Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype.
BACKGROUND
P426L and I179S are the two most frequent mutations in juvenile and adult metachromatic leukodystrophy (late-onset MLD), which, in contrast to infantile MLD, show marked phenotypic heterogeneity.


OBJECTIVE
To search for genotype-phenotype correlations in late-onset MLD.


METHODS
The authors reviewed the clinical course of 22 patients homozygous for mutation P426L vs 20 patients heterozygous for mutation I179S, in which the second arylsulfatase A (ASA) mutation had also been determined.


RESULTS
P426L homozygotes principally presented with progressive gait disturbance caused by spastic paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at the onset of disease but became more apparent as the disease evolved. In contrast, compound heterozygotes for I179S presented with schizophrenia-like behavioral abnormalities, social dysfunction, and mental decline, but motor deficits were scarce. Reduced peripheral nerve conduction velocities and less residual ASA activity were present in P426L homozygotes vs I179S heterozygotes.


CONCLUSIONS
The characteristic clinical differences between homozygous P426L and compound heterozygous I179S patients establish a distinct genotype-phenotype correlation in late-onset metachromatic leukodystrophy.
Rauschka
H
H
Center for Brain Research, Medical University of Vienna, Department of Neurology, Hospital Lainz, Austria.
Colsch
B
B
Baumann
N
N
Wevers
R
R
Schmidbauer
M
M
Krammer
M
M
Turpin
J-C
JC
Lefevre
M
M
Olivier
C
C
Tardieu
S
S
Krivit
W
W
Moser
H
H
Moser
A
A
Gieselmann
V
V
Zalc
B
B
Cox
T
T
Reuner
U
U
Tylki-Szymanska
A
A
Aboul-Enein
F
F
LeGuern
E
E
Bernheimer
H
H
Berger
J
J
D000293:Adolescent; D000328:Adult; D002553:Cerebroside-Sulfatase / Q000235:genetics* / Q000378:metabolism; D002648:Child; D004569:Electroencephalography / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D007930:Leucine / Q000235:genetics; D007966:Leukodystrophy, Metachromatic / Q000235:genetics* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009154:Mutation; D009431:Neural Conduction / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D011392:Proline / Q000235:genetics; D018709:Statistics, Nonparametric
D007532:Isoleucine; D011392:Proline; D002553:Cerebroside-Sulfatase; D007930:Leucine