背景:患有衔接蛋白复合物4(AP-4)遗传缺陷的患者表现出早期发育迟缓,痉挛性双瘫,智力残疾,言语障碍。该表型与其他遗传性痉挛性截瘫和脑瘫重叠。高热惊厥在发病时很常见。癫痫已在超过一半的病例中被描述,出现在婴儿早期,常伴有癫痫持续状态,但是到目前为止,尚未发现典型的癫痫发作符号学或脑电图特征。
目的:我们旨在专门研究该综合征的癫痫学特征,以揭示AP-4缺乏症中癫痫发作发展和预后的可能生物标志物。
方法:对AP-4亚单位双等位基因致病变异和癫痫患者的观察性队列研究。我们专注于癫痫发作的符号学,脑电图特征和对抗癫痫药物的反应。
结果:患者携带AP4S1(n=5)或AP4M1(n=1)的致病变异。表型包括痉挛性轻瘫,智力残疾,言语/语言障碍,小头畸形,和MRI证据显示call体发育不全。在66%的患者中,高热惊厥先于癫痫发作,从婴儿期到青春期(范围=14个月-13岁)。缺如(66%)和局灶性运动性癫痫发作(50%)很常见。没有患者符合耐药标准。癫痫发作后出现了特殊的脑电图特征,并在长期随访中持续存在:双侧和异步局灶性放电,并伴有独立的弥漫性尖峰波放电(100%)和反射异常(66%)。
结论:在AP-4复杂疾病中,癫痫可能出现在婴儿早期之后,直到青春期,全身性和局灶性癫痫发作的可变组合。预后良好。我们观察到一个常见的脑电图特征-局灶性/全身性和反射异常的组合-这可能构成AP-4缺乏与癫痫的生物标志物。适用于基因检测和鉴别诊断。
BACKGROUND: Patients with genetic deficiency of the adaptor protein complex 4 (AP-4) exhibit earlyonset developmental delay, spastic diplegia, intellectual disability, speech impairment. The phenotype overlaps with other hereditary spastic paraplegias and cerebral palsies. Febrile seizures are common at onset. Epilepsy has been described in more than half of cases, arising in early infancy often with status epilepticus, but no typical seizure semiology or electroencephalographic features have been identified thus far.
OBJECTIVE: We aimed to specifically investigate the epileptological characteristics of the syndrome to unveil possible biomarkers of seizure development and prognosis in AP-4 deficiency.
METHODS: Observational cohort study on patients with bi-allelic pathogenic variants in AP-4 subunits and epilepsy. We focused on the seizure semiology, electroencephalographic characteristics and response to antiseizure medications.
RESULTS: Patients harboured pathogenic variants in AP4S1 (n = 5) or AP4M1 (n = 1). The phenotype included spastic paraparesis, intellectual disability, speech/language impairment, microcephaly, and MRI evidence of hypoplasia of the corpus callosum. In 66 % of the patients, febrile seizures preceded the onset of epilepsy, which spanned from infancy to adolescence (range=14 months-13 years). Absences (66 %) and focal motor seizures (50 %) were common. No patient met the criteria for drug-resistance. Peculiar electroencephalographic features arose after the epilepsy onset and persisted at long-term follow-up: bilateral and asynchronous focal discharges combined with independent diffuse spike-wave-discharges (100 %) and reflex abnormalities (66 %).
CONCLUSIONS: In AP-4 complex disease, epilepsy could arise beyond early infancy, until adolescence, with variable combination of generalized and focal seizures. The prognosis was favourable. We observed a common electroencephalographic signature - combined focal/generalized and reflex abnormalities - which may constitute a biomarker of AP-4 deficiency with epilepsy, applicable to inform genetic testing and disentangle the differential diagnosis.