Skip to main content
SpringerLink
Log in
Book cover

Neuronal Tissue-Nonspecific Alkaline Phosphatase (TNAP) pp 309–322Cite as

Neurological Symptoms of Hypophosphatasia

  • Chapter
  • First Online:

Part of the book series: Subcellular Biochemistry ((SCBI,volume 76))

Abstract

Hypophosphatasia (HPP) is a bone metabolic disorder caused by mutations in the liver/bone/kidney alkaline phosphatase gene (ALPL), which encodes tissue-nonspecific alkaline phosphatase (TNAP). This disease is characterized by disrupted bone and tooth mineralization, and reduced serum AP activity. Along with bone and tooth symptoms, many neurological symptoms , seizure, encephalopathy, intracranial hypertension , mental retardation , deafness, and growth hormone deficiency (GHD) , are frequently found in HPP patients. Seizure occurs in severe HPP types soon after birth, and responds to pyridoxine, but is an indicator of lethal prognosis. Encephalopathy rarely presents in severe HPP types, but has severe sequelae. Intracranial hypertension complicated in mild HPP types develops after the age of 1 year and sometimes need neurosurgical intervention. Mental retardation, deafness and GHD are more frequently found in Japanese HPP patients. Mental retardation occurs in all HPP types. Deafness in perinatal lethal type is both conductive and sensorineural . GHD develops in all but perinatal lethal type and the diagnosis tends to delay. The pathogenesis of these neural features of HPP might be due to impairment of both vitamin B6 metabolism and central nervous system development by ALPL mutations.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Balasubramaniam S, Bowling F, Carpenter K, Earl J, Chaitow J, Pitt J, Mornet E, Sillence D, Ellaway C (2010) Prenatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5′-phosphate availability. J Inherit Metab Dis 33(Suppl 3):25–33

    Google Scholar 

  • Basura GJ, Hagland SP, Wiltse AM, Gospe SM Jr (2009) Clinical features and the management of pyridoxine-dependent and pyridoxine-responsive seizures: review of 63 North American cases submitted to a patient registry. Eur J Pediatr 168(6):697–704

    Article  PubMed  Google Scholar 

  • Baumgartner-Sigl S, Haberlandt E, Mumm S, Scholl-Bürgi S, Sergi C, Ryan L, Ericson KL, Whyte MP, Högler W (2007) 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. Bone 40(6):1655–1661

    Article  CAS  PubMed  Google Scholar 

  • Baxter P (2003) Pyridoxine-dependent seizures: a clinical and biochemical conundrum. Biochim Biophys Acta 1647(1–2):36–41

    Article  CAS  PubMed  Google Scholar 

  • Bethenod M, Cotte MF, Collombel C, Frederich A, Cotte J. (1967) Neonatal discovery of hypophosphatasia. Bone improvement, fatal convulsant encephalopathy. Ann Pediatr (Paris) 14(12):835–841

    Google Scholar 

  • Belachew D, Kazmerski T, Libman I, Goldstein AC, Stevens ST, Deward S, VockleyJ Sperling MA, Balest AL (2013) Infantile hypophosphatasia secondary to a novel compound heterozygous mutation presenting with pyridoxine-responsive seizures. JIMD Rep 11:17–24

    Article  PubMed Central  PubMed  Google Scholar 

  • Brun-Heath I, Chabrol E, Fox M, Drexler K, Petit C, Taillandier A, De azancourt P, Serre JL, Mornet E (2008) A case of lethal hypophosphatasia providing new insights into the perinatal benign form of hypophosphatasia and expression of the ALPL gene. Clin Genet 73(3):245–250

    Google Scholar 

  • Cahill RA, Wenkert D, Perlman SA, Steele A, Coburn SP, McAlister WH, Mumm S, Whyte MP (2007) Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts. J Clin Endocrinol Metab 92(8):2923–2930

    Article  CAS  PubMed  Google Scholar 

  • Collmann H, Mornet E, Gattenlöhner S, Beck C, Girschick H (2009) Neurosurgical aspects of childhood hypophosphatasia. Childs Nerv Syst 25(2):217–223

    Article  CAS  PubMed  Google Scholar 

  • Demirbilek H, Alanay Y, Alikaşifoğlu A, Topçu M, Mornet E, Gönç N, Özön A, Kandemir N (2012) Hypophosphatasia presenting with pyridoxine-responsive seizures, hypercalcemia, and pseudotumor cerebri: case report. J Clin Res Pediatr Endocrinol 4(1):34–38

    Article  PubMed Central  PubMed  Google Scholar 

  • Deracinois B, Duban-Deweer S, Pottiez G, Cecchelli R, Karamanos Y, Flahaut C (2012) TNAP and EHD1 are over-expressed in bovine brain capillary endothelial cells after the re-induction of blood-brain barrier properties. PLoS One 7(10):e48428

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Díez-Zaera M, Díaz-Hernández JI, Hernández-Álvarez E, Zimmermann H, Díaz-Hernández M, Miras-Portugal MT (2011) Tissue-nonspecific alkaline phosphatase promotes axonal growth of hippocampal neurons. Mol Biol Cell 22(7):1014–1024

    Article  PubMed Central  PubMed  Google Scholar 

  • Fonta C, Négyessy L, Renaud L, Barone P (2004) Areal and subcellular localization of the ubiquitous alkaline phosphatase in the primate cerebral cortex: evidence for a role in neurotransmission. Cereb Cortex 14(6):595–609

    Article  PubMed  Google Scholar 

  • Fonta C, Negyessy L, Renaud L, Barone P (2005) Postnatal development of alkaline phosphatase activity correlates with the maturation of neurotransmission in the cerebral cortex. J Comp Neurol 486(2):179–196

    Article  PubMed  Google Scholar 

  • Gospe SM Jr (2010) Neonatal vitamin-responsive epileptic encephalopathies. Chang Gung Med J 33(1):1–12

    PubMed  Google Scholar 

  • Hanics J, Barna J, Xiao J, Millán JL, Fonta C, Négyessy L (2012) Ablation of TNAP function compromises myelination and synaptogenesis in the mouse brain. Cell Tissue Res 349(2):459–471

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hofmann C, Liese J, Schwarz T, Kunzmann S, Wirbelauer J, Nowak J, Hamann J, Girschick H, Graser S, Dietz K, Zeck S, Jakob F, Mentrup B (2013) Compound heterozygosity of two functional null mutations in the ALPL gene associated with deleterious neurological outcome in an infant with hypophosphatasia. Bone 55(1):150–157

    Article  CAS  PubMed  Google Scholar 

  • Kaplan SB, Kemp SS, Oh KS (1991) Radiographic manifestations of congenital anomalies of the skull. Radiol Clin North Am 29(2):195–218

    CAS  PubMed  Google Scholar 

  • Komaru K, Ishida Y, Amaya Y, Goseki-Sone M, Orimo H, Oda K (2005) Novel aggregate formation of a frame-shift mutant protein of tissue-nonspecific alkaline phosphatase is ascribed to three cysteine residues in the C-terminal extension. Retarded secretion and proteasomal degradation. FEBS J 272(7):1704–1717

    Article  CAS  PubMed  Google Scholar 

  • Litmanovitz Reish O, Dolfin T, Arnon S, Regev R, Grinshpan G, Yamazaki M, Ozono K (2002) Glu274Lys/Gly309Arg mutation of the tissue-nonspecific alkaline phosphatase gene in neonatal hypophosphatasia associated with convulsions. J Inherit Metab Dis 25(1):35–40

    Article  CAS  PubMed  Google Scholar 

  • Macpherson RI, Kroeker M, Houston CS (1972) Hypophosphatasia. J Can Assoc Radiol 23(1):16–26

    CAS  PubMed  Google Scholar 

  • Michigami T, Uchihashi T, Suzuki A, Tachikawa K, Nakajima S, Ozono K (2005) Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia. Eur J Pediatr 164(5):277–282

    Article  CAS  PubMed  Google Scholar 

  • Mornet E (2000) Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene. Hum Mutat 15(4):309–315

    Google Scholar 

  • Mornet E (2008) Hypophosphatasia. Best Pract Res Clin Rheumatol 22(1):113–127

    Article  CAS  PubMed  Google Scholar 

  • Mornet E, Yvard A, Taillandier A, Fauvert D, Simon-Bouy B (2011) A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Ann Hum Genet 75(3):439–445

    Article  PubMed  Google Scholar 

  • Narisawa S, Wennberg C, Millán JL (2001) Abnormal vitamin B6 metabolism in alkaline phosphatase knock-out mice causes multiple abnormalities, but not the impaired bone. J Pathol 193(1):125–133

    Article  CAS  PubMed  Google Scholar 

  • Nishioka T, Tomatsu S, Gutierrez MA, Miyamoto K, Trandafirescu GG, Lopez PL, Grubb JH, Kanai R, Kobayashi H, Yamaguchi S, Gottesman GS, Cahill R, Noguchi A, Sly WS (2006) Enhancement of drug delivery to bone: characterization of human tissue-nonspecific alkaline phosphatase tagged with an acidic oligopeptide. Mol Genet Metab 88(3):244–255

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Négyessy L, Xiao J, Kántor O, Kovács GG, Palkovits M, Dóczi TP, Renaud L, Baksa G, Glasz T, Ashaber M, Barone P, Fonta C (2011) Layer-specific activity of tissue non-specific alkaline phosphatase in the human neocortex. Neuroscience 172:406–418

    Article  PubMed  Google Scholar 

  • Nunes ML, Mugnol F, Bica I, Fiori RM (2002) Pyridoxine-dependent seizures associated with hypophosphatasia in a newborn. J Child Neurol 17(3):222–224

    Article  PubMed  Google Scholar 

  • Ozono K, Yamagata M, Michigami T, Nakajima S, Sakai N, Cai G, Satomura K, Yasui N, Okada S, Nakayama M (1996) Identification of novel missense mutations (Phe310Leu and Gly439Arg) in a neonatal case of hypophosphatasia. J Clin Endocrinol Metab 81(12):4458–4461

    CAS  PubMed  Google Scholar 

  • Ozono K, Michigami T (2011) Hypophosphatasia now draws more attention of both clinicians and researchers: A Commentary on prevelance of c. 1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasias in Japanese and effects of the mutation on heterozygous carriers. J Hum Genet 56(3):174–176

    Article  CAS  PubMed  Google Scholar 

  • Plecko B, Stöckler S (2010) Vitamin B6 dependent seizures. Can J Neurol Sci 36(Suppl 2):S73–S77

    Google Scholar 

  • Sia C, Wapnir R, Sokal M, Harper RG, Intizar S, Lifshitz F (1975) Effects of pyridoxine on neonatal hypophosphatasia. Pediatr Res 9:355

    Google Scholar 

  • Smilari P, Romeo DM, Palazzo P, Meli C, Sorge G (2005) Neonatal hypophosphatasia and seizures. A case report. Minerva Pediatr 57(5):319–323

    CAS  PubMed  Google Scholar 

  • Surtees R, Mills P, Clayton P (2006) Inborn errors affecting vitamin B6 metabolism. Future Neurol 1:615–620

    Article  CAS  Google Scholar 

  • Tadokoro M, Kanai R, Taketani T, Uchio Y, Yamaguchi S, Ohgushi H (2009) New bone formation by allogeneic mesenchymal stem cell transplantation in a patient with perinatal hypophosphatasia. J Pediatr 154(6):924–930

    Article  CAS  PubMed  Google Scholar 

  • Taketani T, Onigata K, Kobayashi H, Mushimoto Y, Fukuda S, Yamagichi S (2014) Clinical and genetic aspects of Hypophosphatasia in Japanese patients. Arch Dis Child 99(3):211–215

    Article  PubMed  Google Scholar 

  • Watanabe A, Karasugi T, Sawai H, Naing BT, Ikegawa S, Orimo H, Shimada T (2011) Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers. J Hum Genet 56(2):166–168

    Article  CAS  PubMed  Google Scholar 

  • Waymire KG, Mahuren JD, Jaje JM, Guilarte TR, Coburn SP, MacGregor GR (1995) Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6. Nat Genet 11(1):45–51

    Article  CAS  PubMed  Google Scholar 

  • Wenkert D, McAlister WH, Coburn SP, Zerega JA, Ryan LM, Ericson KL, Hersh JH, Mumm S, Whyte MP (2011) Hypophosphatasia: nonlethal disease despite skeletal presentation in utero (17 new cases and literature review). J Bone Miner Res 26(10):2389–2398

    Article  CAS  PubMed  Google Scholar 

  • Whyte MP, Mahuren JD, Fedde KN, Cole FS, McCabe ER, Coburn SP (1988) Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5′-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase. J Clin Invest 81(4):1234–1239

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Whyte M (2001) Hypophosphatasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The metabolic and molecular bases of disease, 8th edn. McGraw-Hill Book Company, New York, pp 5313–5329

    Google Scholar 

  • Whyte MP, Kurtzberg J, McAlister WH, Mumm S, Podgornik MN, Coburn SP, Ryan LM, Miller CR, Gottesman GS, Smith AK, Douville J, Waters-Pick B, Armstrong RD, Martin PL (2003) Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res 18(4):624–636

    Article  PubMed  Google Scholar 

  • Whyte MP (2010) Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci 1192:190–200

    Article  CAS  PubMed  Google Scholar 

  • Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millán JL, Skrinar AM, Crine P, Landy H (2012) Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med 366(10):904–913

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto H, Sasamoto Y, Miyamoto Y, Murakami H, Kamiyama N (2004) A successful treatment with pyridoxal phosphate for West syndrome in hypophosphatasia. Pediatr Neurol 30(3):216–218

    Google Scholar 

  • Zurutuza L, Muller F, Gibrat JF, Taillandier A, Simon-Bouy B, Serre JL, Mornet E (1999) Correlations of genotype and phenotype in hypophosphatasia. Hum Mol Genet 8(6):1039–1046

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of Interest

The author declares no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Shimane University Faculty of Medicine, 89-1, Enya, Izumo, Shimane, 693-8501, Japan

    Takeshi Taketani

Authors
  1. Takeshi Taketani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takeshi Taketani .

Editor information

Editors and Affiliations

  1. National Centre for Scientific Research (CNRS), University of Toulouse-UPS, Toulouse, France

    Caroline Fonta

  2. Wigner Research Centre for Physics, Hungarian Academy of Sciences, Budapest, Hungary

    László Négyessy

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Taketani, T. (2015). Neurological Symptoms of Hypophosphatasia. In: Fonta, C., Négyessy, L. (eds) Neuronal Tissue-Nonspecific Alkaline Phosphatase (TNAP). Subcellular Biochemistry, vol 76. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-7197-9_14

Download citation

Publish with us

Policies and ethics

Search

Navigation