Belachew Dina, Kazmerski Traci, Libman Ingrid, Goldstein Amy C, Stevens Susan T, Deward Stephanie, Vockley Jerry, Sperling Mark A, Balest Arcangela L
Department of Pediatric Endocrinology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, USA.
JIMD Rep. 2013;11:17-24. doi: 10.1007/8904_2013_217. Epub 2013 Mar 12.
Hypophosphatasia (HPP) is a rare metabolic disease with the hallmark finding of deficient serum tissue nonspecific alkaline phosphatase (TNSALP) activity. TNSALP is primarily known for its role in mineralization; hence, HPP is characterized by defective mineralization of bone and/or teeth. TNSALP is also necessary for proper vitamin B6 metabolism and its participation as a cofactor for neurotransmitters in the central nervous system. Defective TNSALP activity in the brain can result in intractable seizures responsive to pyridoxine. The pathophysiology of pyridoxine-responsive seizures (PRS) in severe HPP remains to be clearly defined. We review the case of a 2-month-old Caucasian boy presenting with seizures refractory to conventional antiepileptic medications. Empiric treatment with favorable response to pyridoxine in conjunction with severe metabolic bone disease, extremely low serum alkaline phosphatase, elevated phosphoethanolamine, hypercalcemia, hypercalciuria, and nephrocalcinosis led to a clinical diagnosis of infantile HPP. Sequence analysis revealed compound heterozygosity of the TNSALP gene with a novel mutation in exon 9 and a previously reported mutation in exon 12. This case reminds the physician that severe infantile HPP can present with PRS as its major initial manifestation and should alert clinicians to consider HPP in their differential of PRS. In addition, despite this severe genotype, the clinical diagnosis of our patient was delayed because of minimal phenotypic features initially. This highlights that the phenotype-genotype correlation could be variable even in severe disease. This case also demonstrates that HPP should be classified as PRS and not a form of pyridoxine-dependent epilepsy (PDE) as our patient was able to stop the pyridoxine supplementation without seizure recurrence once enzyme replacement was initiated. With the advent of enzyme replacement therapy, this once fatal disease may have improved morbidity and mortality.
低磷酸酯酶症（HPP）是一种罕见的代谢性疾病，其标志性表现是血清组织非特异性碱性磷酸酶（TNSALP）活性缺乏。TNSALP主要因其在矿化过程中的作用而闻名；因此，HPP的特征是骨骼和/或牙齿矿化缺陷。TNSALP对于适当的维生素B6代谢也是必需的，并且它作为中枢神经系统中神经递质的辅助因子发挥作用。大脑中TNSALP活性缺陷可导致对吡哆醇有反应的顽固性癫痫发作。严重HPP中吡哆醇反应性癫痫发作（PRS）的病理生理学仍有待明确界定。我们回顾了一名2个月大的白人男孩的病例，该男孩出现对传统抗癫痫药物难治的癫痫发作。经验性使用吡哆醇治疗取得良好反应，同时伴有严重的代谢性骨病、极低的血清碱性磷酸酶、磷酸乙醇胺升高、高钙血症、高钙尿症和肾钙质沉着症，从而得出婴儿HPP的临床诊断。序列分析显示TNSALP基因的复合杂合性，外显子9有一个新突变，外显子12有一个先前报道的突变。该病例提醒医生，严重婴儿HPP可能以PRS作为主要初始表现，应提醒临床医生在鉴别PRS时考虑HPP。此外，尽管基因型严重，但我们患者的临床诊断最初因表型特征不明显而延迟。这突出表明，即使在严重疾病中，表型-基因型相关性也可能存在差异。该病例还表明，HPP应归类为PRS，而不是吡哆醇依赖性癫痫（PDE）的一种形式，因为我们的患者在开始酶替代治疗后能够停止补充吡哆醇且无癫痫复发。随着酶替代疗法的出现，这种曾经致命的疾病的发病率和死亡率可能会有所改善。
