Lehesjoki Anna-Elina, Kälviäinen Reetta
Folkhälsan Research Center and University of Helsinki, Helsinki, Finland
Kuopio Epilepsy Center, Kuopio University Hospital, Member, EpiCARE ERN, University of Eastern Finland, Kuopio, Finland
Progressive myoclonic epilepsy type 1(EPM1) is a neurodegenerative disorder characterized by onset from age six to 15 years, stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures. Some years after the onset, ataxia, incoordination, intentional tremor, and dysarthria develop. Individuals with EPM1 are cognitively mostly within the normal range, but show emotional lability and depression. The epileptic seizures are usually well controlled by anti-seizure medication, but the myoclonic jerks are progressive, action activated, and treatment resistant, and can be severely disabling.
DIAGNOSIS/TESTING: The diagnosis of EPM1 is established in a proband with suggestive findings and either biallelic abnormal CCC-CGC-CCC-GCG dodecamer repeat expansions in or compound heterozygosity for a dodecamer repeat expansion and a sequence variant (i.e., single-nucleotide variant or indel) identified by molecular genetic testing.
Symptomatic pharmacologic and rehabilitative management, including psychosocial support, are the mainstay of care; valproic acid, the first drug of choice, diminishes myoclonus and the frequency of generalized seizures; clonazepam, approved by FDA for the treatment of myoclonic seizures, is an add-on therapy; high-dose piracetam is used to treat myoclonus; levetiracetam, brivaracetam, and perampanel appear to be effective for both myoclonus and generalized seizures. Topiramate and zonisamide may also be used as add-on therapy. Lifelong clinical follow up including evaluation of drug treatment and rehabilitation. Phenytoin aggravates neurologic symptoms or even accelerates cerebellar degeneration; sodium channel blockers (carbamazepine, oxcarbazepine), GABAergic drugs (tiagabine, vigabatrin), and gabapentin and pregabalin may aggravate myoclonus and myoclonic seizures.
EPM1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once both pathogenic variants in a family are known, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.
1型进行性肌阵挛癫痫（EPM1）是一种神经退行性疾病，其特征为发病年龄在6至15岁之间，对刺激敏感的肌阵挛，以及强直阵挛性癫痫发作。发病数年之后，会出现共济失调、不协调、意向性震颤和构音障碍。EPM1患者的认知功能大多在正常范围内，但表现出情绪不稳定和抑郁。癫痫发作通常可用抗癫痫药物得到良好控制，但肌阵挛性抽搐是进行性的、动作激活的且对治疗有抵抗性，可能会导致严重残疾。
诊断/检测：EPM1的诊断是在具有提示性发现的先证者中确立的，且存在双等位基因异常的CCC-CGC-CCC-GCG十二聚体重复序列扩增，或者通过分子遗传学检测鉴定出十二聚体重复序列扩增和序列变异（即单核苷酸变异或插入缺失）的复合杂合性。
对症药物治疗和康复管理，包括心理社会支持，是主要的治疗方法；丙戊酸是首选药物，可减少肌阵挛和全身性癫痫发作的频率；经美国食品药品监督管理局（FDA）批准用于治疗肌阵挛性癫痫发作的氯硝西泮是一种附加治疗药物；高剂量吡拉西坦用于治疗肌阵挛；左乙拉西坦、布瓦西坦和佩罗酰胺似乎对肌阵挛和全身性癫痫发作均有效。托吡酯和唑尼沙胺也可用作附加治疗。需要进行终身临床随访，包括评估药物治疗和康复情况。苯妥英会加重神经症状，甚至加速小脑变性；钠通道阻滞剂（卡马西平、奥卡西平）、GABA能药物（替加宾、氨己烯酸）以及加巴喷丁和普瑞巴林可能会加重肌阵挛和肌阵挛性癫痫发作。
EPM1以常染色体隐性方式遗传。在受孕时，受影响个体的每个同胞有25%的几率受到影响，50%的几率为无症状携带者，25%的几率不受影响且不是携带者。一旦确定了家族中的两个致病变异，就可以对有风险的亲属进行携带者检测、对高风险妊娠进行产前检测以及进行植入前基因检测。
