【佳学基因检测】癫痫基因检测与遗传咨询

癫痫基因检测遗传咨询导读：

尽管基因检测从未像现在这样广泛应用于癫痫的患者和家庭成员。但佳学基因认为，开始检测之前，应考虑许多关于癫痫基因检测社会、伦理、心理问题。每种基因检测，包括单基因测序、染色体微阵列基因检测、基因检测包、医学全外显子、全外显子组或全基因组测序基因检测——都有各自需要考虑的因素。由训练有素的遗传学专业人员提供的遗传咨询有助于患者和家庭应对这些复杂、必需考虑的因素。关于遗传咨询对癫痫患者及其家庭成员的影响，一般受检者知之甚少。但是在其他病的基因检测中，正确的遗传咨询已被证明在基因检测及疾病知识普及、准确理解疾病风险、减少不同形式的焦虑方面具有很大的帮助作用。国际抗癫痫联盟（ILAE）建议将遗传咨询作为所有婴儿癫痫发作患者、Dravet综合征和其他婴儿癫痫性脑病的遗传评估的基本内容。同样地，最近制定的智力和发育残疾成年人癫痫治疗建议将基因检测作为该患者群体治疗的标准组成部分。尽管有这些建议，基因检测及遗传咨询服务在临床神经病学实践中的应用往往不一致，到目前为止，临床医生没有正式的实践指南可供依赖。最近对美国神经学家的一项调查发现，大多数接受调查的儿童神经学家会要求对一名18岁的婴儿痉挛史患者进行诊断性基因检测，该病发展为Lennox-Gastaut综合征。然而，大多数接受调查的成年神经学家表示，他们不会为同一个假想患者安排诊断性基因检测。这种差异突出了为癫痫患者提供基因检测及遗传服务的不一致性。

遗传咨询对癫痫患者有几个好处。首先，基因咨询可以帮助个人和家庭在对基因检测和遗传风险充分了解后做出基于知识和最新科技进步的决定，也就是基因检测的知情决定。其次，它有助于了解基因检测的可能结果以及这些结果对诊断和治疗的意义。第三，它有助于个人了解未来子女和其他家庭成员的再次发生这种病的风险，并帮助患者从基因检测中找到任何次要或意外的发现。第四，它可以使患者接受更为正确的治疗。佳学基因分享一些遗传性癫痫的例子以及常见的、已建立的和/或与遗传咨询和临床诊断与治疗相关的潜在基因。

癫痫基因检测中出现的意义不确定、意义未明的变异和新基因

（VUS）是一种对于检测机构、临床医生来说，其致病性和在疾病中的作用尚不清楚。在临床基因检测采用下一代测序技术（NGS)之前，由于基因检测只涉及到已知的意义明确的基因位点，意义未明的基因变异位点（VUS)相对少见。但现在大约有10%的癫痫患者进行了全外显子组测序，所检测的位点及其变异大多数没有在基因检测数据库列出。即使采用癫痫基因检测包进行基因检测，这是一种为了降低检测价格，大幅度减少检测范围的一种基因检测，在采用数据库比对而不是基因解码技术进行分析的机构中，也会有高达40%的基因检测报告出具的是意义未明基因检测结果（VUS）。根据美国医学遗传学和基因组学学院（ACMG），基因检测结果是临床意义未明时，不能用于指导临床诊断和治疗的决策依据。在基因检测后，获得提是临床意义未明的结果，可能会引起患者、家庭成员和临床医生的焦虑，因为他们在解释基因检测结果方面经验较少。遗传咨询，最好在基因检测前后提供，可以帮助患者和家属为可能的临床意义未明的结果做心理准备，并了解不同性质的变异结果可能意味着什么和它不意味着什么。值得指出的是尽管基因解码技术被认为是一种可以大幅度提升检测阳性率、降低意义未明结果的新型基因密码破解技术。它在数据库比对的基础上，增加了基于结构与功能的分析方法，原则上可以检出一部分未报道的新型变异，但是也仍有一部分意义未明的基因检测报告。因此，不管采用什么基因检测技术和分析技术，在检测前进行遗传咨询都是有帮助的。

如果在癫痫患者中没有发现致病基因突变，只发现了意义未明的突变，则在其他家庭成员（通常是父母双方）中检测该基因突变的存在有可能有助于进一步评估该变异的致病性。对于与严重、早发常染色体显性或X连锁癫痫综合征相关的基因变异，父母测试可能会确认该变异是新发的，这意味着在父母中找不到该变异，并提供了该变异具有致病性的额外证据。然而，如果显示该变异是从健康的父母那里遗传的，则该变异可能被认为不太可能导致疾病。对于与常染色体隐性遗传疾病来说的两个杂合或者是纯合变异，对父母进行测试助于确定变异产生的方式和时间。对于家族性癫痫，在其他家族成员中进行基因检测可以明确被标记为意义未明的基因突变是否在家族内存在疾病表现与基因型存在共分离的现象。在基因解码中这种具有更高分析能力的基因科技术，临床表型和基因型的共分离现象是数据库比对之处的另一种收集基因突变是否具有致病性的证据。

此外，全外显子组或全基因组测序可以确定没有明确或尚未建立的基因-疾病关系的基因序列，即所谓的新基因或候选基因。这些检测结果在以数据库比对基础分析方法的检测机构中也会被标记为意义不确定的结果。这些结果由于通常不用于临床决策，但也可能给患者、家属和临床医生带来相当大的不确定感觉。为了进一步研究基因与疾病关联证据有限的基因突变的致病性，通常需要进行额外的研究，包括对具有相似临床症状的患者时行致病基因鉴定、对其他家族成员进行基因检测，以为基因表型和症状的分訑收集证据。

癫痫基因检测与癫痫的复发风险评估

遗传咨询还可以帮助癫痫患者家庭了解未来儿童和其他家庭成员的复发风险。许多严重的早发性癫痫，包括癫痫性脑病，都是新发突变的结果。在这种情况下，父母不含有导致癫痫发生的基因突变，因此遗传到其他家庭成员的分险极低。通常，对于已确认的新发变异，未来妊娠也就是生育下一胎再次罹患同样疾病的风险<1%。然而，先进的基因的基因检测机构，采用改进的下一代测序技术，在没有出现疾病表征的、或者只受影响的父母中，能够鉴别出存在具有新发突变的性腺或体细胞镶嵌，这大大增加了下一胎疾病风险的灵敏度。根据《癫痫疾病发生的遗传变异多样性》，“遗传镶嵌”是指由具有不同基因型的细胞组成的细胞群体。曾在遗传镶嵌的个体，所有器官或者是某些器官变异型和野生型细胞的混合而成的。如果变异率低，由于致病性基因突变细胞未包含基因检测所使用的细胞或组织类型中，采用血液DNA测序可能会错过存在的突变。在这些情况下，可能需要对头发、皮肤或唾液等其他组织进行测序。基因解码做的研究发现，Dravet综合征患者中大约10%的SCN1A新变突变实际上是父母的体细胞镶嵌。在这些情况下，无法提供精确的关于后代是否复发的判断，但可能接近50%。新出现的数据也表明，尽管大多数严重早发性癫痫是散发性的，但在一些较大的患者系列中，高达20%的基因解码分析确认癫痫性脑病为常染色体隐性遗传。如果没有基因解码、基因检测的指导并采用可干预的生育方式，再生育的每一个孩子的复发风险25%。

癫痫基因检测额外发现

随着诊断性全外显子组和基因组测序在临床实践中变得越来越普遍，通过诊断性基因测试在一些患者中发现了更多的额外的发现。这些额外发现是与主要检测指征无关的遗传发现，但对患者的健康具有医学价值。ACMG已鉴定出59个医学上可干预的基因，并建议基因检测报告在这些基因中发现的可能致病性和/或致病性基因突变。据估计，接受全外显子组测序并进行基因解码分析基因检测中，约有1-3%会有医学上可干预的额外。建议患者在开始基因组诊断测试之前了解接收额外发现选项，这可能会多增加一些少量的费用。理想情况下基因检测结构通过知情同意程序，让患者选择在报告中接受或不接受此类信息。此外，如果检测是采用三人全外显子基因检测方案，由于全外显子组或全基因组测序是在父母-子女三人组的基础上进行的，因此测试可能会发现有关家庭关系的意外结果，基因突变的来源，甚至会发现或非亲子关系。提出基因检测的这种可能性通常是基因检测开始前知情同意的一部分内容。

癫痫基因检测的社会心理学影响

接受基因诊断可能会改变家庭的生活。许多具有癫痫病的儿童或年轻成人的家庭已经进行了多年的“癫痫病诊断之旅”，这可能会带来身体上的困难、经济上的负担和情感上的枯竭。尽管许多家庭对获得基因检测的结果后感到轻松，但接受基因诊断可能会导致内疚、焦虑、沮丧或孤独感。因为许多基因导致的癫痫是罕见的疾病，可用信息有限，与具有相同诊断结果的其他家庭联系的能力有限。此外，基因测试可能无法给出最终答案。接受全外显子组测序基因检测的癫痫患者中约有50-70%得到阴性结果。负面结果可能令人失望，而遗传咨询可以帮助家庭预测基因检测的可能结果，并帮助他们在收到基因诊断或不确定结果后确定应对的方式。

遗传性癫痫举例及其基因检测

遗传性全身性癫痫（GGE）

儿童和青少年失神癫痫（CAE、JAE）、青少年肌阵挛性癫痫（JME）和觉醒时全身强直阵挛发作癫痫（EGMA）呈现出是典型的GGE临床表征。这些癫痫亚型在发作开始时间、发作类型和脑电图（脑电图）形式方面有清晰的特征。如存在广义棘波和多棘波复合形式。CAE中的失神癫痫发作通常出瑞在3至10岁之间，持续时间短，通常约10秒，每天发作高达100次。在青春期，这些患者很少出现全身强直阵挛发作。JAE中的失神性癫痫发作基本相似，但频率较低，在青春期开始发病，青春期的全身强直阵挛发作更频繁。肌阵挛性抽搐，尤其是上肢的抽搐，没有意识丧失，是JME的临床特征。该病也是在青春期出现，发作通常在醒时发生，因前一晚缺少睡眠或饮酒而引引起。大约75%的患者出现全身强直阵挛发作。在青春期，癫痫在觉醒时出现全身强直阵挛发作。癫痫发作通常发生在患者醒来后两小时内，与白天无关。在个体患者或家庭患者所有临床综合征会出现中重叠。大脑成像不明显。

基因解码研究表明，GGE的不同亚型的遗传方式复杂，只有少数罕见的大家族呈现明显的常染色体显性遗传。致病基因鉴定基因解码在编码GABAA受体α1亚基的基因发现第一个突变，引起家族性JME的发生。第二个突变在CAE患者中发现。基因解码研究人员为了验证致病基因突变所导致的功能性变化，当在爪蟾卵母细胞或哺乳动物细胞中表达时突变的基因序列进，α1亚基突变导致GABAA受体功能显著丧失。这使得基因基因解码为癫痫的基因检测提供了坚实的证据。

《癫痫发生的遗传学基础》把微缺失列为GGE产生的风险因素之一。癫痫的致病基因鉴定基因解码在1.0-2.5%的GGE患者发现染色体微缺失基因突变，这些微缺失基因突变存在于染色体15q13.3、15q11或16p13上存在微缺失。微缺失基因突变特别是在具有GGE表型和发育问题或智力残疾的患者中比较明显。

泛发性癫痫的另一种形式是泛发性（遗传性）癫痫伴热性惊厥综合征（GEFS+）。《癫痫的各种亚型及其基因检测结果的异同》中GEFS+用来指儿童期发作的常染色体显性综合征，包括发热性惊厥和多种非热性癫痫发作类型，如同一家系中的全身强直阵挛发作、失神性癫痫、无张力或肌阵挛性发作性癫痫。极少病例中出现部分癫痫发作。有家族史，但家族成员癫痫形式可能不同。虽然GEFS+范畴内的癫痫大多是良性的，但少数家族成员会出现更严重的癫痫症状和发育问题，类似于肌阵挛性无张力发作（MAE）或Dravet综合征癫痫。这使得遗传咨询变得重要但困难。致病基因鉴定基因解码在为这一类癫痫的基因检测提供的一个基因突变位点是编码电压门控钠离子通道β1亚基的SCN1B基因。这一基因缺陷是在大型GEFS+家族中发现的]。基因解码研究的功能和结构解析，从而可以明确疾病的发病机理，并为新药研究和治疗提供依据。在这一类病例中，明确了致病基因编码钠通道α。如果只检测SCNA1,只有10%的GEFS+患者会出阳性基因检测结果。GGE中一种重要的、与治疗相关但罕见的情况是患者出现葡萄糖转运蛋白1型基因SLC2A1的突变，这一基因突变使得携带有突变的孩子在4岁之前出现开始的早发失神发作（EOAE），很少出现经典CAE。

GGE患者的基因检测：在单一家族中，该疾病组中仅描述了少数基因的明显效应。基因检测应包含这些基因。在多种治疗效果不佳的癫痫患者，尤其应当选择基因覆盖范围大的致病基因鉴定基因解码。如果发现患者是因为SLC2A1突变而引起，可以从生酮饮食中获益。而如果基因检测发现是SCN1A突变引起的，则应避免使用钠通道阻滞剂。阵列CGH可以检测患者是否存在染色体微缺突变，在于存在智力残疾的患者，尤其应当考虑这一检测方案。

遗传性局灶性癫痫

3.6.2 Genetic focal epilepsies.
Familial epilepsies in early childhood comprise the syndromes of benign familial neonatal, infantile-neonatal and infantile seizures (BFNS, BFNIS, BFIS). They are characterized by clusters of seizures in the first days or months of life, up to one year of age, resolving spontaneously after weeks to months. Seizures might present as focal or generalized. Interictal EEGs are usually normal. The rare ictal EEG recordings showed focal and generalized discharges. The risk of seizure recurrence later in life is about 15%. Although psychomotor development is usually normal, an increasing number of cases with intellectual disability has been described [52]. In up to 50% of BFIS cases a movement disorder, presenting as paroxysmal kinesigenic dyskinesia (PKD), can occur in school age. It is characterized by involuntary short lasting dyskinesias induced by fast voluntary movements. The combination of both diseases is called ICCA (infantile convulsions and choreoathetosis [53]. Both syndromes respond very well on different anticonvulsive drugs. Mutations in KCNQ2 and KCNQ3 have been identified to cause BFNS [9-11]. KCNQ2 and KCNQ3 channels give rise to the M-current, a slowly activating potassium current which can be suppressed by the activation of muscarinic acetylcholine receptors [54]. Co-expression of heteromeric wild type and mutant KCNQ2/3 channels usually revealed a reduction of the resulting potassium current of about 20-30% which is apparently sufficient to cause BFNS [55]. Mutations in the SCN2A gene encoding one of the α-subunits of voltage-gated sodium channels expressed in mammalian brain are found in BFNIS [56]. The first functional investigations revealed small gain-of-function effects of some mutations predicting an increased neuronal excitability [57,58]. For BFIS, PKD and ICCA, two different loci have been described. In up to 80% of patients, mutations were found in PRRT2 coding for the proline-rich transmembrane domain 2 which is the major gene in these syndromes [59]. Recently, a novel mutation was described in the potassium channel subtype gene SCN8A associated to ICCA [60]. Mutations in SCN8A were also found in severe epileptic encephalopathy (see below) and isolated intellectual disability [61]. In all these syndromes the penetrance is high, up to 80% [62,63].

Patients with mutations in DEPDC5 (Dep domain-containing protein 5) present with a broad spectrum of focal epilepsy syndromes spanning from benign Rolandic epilepsy [64] up to the severe familial focal epilepsy with variable foci (FFEVF). DEPDC5 is part of the GATOR1 complex which acts as an inhibitor of the mTORC1 complex [65,66]. mTORC1 regulates several cellular functions like cell growth, migration and proliferation [67]. In the last years, mutations were found in several genes relevant in the mTOR signaling pathway associated to focal cortical dysplasias which frequently lead to focal epilepsies. Mutations were found in DEPDC5, MTOR, NPRL2/3, PIK3CA and TSC1/TSC2 as germline and somatic mutations. These findings have therapeutical implications since a therapy with mTOR inhibitors (e.g. rapamycin) improve seizures in animal models and patients (for review see [68]). Rolandic epilepsy, also called benign epilepsy of childhood with centrotemporal spike (BECTS), typically presents at the age of 5-6 years with nocturnal focal seizures of the face and vocal tract [69]. It is considered benign since the epilepsy resolves with puberty and most patients show normal psychomotor development. FFEVF is characterized by focal seizures arising from different cortical areas combined with intellectual disability. The onset ranges from infancy to adulthood [70,71]. Mesial (familial mesial temporal lobe epilepsy, FMTLE) [72] or lateral temporal lobe epilepsy (autosomal dominant epilepsy with auditory features, ADLTE) [73] can also be associated to DEPDC5 mutations as well as ADNFLE (autosomal dominant nocturnal frontal lobe epilepsy, see below). FMTLE and ADLTE syndromes are characterized by onset in infancy up to adulthood and benign outcome. In addition to germline mutations of DEPDC5 resulting in these familial epilepsy syndromes, somatic mutations in DEPDC5 as well as other genes of the mTOR pathway were identified in brain specimens of focal cortical dysplasias [73].
The first mutations described for ADLTE were found in LGI1 which was initially described as a tumor gene [74]. LGI1 is important in the regulation of postnatal glutamatergic synapse development and can therefore indirectly influence synaptic processing [75]. Up to 50% of patients with ADLTE are positive for alterations in this gene [76].
For ADNFLE, a first mutation was identified in CHRNA4 encoding the α4-subunit of a neuronal nicotinic acetylcholine receptor (nAChR) as the first ion channel mutation found in an inherited form of epilepsy [7]. Later, mutations in the CHRNB2 gene encoding the β2- subunit of neuronal nAChR and CHRNA2, encoding the nAChR α2-subunit were detected [77,78]. All these mutations reside in the pore-forming M2 transmembrane segments. Different effects on gating of heteromeric α4β2 channels leading either to a gain-of-function or a loss-of-function were reported when most of the known mutations were functionally expressed in Xenopus oocytes or human embryonic kidney (HEK) cells. The exact pathomechanism is not fully understood, but an increased acetylcholine sensitivity could be the main common gating defect of the mutations [77,78]. Only 5-10% of families are positive for nAChR subtypes [79].
Genetic testing in focal epilepsy patients: Genetic testing can be performed in patients with benign and early onset epilepsies belonging to the spectrum of BFNS, BFIS or BFIS since genetic confirmation of the diagnosis allows for genetic counseling, may have implications on therapeutic decisions in difficult-to-treat cases (for example more severe early-onset epilepsies with KCNQ2 or SCN2A mutations profit from sodium channel blockers [80] and prevents further unnecessary and stressful diagnostic procedures. Depending on the age of onset, sequencing of the respective genes (KCNQ2/3, SCN2A, PRRT2, better panel sequencing if possible) should be initiated. For all other forms of (familial) focal epilepsies described above, genetic variants are detected only in a small percentage of families and are even less frequent in single patients. A gene panel analysis including the above-mentioned genes might be useful as positive results would have implications for genetic counseling in families. In case of panels are not available, sequencing of LGI1 in ADTLE and DEPDC5 in various other forms of familial focal epilepsies might generate positive results.
3.6.3 Early Infantile Epileptic Encephalopathies (EIEE) and severe epilepsies of infancy. The term EIEE comprises a large group of epilepsies with the common features of early onset epilepsy (before the age of 3 years) and developmental problems such as psychomotor delay or regression [1]. Within this group of early onset epilepsies, the term “epileptic encephalopathy” is often used in the broader sense of severe epilepsies accompanied by developmental problems. However, according to the definition given by the ILAE, the term “epileptic encephalopathy” should be reserved to situations in which the epilepsy itself causes ongoing cognitive deficits. Recent studies revealed that the activity of the epilepsy is often unrelated to the severity level of the developmental disturbance. In these cases, the main pathophysiological component might be the genetic defect itself leading to epilepsy as well as to disturbances of brain development. Table 1 summarizes the main forms of EE, the most common underlying genes and their relevance for genetic counselling and/or treatment. The different EE syndromes are defined by the onset of seizures, semiology (seizure types) and EEG characteristics. The spectrum includes well known entities such as Ohtahara syndrome, West syndrome, Dravet syndrome and Lennox-Gastaut syndrome as well as less defined clinical pictures (unclassified EE). Figure 2 shows an overview of the main syndromes and the respective genes sorted by the age of onset.
Ohtahara syndrome (OS) is characterized by frequent tonic spasms starting in the first days and weeks of life which are highly pharmaco-resistant. Other seizure types can occur such as focal motor, hemiclonic or generalized tonic-clonic seizures. The EEG shows a characteristic burst suppression pattern (Figure 3). Most patients have developmental problems such as severe global developmental delay and intellectual disability and the mortality rate is high. In 75% of patients, the epilepsy converts into West syndrome, and about 12% of patients present with Lennox-Gastaut syndrome later in life [81].
West syndrome (infantile spasms, IS) starts between 3 and 12 months of age with clustered and frequent infantile spasms, developmental delay, and the characteristic EEG pattern of hypsarrhythmia. It is defined by high amplitude slow waves combined with multifocal irregular epileptic potentials (Figure 3). The criteria (i) early onset, (ii) other seizures types than spasms and (iii) a recurrence of seizures after seizure freedom are negative predicting factors. In contrast, normal MRI and fast responsiveness to therapy are predictive factors for positive outcome [82]. First line therapeutic options are vigabatrin and steroids.
All these syndromes are genetically heterogeneous since several genes were described for each of them (Table 1). OS and IS are genetically overlapping as mutations in genes like ARX, SCN2A, STXBP1 and CDKL5 were found in both syndromes [83,84]. ARX (aristalessrelated homeobox protein) is a transcription factor involved in brain development [85]. ARX mutations are also found in patients with a lissencephaly, a severe disturbance of cortical integrity [86]. Several genes affected in early onset epilepsies and epileptic encephalopathies are involved in the (pre-)synaptic vesicle cycle. Examples are STXBP1 (encoding for syntaxin binding protein 1), STX1B and DNM1 [for overview see 87]. CDKL5 is involved in RNA processing and interacts with MeCP2 by mediating MeCP2 phosphorylation [88,89). Malignant migrating partial seizures in infancy (MMPSI) is a highly pharmaco-resistant epilepsy syndrome starting before 6 months of age. Polymorphic seizures with migrating ictal EEG discharges during the seizures are characteristic for the syndrome. A plateau or regression in psychomotor development is a defining attribute [90]. An important gene for MMPSI is KCNT1 [91] which is coding for a sodium-activated potassium channel. The mutations lead to a gain of function which can be reversed by the potassium channel blocker quinidine that has been reported to be useful in single patients [92,93].
Dravet syndrome (previously known as severe myoclonic epilepsy of infancy, SMEI) is characterized by prolonged and frequent febrile seizures in the first year of life. Later on, patients develop afebrile hemi- or generalized clonic or tonic-clonic seizures, myoclonic seizures and absences, as well as simple and complex partial seizures. Frequently, obtundation status occurs. Cognitive deterioration appears in early childhood. The epilepsy is resistant to pharmacotherapy in most cases [94]. The major gene in this syndrome as well as the most common epilepsy gene in general is SCN1A, encoding a sodium channel alphasubunit [95]. Functional analysis using heterologous expression systems revealed a predominant loss of function mechanism in inhibitory neurons leading to system hyperexcitability [96]. Genetic testing results are relevant to treatment decisions as sodium channel blockers can aggravate seizure frequency in some Dravet patients [97] while specific orphan drugs such as stiripentol can be used. Although SCN1A mutations occur de novo in most patients, mosaic status in parents is possible and should be ruled out carefully (see above and 37].
Patients with MAE (Doose syndrome) present between ages 1 to 3 years with generalized tonic-clonic, myoclonic and atonic seizures as well as absences. In many patients, the genetic background of the disease remains unknown. However, mutations in the GABA transporter gene SLC6A1 are found in about 4% of cases [98]. Mutations in SLC2A1 are rare but identification of these patients allows for a specific therapy, i.e. the ketogenic diet [99]. Lennox-Gastaut syndrome (LGS) is characterized by polymorphic seizures combined with developmental delay or regression with onset between 3 to 5 years of age. Frequently, the disease starts as Ohtahara or West syndrome and evolves into Lennox-Gastaux syndrome. Seizure types characterizing LGS are atypical absences, tonic, atonic or generalized tonicclonic seizures including (tonic) drop attacks with high risk for injuries. EEG characteristics are slow spike wave complexes and polyspikes (Figure 3). LGS is very heterogeneous since causing mutations were described in a bunch of genes such as SCN1A, STXBP1, SCN2A and CDKL5, especially when the disease starts in early childhood (see above) [100].
Common metabolic forms of early infantile epileptic encephalopathies comprise Glut1 deficiency and pyridoxine-dependent epilepsies. Glut1-Deficiency syndrome starts in the first few months of age with clusters of dyscognitive seizures and non-convulsive status epilepticus predominantly in fasting state e.g. just before to breakfast. The children development a severe psychomotor retardation, dystonic features and ataxia (Seidner) [101]. The spectrum of glucose transporter type 1, the glucose transporter of the blood-brainbarrier, associated syndromes is broad since also paroxysmal exercise induced movement disorder (PED), childhood absence epilepsy (CAE) and early onset absence epilepsy (EOAE) starting before 3 years of age were found to be caused by mutations in SLC2A1 coding for Glut1 [15,51,102]. With the ketogenic diet, which bypasses the defect in glucose metabolism, a specific therapy is available.
Vitamin B6 (pyridoxine) dependent epilepsies typically start in the first days of life or are even recognized as intrauterine seizures during pregnancy. The seizures are highly pharmacoresistant. Burst suppression patterns and hypsarrhythmia in EEG have been described (Mills) [97]. Affected children show global developmental delay. Sometimes, a history of perinatal problems such as premature delivery or asphyxia pretends symptomatic epilepsy. Biallelic mutations in ALDH7A1 (coding for the alpha-aminoadipic semialdehyde dehydrogenase antiquitin) and more rarely PNPO (coding for pyridoxamine phosphate oxidase) involved in the pyridoxin metabolism are responsible for these metabolic epilepsies and an early therapy with pyridoxine (in antiquitin deficiency) or pyridoxal-5-phosphate (in pyridoxamine phosphate-oxidase deficiency) should be started [103].
There are many children who present with non-specific phenotypes rendering targeted genetic testing impossible. In this context, two additional genes should be mentioned since the detection of mutations in these genes might have implications on therapy. Mutations were found in in the potassium channel gene KCNA2 in a Dravet-like phenotype [104] and mutations in the NMDA glutamate receptor genes GRIN2A and GRIN2B are found in patients with non-specific epileptic encephalopathies or epilepsy-aphasia-spectrum disorders. Pathological effects of gain-of-function mutations might be specifically blocked by memantine [18,105].
Last but not least CNVs were described in several forms of EE in up to 5% of cases including specific phenotypes such as LGS as well as unclassified EE [106].
Genetic testing in patients with EIEE and severe epilepsies in infancy: For all subtypes of EE genetic testing is highly recommended since a positive result avoids further diagnostics, allows for prognostic estimations and might have implications on therapeutic decisions. In this group of epilepsies, many private and de novo mutations are found. Few genes follow autosomal-recessive inheritance. Due to phenotypic and genotypic heterogeneity, a gene panel approach combined with a CNV analysis is recommended. In few cases, e.g. in typical Dravet syndrome or pyridoxine-responsive epilepsy, a targeted gene analysis will be effective. Prior to initiation of genetic testing as well as in cases with positive results, genetic counselling should be offered to parents.
Genetic testing is recommended in all forms of epileptic encephalopathies since it has important influence in patient`s management. The genetic result helps to define a diagnosis, can spare further diagnostics, give advice for prognosis and genetic counseling and may influence therapy decisions. Prior to genetic testing a detailed genetic counseling is necessary to prevent negative socio-psychological effects in the affected families and unnecessary health costs. To date, only in a few of the common forms of generalized and focal epilepsies genetic testing should be performed as a routine diagnostic step, since major genes and consequences for clinical management are missing in most cases.