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Fenilketonurija je nasljedni metabolički poremećaj uzrokovan nedostatkom enzima fenilalaninhidroksilaze, nužnog za pretvorbu aminokiseline fenilalanin u tirozin. U ovom radu bit će riječ o važnosti pravovremenog otkrivanja poremećaja putem novorođenačkog probira, procesu nastanka neuroloških oštećenja oboljelih, kao i o dijetoterapiji prilagođenoj posebnim skupinama. Cilj rada je upoznati se s metaboličkom pozadinom fenilketonurije te objasniti kako bi trebao izgledati prehrambeni plan oboljelih sa svrhom postizanja što boljeg ishoda liječenja. Presudno je započeti liječenje već u prvim danima života. Niskoproteinska prehrana bi trebala osigurati dovoljnu količinu fenilalanina potrebnu za rast i razvoj, a da pri tome ne dođe do prekomjernog nakupljanja u tjelesnim tekućinama. Kod pojedinaca koji se pridržavaju propisanog prehrambenog plana uočen je znatan napredak u oporavku., Phenylketonuria is an inherited metabolic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase, necessary for the conversion of the amino acid phenylalanine to tyrosine. This thesis will discuss the importance of timely detection of disorders through neonatal screening, the process of neurological damage in patients, as well as diet therapy adapted to special groups. The aim of this thesis is to get acquainted with the metabolic background of phenylketonuria and to explain how the diet plan of patients should look like in order to achieve the best possible treatment outcome. It is crucial to start treatment in the first days of life. A low-protein diet should provide the sufficient amount of phenylalanine needed for growth and development without excessive accumulation in body fluids. Significant progress in recovery has been observed in individuals who adhere to the prescribed diet plan.

Cilj: ispitati i prikazati pojavnost retinopatije nedonoščadi na Odjelu za neonatologiju Klinike za ženske bolesti i porode KBC Split u razdoblju od siječnja 2012. do prosinca 2016. godine te odrediti rizične čimbenike i njihovu pojavnost s nastankom ROP-a (engl. retinopathy of prematurity). Pacijenti i metode: u studiju je uključeno 247 nedonoščadi liječene na Odjelu za neonatologiju u razdoblju od 2012. – 2016. godine. Uključni kriteriji su bili porodna masa ≤ 1500 g i/ili dob trudnoće ≤ 32 tjedna te porodna masa između 1500 i 2000 grama i dob trudnoće > 32 tjedna ukoliko je klinički tijek bolesti nestabilan i/ili su prisutni udruženi rizični čimbenici za ROP. Na temelju podataka dobivenih iz povijesti bolesti Klinike za ženske bolesti i porode KBC Split analizirane su sljedeće varijable: dob trudnoće i porodna masa, terapija kisikom, trajanje invazivne i neinvazivne mehaničke ventilacije, primjena surfaktanta, postojanje KBP, intraventrikularnog krvarenja ≥ gradus II i apneja, transfuzija krvnih pripravaka te sepsa. Rezultati: incidencija retinopatije u rizičnoj skupini nedonoščadi u promatranom petogodišnjem razdoblju bila je 23,9%. Glavni rizični čimbenici za nastanak ROP-a bili su niska porodna masa i dob trudnoće, oba uz postojanje širokog raspona među vrijednostima. Najveću pojavnost ROP-a zabilježili smo u skupini ekstremno nezrele nedonoščadi. Nije pronađena statistički značajna povezanost pojave ROP-a sa spolom, intrauterinim zastojem u rastu, transfuzijom krvnih pripravaka te intraventrikularnim krvarenjem ≥ gradus II. Nedonoščad sa slabijom ocjenom vitalnosti pri porodu (Apgar zbroj < 6) statistički su značajno češće imala ROP. Recidivirajuće apneje, kronična plućna bolest, duljina trajanja oksigenoterapije, duljina trajanja neinvazivne i duljina trajanja invazivne ventilacije značajno su bili povezani s pojavnošću ROP-a. Zaključak: najznačajniji rizični čimbenici za nastanak i razvoj retinopatije nedonoščadi su niska porodna masa i dob trudnoće pri porodu. Zbog postojanja širokog raspona vrijednosti PM i DT, naše je istraživanje svrstano u takozvanu treću epidemiju ROP-a. Slabija ocjena vitalnosti u prvoj minuti nakon poroda (Apgar < 6) značajno je povezana s nastankom i progresijom ROP-a, kao i prisutnost recidivirajućih apneja, kronične bolesti pluća i ukupne duljine trajanja oksigenoterapije. Produljena terapija kisikom bila je značajno povezana s pojavom težih oblika ROP-a. Precizno definiranje rizične skupine nedonoščadi i uključenje u prikladne programe probira doprinose smanjenju pojavnosti težih oblika ROP-a i kasnijih razornih posljedica, kao što je doživotna sljepoća., Objective: in this research we analysed and showed the incidence of ROP (retinopathy of prematurity) at the Department of Neonatology, Clinic of Gynecology and Obstetrics, University Hospital Center Split in the period from January 2012 to December 2016 and determined the risk factors and their association with occurence of ROP. Patients and methods: the study included 247 premature infants treated at the Department of Neonatology in the period 2012 - 2016 year. Inclusion criteria were birth weight ≤ 1500 g and/or gestational age ≤ 32 weeks and birth weight between 1500 and 2000 grams and gestational age > 32 weeks if the clinical course of the disease is unstable and/or risk factors associated with the ROP were present. Based on the data obtained from the medical history of the Clinic of Gynecology and Obstetrics of Split, the following variables were analysed: gestational age and birth weight, oxygen therapy, duration of invasive and noninvasive mechanical ventilation, the use of surfactant, the existence of chronic lung disease, intraventricular haemorrhage ≥ gr II and apnea, blood products transfusion and sepsis. Results: the incidence of retinopathy in a risk group of preterm infants in the five year period was 23.9%. Major risk factors for ROP were low birth weight and gestational age, both with the existence of a wide range of values. The highest incidence of ROP was recorded in a group of extremely immature preterm infants. There was no statistically significant correlation between the appearance of the ROP to sex, intrauterine growth restriction (IUGR), blood products transfusion and intraventricular haemorrhage ≥ gradus II. Premature infants with lower grade of vitality at birth (Apgar score < 6) significantly more often developed ROP. Recurrent apnea, chronic lung disease, duration of oxygen therapy, duration of noninvasive and invasive ventilation duration were significantly associated with the occurrence of ROP. Conclusion: the most important risk factors for the onset and development of retinopathy of prematurity are low birth weight and gestational age at birth. Due to the existence of a wide range of value birth weight and gestational age, our research is classified in so-called third epidemic of ROP. Lower grade of vitality in the first minute after birth (Apgar < 6) was significantly associated with the development and progression of ROP, as well as the presence of recurrent apnea, chronic lung disease and the total duration of oxygen therapy. Prolonged oxygen therapy was significantly associated with the occurrence of severe forms of ROP. The precise definition of risk groups of premature infants and engaging in appropriate screening programs contribute to reducing the incidence of severe forms of ROP and subsequent devastating effects, such as lifelong blindness.

Klasična homocistinurija je aminoacidopatija prvi put opisana 1962. godine. Nastaje kao posljedica nemogućnosti razgradnje i povećane koncentracije aminokiseline homocisteina u cirkulaciji. Do povećane koncentracije homocisteina u plazmi/serumu i urinu mogu dovesti različiti nasljedni metabolički poremećaji kao i neka stečena stanja. Od nasljednih metaboličkih poremećaja koji dovode do homocisteinemije i homocistinurije najučestalija je autosomno recesivna bolest klasična homocistinurija (McKusick 236200) uzrokovana nedostatkom enzima cistationin beta-sintaze (CBS; EC 4.2.1.22). Ako se ne počne pravodobno liječiti, bolest može dovesti do ozbiljnih komplikacija koje se manifestiraju promjenama na središnjem živčanom sustavu, očima, kostima i krvnim žilama, a poglavito u vidu tromboembolijskih procesa. Novorođenački probir, koji bi prethodio procesu liječenja, ne provodi se u mnogim zemljama, pa tako niti u Republici Hrvatskoj. S postavljanjem dijagnoze u kasnijoj životnoj dobi značajno se kasni zbog nedovoljne osjetljivosti liječnika na postojanje ove bolesti te njenom povezanošću s čitavom lepezom kliničkih simptoma. Bolesnici se dugo upućuju raznim specijalistima koji se posvećuju liječenju pojedinih kliničkih manifestacija, uglavnom bez rezul tata. Bez liječenja osnovne bolesti promjene stalno napreduju. Poseban dijagnostički problem su bolesnici s nedostatkom CBS-a u kojih karakteristična vanjska klinička obilježja nisu prisutna. Homocistein je samo intermitentno povišen, i to u situacijama kad ne uzimaju piridoksin, a najčešće su tromboembolijski događaji jedina manifestacija bolesti. Na osnovi vlastitih iskustava prikazanih u ovom radu, kao i podataka iz dostupne literature, možemo zaključiti da je u bolesnika dječje, adolescentske ili odrasle dobi s visokom ili brzoprogredirajućom miopijom, subluksacijom leća, marfanoidnim izgledom i/ili tromboembolijskim incidentom potrebno izmjeriti koncentraciju homocisteina u plazmi te provesti obiteljski probir., Classical homocystinuria is aminoacidopathy fi rst described in 1962. It results from the inability of degradation and consequential accumulation of the amino acid homocysteine in the circulation. Increased plasma/serum and urine homocysteine levels can be caused by diff erent inherited metabolic disorders or by some acquired conditions. Classical homocystinuria (McKusick 236200) is a pathologic condition that arises from elevated concentrations of homocysteine in the plasma, most frequently due to cystathionine β-synthase defi ciency (CBS; EC 4.2.1.22). If not treated in time, the disease can lead to serious central nervous system, eye, bone and blood vessel complications, mainly thromboembolism. However, newborn screening for homocystinuria is not routinely performed in many countries, including Croatia. In spite of various reasons that may cause delay in the diagnosis of homocystinuria, the predominant one is that physicians often fail to connect a cluster of common symptoms with this rare disease. Patients are referred to various specialists who focus on the treatment of diff erent clinical manifestations of homocystinuria, mostly without success. Without treatment of the underlying disease, chronic complications of homocystinuria progress and patients are jeopardized by sometimes even life-threatening thromboembolism. Patients with CBS defi ciency in whom typical clinical phenotype is absent, represent a particular diagnostic problem, as homocysteine is usually only periodically increased when pyridoxine is omitted from therapy. Within these patients recurrent episodes of thromboembolism are commonly the only clinical feature of homocystinuria. Based on our experience and data from the literature, early recognition of severe or rapidly progressing myopia, subluxation of ocular lenses, ‘marphanoid’ appearance and/or thromboembolism should be an indication for plasma homocysteine measurement and family screening.

Pojavnost prirođenog oštećenja sluha je najmanje 1/1000 novorođene djece. Oko polovice oštećenja sluha je nasljedno, od čega se trećina javlja u sklopu različitih sindroma (sindromska gluhoća), a u dvije trećine slučajeva gluhoća je jedini simptom (nesindromska gluhoća). Smatra se da oko 200 različitih gena uzrokuje pojedine oblike nasljedne gluhoće. Razvoj molekularne genetike omogućio je značajan napredak u detekciji i lokalizaciji ovih gena. Mutacije gena koji kodira sintezu koneksina-26 uzrokuju više od polovice svih slučajeva nasljedne gluhoće. Guilford je 1994. prvi ­opisao autosomno recesivnu nesindromsku gluhoću u lokusu DFNB1 13q11-q12 na 13. kromosomu. U unutarnjem uhu koneksin-26 ima ulogu u recikliranju kalijevih iona od baze dlakavih stanica, preko potpornih stanica i fibroblasta do strije vaskularis, odakle se dalje posebnim kanalima izbacuju u endolimfu. Na tom putu kalijevi ioni prolaze kroz zjapne veze koje izgrađuju koneksin-26, koneksin-30 i koneksin-31. Mutacija u bilo kojem od gena koji kodiraju koneksine mijenja ionski sastav osjetnih stanica i rezultira nastankom gluhoće. Novorođenački probir na oštećenje sluha počeo se razvijati prije četrdesetak godina. Audiološkim probirom metodom evocirane otoakustičke emisije (E-OAE) nastoji se otkriti što više djece s oštećenim sluhom. Djeca u koje se ovom metodom postavi sumnja na oštećenje sluha, upućuju se na automatsko bilježenje evociranih potencijala moždanog debla. U djece s pozitivnim audiološkim nalazom, molekularno-genetsko testiranje danas je moguće za veliki broj gena, ali zbog velike prevalencije mutacija u koneksinskim genima, samo takvo testiranje je šire prihvaćeno. Kombinacija audiološke i molekularno-genetske analize pokazala se komplementarnom, korisnom i praktički primjenjivom., The incidence of congenital hearing impairment is at least 1/1000 newborns. Approximately one half of hearing impairments is hereditary, out of which one third occurs as part of different syndromes (syndromic deafness), and in two thirds of these cases deafness is the only symptom (non-syndromic deafness). It is considered that around 200 ­different genes cause various forms of hereditary deafness. The development of molecular genetics has enabled significant progress in the detection and localization of these genes. Mutations of the gene that encodes the connexin-26 synthesis cause more than half of all hereditary deafness cases. In 1994, Guilford first described autosomal recessive non-syndromic deafness in locus DFNB1 13q11-q12 on the 13th chromosome. In the inner ear, connexin-26 plays a role in the recycling of potassium ions from hairy cells base, through supporting cells and fibroblasts to stria vascularis, from where they are then discharged into endolymph via special channels. On its way, potassium ions pass through gap junctions composed of connexin-26, connexin-30 and connexin-31. Mutation in any of the genes that encode connexins alters the ionic composition of sensory cells and results in the development of deafness. Newborn hearing impairment screening started developing some 40 years ago. Audiologic screening by evoked otoacoustic emission method (E-OAE) aims at detecting as many children as possible with hearing impairment. Children who after using this method are suspected of having hearing impairment are then referred for automated auditory brainstem response. In children with positive audiologic findings, molecular-genetic testing is today possible for a large number of genes, however, due to the significant prevalence of mutations in the connexin genes, only such a testing is more widely accepted. Combination of audiologic and molecular-genetic analysis has proven to be complementary, useful and applicable in practice.