Ohba Chihiro, Osaka Hitoshi, Iai Mizue, Yamashita Sumimasa, Suzuki Yume, Aida Noriko, Shimozawa Nobuyuki, Takamura Ayumi, Doi Hiroshi, Tomita-Katsumoto Atsuko, Nishiyama Kiyomi, Tsurusaki Yoshinori, Nakashima Mitsuko, Miyake Noriko, Eto Yoshikatsu, Tanaka Fumiaki, Matsumoto Naomichi, Saitsu Hirotomo
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan,
Neurogenetics. 2013 Nov;14(3-4):225-32. doi: 10.1007/s10048-013-0375-8. Epub 2013 Oct 4.
Cerebellar and/or vermis atrophy is recognized in various types of childhood disorders with clinical and genetic heterogeneity. Although careful evaluation of clinical features and neuroimaging can lead to correct diagnosis of disorders, their diagnosis is sometimes difficult because clinical features can overlap with each other. In this study, we performed family-based whole exome sequencing of 23 families including 25 patients with cerebellar and/or vermis atrophy in childhood, who were unable to be diagnosed solely by clinical examination. Pathological mutations of seven genes were found in ten patients from nine families (9/23, 39.1 %): compound heterozygous mutations in FOLR1, C5orf42, POLG, TPP1, PEX16, and de novo mutations in CACNA1A, and ITPR1. Patient 1A with FOLR1 mutations showed extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid and serum, and Patient 6 with TPP1 mutations demonstrated markedly lowered tripeptidyl peptidase 1 activity in leukocytes. Furthermore, Patient 8 with PEX16 mutations presented a mild increase of very long chain fatty acids in the serum as supportive data for genetic diagnosis. The main clinical features of these ten patients were nonspecific and mixed, and included developmental delay, intellectual disability, ataxia, hypotonia, and epilepsy. Brain MRI revealed both cerebellar and vermis atrophy in eight patients (8/10, 80 %), vermis atrophy/hypoplasia in two patients (2/10, 20 %), and brainstem atrophy in one patient (1/10, 10 %). Our data clearly demonstrate the utility of whole exome sequencing for genetic diagnosis of childhood cerebellar and/or vermis atrophy.
小脑和/或蚓部萎缩在各种具有临床和遗传异质性的儿童疾病中均可被识别。尽管对临床特征和神经影像学进行仔细评估有助于正确诊断疾病，但有时诊断仍很困难，因为临床特征可能相互重叠。在本研究中，我们对23个家庭进行了基于家系的全外显子组测序，这些家庭中有25例儿童小脑和/或蚓部萎缩患者，他们无法仅通过临床检查确诊。在9个家庭的10例患者中发现了7个基因的病理性突变（9/23，39.1%）：FOLR1、C5orf42、POLG、TPP1、PEX16的复合杂合突变，以及CACNA1A和ITPR1的新发突变。携带FOLR1突变的患者1A脑脊液和血清中5-甲基四氢叶酸浓度极低，携带TPP1突变的患者6白细胞中三肽基肽酶1活性显著降低。此外，携带PEX16突变的患者8血清中极长链脂肪酸轻度升高，作为基因诊断的支持性数据。这10例患者的主要临床特征是非特异性且混合的，包括发育迟缓、智力障碍（智力残疾）、共济失调、肌张力减退和癫痫。脑部MRI显示8例患者（8/10，80%）存在小脑和蚓部萎缩，2例患者（2/10，20%）存在蚓部萎缩/发育不全，1例患者（1/10，10%）存在脑干萎缩。我们的数据清楚地证明了全外显子组测序在儿童小脑和/或蚓部萎缩基因诊断中的实用性。
