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

  • Dina Belachew
  • Traci Kazmerski
  • Ingrid Libman
  • Amy C. Goldstein
  • Susan T. Stevens
  • Stephanie DeWard
  • Jerry Vockley
  • Mark A. Sperling
  • Arcangela L. BalestEmail author
Case Report
Part of the JIMD Reports book series (JIMD, volume 11)


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 phenotype-genotype 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.


Enzyme Replacement Therapy Neonatal Abstinence Syndrome Pipecolic Acid Inorganic Pyrophosphate Tissue Nonspecific Alkaline Phosphatase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Alkaline phosphatase


Cerebrospinal fluid


Computerized tomography






Herpes simplex virus


Magnetic resonance imaging


Polymerase chain reaction




Pyridoxine-responsive seizures


Parathyroid hormone


Tissue nonspecific alkaline phosphatase



The authors would like to thank Dr. Keith Hyland at Medical Neurogenetics, Atlanta, Georgia, for processing the CSF samples for neurotransmitters and PLP level.


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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Dina Belachew
    • 1
  • Traci Kazmerski
    • 2
  • Ingrid Libman
    • 1
  • Amy C. Goldstein
    • 3
  • Susan T. Stevens
    • 4
  • Stephanie DeWard
    • 5
  • Jerry Vockley
    • 6
  • Mark A. Sperling
    • 7
  • Arcangela L. Balest
    • 8
    Email author
  1. 1.Department of Pediatric EndocrinologyChildren’s Hospital of Pittsburgh of UPMCPittsburghUSA
  2. 2.Department of PediatricsChildren’s Hospital of Pittsburgh of UPMCPittsburghUSA
  3. 3.Department of Pediatric NeurologyUniversity of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMCPittsburghUSA
  4. 4.Kids Plus PediatricsPittsburghPA
  5. 5.Department of Medical GeneticsChildren’s Hospital of Pittsburgh of UPMCPittsburghUSA
  6. 6.School of Medicine, Children’s Hospital of Pittsburgh of UPMCUniversity of PittsburghPittsburghUSA
  7. 7.Department of Pediatric EndocrinologyUniversity of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMCPittsburghUSA
  8. 8.Department of PediatricsChildren’s Hospital of Pittsburgh of UPMCPittsburghUSA

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