Ravenscroft Gianina, Di Donato Nataliya, Hahn Gabriele, Davis Mark R, Craven Paul D, Poke Gemma, Neas Katherine R, Neuhann Teresa M, Dobyns William B, Laing Nigel G
Centre for Medical Research, The University of Western Australia and Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, TU Dresden, Dresden, Germany.
Neuromuscul Disord. 2016 Nov;26(11):744-748. doi: 10.1016/j.nmd.2016.09.009. Epub 2016 Sep 19.
Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita (AMC) and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, microcephaly and bilateral perisylvian polymicrogyria. Patient 1 is 4 years of age and stable, but shows significant motor developmental delay and delayed speech. Patient 2 passed away at 7 weeks of age. Through next generation sequencing we identified the same missense substitution in BICD2 (p.Arg694Cys) in both probands. Sanger sequencing showed that in both cases the mutation arose de novo. The in utero onset in both cases suggests that the p.Arg694Cys substitution may have a more deleterious effect on BICD2 function than previously described mutations. Our results broaden the phenotypes associated with BICD2 mutations to include AMC and cortical malformations and therefore to a similar phenotypic spectrum to that associated with its binding partner DYNC1H1.
BICD2的常染色体显性遗传突变与以下肢为主的先天性脊髓性肌萎缩相关。少数病例还表现出上运动神经元病变，包括呈现类似遗传性痉挛性截瘫的特征。已发表家系的发病年龄通常在出生时，但也包括儿童期和成人期发病的病例。在本报告中，我们描述了两名孤立的先证者，他们在子宫内就表现出与胎儿活动减少相关的特征。两例均在出生时被诊断为先天性多发性关节挛缩症（AMC）和肌张力减退。其他可变特征包括先天性骨折、髋关节脱位、小颌畸形、呼吸功能不全、小头畸形和双侧外侧裂周围多小脑回。患者1 4岁，病情稳定，但存在明显的运动发育迟缓及语言发育延迟。患者2在7周龄时死亡。通过下一代测序，我们在两名先证者中均鉴定出BICD2基因相同的错义替代（p.Arg694Cys）。桑格测序显示，两例中的突变均为新发突变。两例在子宫内发病提示p.Arg694Cys替代对BICD2功能的损害可能比先前描述的突变更严重。我们的结果拓宽了与BICD2突变相关的表型，包括AMC和皮质畸形，因此与它的结合伴侣DYNC1H1相关的表型谱相似。
