| Abstract | Deficijencija PAH-a je metabolička autosomno recesivna bolest uzorokovana varijantama sekvence gena za PAH ili deficijencijom kofaktora BH4 potrebnog za pretvorbu fenilalanina u tirozin. Karakterizirana je povećanim koncentracijama aminokiseline fenilalanina u krvi te fenilpiruvične kiseline u mokraći. U kliničkoj slici javlja se specifičan tjelesni miris, intelektualno zaostajanje, epileptični napadi, mikrocefalija. Simptomi variraju od blagih do teških. U ranom prepoznavanju deficijencije PAH-a, veliku važnost ima novorođenački probir. Ukoliko novorođenački probir ukaže na postojanje deficijencije PAH-a, provodi se dijagnostičko genetičko testiranje. Određivanje statusa nositelja kod srodnika provodi se nakon dijagnosticiranja bolesti u probanda. Ako su oba partnera nositelji, rizik za autosomno recesivnu bolest iznosi 25 %. Osnovni korak liječenja deficijencije PAH-a je kontrolirana prehrana, a mogu se primjeniti sapropterin i transporteri za velike neutralne aminokiseline. Također, istražuje se učinak fenilalanin-amonij-lijaze i transplantacije hepatocita. Kod žena koje imaju povišene koncentracije fenilalanina u plazmi tijekom trudnoće, postoji visoki rizik nastanka disrupcija i intelektualnog zaostajanja kod djeteta. Iz tog razloga se preporučuje prekoncepcijsko genetičko savjetovanje te postizanje i održavanje koncentracije fenilalanina u majčinom serumu manjom od 360 μmol / L tri mjeseca prije začeća. U posljednje vrijeme, provodi se prošireni genomski probir statusa nositelja čime se, uz informiranje javnosti i genetičko savjetovanje, može spriječiti pojava autosomno recesivnih bolesti. Cilj rada je opisati mogućnosti novorođenačkog probira i genetičkog testiranja u svrhu što ranije dijagnostike deficijencije PAH-a, ali i istaknuti važnost prepoznavanja kliničkih obilježja te modernog pristupa genetičkom testiranju kojim se otkrivaju nositelji autosomno recesivnih bolesti |
| Abstract (english) | Deficiency of PAH is a metabolic autosomal recessive disease caused by a PAH gene sequence variants or a BH4 cofactor deficiency required to convert phenylalanine to tyrosine. It is characterized by increased levels of the amino acid phenylalanine in the blood and phenylpyruvic acid in the urine. In the clinical presentation there is a specific body odor, intellectual retardation, seizures, microcephaly. Symptoms range from mild to severe. In the early recognition of PAH deficiency, neonatal screening is of great importance. If newborn screening indicates PAH deficiency, diagnostic genetic testing is performed. Determination of the status of the carrier in a relative is made after the diagnosis of the disease in the proband. If both partners are carriers, the risk of autosomal recessive disease is 25%. A basic step in the treatment of PAH deficiency is a controlled diet, and sapropterin and transporters for large neutral amino acids can be used. The effect of phenylalanine-ammonium lyase and hepatocyte transplantation is also being investigated. In women with elevated plasma phenylalanine concentrations during pregnancy, there is a high risk of dysfunction and intellectual disability in the newborn. For this reason, pre-conceptual genetic counseling and the attainment and maintenance of maternal serum phenylalanine concentrations less than 360 μmol / L for three months prior to conception are recommended. Recently, an extended genomic screening of carrier status has been carried out, which, in addition to general public education and genetic counseling, can prevent the occurrence of autosomal recessive diseases. The aim of this study is to describe the possibilities of newborn screening and genetic testing for early diagnosis of PAH deficiency, but also to emphasize the importance of recognizing clinical features and a modern approach to genetic testing revealing carriers of autosomal recessive diseases. is a metabolic autosomal recessive disease caused by a PAH gene sequence variants or a BH4 cofactor deficiency required to convert phenylalanine to tyrosine. It is characterized by increased levels of the amino acid phenylalanine in the blood and phenylpyruvic acid in the urine. In the clinical presentation there is a specific body odor, intellectual retardation, seizures, microcephaly. Symptoms range from mild to severe. In the early recognition of PAH deficiency, neonatal screening is of great importance. If newborn screening indicates PAH deficiency, diagnostic genetic testing is performed. Determination of the status of the carrier in a relative is made after the diagnosis of the disease in the proband. If both partners are carriers, the risk of autosomal recessive disease is 25%. A basic step in the treatment of PAH deficiency is a controlled diet, and sapropterin and transporters for large neutral amino acids can be used. The effect of phenylalanine-ammonium lyase and hepatocyte transplantation is also being investigated. In women with elevated plasma phenylalanine concentrations during pregnancy, there is a high risk of dysfunction and intellectual disability in the newborn. For this reason, pre-conceptual genetic counseling and the attainment and maintenance of maternal serum phenylalanine concentrations less than 360 μmol / L for three months prior to conception are recommended. Recently, an extended genomic screening of carrier status has been carried out, which, in addition to general public education and genetic counseling, can prevent the occurrence of autosomal recessive diseases. The aim of this study is to describe the possibilities of newborn screening and genetic testing for early diagnosis of PAH deficiency, but also to emphasize the importance of recognizing clinical features and a modern approach to genetic testing revealing carriers of autosomal recessive diseases. |
