Hipofosfatazija u djece

master's thesis

• Title (english): Hypophosphatasia in children
• Author: Ana Smajo
• Mentor: Danijela Petković Ramadža (mentor)
• Committee member: Ivo Barić (predsjednik povjerenstva)
• Committee member: Marija Jelušić (član povjerenstva)
• Committee member: Danijela Petković Ramadža (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Pediatrics); Zagreb
• Defense date and country: 2020-07-17, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Pediatrics

Abstract

Hipofosfatazija (HP) je rijetka nasljedna metabolička bolest kostiju čije je glavno biokemijsko obilježje za dob i spol niska aktivnost serumske alkalne fosfataze (hipofosfatazemija). Bolest nastaje zbog mutacija gena ALPL koji kodira enzim tkivno nespecifičnu alkalnu fosfatazu (TNSALP). TNSALP je eksprimiran u jetri, bubrezima i kostima, a njegovi supstrati su anorganski pirofosfat (PPi), piridoksal-5-fosfat (PLP) / vitamin B6 i fosfoetanolamin (PEA). Stoga su, osim niske alkalne fosfataze, dodatna obilježja HP povišene koncentracije PLP i PEA. Ovaj enzim ima ključnu ulogu u procesu mineralizacije kostiju, a njegova nedostatna funkcija uzrokuje rahitis ili osteomalaciju. Rahitis je u pacijenata s HP obilježen povišenim koncentracijama kalcija i fosfora u serumu, posljedičnom hiperkalciurijom te niskom aktivnošću ALP. HP se može podijeliti na sedam kliničkih oblika prema dobi i simptomima. Perinatalni letalni, infantilni, dječji i odrasli tip četiri su glavna oblika, a uz njih još postoje perinatalni benigni, odontohipofosfatazija i pseudohipofosfatazija. Međutim, postoji znatna genetska i fenotipska varijabilnost. Teški infantilni oblici HP obilježeni su hipomineralizacijom i iskrivljenim udovima ili gotovo potpuno odsutnom mineralizacijom kostura, a rana smrt je posljedica zatajenja disanja. Hiperkalcemijske krize i zastoj u rastu i razvoju javljaju se u dojenčadi s infantilnim oblikom HP. Kraniosinostoza je česta u ranim oblicima bolesti, a epilepsija ovisna o vitaminu B6 je pretkazatelj lošeg ishoda bolesti. Prijelomi su uobičajeni i kod infantilnih i kod adultnih oblika bolesti, a u odraslih se javljaju kronična bol i umor. Odontohipofosfatazija se očituje izoliranim preranim gubitkom zuba, a dio je kliničke slike i u ostalim oblicima HP. Liječenje je suportivno, a za teške oblike HP odnedavno je dostupna i enzimska nadomjesna terapija. Iako se lijek pokazao vrlo djelotvornim, posebno za infantilni tip bolesti, još uvijek nisu poznati dugoročni učinci.

Abstract (english)

Hypophosphatasia (HP) is a rare inherited metabolic bone disease characterized by low serum alkaline phosphatase activity (hypophosphatasaemia) for the age and gender. The disease is caused by pathogenic mutations in the gene that encodes the enzyme tissue-nonspecific alkaline phosphatase (TNSALP). TNSALP is expressed in the liver, kidney and bone, and its substrates are inorganic pyrophosphate (PPi), pyridoxal-5’-phosphate (PLP) / vitamin B6 and phosphoethanolamine (PEA). Therefore, besides low alkaline phosphatase major hallmarks of HP are elevated PLP and PEA concentrations. This ubiquitous enzyme plays a crucial role in the process of bone mineralization and it's deficiency causes rickets or osteomalacia in HP patients. Rickets in HP patients is associated with high levels of calcium and phosphorus, resulting in hypercalciuria and nephrocalcinosis, together with low ALP. HP is divided into seven clinical forms according to the age of onset and symptoms. Perinatal lethal, infantile, childhood and adult type are the four main types, and others are perinatal benign type, odontohypophosphatasia and pseudohypophosphatasia. However, there is considerable genetic and phenotypic variability within different subtypes. The most severe perinatal form of HP presents with severe hypomineralisation and deformed limbs, or even with near abscence of bones and skull. Premature death occurs as a result of respiratory insufficiency. Respiratory failure and seizures due to vitamin B6 deficiency are indicative of a poor prognosis. Craniosynostosis, hypercalcaemia and failure to thrive are frequent features in infants. Fractures are common both in infantile and adult forms of the disease, concomitantly occurring with unexplained chronic pain and fatigue. Premature loss of teeth, is also common in HP, and as an isolated feature found in odontohypophosphatasia. A novel enzyme replacement therapy for HP, asfotase alfa, specifically targeting mineralised tissues, has been available since recently. Even though this is a promising treatment, especially for infantile HP, more knowledge is needed regarding long-term effects and potential secondary adverse effects.

• Keywords: hipofosfatazija; tkivno nespecifična alkalna fosfataza; asfotaza alfa; rahitis
• Keywords (english): hypophosphatasia; tissue-nonspecific alkaline phospahatase; asfotase alfa; rickets
• Language: croatian
• URN:NBN: urn:nbn:hr:105:498843
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2021-08-31 11:33:53