Paroxysmal Kinesigenic Dyskinesia Secondary to Brain Calcification with a Homozygous MYORG Mutation
Paroxysmal Kinesigenic Dyskinesia Secondary to Brain Calcification with a Homozygous MYORG Mutation
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DOI：
10.1002/mds.28720
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发表时间：
2021-08
影响因子：
8.6
通讯作者：
Juanjuan Du;Xue Zhu;Jun Liu;Yu-yan Tan
中科院分区：
文献类型：
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作者：
Juanjuan Du;Xue Zhu;Jun Liu;Yu-yan Tan
原发性家族性脑钙化（PFBC），也称为法尔病，表现为基底节、皮质下白色物质、小脑、丘脑和其他脑区域的双侧钙化。MYORG在2018年首次被确定为常染色体隐性PFBC的致病基因。在这里，我们描述了一个纯合子MYORG突变引起PFBC和表现为孤立的阵发性运动诱发性运动障碍（PKD）。一例来自湖南省的22岁男性患者（图1A，II-1）。我国肢体反复不自主运动已有8年。他的父母是同父异母的兄弟姐妹。他的父母和姐姐都没有症状。他的出生和发展里程碑是不起眼的。14岁时，患者在长时间坐着后开始跑步或从坐姿站起来时出现阵发性肌张力障碍（视频S1）。当他紧张或疲劳时，突发性事件更容易由突然的动作触发。这些事件只持续了几秒钟到一分钟。在发作期间，没有疼痛、意识丧失或失禁。一般体格和神经系统检查，包括认知功能（简易精神状态检查/30，蒙特利尔认知评估/28）在发作间期正常。否认中毒和创伤病史。通过广泛的血液和影像学检查排除了其他次要原因，包括磷酸钙代谢紊乱、脱髓鞘疾病、甲状腺功能亢进、核黄疸、自身免疫性疾病和感染。在签署书面知情同意书后，为该家庭安排了一系列辅助检查。脑电图记录正常。头颅神经影像学检查（MRI和CT）显示小脑、基底节和丘脑广泛钙化（图1B-F）。先证者母亲的头颅CT显示基底节钙化（图S1 A），其父亲和姐姐无明显钙化（图S1 B、C）。服用奥卡西平（600 mg/d）和氯硝西泮（0.5 mg/d）后，发作缓解约70%-80%。我们通过对先证者的全外显子组测序鉴定了一个新的MYORG纯合重复变异体（NM_ 020702.4，c.337_348dup，p.L113_R116dup）。进一步的桑格测序验证显示，该突变遗传自父母双方，且先证者的父母均为杂合子携带者（图1G）。MYORG，以前称为KIAA 1161或NET 37，由Yao等人在2018年基于对6个中国家族的分析首次发现。迄今为止，在先前的报告中，MYORG共记录了47个致病性突变（图1H和表S1）。伴有MYORG突变的PFBC的临床谱包含一系列神经系统症状，包括帕金森综合征和其他运动障碍、延髓体征、小脑共济失调和认知障碍伴大脑广泛钙化（表S1）。但孤立的PKD很少报道。据我们所知，唯一报告的病例（2020年在Brain杂志上）是Gerard等人，他报告了MYORG中的纯合突变（c.1831C>T，p.R611W），显示PFBC伴孤立的PKD。我们的病例报告了另一种纯合子MYORG变体（c.337_348dup），其唯一症状为PKD，尽管钙化发生在大脑的多个区域。这与先前报道的具有复合杂合MYORG变体（c.1831C>T/c.337_348dup）的患者的表型完全不同，该患者表现为构音障碍、共济失调、震颤和帕金森综合征，但没有PKD症状。我们的报告扩大了MYORG相关PFBC的表型和遗传谱。
Primary familial brain calcification (PFBC), also known as Fahr’s disease, manifests as bilateral calcification in the basal ganglia, subcortical white matter, cerebellum, thalamus, and other brain regions. MYORG was identified as the causative gene for autosomal-recessive PFBC in 2018 for the first time. Here, we describe a homozygous MYORG mutation causing PFBC and manifesting as isolated paroxysmal kinesigenic dyskinesia (PKD). A 22-year-old male patient (Fig. 1A, II-1) from Hunan province. China has had recurrent involuntary movements of the limbs for 8 years. He was born to consanguineous parents who are half-siblings. Both his parents and elder sister are asymptomatic. His birth and developmental milestones were unremarkable. At age 14, the patient developed paroxysmal dystonia when he started to run or stood up from a seated position after sitting for a prolonged time (Video S1). The paroxysmal events were more likely to be triggered by sudden movements when he was nervous or tired. These episodes only lasted for seconds to 1 minute. During the attack, there was no pain, loss of consciousness, or incontinence. General physical and neurological examinations including cognitive function (Mini–Mental Status Examination/30, Montreal Cognitive Assessment/28) were normal interictally. A medical history of poisoning and trauma was denied. Other secondary causes, including calcium-phosphate metabolic disorders, demyelinating diseases, hyperthyroidism, kernicterus, autoimmune diseases, and infections were ruled out through extensive blood and imaging workup. After signing written informed consents, a series of auxiliary examinations were arranged for the family. An electroencephalogram recording was normal. Cranial neuroimaging (MRI and CT) showed extensive calcifications involving the cerebellum, basal ganglia, and thalamus (Fig. 1B–F) The cranial CT of the proband’s mother revealed basal ganglia calcification (Fig. S1A), which was unremarkable in his father and sister (Fig. S1B,C). Since taking oxcarbazepine (600 mg per day) and clonazepam (0.5 mg per day), the paroxysmal attacks have been relieved by approximately 70%–80%. We identified a new homozygous duplication variant (NM_ 020702.4, c.337_348dup, p.L113_R116dup) of MYORG through whole-exome sequencing of the proband. Further Sanger sequencing verification revealed that this mutation was inherited from both parents, and the proband’s parents are all heterozygous carriers (Fig. 1G). MYORG, previously known as KIAA1161 or NET37, was first identified by Yao et al in 2018 based on analysis of 6 Chinese families. To date, a total of 47 pathogenic mutations have been recorded for MYORG in previous reports (Fig. 1H and Table S1). The clinical spectrum of PFBC with MYORG mutation contains a series of neurological symptoms including parkinsonism and other movement disorders, bulbar signs, cerebellar ataxia, and cognitive impairments with extensive calcification in the brain (Table S1). But isolated PKD was rarely reported. To our knowledge, the only reported case (in 2020 in the Brain journal) is by Gerard et al, who reported a homozygous mutation (c.1831C>T, p.R611W) in MYORG showing PFBC with isolated PKD. Our case reported another homozygous MYORG variant (c.337_348dup) with PKD as the only symptom, even though calcification occurred in multiple areas of the brain. This is quite different from the phenotype of the patient reported previously with the compound heterozygous MYORG variant (c.1831C>T/c.337_348dup) who presented with dysarthria, ataxia, tremor, and parkinsonism but no PKD symptoms. Our report expanded the phenotypic and genetic spectrum of MYORG-associated PFBC.