Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease, Rockefeller University, New York, NY.
Department of Neurosurgery, Yale School of Medicine, New Haven, CT.
Ann Neurol. 2018 Nov;84(5):638-647. doi: 10.1002/ana.25327. Epub 2018 Oct 4.
To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome.
Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression.
All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth.
DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655.
明确常染色体隐性遗传发育不良性中脑-间脑交界区畸形（DMJD）综合征的病因。
对 8 个 DMJD 家系进行全外显子或靶向测序，并进行详细的临床和影像学特征分析。从患者诱导多能干细胞中分化出神经前体细胞和内皮细胞，研究基因表达。
所有患者均携带非簇集性原钙黏蛋白 12（PCDH12）基因的双等位基因突变。典型临床表现包括进行性小头畸形、颅面畸形、精神运动障碍、癫痫、轴向低张力伴不同程度的四肢痉挛。脑影像学显示脑干畸形，胼胝体变薄伴点状脑钙化，反映出 PCDH12 在神经和内皮细胞中的表达。这些细胞表现出 PCDH12 表达缺失和神经突生长受损。
DMJD 患者 PCDH12 存在双等位基因突变，导致蛋白表达缺失。这些患者表现为典型的小头畸形和白质束异常。此类致病变异预示着由于脑干畸形和白质束缺陷的证据，预后不良，并且应将其添加到与 PCDH12 相关疾病相关的表型谱中。神经病学 2018;84:646-655.
