Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease.
Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease.
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DOI：
10.1002/jimd.12298
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发表时间：
2020-11
影响因子：
4.2
通讯作者：
Ahrens-Nicklas RC
中科院分区：
文献类型：
--
作者：
Adang LA;Schlotawa L;Groeschel S;Kehrer C;Harzer K;Staretz-Chacham O;Silva TO;Schwartz IVD;Gärtner J;De Castro M;Costin C;Montgomery EF;Dierks T;Radhakrishnan K;Ahrens-Nicklas RC
多发性硫酸酯酶缺乏症（MSD）是一种由SUMF 1致病性变体引起的极其罕见的神经退行性疾病。该基因编码甲酰甘氨酸生成酶（FGE），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叠加效应引起，包括异染性脑白质营养不良（MLD）、几种粘多糖沉积症（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和严重的表型，但基因型-表型关系和详细的临床病程尚不清楚。我们报告了35例纳入我们的回顾性自然病史研究，n = 32详细的历史。采用回顾性量表对神经功能进行纵向评估。进行了新型SUMF 1变体的生物化学和计算建模。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。症状发作时的中位年龄为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。所有的人都表现出发育迟缓，只有一个子集的人达到了amperatum和口头交流。所有受试者均经历了累积的全身症状负担。早期症状发作和严重变异致病性与神经功能预后不良相关。使用回顾性的深度表型和详细的变异分析，我们定义了MSD的自然史。我们发现减毒病例可以通过发病年龄、获得免疫抑制和基因型与重症病例区分。这项研究的结果可以帮助告知预后和促进未来的研究设计。
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.
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影响因子：
3.8
作者：
Jaszczuk, Ilona;Schlotawa, Lars;Lugowska, Agnieszka
通讯作者：
Lugowska, Agnieszka
影响因子：
3.5
作者：
Sardiello, M;Annunziata, I;Ballabio, A
通讯作者：
Ballabio, A
影响因子：
5.2
作者：
Schlotawa, Lars;Ennemann, Eva Charlotte;Gaertner, Jutta
通讯作者：
Gaertner, Jutta
DOI：
10.3390/children4040030
发表时间：
2017-04-24
期刊：
Children (Basel, Switzerland)
影响因子：
--
作者：
Paulson A;Vargus-Adams J
通讯作者：
Vargus-Adams J
DOI：
10.1111/j.1469-8749.2010.03821.x
发表时间：
2011-02-01
影响因子：
3.8
作者：
Kehrer, Christiane;Blumenstock, Gunnar;Kraegeloh-Mann, Ingeborg
通讯作者：
Kraegeloh-Mann, Ingeborg