Multiple sulfatase deficiency (MSD) is an ultra‐rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine‐generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X‐linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype‐phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25 years; median age at diagnosis was 2.7 years; and median age at death was 13 years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden. Earlier age at symptom onset and severe variant pathogenicity correlated with poor neurologic outcomes. Using retrospective deep phenotyping and detailed variant analysis, we defined the natural history of MSD. We found that attenuated cases can be distinguished from severe cases by age of onset, attainment of ambulation, and genotype. Results from this study can help inform prognosis and facilitate future study design.

中文翻译：

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多种硫酸酯酶缺乏症的自然史：回顾性表型和功能变异分析，以表征一种极其罕见的疾病。

多硫酸酯酶缺乏症 (MSD) 是一种由SUMF1致病变异引起的极罕见的神经退行性疾病. 该基因编码甲酰甘氨酸生成酶 (FGE)，这是一种硫酸酯酶激活所需的蛋白质。MSD 的临床病程由每种硫酸酯酶缺乏症的累加效应引起，包括异染性脑白质营养不良 (MLD)、几种粘多糖贮积症（MPS II、IIIA、IIID、IIIE、IVA、VI）、点状软骨发育不良和 X 连锁鱼鳞病。虽然已知受影响的个体表现出复杂而严重的表型，但基因型-表型关系和详细的临床过程尚不清楚。我们报告了 35 例参加我们的回顾性自然史研究的病例，n = 32 有详细的病史。用回顾性量表纵向评估神经功能。新型SUMF1 的生化和计算建模进行了变体。根据预测的功能变化对基因型进行分类，并为每个个体分配一个基因型严重程度评分。出现症状的中位年龄为 0.25 岁；诊断时的中位年龄为 2.7 岁；死亡时的中位年龄为 13 岁。所有个体都表现出发育迟缓，只有一部分个体能够行走和进行语言交流。所有受试者都经历了累积的全身症状负担。出现症状的年龄较早和严重的变异致病性与较差的神经系统结果相关。使用回顾性深度表型分析和详细的变异分析，我们定义了 MSD 的自然病程。我们发现可以通过发病年龄、活动能力和基因型将轻症病例与重症病例区分开来。