SLC13A5 citrate transporter disorder

SLC13A5 citrate transporter disorder, also known as SLC13A5 epilepsy, is a rare autosomal recessive neurological disorder caused by mutations in the SLC13A5 gene, encoding a sodium-dependent citrate transporterSLC13A5 柠檬酸转运体病，也称为 SLC13A5 癫痫，是一种由 SLC13A5 基因突变引起的罕见常染色体隐性神经学疾病，该基因编码钠依赖性柠檬酸转运体。

The disorder presents with severe seizures beginning in the first days of life, along with developmental delay, ataxia, dystonia and tooth hypoplasia该病表现为生命最初几天开始的严重癫痫发作，伴有发育迟缓、共济失调、肌张力障碍和牙齿发育不良。

The condition was linked to SLC13A5 mutations in 2014 by means of exome sequencing, and it is classified as early infantile epileptic encephalopathy 25该病于2014年通过外显子组测序与 SLC13A5 突变联系起来，被归类为早期婴儿癫痫性脑病25型。

Terminology and classification

• SLC13A5 citrate transporter disorder is classified as a rare genetic epileptic encephalopathy with developmental and movement featuresSLC13A5 柠檬酸转运体病归类为具有发育和运动特征的罕见遗传性癫痫性脑病。^[1]
• The condition is also known as early infantile epileptic encephalopathy 25 (EIEE25) and developmental and epileptic encephalopathy 25该病也称为早期婴儿癫痫性脑病25型（EIEE25）和发育性癫痫性脑病25型。
• MONDO catalogues the condition as MONDO:0014392 (developmental and epileptic encephalopathy 25), and OMIM 615905 records the causative locusMONDO 将该病编目为 MONDO:0014392（发育性癫痫性脑病25型），OMIM 615905 记录致病位点。
• The condition is caused by biallelic loss-of-function mutations in the SLC13A5 gene on chromosome 17p13.1该病由染色体17p13.1上 SLC13A5 基因的双等位基因功能丧失突变引起。^[1]
• The disorder is classified as an ultra-rare disease, and the Chinese rare disease criterion of fewer than 140,000 patients nationwide is met该病归类为超罕见病，符合中国罕见病标准（全国患者数少于14万）。
• SLC13A5 epilepsy is distinguished from other early infantile epileptic encephalopathies by the specific combination of seizures, movement disorder and tooth hypoplasiaSLC13A5 癫痫通过癫痫发作、运动障碍和牙齿发育不良的特定组合与其他早期婴儿癫痫性脑病区分。^[1]

History

• In 2014, exome sequencing identified mutations in the SLC13A5 gene as the cause of a rare form of early infantile epileptic encephalopathy2014年，外显子组测序鉴定出 SLC13A5 基因突变是一种罕见早期婴儿癫痫性脑病的原因。^[1]
• The identification of SLC13A5 mutations established a new class of epilepsy associated with defective citrate transport and brain energy metabolismSLC13A5 突变的鉴定建立了一类新的与柠檬酸转运缺陷和脑能量代谢相关的癫痫。^[1]
• Subsequent studies characterized the clinical spectrum, showing that seizures begin in the first days of life and are often refractory to treatment后续研究表征了临床谱系，显示癫痫发作在生命最初几天开始且常难以治疗。^[1]
• Recent research has focused on the role of the citrate transporter in brain energy metabolism and potential therapeutic strategies targeting the transporter最近的研究集中在柠檬酸转运体在脑能量代谢中的作用以及针对该转运体的潜在治疗策略。^[2]

Epidemiology

• SLC13A5 epilepsy is a rare disorder, with fewer than 100 patients reported worldwide since the condition was first describedSLC13A5 癫痫是一种罕见病，自该病首次描述以来全球报告的患者不到100例。^[1]
• The condition is inherited in an autosomal recessive pattern, with affected individuals having biallelic SLC13A5 mutations该病以常染色体隐性模式遗传，受累个体具有双等位基因 SLC13A5 突变。^[1]
• Both sexes are affected equally, and the condition has been reported across diverse ethnic backgrounds两性均等受累，该病已在不同种族背景中报告。
• Symptoms begin in the first days of life, and the condition is typically diagnosed in the neonatal period症状在生命最初几天开始，该病通常在新生儿期确诊。^[1]
• Risk factors include consanguinity, consistent with the autosomal recessive inheritance pattern危险因素包括近亲结婚，与常染色体隐性遗传模式一致。^[1]

Pathophysiology

• The SLC13A5 gene encodes a sodium-dependent citrate transporter that is highly expressed in the brain, liver and other tissuesSLC13A5 基因编码在脑、肝和其他组织中高度表达的钠依赖性柠檬酸转运体。^[1]
• The transporter mediates the uptake of citrate into cells, where it participates in energy metabolism and the synthesis of lipids and neurotransmitters该转运体介导柠檬酸摄取进入细胞，在那里参与能量代谢以及脂质和神经递质的合成。^[1]
• Loss of SLC13A5 function impairs citrate uptake in neurons, disrupting brain energy metabolism and causing seizuresSLC13A5 功能丧失损害神经元中的柠檬酸摄取，破坏脑能量代谢并引起癫痫发作。^[1]
• Impaired citrate transport also affects enamel formation, explaining the tooth hypoplasia characteristic of the disorder柠檬酸转运受损还影响牙釉质形成，解释了该病的牙齿发育不良特征。^[1]
• The condition is associated with developmental delay, which is thought to result from chronic brain energy deficiency该病与发育迟缓相关，被认为源于慢性脑能量缺乏。^[1]
• The movement disorder features, including ataxia and dystonia, reflect the involvement of the basal ganglia and cerebellum包括共济失调和肌张力障碍在内的运动障碍特征反映基底神经节和小脑的受累。^[1]

Clinical features

• The cardinal feature is severe, refractory seizures with onset in the first days of life, often presenting as multifocal clonic seizures主要特征是生命最初几天发作的严重难治性癫痫，常表现为多灶性阵挛性发作。^[1]
• Developmental delay is universal, with affected individuals showing delayed motor, language and cognitive milestones发育迟缓是普遍存在的，受累个体表现出运动、语言和认知里程碑延迟。^[1]
• Movement disorder features include ataxia, dystonia and choreoathetosis, which may emerge as the child grows运动障碍特征包括共济失调、肌张力障碍和手足徐动症，可能随儿童成长而出现。^[1]
• Tooth hypoplasia is a characteristic feature, with widely spaced teeth and abnormal enamel formation牙齿发育不良是特征性表现，牙齿间距宽且牙釉质形成异常。^[1]
• Speech is typically severely affected, with poor communication skills and difficulty standing or walking言语通常严重受累，沟通能力差，站立或行走困难。^[1]
• Complications include status epilepticus, injuries from falls and lifelong dependence on caregivers并发症包括癫痫持续状态、跌倒受伤和终身依赖护理者。^[1]

Diagnosis

• Diagnosis is suspected based on the clinical presentation of neonatal-onset seizures with developmental delay and tooth hypoplasia诊断基于新生儿期起病癫痫伴有发育迟缓和牙齿发育不良的临床表现怀疑。^[1]
• Genetic testing for SLC13A5 mutations by next-generation sequencing or exome sequencing confirms the diagnosis通过下一代测序或外显子组测序的 SLC13A5 突变基因检测确认诊断。^[1]
• Electroencephalography shows multifocal epileptiform discharges, and brain MRI may show non-specific findings or atrophy脑电图显示多灶性癫痫样放电，脑 MRI 可能显示非特异性发现或萎缩。^[1]
• The differential diagnosis includes other early infantile epileptic encephalopathies such as KCNQ2 and STXBP1 encephalopathies鉴别诊断包括其他早期婴儿癫痫性脑病，如 KCNQ2 和 STXBP1 脑病。^[1]
• Dental examination documents the characteristic tooth hypoplasia, which is a distinguishing diagnostic clue牙科检查记录特征性牙齿发育不良，这是区分性的诊断线索。^[1]
• Genetic counselling is important for families given the autosomal recessive inheritance and 25 per cent recurrence risk鉴于常染色体隐性遗传和25%的再发风险，遗传咨询对家庭很重要。^[1]

Management

• There is no cure for SLC13A5 epilepsy, and management focuses on seizure control and supportive careSLC13A5 癫痫目前无法治愈，管理侧重于癫痫控制和支持性护理。^[1]
• Anti-seizure medications are used, though seizures are often refractory to multiple agents使用抗癫痫药物，尽管癫痫发作常对多种药物难治。^[1]
• The ketogenic diet has been reported to be beneficial in some patients, potentially by providing alternative energy substrates to the brain据报道生酮饮食对部分患者有益，可能通过为脑提供替代能源底物。^[1]
• Physical, occupational and speech therapy are important for managing developmental delay and movement disorder物理、作业和言语治疗对于管理发育迟缓和运动障碍很重要。^[1]
• Dental care is important for managing tooth hypoplasia and preventing dental complications牙科护理对于管理牙齿发育不良和预防牙科并发症很重要。^[1]
• The prognosis is variable, with seizures often persisting and developmental delay being lifelong预后各异，癫痫发作常持续，发育迟缓为终身性。^[1]

Research and controversies

• The exact mechanism linking impaired citrate transport to seizures and developmental delay is not fully understood将柠檬酸转运受损与癫痫发作和发育迟缓联系起来的确切机制尚未完全理解。^[1]
• The role of the ketogenic diet in the management of SLC13A5 epilepsy is an area of active investigation生酮饮食在 SLC13A5 癫痫管理中的作用是活跃的研究领域。^[1]
• Potential therapies targeting the citrate transporter or downstream metabolic pathways are under investigation针对柠檬酸转运体或下游代谢通路的潜在治疗正在研究中。^[2]
• Several clinical trials are registered on ClinicalTrials.gov for treatments of SLC13A5 epilepsyClinicalTrials.gov 上注册了多项 SLC13A5 癫痫治疗的临床试验。^[2]
• The long-term outcomes and quality of life for patients with SLC13A5 epilepsy are not well characterizedSLC13A5 癫痫患者的长期结局和生活质量尚未充分描述。^[1]

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