Hypophosphatasia is a rare inherited disorder of bone and mineral metabolism caused by a number of loss-of-function mutations in the ALPL gene. It is characterized by defective bone and tooth mineralisation associated with low serum and bone alkaline phosphatase activity. The clinical presentation of this disease is extremely variable. For this reason, the diagnosis can be difficult and is often missed out or delayed. Hypophosphatasia is classified into subtypes based on the age of onset and clinical features. The clinical severity is associated with the age at diagnosis and the lack of tissue-nonspecific alkaline phosphatase activity; the severe forms of hypophosphatasia are primarily perinatal and infantile forms. Severe forms may present with many neurological problems such as seizures, hypotonia, irritability. Herein, we report the case of an infantile hypophosphatasia patient who presented with pyridoxineresponsive seizures and a novel homozygous mutation in the ALPL gene was detected. There is a limited number of hypophosphatasia patients with pyridoxine-responsive seizures in the literature, so early diagnosis of infantile hypophosphatasia in the clinically compatible patients allows more effective postnatal care/management and genetic counseling for further pregnancies.
Rathbun JC. Hypophosphatasia: a new developmental anomaly. Am J Dis Child 1948;75:822-834.
Whyte MP. Hypophosphatasia. In: Thakker RV, Whyte MP, Eisman J, Igarashi T (eds). Genetics of bone biology and skeletal disease. London, Academic Press, 2012;337-360.
Taillandier A, Sallinen SL, Brun-Heath I, De Mazancourt P, Serre JL, Mornet E. Childhood hypophosphatasia due to a de novo missense mutation in the tissue-nonspecific alkaline phosphatase gene. J Clin Endocrinol Metab 2005;90:2436- 2439. Epub 2005 Jan 25
Fauvert D, Brun-Heath I, Lia-Baldini AS, Bellazi L, Taillandier A, Serre JL, de Mazancourt P, Mornet E. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Med Genet 2009;10:51.
Spentchian M, Merrien Y, Herasse M, Dobbie Z, Gläser D, Holder SE, Ivarsson SA, Kostiner D, Mansour S, Norman A, Roth J, Stipoljev F, Taillemite JL, van der Smagt JJ, Serre JL, Simon-Bouy B, Taillandier A, Mornet E. Severe hypophosphatasia: characterization of fifteen novel mutations in the ALPL gene. Hum Mutat 2003;22:105-106.
Sergi C, Mornet E, Troeger J, Voigtlaender T. Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Am J Med Genet 2001;103:235-240.
Whyte MP. Hypophosphatasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 2001:5313-5329.
Hollis A, Arundel P, High A, Balmer R. Current concepts in hypophosphatasia: case report and literature review. Int J Paediatr Dent 2013;23:153-159. Epub 2012 Jun 4
Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci 2010;1192:190-200.
Bianchi ML. Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int 2015;26:2743-2757. Epub 2015 Aug 6
Baumgartner-Sigl S, Haberlandt E, Mumm S, Scholl-Bürgi S, Sergi C, Ryan L, Ericson KL, Whyte MP, Högler W. 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 2007;40:1655-1661. Epub 2007 Feb 14
Nunes ML, Mugnol F, Bica I, Fiori RM. Pyridoxine-dependent seizures associated with hypophosphatasia in a newborn. J Child Neurol 2002;17:222-224.
Baxter P. Pyridoxine-dependent seizures: a clinical and biochemical conundrum. Biochim Biophys Acta 2003;1647:36- 41.
Litmanovitz I, Reish O, Dolfin T, Arnon S, Regev R, Grinshpan G, Yamazaki M, Ozono K. Glu274Lys/Gly309Arg mutation of the tissue-nonspecific alkaline phosphatase gene in neonatal hypophosphatasia associated with convulsions. J Inherit Metab Dis 2002;25:35-40.
Yamamoto H, Sasamoto Y, Miyamoto Y, Murakami H, Kamiyama N. A successful treatment with pyridoxal phosphate for West syndrome in hypophosphatasia. Pediatr Neurol 2004;30:216-218.
Demirbilek H, Alanay Y, Alikaşifoğlu A, Topçu M, Mornet E, Gönç N, Özön A, Kandemir N. Hypophosphatasia presenting with pyridoxine-responsive seizures, hypercalcemia, and pseudotumor cerebri: case report. J Clin Res Pediatr Endocrinol 2012;4:34-38.
Wei KW, Xuan K, Liu YL, Fang J, Ji K, Wang X, Jin Y, Watanabe S, Watanabe K, Ojihara T. Clinical, pathological and genetic evaluations of Chinese patients with autosomal- dominant hypophosphatasia. Arch Oral Biol 2010;55:1017- 1023. Epub 2010 Sep 9
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. Enzyme-replacement therapy in life- threatening hypophosphatasia. N Engl J Med 2012;366:904- 913.