Infantile Hypophosphatasia Secondary to a Novel Compound Heterozygous Mutation Presenting with Pyridoxine-Responsive Seizures

Abstract

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 phenotypegenotype 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.

Vitamin B-6 Metabolism and Interactions with TNAP

“…This was confirmed in knockout mice lacking TNAP which died from seizures (Waymire et al 1995). Pyridoxal phosphate in cerebrospinal fluid was above the normal range in three infants with hypophosphatasia (Baumgartner-Sigl et al 2007;Hofmann et al 2013;Belachew et al 2013) supporting the hypothesis that low alkaline phosphatase activity restricted uptake of vitamin B-6 by the brain. Waymire et al (1995) hypothesized that the seizures resulted from decreased concentration of the inhibitory neurotransmitter, gamma-aminobutyrate (GABA).…”

“…Analysis of cerebrospinal fluid in infants with hypophosphatasia detected reduced 5-hydroxyindoleacetic acid and homovanillic acid in two out of four cases (Balasubramaniam et al 2010;Hofmann et al 2013;Belachew et al 2013). 3-O-methyldopa and 5-hydroxytryptophan were elevated in the only cases where they were measured (Baumgartner-Sigl et al 2007;Balasubramaniam et al 2010).…”

“…Bethenod et al did administer pyridoxine but it was not effective in relieving the seizures. Since then there have been multiple reports in which vitamin B-6 supplementation was beneficial (Sia et al 1975;Litmanovitz et al 2002;Nunes et al 2002;Yamamoto et al 2004;Arun et al 2005;Baumgartner-Sigl et al 2007;Balasubramaniam et al 2010;Demirbilek et al 2012;Belachew et al 2013). Vitamin B-6 supplementation also corrected seizures in mice lacking alkaline phosphatase (Waymire et al 1995;Narisawa et al 2001).…”

Reference intervals for alkaline phosphatase activity in blood serum in children. Laboratory diagnosis of hypophosphatasia

“…Повышение ЩФ происходит в по-следнем триместре беременности, после менопаузы, при недостатке кальция и фосфатов в пище, от пере-дозировки витамина С, а так же как следствие при-ема некоторых лекарственных препаратов (оральных контрацептивов, содержащих эстроген и прогесте-рон, антибиотиков и других) [18,19].…”

“…Купируемые витамином В 6 судороги, наблюдаемые у наиболее тяжелых больных ГФФ, чаще всего становятся ре-зультатом дефицита ПЛФ в ЦНС. Тот факт, что у наиболее тяжелых пациентов с ГФФ наблюдает-ся нормальная или немного повышенная концен-трация пиридоксаля в плазме, отсутствуют суще-ственные нарушения статуса витамина В 6 , а также редкость возникновения судорог, свидетельствует о другом механизме дефосфорилирования ПЛФ во внеклеточном пространстве [14,18,19]. ПЛФ изме-ряется при рутинном клиническом исследовании, которое чаще всего называют определением вита-мина В 6 .…”