Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy; Tuscany PhD Programme in Neurosciences, Florence, Italy.
Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy.
Seizure. 2024 Oct;121:186-193. doi: 10.1016/j.seizure.2024.08.009. Epub 2024 Aug 24.
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.
We aimed to specifically investigate the epileptological characteristics of the syndrome to unveil possible biomarkers of seizure development and prognosis in AP-4 deficiency.
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.
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 %).
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.
患有衔接蛋白复合物 4（AP-4）遗传缺陷的患者表现为早发性发育迟缓、痉挛性双瘫、智力障碍、言语障碍。表型与其他遗传性痉挛性截瘫和脑瘫重叠。发病时常见热性惊厥。已有超过一半的病例描述了癫痫，通常在婴儿早期出现，伴有癫痫持续状态，但迄今为止尚未确定典型的发作症状学或脑电图特征。
我们旨在专门研究该综合征的癫痫学特征，以揭示 AP-4 缺乏症中可能的发作发展和预后的生物标志物。
对具有 AP-4 亚基双等位致病性变异和癫痫的患者进行观察性队列研究。我们重点关注发作症状学、脑电图特征和抗癫痫药物的反应。
患者携带 AP4S1（n=5）或 AP4M1（n=1）的致病性变异。表型包括痉挛性截瘫、智力障碍、言语/语言障碍、小头畸形和胼胝体发育不全的 MRI 证据。在 66%的患者中，热性惊厥先于癫痫发作，癫痫发作从婴儿期到青春期（范围=14 个月至 13 岁）。失神发作（66%）和局灶性运动性发作（50%）较为常见。没有患者符合耐药标准。癫痫发作后出现了独特的脑电图特征，并在长期随访中持续存在：双侧和异步局灶性放电，伴有独立的弥漫性棘慢波放电（100%）和反射异常（66%）。
在 AP-4 复合疾病中，癫痫可能在婴儿期后出现，直到青春期，具有广泛和局灶性发作的不同组合。预后良好。我们观察到一种常见的脑电图特征——合并局灶性/全面性和反射异常——这可能构成具有癫痫的 AP-4 缺乏症的生物标志物，可用于遗传检测并阐明鉴别诊断。
