Metachromatic leukodystrophy (MLD) is a glycosphingolipid storage disease caused by deficiency of the lysosomal enzyme arylsulfatase A (ASA) or its activator protein saposin B. MLD can affect all age groups in severity varying from a severe fatal form to milder adult onset forms. Diagnosis is usually made by measuring leukocyte ASA activity. However, this test can give false negative or false positive laboratory results due to pseudodeficiency of ASA and saposin B deficiency, respectively. Therefore, we aimed to evaluate patients with suspected MLD in a Turkish population by comprehensive clinical, biochemical, radiological, and genetic analyses for molecular and phenotypic characterization. We analyzed 28 suspected MLD patients and 41 relatives from 24 families. ASA activity was found to be decreased in 21 of 28 patients. Sixteen patients were diagnosed as MLD (11 late infantile, 2 juvenile and 3 adult types), 2 MSD, 2 pseudodeficiency (PD) and the remaining 8 patients were diagnosed as having other leukodystrophies. Enzyme analysis showed that the age of onset of MLD did not correlate with residual ASA activity. Sequence analysis showed 11 mutations in ARSA, of which 4 were novel (p.Trp195GlyfsTer5, p.Gly298Asp, p.Arg301Leu, and p.Gly311Asp), and 2 mutations in SUMF1 causing multiple sulfatase deficiency, and confirmed the diagnosis of MLD in 2 presymptomatic relatives. All individuals with confirmed mutations had low ASA activity and urinary sulfatide excretion. Intra- and inter-familial variability was high for the same ARSA missense genotypes, indicating the contribution of other factors to disease expression. Imaging findings were evaluated through a modified brain MRI scoring system which indicated patients with protein-truncating mutations had more severe MRI findings and late-infantile disease onset. MRI findings were not specific for the diagnosis. Anti-sulfatide IgM was similar to control subjects, and IgG, elevated in multiple sulfatase deficiency. In conclusion, the knowledge on the biochemical, clinical and genetic basis of MLD was expanded, a modified diagnostic laboratory algorithm for MLD based on integrated evaluation of ASA activity, urinary sulfatide excretion and genetic tests was devised.

变色性白细胞营养不良（MLD）是由溶酶体酶芳基硫酸酯酶A（ASA）或其激活蛋白saposin B缺乏引起的糖鞘脂贮积病。MLD可以影响所有年龄组，其严重程度从严重的致命性疾病到轻度的成人发作形式不等。通常通过测量白细胞ASA活性进行诊断。但是，由于ASA的假缺乏和saposin B缺乏，该测试可能会给出假阴性或假阳性实验室结果。因此，我们旨在通过全面的临床，生化，放射学和遗传学分析对分子和表型特征进行评估，以评估土耳其人群中疑似MLD的患者。我们分析了28个可疑MLD患者和来自24个家庭的41个亲属。发现28名患者中有21名ASA活性降低。16例被诊断为MLD（11例晚期婴儿，2例少年和3例成人类型），2例MSD，2例假缺陷（PD），其余8例被诊断为患有其他白细胞营养不良。酶分析显示，MLD的发病年龄与残留的ASA活性无关。序列分析显示11个突变ARSA，其中4个是新颖的（p.Trp195GlyfsTer5，p.Gly298Asp，p.Arg301Leu和p.Gly311Asp），以及SUMF1中的2个突变导致多种硫酸酯酶缺乏症，并证实了2个有症状前亲属的MLD诊断。所有已确认突变的个体均具有较低的ASA活性和尿中的硫酸脂类排泄物。同一ARSA的家族内和家族间变异性较高错义基因型，表明其他因素对疾病表达的贡献。通过改良的脑部MRI评分系统对影像学表现进行评估，该系统表明具有蛋白截断突变的患者具有更严重的MRI表现和晚期婴儿疾病发作。MRI检查结果并非特定于诊断。抗硫酸盐IgM与对照组相似，而IgG在多种硫酸酯酶缺乏症中升高。最后，扩展了关于MLD的生化，临床和遗传基础的知识，设计了一种基于ASA活性，尿液中尿硫酸酯类排泄物和基因检测综合评估的MLD改良诊断实验室算法。