Isolated peripheral neuropathy in atypical metachromatic leukodystrophy: a recurrent mutation.
BACKGROUND
Metachromatic leukodystrophy (MLD) is a genetic neurodegenerative disorder resulting from a deficiency of arylsulfatase A. Late onset forms are relatively rare. Central nervous system (CNS) involvement is characteristic at all ages.


METHODS
A patient in her late 40s with peripheral neuropathy was assessed by EEG, evoked potentials, CT and nerve conduction studies. Nerve and muscle biopsy samples were investigated by electron microscopy. Arylsulfatase A activity in leukocytes and excreted cerebroside sulfate were determined. The arylsulfatase A gene was investigated for mutations using polymerase chain reaction (PCR) and DNA sequencing. The identified mutation was expressed transiently in African green monkey kidney (COS) cells to determine the effect of the mutation on arylsulfatase A activity.


RESULTS
Central nervous system functions were normal. Nerve conduction velocities were decreased. Sural nerve biopsy showed inclusions typical of MLD. Arylsulfatase A was less than 5% of normal. A homozygous mutation thr286pro was identified in the arylsulfatase A gene and demonstrated to be deleterious through transient expression studies.


CONCLUSIONS
Our patient has a progressive peripheral neuropathy but has apparently intact CNS function at her present age of 57 years. Biochemical, physiological and pathological findings are consistent with a diagnosis of MLD. A homozygous mutation, thr286pro, found in her arylsulfatase A gene, decreased enzyme activity to a level consistent with a late onset form of MLD.
Coulter-Mackie
Marion B
MB
Department of Pediatrics, University of British Columbia, Vancouver, Canada.
Applegarth
Derek A
DA
Toone
Jennifer R
JR
Gagnier
Liane
L
Anzarut
André R
AR
Hendson
Glenda
G
D000818:Animals; D001706:Biopsy; D019556:COS Cells; D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000172:deficiency; D002554:Cerebrosides / Q000652:urine; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007194:India; D007962:Leukocytes / Q000378:metabolism; D007966:Leukodystrophy, Metachromatic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000648:ultrastructure; D020125:Mutation, Missense; D009431:Neural Conduction / Q000235:genetics / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013497:Sural Nerve / Q000648:ultrastructure
D002554:Cerebrosides; C083015:cerebroside sulfate; D002553:Cerebroside-Sulfatase