Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene
Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene
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DOI：
10.1016/j.bone.2007.01.020
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发表时间：
2007-06-01
期刊：
影响因子：
4.1
通讯作者：
Hoegler, Wolfgang
中科院分区：
文献类型：
--
作者：
Baumgartner-Sigl, Sara;Haberlandt, Edda;Hoegler, Wolfgang
吡哆醇反应性癫痫发作（PRS）和吡哆醇（PN，维生素B-6）在低磷酸酶症（HPP）中的作用尚未完全了解。通常，PRS和HPP是罕见的、独立的代谢性疾病。在PRS中，癫痫发作抵抗除PN外的标准抗惊厥药，但预后良好。在HPP中，组织非特异性碱性磷酸酶同工酶（TNSALP）的失活损害骨骼矿化，并导致婴儿佝偻病，这可能是致命的。在这里，我们报告一个7个月大的女孩，新诊断为婴儿HPP，谁提出了作为一个新生儿与PRS，但没有骨骼异常。脑脊液（CSF）中生物胺的分析表明脑5 '-磷酸吡哆醛（PLP）缺乏，尽管CSF中的PLP没有降低。她有正常的认知里程碑，但未能茁壮成长和佝偻病。几乎检测不到的血清ALP活性，血浆PLP和尿磷酸乙醇胺（PEA）和无机焦磷酸盐（PPi）水平升高，高钙血症，高钙尿症和肾钙质沉着症与婴儿HPP一致。只有泼尼松龙降低血清钙水平。尽管生长和体重增加有所改善，但她仍发生肋骨骨折，并在9个月大时死于呼吸衰竭。TNSALP基因的序列分析揭示了外显子7（c.677T>C，p.M226T）和外显子10（c.677T>C，p.M226T）的新错义突变。1112 C>T，p.T3711）。我们的患者证明，新生儿的PRS可能不一定是“特发性”;相反，这种癫痫发作可能是由严重的HPP引起的，在婴儿期后期临床上变得明显。HPP中PRS的病理生理学不同于已知引起PRS的其他三种遗传缺陷，但所有这些都可能导致脑PLP缺乏降低癫痫发作阈值。所有报告的HPP新生儿癫痫患者在出生后18个月内死亡，表明PRS是HPP严重程度和致死性预后的指标。我们建议对任何有PRS的新生儿的评估应包括血清ALP活性的测量。(c)2007年爱思唯尔公司All rights reserved.
Pyridoxine-responsive seizures (PRS) and the role of pyridoxine (PN, vitamin B-6) in hypophosphatasia (HPP) are incompletely understood. Typically, PRS and HPP are rare, independent, metabolic disorders. In PRS, seizures resist standard anticonvulsants apart from PN, yet have a good prognosis. In HPP, inactivation of the tissue nonspecific isoenzyme of alkaline phosphatase (TNSALP) impairs skeletal mineralization and causes rickets in infants that can be fatal. Here, we report a 7-month-old girl, newly diagnosed with infantile HPP, who presented as a neonate with PRS but without bony abnormalities. Analysis of biogenic amines in cerebrospinal fluid (CSF) suggested brain pyridoxal 5'-phosphate (PLP) deficiency, although PLP in CSF was not decreased. She had normal cognitive milestones but failure to thrive and rickets. Nearly undetectable serum ALP activity, elevated plasma PLP and urinary phosphoethanolamine (PEA) and inorganic pyrophosphate (PPi) levels, hypercalcemia, hypercalciuria and nephrocalcinosis were consistent with infantile HPP. Only prednisolone reduced serum calcium levels. Despite improved growth and weight gain, she developed rib fractures and died from respiratory failure at age 9 months. Sequence analysis of the TNSALP gene revealed novel missense mutations in exon 7 (c.677T>C, p.M226T) and exon 10 (c. 1112C>T, p.T3711). Our patient demonstrated that PRS in neonates may not necessarily be "idiopathic"; instead, such seizures can be caused by severe HPP that becomes clinically apparent later in infancy. The pathophysiology of PRS in HPP differs from the three other genetic defects known to cause PRS, but all may lead to brain PLP deficiency reducing seizure thresholds. All reported HPP patients with neonatal seizures died within 18 months of birth, suggesting that PRS is an indicator of HPP severity and lethal prognosis. We recommend that assessment of any neonate with PRS should include measurement of serum ALP activity. (c) 2007 Elsevier Inc. All rights reserved.