Alhaddad Bader, Schossig Anna, Haack Tobias B, Kovács-Nagy Reka, Braunisch Matthias C, Makowski Christine, Senderek Jan, Vill Katharina, Müller-Felber Wolfgang, Strom Tim M, Krabichler Birgit, Freisinger Peter, Deshpande Charu, Polster Tilman, Wolf Nicole I, Desguerre Isabelle, Wörmann Friedrich, Rötig Agnès, Ahting Uwe, Kopajtich Robert, Prokisch Holger, Meitinger Thomas, Feichtinger René G, Mayr Johannes A, Jungbluth Heinz, Hubmann Michael, Zschocke Johannes, Distelmaier Felix, Koch Johannes
Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
Neuropediatrics. 2018 Oct;49(5):330-338. doi: 10.1055/s-0038-1661396. Epub 2018 Jun 25.
Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic mutations.
Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms.
We identified bi-allelic mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the gene and part of the neighboring gene.
deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.
双等位基因突变患者的核心临床表型被认为是原发性小头畸形和严重的全面发育迟缓。
对一个多人家庭进行连锁分析和全外显子组测序（WES），并从一个包含571名患有严重发育障碍和神经症状儿童的WES数据库中提取更多病例。
我们在来自六个无关家庭的12名儿童中鉴定出双等位基因突变。所有存活超过6个月的患者均有早发性全面发育迟缓、双侧痉挛性轻瘫、吞咽困难和难以治疗的癫痫发作，而先天性或后期出现的小头畸形并非一致的表现。脑部MRI显示有不同的异常，包括进行性大脑和小脑萎缩以及T2高信号脑干病变。5例记录有周围神经病变。所有患者的病程均为进行性，8名儿童在生命的第一个十年或第二个十年早期死亡。除了先前报道的错义突变p.(Asp106Asn)，我们还观察到一个新的纯合错义变体p.(Leu172Pro)和一个纯合的相邻基因缺失，该缺失涵盖了大部分基因和部分相邻基因。
基因缺陷导致严重的早发性疾病，影响中枢和周围神经系统。小头畸形可能不是一个普遍特征。
