Department of Neuropediatrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin und Humboldt Universität zu Berlin, Berlin, Germany.
HELIOS Kliniken - Helios Klinikum Hohenstücken, Berlin, Germany.
Eur J Hum Genet. 2021 Jul;29(7):1121-1128. doi: 10.1038/s41431-021-00846-5. Epub 2021 Mar 26.
Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND, OMIM #617519) is an autosomal recessive disease caused by homozygous or compound heterozygous variants in SPTBN4 coding for type 4 βIV-spectrin, a non-erythrocytic member of the β-spectrin family. Variants in SPTBN4 disrupt the cytoskeletal machinery that controls proper localization of ion channels and the function of axonal domains, thereby generating severe neurological dysfunction. We set out to analyze the genetic causes and describe the clinical spectrum of suspected cases of NEDHND. Variant screening was done by whole exome sequencing; clinical phenotypes were described according to the human phenotype ontology, and histochemical analysis was performed with disease-specific antibodies. We report four families with five patients harboring novel homozygous and compound heterozygous SPTBN4 variants, amongst them a multi-exon deletion of SPTBN4. All patients presented with the key features of NEDHND; severe muscular hypotonia, dysphagia, absent speech, gross motor, and mental retardation. Additional symptoms comprised horizontal nystagmus, epileptiform discharges in EEG without manifest seizures, and choreoathetosis. Muscle histology revealed both characteristics of myopathy and of neuropathy. This report expands the SPTBN4 variant spectrum, highlights the spectrum of morphological phenotypes of NEDHND-patients, and reveals clinical similarities between the NEDHND, non-5q SMA, and congenital myopathies.
神经发育障碍伴肌张力减退、周围神经病和耳聋（NEDHND，OMIM#617519）是一种常染色体隐性疾病，由编码 4 型 βIV- spectrin 的 SPTBN4 同源或复合杂合变异引起，βIV-spectrin 是非红细胞 β- spectrin 家族的成员。SPTBN4 中的变异会破坏细胞骨架机制，从而控制离子通道的正确定位和轴突区域的功能，从而产生严重的神经功能障碍。我们着手分析疑似 NEDHND 病例的遗传原因和描述其临床谱。通过全外显子组测序进行变异筛选；根据人类表型本体描述临床表型，并使用疾病特异性抗体进行组织化学分析。我们报告了四个家系的五名患者携带新的纯合和复合杂合 SPTBN4 变异，其中包括 SPTBN4 的多外显子缺失。所有患者均表现出 NEDHND 的主要特征；严重的肌肉张力减退、吞咽困难、无言语、粗大运动和智力迟钝。其他症状包括水平性眼球震颤、脑电图中有癫痫样放电而无明显癫痫发作、舞蹈手足徐动症。肌肉组织学显示既有肌病特征又有神经病特征。本报告扩展了 SPTBN4 变异谱，强调了 NEDHND 患者的形态表型谱，并揭示了 NEDHND、非 5q SMA 和先天性肌病之间的临床相似性。
