Ogawa Eri, Shimura Kazuhiro, Yoshihashi Hiroshi, Miyama Sahoko
Department of Pediatric Neurology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
Department of Pediatric Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
Pediatr Neurol. 2022 May;130:4-6. doi: 10.1016/j.pediatrneurol.2021.12.009. Epub 2021 Dec 28.
Hypophosphatasia (HPP), an inherited, metabolic disorder caused by loss-of-function mutations in the ALPL gene, affects not only bone and tooth mineralization but also central nervous system (CNS) function, resulting in vitamin B6/pyridoxine-responsive seizures. Asfotase alfa treatment mainly improves the skeletal manifestations of HPP. As of yet, there are no reports demonstrating seizure exacerbation caused by asfotase alfa interruption.
The patient was a 2-year and 8-month-old female with clinical and genetic diagnosis of perinatal severe HPP. Genetic analysis of ALPL identified compound heterozygous variants. Asfotase alfa and pyridoxine administration begun on postnatal day 2 restored normal development and suppressed seizures except for simple febrile seizures. From age 2 years when her asfotase alfa injections became irregular, she began experiencing seizure exacerbation, including status epilepticus, leading to acute encephalopathy and severe sequelae. The seizure exacerbations always coincided with low alkaline phosphatase (ALP) activity caused by the interruption of asfotase alfa administration.
The clinical course of the present case demonstrated the effect of asfotase alfa on CNS symptoms and a clear correlation between low serum ALP activity and seizure exacerbation. Serum ALP activity measurements were useful as a therapeutic marker in the present case. Furthermore, the risk of seizure exacerbation in the patient could have been predicted, given the genotype-phenotype correlation related to the ALPL gene in the Japanese population.
Regular asfotase alfa injections are needed to prevent seizure exacerbation in patients with HPP. Educating patients and their family about the need for regular asfotase alfa treatment is crucial to preventing disease exacerbation.
低磷酸酯酶症（HPP）是一种由ALPL基因突变导致功能丧失引起的遗传性代谢紊乱疾病，不仅影响骨骼和牙齿矿化，还会影响中枢神经系统（CNS）功能，导致维生素B6/吡哆醇反应性癫痫发作。阿法骨化醇治疗主要改善HPP的骨骼表现。截至目前，尚无关于阿法骨化醇中断导致癫痫发作加剧的报道。
该患者为一名2岁8个月大的女性，临床和基因诊断为围产期重度HPP。对ALPL进行基因分析发现复合杂合变异。出生后第2天开始给予阿法骨化醇和吡哆醇，除单纯热性惊厥外，恢复了正常发育并抑制了癫痫发作。从2岁起，她的阿法骨化醇注射变得不规律，开始出现癫痫发作加剧，包括癫痫持续状态，导致急性脑病和严重后遗症。癫痫发作加剧总是与阿法骨化醇给药中断导致的碱性磷酸酶（ALP）活性降低同时出现。
本病例的临床过程显示了阿法骨化醇对中枢神经系统症状的影响，以及血清ALP活性降低与癫痫发作加剧之间的明显相关性。在本病例中，血清ALP活性测量作为治疗指标很有用。此外，鉴于日本人群中与ALPL基因相关的基因型-表型相关性，该患者癫痫发作加剧的风险本可以预测。
需要定期注射阿法骨化醇以防止HPP患者癫痫发作加剧。对患者及其家属进行关于定期阿法骨化醇治疗必要性的教育对于预防疾病加剧至关重要。
