Late-onset metachromatic leukodystrophy - Genotype strongly influences phenotype
Late-onset metachromatic leukodystrophy - Genotype strongly influences phenotype
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DOI：
10.1212/01.wnl.0000234129.97727.4d
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发表时间：
2006-09-12
期刊：
影响因子：
9.9
通讯作者：
Berger, J.
中科院分区：
文献类型：
--
作者：
Rauschka, H.;Colsch, B.;Berger, J.
背景：P426L和I179S是青少年和成人变色差性脑白质营养不良（迟发型MLD）中最常见的两个突变，与婴儿MLD相比，P426L和I179S表现出明显的表型异质性。目的：探讨迟发性MLD基因型与表型的相关性。方法：对22例突变为P426L纯合子的患者和20例突变为I179S杂合子的患者的临床病程进行回顾性分析，其中还确定了第二芳基磺化酶A （ASA）突变。结果：P426L纯合子主要表现为痉挛性截瘫或小脑性共济失调引起的进行性步态障碍；精神障碍在发病时不存在或不明显，但随着疾病的发展而变得更加明显。相比之下，I179S的复合杂合子表现为精神分裂症样行为异常、社交功能障碍和智力下降，但很少出现运动缺陷。与I179S杂合子相比，P426L纯合子周围神经传导速度降低，残余ASA活性降低。结论：纯合子P426L与复合杂合子I179S患者的特征性临床差异在迟发性异色性脑白质营养不良中建立了明显的基因型-表型相关性。
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. Conclusion: The characteristic clinical differences between homozygous P426L and compound heterozygous I179S patients establish a distinct genotype-phenotype correlation in late-onset metachromatic leukodystrophy.