Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.

中文翻译：

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NUBPL 的致病变异导致复合物 I 的基质臂组装失败，并导致丘脑受累的复杂白质脑病。

白质疾病在遗传上具有很大的异质性，包括涉及线粒体生物能学的几个基因。神经影像模式识别和下一代测序有助于根本原因的诊断。最近，复合物 I 组装因子 NUBPL 的遗传变化的特点是影响深部白质（包括胼胝体和小脑）的白质脑病的一致可识别模式。在这里，我们报告了 NUBPL 中具有双等位基因变异的双胞胎男孩，这是一个未报告的 c.351 G > A；p.(Met117Ile) 和先前报道的病理变异 c. 693 + 1 G > A。脑磁共振成像显示异常 T2 高信号，涉及脑室周围白质、外囊、胼胝体，尤其是双侧丘脑。神经影像学模式经过 18 个月的演变，出现明显的弥漫性白质信号异常、体积损失以及小脑叶和蚓部出现新的信号异常区域。磁共振波谱显示乳酸升高。培养的成纤维细胞的功能研究证实了遗传变异的致病性。通过分光光度法和凝胶内活性染色的蓝色天然凝胶，呼吸链的复合物 I 活性不足。当用 NDUFS2 抗体追踪时，复合物 I 的基质臂蛋白质不存在组装和丢失，而当用 NDUFB6 抗体追踪时，膜臂组装不完整。与对照组相比，患者成纤维细胞的蛋白质印迹显示 NUBPL 蛋白减少。NUBPL 活性受损会损害复合物 I 基质臂的组装，并产生严重的、快速进展的白质脑病，MRI 上显示丘脑受累，进一步扩大了神经影像表型。