TY - JOUR
T1 - 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
AU - Baumgartner-Sigl, Sara
AU - Haberlandt, Edda
AU - Mumm, Steven
AU - Scholl-Bürgi, Sabine
AU - Sergi, Consolato
AU - Ryan, Lawrence
AU - Ericson, Karen L.
AU - Whyte, Michael P.
AU - Högler, Wolfgang
N1 - Funding Information:
We are grateful to Dr. Xiafang Zhang, Washington University, MO, USA for assistance with the molecular studies and to Dr. Nenad Blau, University of Zurich, CH for neurotransmitter analysis in CSF. Shriners Hospitals for Children, The Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund and The Hypophosphatasia Research Fund provided financial support for biochemical and molecular genetic analyses. Shrine volunteer, Cindy Webster, expertly assisted in the preparation of the manuscript. Furthermore, we thank Dr. Robert Sweazey of the CNS Tissue Bank for Alzheimer's Disease and Related Disorders, Indiana University School of Medicine, Fort Wayne, IN, USA for providing CSF samples for validation.
PY - 2007/6
Y1 - 2007/6
N2 - 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.
AB - 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.
KW - Epilepsy
KW - Phosphoethanolamine
KW - Pyridoxal phosphate
KW - Rickets
KW - Vitamin B
UR - http://www.scopus.com/inward/record.url?scp=34248573295&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2007.01.020
DO - 10.1016/j.bone.2007.01.020
M3 - Article
C2 - 17395561
AN - SCOPUS:34248573295
SN - 8756-3282
VL - 40
SP - 1655
EP - 1661
JO - Bone
JF - Bone
IS - 6
ER -