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Summary Background: Phenylketonuria (PKU) is a metabolic disorder caused by phenylalanine hydroxylase gene (PAH) mutations. If left untreated, PKU patients develop severe mental retardation potentially due to neurodegeneration. This is the first study that investigates presence of mitochondrial DNA variants in PKU patients, m.10398A, reportedly associated with neurodegenerative diseases and m.10410T. Methods: We analyzed 64 PKU patients and 50 healthy controls from Serbian population. PKU patients were categorized into groups according to time of diagnosis and compliance to low-phenylalanine diet. The IQ was determined according to age-appropriate scales. Results: We detected m.10398A and m.10410T variants by direct sequencing. Frequency of m.10398A was similar in patients and healthy controls (82.81% and 82.00% respectively) suggesting their identical ethnic background. No variation was detected for m.10410. In group with late diagnosis and poorly controlled diet, no statistically significant difference in average IQ was found between patients with m.10398A and m.10398G. The same was shown for PKU patients with higher IQ, diagnosed at neonatal screening and treated with low-phenylalanine diet. However, when patients carrying p.L48S, a PAH mutation with inconsistent effect, were excluded from the study, presence of m.10398A variant was associated with lower IQ. Conclusions: This study emphasizes the importance of neonatal screening and good control of low-phenylalanine diet in PKU patients. Statistical analysis did not indicate clear impact of mitochondrial DNA variant m.10398A on IQ of PKU patients, except when PAH genotype was also considered. Studies in larger cohorts will elucidate the association between PAH gene mutations, mitochondrial DNA variants and complex PKU cognitive phenotype. Kratak sadržaj Uvod: Fenilketonurija (PKU) je metaboličko oboljenje uzro- kovano mutacijama u genu za fenilalanin hidroksilazu (PAH). Ukoliko se ne leče, pacijenti sa fenilketonurijom razvijaju tešku mentálnu retardaciju, koja može biti i posledica neu- rodegeneracije. Ovo je prva študija koja istražuje prisustvo mitohondrijalnih DNK varijanti kod pacijenata sa fenilketonurijom, m.10398A, za koju je pokazana povezanost sa neurodegenerativnim oboljenjima, kao i m.10410T. Metode: U ovoj študiji je analizirano 64 pacijenta sa fenilke- tonurijom i 50 zdravih kontrola iz srpske populacije. Pacijenti su podeljeni u grupe prema uzrastu u kome je postav- ljena dijagnoza i odnosu prema dijeti sa niskim sadržajem fenilalanina. IQ je odreden pomoču odgovarajučih uzrasnih skala. Rezultati: Mitohondrijalne DNK varijante, m.10398A i m.10410T, su detektovane sekvenciranjem. Učestalost m.10398A je bila jednaka kod pacijenata i zdravih kontro- la (82,81% i 82,00%), što ukazuje na isto etničko poreklo ovih ispitanika. U slučaju m.10410, nisu detektovane različite varijante. U grupi pacijenata kojima je kasno postavlje- na dijagnoza i koji su neadekvatno lečeni, nije pronadena statistička značajnost u srednjoj vrednosti IQ izmedu paci- jenata sa m.10398A i m.10398G. Isto je pokazano i za pacijente sa visim IQ koji su otkriveni prilikom neonatalnog skrininga i koji su pravilno lečeni. Medutim, kada su iz ove grupe isključeni pacijenti koji nose p.L48S mutaciju u PAH genu, koja ima nekonzistentan uticaj na fenotip, prisustvo m.10398A alela je povezano sa nižim IQ. Zaključak: Ova študija je potvrdila važnost neonatalnog skrininga i pravilnog sprovodenja dijete kod pacijenata sa fenilketonurijom. Štatistické analize nisu jasno utvrdile uti- caj mitohondrijalne DNK varijante, m.10398A, na IQ ovih pacijenata, osim kad je i PAH genotip uključen u analizu. Študije u večim grupama če rasvetliti povezanost izmedu mutacija u PAH genu, mitohondrijalnih DNKvarijanti i slo- ženog kognitivnog fenotipa kod pacijenata sa PKU.

journal of medical biochemistry

Association of Mitochondrial DNA Variants and Cognitive Impairment of Phenylketonuria Patients / POVEZANOST VARIJANTI U MITOHONDRIJALNOJ DNK I KOGNITIVNOG FENOTIPA KOD PACIJENATA SA FENILKETONURIJOM