Phenylalanine / Q000235:genetics; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D013497:Sural Nerve / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D014162:Transfection / Q000379:methods; D014633:Valine / Q000235:genetics
chemical_list: D000644:Quaternary Ammonium Compounds; D019343:Citric Acid; D010649:Phenylalanine; C481046:ammonium citrate; D002553:Cerebroside-Sulfatase; D014633:Valine