Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.
Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands.
Ann Neurol. 2015 Oct;78(4):649-58. doi: 10.1002/ana.24496. Epub 2015 Aug 21.
To identify the etiology of a novel, heritable encephalopathy in a small group of patients.
Magnetic resonance imaging (MRI) pattern analysis was used to select patients with the same pattern. Homozygosity mapping and whole exome sequencing (WES) were performed to find the causal gene mutations.
Seven patients from 4 families (2 consanguineous) were identified with a similar MRI pattern characterized by T2 signal abnormalities and diffusion restriction in the posterior limb of the internal capsule, often also optic radiation, brainstem tracts, and cerebellar white matter, in combination with delayed myelination and progressive brain atrophy. Patients presented with early infantile onset encephalopathy characterized by progressive microcephaly, seizures, variable cardiac defects, and early death. Metabolic testing was unrevealing. Single nucleotide polymorphism array revealed 1 overlapping homozygous region on chromosome 20 in the consanguineous families. In all patients, WES subsequently revealed recessive predicted loss of function mutations in ITPA, encoding inosine triphosphate pyrophosphatase (ITPase). ITPase activity in patients' erythrocytes and fibroblasts was severely reduced.
Until now ITPA variants have only been associated with adverse reactions to specific drugs. This is the first report associating ITPA mutations with a human disorder. ITPase is important in purine metabolism because it removes noncanonical nucleotides from the cellular nucleotide pool. Toxicity of accumulated noncanonical nucleotides, leading to neuronal apoptosis and interference with proteins normally using adenosine triphosphate/guanosine triphosphate, probably explains the disease. This study confirms that combining MRI pattern recognition to define small, homogeneous patient groups with WES is a powerful approach for providing a fast diagnosis in patients with an unclassified genetic encephalopathy.
确定一小群患者中一种新型遗传性脑病的病因。
使用磁共振成像（MRI）模式分析来选择具有相同模式的患者。进行纯合子作图和全外显子组测序（WES）以寻找因果基因突变。
从 4 个家庭（2 个近亲）的 7 名患者中发现了具有相似 MRI 模式的患者，其特征为后内囊体的 T2 信号异常和弥散受限，通常还包括视辐射、脑干束和小脑白质，以及髓鞘形成延迟和进行性脑萎缩。患者表现为早发性婴儿脑病，其特征为进行性小头畸形、癫痫发作、可变的心脏缺陷和早期死亡。代谢测试无异常。单核苷酸多态性阵列揭示了在近亲家庭中染色体 20 上有 1 个重叠的纯合区域。在所有患者中，WES 随后发现编码肌苷三磷酸磷酸酶（ITPase）的 ITPA 基因隐性预测失功能突变。患者的红细胞和成纤维细胞中的 ITPase 活性严重降低。
到目前为止，ITPA 变体仅与特定药物的不良反应有关。这是首次报道 ITPA 突变与人类疾病有关。ITPase 在嘌呤代谢中很重要，因为它从细胞核苷酸池中去除非典型核苷酸。积累的非典型核苷酸的毒性导致神经元凋亡，并干扰通常使用腺苷三磷酸/鸟苷三磷酸的蛋白质，这可能解释了这种疾病。本研究证实，将 MRI 模式识别与 WES 相结合，定义具有小而同质的患者群体，是为未分类遗传性脑病患者提供快速诊断的有力方法。
