The many faces of peroxisomal disorders: Lessons from a large Arab cohort
The many faces of peroxisomal disorders: Lessons from a large Arab cohort
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DOI：
10.1111/cge.13481
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发表时间：
2019-02-01
影响因子：
3.5
通讯作者：
Alkuraya, Fowzan S.
中科院分区：
文献类型：
--
作者：
Alshenaifi, Jumanah;Ewida, Nour;Alkuraya, Fowzan S.
过氧化物酶体生物发生和/或功能的缺陷导致过氧化物酶体疾病。在这项研究中，我们描述了迄今为止最大的阿拉伯过氧化物酶体疾病患者队列（72 个家庭）的临床、生化和分子特征。在分子水平上，我们鉴定了 43 种致病变异，其中一半是新的。许多变异的创始人性质使我们能够计算出这些疾病在我们人群中的最低疾病负担，类似于 1:30 000，这比之前对其他人群的估计要高得多。在临床上，我们发现了长期生存方面基因型/表型相关性的有趣趋势。近一半 (40/75) 的过氧化物酶体疾病患者的生存期超过 1 岁。长期幸存者中最不寻常的是一个多重家庭，其中受影响的成员表现为患有非特异性智力障碍和癫痫的成年人。其他不寻常的表现包括最近描述的过氧化物酶体脂肪酰辅酶 A 还原酶 1 疾病以及 CRD、痉挛性截瘫、白质 (CRSPW) 综合征。我们得出的结论是，过氧化物酶体疾病的临床表现具有高度异质性。我们的数据还证实了“金标准”超长链脂肪酸测定不能排除较温和形式的齐薇格谱系疾病，这凸显了基因组学优先方法在这些病例中的价值。
Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population similar to 1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.