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

Sara Baumgartner-Sigl, Edda Haberlandt, Steven Mumm, Sabine Scholl-Bürgi, Consolato Sergi, Lawrence Ryan, Karen L. Ericson, Michael P. Whyte, Wolfgang Högler

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

Pyridoxine-responsive seizures (PRS) and the role of pyridoxine (PN, vitamin B6) 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.T371I). 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.

Original languageEnglish
Pages (from-to)1655-1661
Number of pages7
JournalBone
Volume40
Issue number6
DOIs
StatePublished - Jun 1 2007
Externally publishedYes

Keywords

  • Epilepsy
  • Phosphoethanolamine
  • Pyridoxal phosphate
  • Rickets
  • Vitamin B

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