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.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.