ppharmПедиатрическая фармакологияPediatric pharmacology1727-57762500-3089Издательство «ПедиатрЪ»10.15690/pf.v15i3.1905ppharm-1632Research ArticleЛЕКЦИЯLECTUREНеврологические и нейрохирургические аспекты гипофосфатазииNeurological and Neurosurgical Aspects of HypophosphatasiaИвановВ. П.IvanovVadim P.СатанинЛ. А.SataninLeonid A.КимА. В.KimAlexander V.https://orcid.org/0000-0001-8077-5313КузенковаЛ. М.KuzenkovaLudmila M.

Кузенкова Людмила Михайловна, доктор медицинских наук, профессор, заведующая отделением, отделение психоневрологии и психосоматической патологии НИИ педиатрии 

Адрес: 119991, Москва Ломоносовский пр-т, д. 2, стр. 3, тел.: +7 (499) 134-04-09 

kuzenkova@nczd.ruhttps://orcid.org/0000-0002-2395-1322МаргиеваТ. В.MargievaTea V.ПоповичС. Г.PopovichSofia G.Национальный медицинский исследовательский центр имени В.А. АлмазоваРоссияAlmazov National Medical Research CentreRussian FederationНациональный медицинский исследовательский центр нейрохирургии имени академика Н.Н. БурденкоРоссияNational Medical Research Center for Neurosurgery n/a Academician N. N. BurdenkoRussian FederationНациональный медицинский исследовательский центр имени В.А. АлмазоваРоссияNational Medical Research Center for Neurosurgery n/a Academician N. N. BurdenkoRussian FederationНациональный медицинский исследовательский центр здоровья детейРоссияNational Medical Research Center for Children’s HealthRussian Federation201806072018153249254Copyright © Иванов В.П., Сатанин Л.А., Ким А.В., Кузенкова Л.М., Маргиева Т.В., Попович С.Г., 20182018Иванов В.П., Сатанин Л.А., Ким А.В., Кузенкова Л.М., Маргиева Т.В., Попович С.Г.Ivanov V.P., Satanin L.A., Kim A.V., Kuzenkova L.M., Margieva T.V., Popovich S.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pedpharma.ru/jour/article/view/1632

Гипофосфатазия — редкое наследственное прогрессирующее заболевание, вызванное мутацией в гене ALPL, вследствие которой угнетается активность щелочной фосфатазы. Из-за нарушения процесса минерализации костной ткани в клинической картине преобладают рахитоподобные деформации скелета, но зачастую возникают и другие системные проявления — нарушение дыхания, поражение мочевыделительной системы и неврологические расстройства. У пациентов выявляют судороги, задержку физического и психомоторного развития, дефицит внимания, мышечную слабость, быструю утомляемость, внутричерепную гипертензию, связанную с развитием краниосиностозов. Тяжесть гипофосфатазии зависит от времени ее манифестации: наибольшая смертность регистрируется при перинатальной и инфантильной формах заболевания. Диагностика основана на выявлении характерных клинических симптомов — задержки роста и развития, деформации скелета, болей в мышцах и суставах, преждевременного выпадения зубов. В лабораторных анализах отслеживается стойкое снижение уровня щелочной фосфатазы с учетом возраста и пола пациента; при низкой активности фермента уровни субстратов щелочной фосфатазы пиридоксаль-5-фосфат в крови и фосфоэтаноламина в моче всегда повышены. На рентгенограммах длинных трубчатых костей обнаруживаются «языки» просветления, проецирующиеся от зоны роста в метафизы, а также гипоминерализация, остеопения и другие деформации. Все пациенты с подозрением на гипофосфатазию должны быть проконсультированы клиническим генетиком и обследованы на выявление мутации в гене ALPL.

КОНФЛИКТ ИНТЕРЕСОВ

Авторы декларируют отсутствие конфликтов интересов, связанных с публикацией настоящей статьи.

Hypophosphatasia is a rare hereditary progressive disease caused by a mutation in ALPL gene and characterized by low activity of alkaline phosphatase. Due to the disruption of the bone mineralization process, ricket-like deformations of the skeleton occur in the clinic picture more frequently but other systemic manifestations can be also observed as respiratory insufficiency, urinary tract damage, and neurological disorders. Seizures, delayed physical and psychomotor development, attention deficit disorder, muscle weakness, fatigue, intracranial hypertension associated with the development of craniosynostosis are revealed in these patients. The severity of the disease depends on age: the highest mortality is reported in younger patients, in perinatal and infantile forms of hypophosphatasia. Diagnosis is based on the identification of specific clinical manifestations: retardation of growth and development, skeletal deformities, pain in muscles and joints, premature tooth loss. In laboratory tests, a steady decrease in alkaline phosphatase level is detected taking into account age and sex specification. If possible, alkaline phosphatase substrates are measured: levels of pyridoxal-5-phosphate in the blood and phosphoethanolamine in urine are higher at low enzyme activity. Radiographs of long bones typically reveal characteristic ‘tongues’ of lucency projecting from growth plates into metaphyses, hypomineralization, osteopenia, various kinds of deformation. All patients with suspected hypophosphatasia should be consulted by a clinical geneticist and evaluated to identify possible mutation in the ALPL gene.

гипофосфатазиясудорогикраниосиностозщелочная фосфатазаhypophosphatasiaseizurescraniosynostosisalkaline phosphataseReferencesWhyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190–200. doi: 10.1111/j.1749-6632.2010.05387.x.Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190–200. doi: 10.1111/j.1749-6632.2010.05387.x.Taketani T. Neurological symptoms of hypophosphatasia. Subcell Biochem. 2015;76:309–322. doi: 10.1007/978-94-017- 7197-9_14.Taketani T. Neurological symptoms of hypophosphatasia. Subcell Biochem. 2015;76:309–322. doi: 10.1007/978-94-017- 7197-9_14.Coburn SP, Whyte MP. Role of phosphatases in the regulation of vitamin B-6 metabolism in hypophosphatasia and other disorders. In: Leklem JE, Reynolds RD, editors. Clinical and physiological applications of vitamin B-6. New York, USA: AR Liss; 1988. pp. 65–93.Coburn SP, Whyte MP. Role of phosphatases in the regulation of vitamin B-6 metabolism in hypophosphatasia and other disorders. In: Leklem JE, Reynolds RD, editors. Clinical and physiological applications of vitamin B-6. New York, USA: AR Liss; 1988. pp. 65–93.Surtees R, Mills P, Clayton P. Inborn errors affecting vitamin B6 metabolism. Future Neurol. 2006;1(5):615–620. doi: 10.2217/14796708.1.5.615.Surtees R, Mills P, Clayton P. Inborn errors affecting vitamin B6 metabolism. Future Neurol. 2006;1(5):615–620. doi: 10.2217/14796708.1.5.615.Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. 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(6):1655–1661. doi: 10.1016/j.bone.2007.01.020.Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. 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(6):1655–1661. doi: 10.1016/j.bone.2007.01.020.Belachew D, Kazmerski T, Libman I, et al. Infantile hypophosphatasia secondary to a novel compound heterozygous mutation presenting with pyridoxine-responsive seizures. JIMD Rep. 2013;11:17–24. doi: 10.1007/8904_2013_217.Belachew D, Kazmerski T, Libman I, et al. Infantile hypophosphatasia secondary to a novel compound heterozygous mutation presenting with pyridoxine-responsive seizures. JIMD Rep. 2013;11:17–24. doi: 10.1007/8904_2013_217.Yamamoto H, Sasamoto Y, Miyamoto Y, et al. A successful treatment with pyridoxal phosphate for West syndrome in hypophosphatasia. Pediatr Neurol. 2004;30(3):216–218. doi: 10.1016/j.pediatrneurol.2003.08.003.Yamamoto H, Sasamoto Y, Miyamoto Y, et al. A successful treatment with pyridoxal phosphate for West syndrome in hypophosphatasia. Pediatr Neurol. 2004;30(3):216–218. doi: 10.1016/j.pediatrneurol.2003.08.003.Fukazawa M, Tezuka J, Sasazuki M, et al. Infantile hypophosphatasia combined with vitamin B6-responsive seizures and reticular formation lesions on magnetic resonance imaging: a case report. Brain Dev. 2018;40(2):140–144. doi: 10.1016/j.braindev.2017.07.015.Fukazawa M, Tezuka J, Sasazuki M, et al. Infantile hypophosphatasia combined with vitamin B6-responsive seizures and reticular formation lesions on magnetic resonance imaging: a case report. Brain Dev. 2018;40(2):140–144. doi: 10.1016/j.braindev.2017.07.015.van Karnebeek CD, Jaggumantri S. Current treatment and management of pyridoxine-dependent epilepsy. Curr Treat Options Neurol. 2015;17(2):335. doi: 10.1007/s11940-014-0335-0.van Karnebeek CD, Jaggumantri S. Current treatment and management of pyridoxine-dependent epilepsy. Curr Treat Options Neurol. 2015;17(2):335. doi: 10.1007/s11940-014-0335-0.Diez-Zaera M, Diaz-Hernandez JI, Hernandez-Alvarez E, et al. Tissue-nonspecific alkaline phosphatase promotes axonal growth of hippocampal neurons. Mol Biol Cell. 2011;22(7):1014–1024. doi: 10.1091/mbc.E10-09-0740.Diez-Zaera M, Diaz-Hernandez JI, Hernandez-Alvarez E, et al. Tissue-nonspecific alkaline phosphatase promotes axonal growth of hippocampal neurons. Mol Biol Cell. 2011;22(7):1014–1024. doi: 10.1091/mbc.E10-09-0740.Mornet E. Hypophosphatasia. Metabolism. 2018;82:142–155. doi: 10.1016/j.metabol.2017.08.013.Mornet E. Hypophosphatasia. Metabolism. 2018;82:142–155. doi: 10.1016/j.metabol.2017.08.013.Bianchi ML. Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int. 2015;26(12):2743–2757. doi: 10.1007/s00198-015-3272-1.Bianchi ML. Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int. 2015;26(12):2743–2757. doi: 10.1007/s00198-015-3272-1.Collmann H, Mornet E, Gattenlöhner S, et al. Neurosurgical aspects of childhood hypophosphatasia. Childs Nerv Syst. 2008;25(2):217–223. doi: 10.1007/s00381-008-0708-3.Collmann H, Mornet E, Gattenlöhner S, et al. Neurosurgical aspects of childhood hypophosphatasia. Childs Nerv Syst. 2008;25(2):217–223. doi: 10.1007/s00381-008-0708-3.Kosnik-Infinger L, Gendron C, Gordon CB, et al. Enzyme replacement therapy for congenital hypophosphatasia allows for surgical treatment of related complex craniosynostosis: a case series. Neurosurg Focus. 2015;38(5):E10. doi: 10.3171/2015.2.FOCUS14847.Kosnik-Infinger L, Gendron C, Gordon CB, et al. Enzyme replacement therapy for congenital hypophosphatasia allows for surgical treatment of related complex craniosynostosis: a case series. Neurosurg Focus. 2015;38(5):E10. doi: 10.3171/2015.2.FOCUS14847.Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12(4):233– 246. doi: 10.1038/nrendo.2016.14.Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12(4):233– 246. doi: 10.1038/nrendo.2016.14.Durussel J, Liu J, Campbell C, et al. Bone mineralizationdependent craniosynostosis and craniofacial shape abnormalities in the mouse model of infantile hypophosphatasia. Dev Dyn. 2016;245(2):175–182. doi: 10.1002/dvdy.24370.Durussel J, Liu J, Campbell C, et al. Bone mineralizationdependent craniosynostosis and craniofacial shape abnormalities in the mouse model of infantile hypophosphatasia. Dev Dyn. 2016;245(2):175–182. doi: 10.1002/dvdy.24370.Poryo M, Meyer S, Eymann R, et al. Clinical images: a cloudy skull — hypophosphatasia as reason for copper-beaten skull. Neuropediatrics. 2016;47(6):410–411. doi: 10.1055/s-0036- 1593532.Poryo M, Meyer S, Eymann R, et al. Clinical images: a cloudy skull — hypophosphatasia as reason for copper-beaten skull. Neuropediatrics. 2016;47(6):410–411. doi: 10.1055/s-0036- 1593532.Linglart A, Biosse-Duplan M. Hypophosphatasia. Curr Osteoporos Rep. 2016;14(3):95–105. doi: 10.1007/s11914-016-0309-0.Linglart A, Biosse-Duplan M. Hypophosphatasia. Curr Osteoporos Rep. 2016;14(3):95–105. doi: 10.1007/s11914-016-0309-0.Баранов А.А., Намазова-Баранова Л.С., Савостьянов К.В., и др. Клинические рекомендации по диагностике и лечению гипофосфатазии у детей // Педиатрическая фармакология. — 2016. — Т.13. — №6 — С. 539–543. [Baranov AA, NamazovaBaranova LS, Savostianov КV, et al. Clinical recommendation to the diagnostics and treatment of hypophosphatasia in children. Pediatric pharmacology. 2016;13(6):539–543. (In Russ).] doi: 10.15690/pf.v13i6.1665.Баранов А.А., Намазова-Баранова Л.С., Савостьянов К.В., и др. Клинические рекомендации по диагностике и лечению гипофосфатазии у детей // Педиатрическая фармакология. — 2016. — Т.13. — №6 — С. 539–543. [Baranov AA, NamazovaBaranova LS, Savostianov КV, et al. Clinical recommendation to the diagnostics and treatment of hypophosphatasia in children. Pediatric pharmacology. 2016;13(6):539–543. (In Russ).] doi: 10.15690/pf.v13i6.1665.Kishnani PS, Rush ET, Arundel P, et al. Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Mol Genet Metab. 2017;122(1–2):4–17. doi: 10.1016/j. ymgme.2017.07.010.Kishnani PS, Rush ET, Arundel P, et al. Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Mol Genet Metab. 2017;122(1–2):4–17. doi: 10.1016/j. ymgme.2017.07.010.Colantonio DA, Kyriakopoulou L, Chan MK, et al. Closing the gaps in pediatric laboratory reference intervals: a CALIPER database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem. 2012;58(5):854–868. doi: 10.1373/ clinchem.2011.177741.Colantonio DA, Kyriakopoulou L, Chan MK, et al. Closing the gaps in pediatric laboratory reference intervals: a CALIPER database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem. 2012;58(5):854–868. doi: 10.1373/ clinchem.2011.177741.sesep.uvsq.fr [Internet]. ALPL mutations database. Hypophosphatasia (MIM 146300, 241500, 241510) [cited 2018 May 15]. available from: http://www.sesep.uvsq.fr/03_hypo_ mutations.php.sesep.uvsq.fr [Internet]. ALPL mutations database. Hypophosphatasia (MIM 146300, 241500, 241510) [cited 2018 May 15]. available from: http://www.sesep.uvsq.fr/03_hypo_ mutations.php.Mornet E, Yvard A, Taillandier A, et al. A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Ann Hum Genet. 2011;75(3):439–445. doi: 10.1111/j.1469-1809.2011.00642.x.Mornet E, Yvard A, Taillandier A, et al. A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Ann Hum Genet. 2011;75(3):439–445. doi: 10.1111/j.1469-1809.2011.00642.x.

The authors declare that there are no conflicts of interest present.