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

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JIMD Reports - Volume 11

Part of the book series: JIMD Reports ((JIMD,volume 11))

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 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.

Competing interests: None declared

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Abbreviations

ALP:

Alkaline phosphatase

CSF:

Cerebrospinal fluid

CT:

Computerized tomography

EEG:

Electroencephalogram

HPP:

Hypophosphatasia

HSV:

Herpes simplex virus

MRI:

Magnetic resonance imaging

PCR:

Polymerase chain reaction

PLP:

Pyridoxal-5′-phosphate

PRS:

Pyridoxine-responsive seizures

PTH:

Parathyroid hormone

TNSALP:

Tissue nonspecific alkaline phosphatase

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Acknowledgements

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

Author information

Authors and Affiliations

  1. Department of Pediatric Endocrinology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, USA

    Dina Belachew & Ingrid Libman

  2. Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, USA

    Traci Kazmerski

  3. Department of Pediatric Neurology, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, USA

    Amy C. Goldstein

  4. Kids Plus Pediatrics, Pittsburgh, PA

    Susan T. Stevens

  5. Department of Medical Genetics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, USA

    Stephanie DeWard

  6. School of Medicine, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, USA

    Jerry Vockley

  7. Department of Pediatric Endocrinology, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, USA

    Mark A. Sperling

  8. Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA

    Arcangela L. Balest

Authors
  1. Dina Belachew
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  2. Traci Kazmerski
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  3. Ingrid Libman
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  4. Amy C. Goldstein
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  5. Susan T. Stevens
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  6. Stephanie DeWard
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  7. Jerry Vockley
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  8. Mark A. Sperling
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  9. Arcangela L. Balest
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Corresponding author

Correspondence to Arcangela L. Balest .

Editor information

Editors and Affiliations

  1. Medizinische Universität Innsbruck Sektionen für Humangenetik und Klinische, Innsbruck, Austria

    Johannes Zschocke

  2. Clinical Pharmacology Unit, Division of Health Sciences Washington State University, Spokane, Washington, USA

    K Michael Gibson

  3. Department of Biochemistry Genetics Unit, University of Oxford, Oxford, United Kingdom

    Garry Brown

  4. Department of Pediatrics IGMD, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Eva Morava

  5. Center for Child and Adolescent Medicine Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: K. Michael Gibson

Appendices

Synopsis

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.

Conflict of Interest

Drs. Belachew, Kazmerski, Libman, Goldstein, Stevens, Sperling, Balest and Ms. DeWard have no financial disclosures. Dr. Vockley discloses research support from Alexion Pharmaceuticals.

The authors attest that this is an original manuscript, and it has never been published. At this time, this manuscript is being submitted only to Journal of Inherited Metabolic Disease Reports and will not be submitted elsewhere while under consideration by this journal.

Contributor’s Statement Page

Dr. Belachew drafted the initial draft of this case report and has made a substantial contribution towards the content, outline, background, discussion, revision, editing, and finalization of this manuscript. Dr. Kazmerski has made a substantial contribution to the content, revision, editing, and finalization of this manuscript. Dr. Libman has made a substantial contribution to the diagnosis of this case, revision and editing of this manuscript. Dr. Goldstein has contributed significantly to the neurological aspect of the manuscript content and to revision and editing of this manuscript. Drs. Vockley and Stevens and Ms. Deward have contributed to the genetic discussion of this manuscript and revision and editing. Dr. Sperling has contributed to the background, content, and editing of this manuscript. Dr. Balest has made substantial contributions to the background, revision, editing, and finalization of this manuscript. All of the authors have reviewed this manuscript and given final approval for its submission for publication.

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Belachew, D. et al. (2013). Infantile Hypophosphatasia Secondary to a Novel Compound Heterozygous Mutation Presenting with Pyridoxine-Responsive Seizures. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Volume 11. JIMD Reports, vol 11. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_217

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  • DOI: https://doi.org/10.1007/8904_2013_217

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