Adult onset metachromatic leukodystrophy without electroclinical peripheral nervous system involvement: a new mutation in the ARSA gene.
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.
Marcão
Ana M
AM
Institute of Physiological Chemistry, University of Bonn, Bonn, Germany.
Wiest
Roland
R
Schindler
Kaspar
K
Wiesmann
Ulrich
U
Weis
Joachim
J
Schroth
Gerhard
G
Miranda
Maria Clara S
MC
Sturzenegger
Matthias
M
Gieselmann
Volkmar
V
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
D000644:Quaternary Ammonium Compounds; D019343:Citric Acid; D010649:Phenylalanine; C481046:ammonium citrate; D002553:Cerebroside-Sulfatase; D014633:Valine