PDF(Pubmed)
Abstract：
Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency of arylsulfatase A (ARSA). Heterozygous carriers of disease-causing variants and individuals harbouring pseudodeficiency alleles in the ARSA gene exhibit reduced ARSA activity. In the context of these genotypes, low ARSA activity has been suggested to lead to an atypical form of MLD or other neurological abnormalities, but data are limited. The aim of our study was to analyse the impact of low ARSA activity in two subjects who are heterozygous for the ARSA pseudodeficiency allele and a disease-causing variant. Biochemical testing included ARSA activity measurements and urinary sulfatide analysis. Biochemical data of a large cohort of MLD patients, heterozygotes, pseudodeficient individuals and healthy controls were analysed. MRI was performed at 3T using T1- and T2-weighted sequences and MR spectroscopy. We present two long-term follow-ups who are heterozygous for the ARSA pseudodeficiency allele and a disease-causing variant in the ARSA gene in cis. The two related index cases exhibit markedly reduced ARSA activity compared to controls and heterozygous carriers. The neurological evaluation and MRI do not reveal any abnormalities. Our data underline that extremely low enzyme activity due to a pseudodeficiency allele and a disease-causing variant in the ARSA gene even in cis does not lead to clinical symptoms or pre-symptomatic MRI changes suspicious for MLD. The review of literature corroborates that any association of low ARSA activity with disease features remains questionable. It seems important to combine the measurement of ARSA activity with elevated sulfatide as well as genetic testing, as done in current newborn screening approaches. Heterozygosity for metachromatic leukodystrophy and an arylsulfatase A pseudodeficiency allele does not cause neurological or neuropsychiatric features.
摘要：
异染性脑白质营养不良（MLD）是一种由芳基硫酸酯酶A（ARSA）缺乏引起的常染色体隐性遗传性溶酶体贮积病。在ARSA基因中具有假性缺陷等位基因的致病变体的杂合携带者和个体表现出降低的ARSA活性。在这些基因型的背景下，低ARSA活性被认为会导致非典型形式的MLD或其他神经系统异常，但数据有限。我们研究的目的是分析低ARSA活性对两名受试者的影响，这些受试者是ARSA假性缺陷等位基因和致病变体的杂合子。生化测试包括ARSA活性测量和尿硫酸盐分析。大量MLD患者的生化数据，杂合子，分析了假缺陷个体和健康对照。使用T1和T2加权序列和MR波谱在3T进行MRI。我们提供了两个长期随访，它们是ARSA假性缺陷等位基因的杂合子和ARSA基因中顺式的致病变异。与对照和杂合携带者相比，两个相关的指标病例显示出ARSA活性显着降低。神经系统评估和MRI未显示任何异常。我们的数据强调，即使在顺式中，由于ARSA基因中的假性缺乏等位基因和致病变异而导致的极低的酶活性也不会导致临床症状或症状前的MRI变化，怀疑MLD。文献综述证实，低ARSA活性与疾病特征的任何关联仍然值得怀疑。将ARSA活性的测量与升高的硫酸脂以及基因检测相结合似乎很重要。正如目前新生儿筛查方法所做的那样。异染性脑白质营养不良和芳基硫酸酯酶A假性缺乏等位基因不引起神经或神经精神特征。
