INTRODUCTION Hypomyelinating leukodystrophies (HLDs) are genetically heterogeneous syndromes, presenting abnormalities in myelin development in the central nervous system. Recently, a recurrent de novo mutation in TMEM106B was identified to be responsible for five cases of HLD. We report the first Japanese case of TMEM106B gene mutation. CASE STUDY A 3-year-old patient presented with nystagmus and muscle hypotonia in his neonatal period, followed by delayed psychomotor development. Brain magnetic resonance images showed delayed myelination. Wave III and subsequent components were not presented by his auditory brainstem response. These features were similar to those observed in Pelizaeus-Merzbacher disease (PMD). METHODS Proteolipid protein 1 (PLP1) gene screening, Mendelian disease panel exome, and whole-exome sequencing (WES) were sequentially performed. RESULTS After excluding mutations in either PLP1 or other known HLD genes, WES identified a mutation c.754G > A, p.(Asp252Asn) in TMEM106B, which appeared to occur de novo, as shown by Sanger sequencing and SalI restriction enzyme digestion of PCR products. DISCUSSION This is the sixth case of HLD with a TMEM106B mutation. All six cases harbored the same variant. This specific TMEM106B mutation should be investigated when a patient shows PMD-like features without PLP1 mutation. Our PCR-SalI digestion assay may serve as a tool for rapid HLD diagnosis.

中文翻译：

---

髓鞘形成性脑白质营养不良的复发性 TMEM106B 突变：快速诊断分析

引言 髓鞘形成性脑白质营养不良 (HLD) 是遗传异质性综合征，表现为中枢神经系统髓鞘发育异常。最近，发现 TMEM106B 中反复发生的从头突变与五例 HLD 相关。我们报告了日本第一例 TMEM106B 基因突变病例。案例研究 一名 3 岁患者在新生儿期出现眼球震颤和肌肉张力减退，随后出现精神运动发育迟缓。脑磁共振图像显示髓鞘形成延迟。他的听觉脑干反应没有呈现第三波和随后的成分。这些特征与在 Pelizaeus-Merzbacher 病 (PMD) 中观察到的特征相似。方法 蛋白脂蛋白 1 (PLP1) 基因筛选，孟德尔疾病面板外显子组，和全外显子组测序（WES）依次进行。结果 在排除了 PLP1 或其他已知 HLD 基因的突变后，WES 在 TMEM106B 中发现了一个突变 c.754G > A, p.(Asp252Asn)，这似乎是从头发生的，如 Sanger 测序和 PCR 的 SalI 限制性内切酶消化所示产品。讨论 这是第六例具有 TMEM106B 突变的 HLD。所有六个案例都包含相同的变体。当患者表现出 PMD 样特征而没有 PLP1 突变时，应研究这种特定的 TMEM106B 突变。我们的 PCR-SalI 消化测定可作为快速 HLD 诊断的工具。如 Sanger 测序和 PCR 产物的 SalI 限制性内切酶消化所示。讨论 这是第六例具有 TMEM106B 突变的 HLD。所有六个案例都包含相同的变体。当患者表现出 PMD 样特征而没有 PLP1 突变时，应研究这种特定的 TMEM106B 突变。我们的 PCR-SalI 消化测定可作为快速 HLD 诊断的工具。如 Sanger 测序和 PCR 产物的 SalI 限制性内切酶消化所示。讨论 这是第六例具有 TMEM106B 突变的 HLD。所有六个案例都包含相同的变体。当患者表现出 PMD 样特征而没有 PLP1 突变时，应研究这种特定的 TMEM106B 突变。我们的 PCR-SalI 消化测定可作为快速 HLD 诊断的工具。