Genetics of the epilepsies in childhood

Ovaj pregledni članak, namijenjen široj medicinskoj javnosti, ima dva cilja: prvi je informirati o primjeni najnovijih teorijskih dostignuća medicinske genetike na području epilepsija, a drugi je cilj procjena rizika obolijevanja članova obitelji bolesnika od epilepsije. U okviru prvog cilja opisano je nekoliko primjera novootkrivenih gena čije su mutacije odgovorne za nastanak nekih neuroloških bolesti praćenih simptomatskom epilepsijom: tu pripadaju neke dominantno nasljedne malformacije, neurokutani sindromi i recesivno nasljedne metaboličke bolesti. Za dalje razumijevanje genetike epilepsija puno je, međutim, važnije identificiranje, mapiranje i kloniranje gena te otkrivanje genskih produkata triju idiopatskih epilepsija, što je ostvareno posljednjih desetak godina. To su: autosomno dominantno nasljedna noćna frontalna epilepsija, dominantno nasljedne benigne neonatalne konvulzije i progresivna mioklonička epilepsija Unverricht Lundborg. Drugi cilj ovoga pregleda usmjerenje na potrebe svakodnevnog rada s bolesnicima koji boluju od epilepsije i njihovih obitelji: iznijeti kvantitativno izražene teorijske i empirijske rizike kojima su izložena braća, sestre i potomci bolesnika u usporedbi s rizicima u općoj populaciji. Takvi podaci, iznijeti u obliku tablica i grafikona, temelj su za argumentirano genetsko infomiranje i savjetovanje bolesnika epileptičara.This review article, written for the broader medical community, has two aims. The first one is to inform about the implementation of the latest theoretical advances in medical genetics as applied to the field of the epilepsies. The second aim is to present data for the genetic counselor in the epileptic clinic about the risk of developing epilepsy in family members of epileptic patients. Recently discovered genes are described, the mutations of which are responsible for the occurence of some neurologic diseases which are the cause of symptomatic epilepsy. Included here are some dominantly inherited cerebral malformations, neurocutaneous syndromes and many recessively inherited metabolic diseases. However, for a deeper insight into the pathogenesis of the epilepsies much more important are the identification, mapping, cloning of genes and defining of the corresponding gene products achieved during the last ten years for three idiopathic epilepsies: the dominantly inherited nocturnal frontal epilepsy, the dominantly inherited benign neonatal convulsions and the progressive myoclonic epilepsy of Unverricht and Lundborg. The second part of this article is intended for the everyday work of the practitioner in the epilepsy clinic in genetic counselling of epileptic patients and their families. Theoretical and empyrical risks of developing epilepsy are provided for siblings and descendants of the epileptic patients. Such data, shown in the form of tables and graphs, are indispensable for scientifically based genetic informing and counseling

Genetics of the epilepsies in childhood

Ovaj pregledni članak, namijenjen široj medicinskoj javnosti, ima dva cilja: prvi je informirati o primjeni najnovijih teorijskih dostignuća medicinske genetike na području epilepsija, a drugi je cilj procjena rizika obolijevanja članova obitelji bolesnika od epilepsije. U okviru prvog cilja opisano je nekoliko primjera novootkrivenih gena čije su mutacije odgovorne za nastanak nekih neuroloških bolesti praćenih simptomatskom epilepsijom: tu pripadaju neke dominantno nasljedne malformacije, neurokutani sindromi i recesivno nasljedne metaboličke bolesti. Za dalje razumijevanje genetike epilepsija puno je, međutim, važnije identificiranje, mapiranje i kloniranje gena te otkrivanje genskih produkata triju idiopatskih epilepsija, što je ostvareno posljednjih desetak godina. To su: autosomno dominantno nasljedna noćna frontalna epilepsija, dominantno nasljedne benigne neonatalne konvulzije i progresivna mioklonička epilepsija Unverricht Lundborg. Drugi cilj ovoga pregleda usmjerenje na potrebe svakodnevnog rada s bolesnicima koji boluju od epilepsije i njihovih obitelji: iznijeti kvantitativno izražene teorijske i empirijske rizike kojima su izložena braća, sestre i potomci bolesnika u usporedbi s rizicima u općoj populaciji. Takvi podaci, iznijeti u obliku tablica i grafikona, temelj su za argumentirano genetsko infomiranje i savjetovanje bolesnika epileptičara.This review article, written for the broader medical community, has two aims. The first one is to inform about the implementation of the latest theoretical advances in medical genetics as applied to the field of the epilepsies. The second aim is to present data for the genetic counselor in the epileptic clinic about the risk of developing epilepsy in family members of epileptic patients. Recently discovered genes are described, the mutations of which are responsible for the occurence of some neurologic diseases which are the cause of symptomatic epilepsy. Included here are some dominantly inherited cerebral malformations, neurocutaneous syndromes and many recessively inherited metabolic diseases. However, for a deeper insight into the pathogenesis of the epilepsies much more important are the identification, mapping, cloning of genes and defining of the corresponding gene products achieved during the last ten years for three idiopathic epilepsies: the dominantly inherited nocturnal frontal epilepsy, the dominantly inherited benign neonatal convulsions and the progressive myoclonic epilepsy of Unverricht and Lundborg. The second part of this article is intended for the everyday work of the practitioner in the epilepsy clinic in genetic counselling of epileptic patients and their families. Theoretical and empyrical risks of developing epilepsy are provided for siblings and descendants of the epileptic patients. Such data, shown in the form of tables and graphs, are indispensable for scientifically based genetic informing and counseling

Promjene u aminokiselinama, proteinima i enzimima u djece s fenilketonurijom

Since children with phenylketonuria have a low incidence of caries, the aim of this study was to examine the changes occuring in the aminoacid and protein composition as well as in the composition of salivary enzymes, which might serve as biochemical indicators, representing the factors of predisposition to the development of caries. For this purpose, the analysis was carried out in the native, unstimulated, mixed salivary specimens taken from the sublingual region of children with late diagnosis of RKU (n — 16), those with early diagnosis of the disorder by means of a systematic diagnostic screeniig program for PKU using Guthrie’s test (n — 7), and a control group of children free of any disturbances of the amino-acid metabolism (n — 44). A method of qualitative chromatography on silica gel was used for separation of aminoacids, while the proportions of each individual aminoacid were determined by a densitometer. The content of total salivary proteins was assessed by the method of Lowry, and the concentration of lysozyme by the method of Prockop. Differences in particular proportions of aminoacids, and an increase in the total protein value as well as in the lysozyme activity, could be taken as the factors of predisposition or resistance to caries.Budući da djeca oboljela od fenilketonurije imaju malu incidenciju karijesa, željeli smo ispitati promjene u sastavu aminokiselina, proteina i fermenata, koje bi mogle — kao biokemijski indikatori — biti predispozicijski činioci za razvoj karijesa. U tu svrhu analizirana je nativna slina sublingvalnog područja u uzorcima djece s kasno otkrivenom fenilketonurijom (n — 16), djece s rano otkrivenom bolešću u sistematskom traganju za fenilketonurijom primjenom Guthrie testa (n — 7) te djece kontrolne skupine bez poremećaja u metabolizmu aminokiselina. Aminokiseliine su razdvajane metodom tankoslojne kromatografije na silika gelu, a proporcije pojedinih aminokiselina određene su denzitometrijski. Sadržaj ukupnih proteina sline određen je po Lowryevoj metodi u mg/dl sline. Za određivanje lizozima korištena je metoda po Prockopu. Razlike u pojedinim proporcijama aminokiselina, kao i povišeni ukupni proteini i povećana aktvnost lizozima, mogle bi se označiti kao faktor sklonosti, odnosno rezistencije prema karijesu

Promjene u aminokiselinama, proteinima i enzimima u djece s fenilketonurijom

Since children with phenylketonuria have a low incidence of caries, the aim of this study was to examine the changes occuring in the aminoacid and protein composition as well as in the composition of salivary enzymes, which might serve as biochemical indicators, representing the factors of predisposition to the development of caries. For this purpose, the analysis was carried out in the native, unstimulated, mixed salivary specimens taken from the sublingual region of children with late diagnosis of RKU (n — 16), those with early diagnosis of the disorder by means of a systematic diagnostic screeniig program for PKU using Guthrie’s test (n — 7), and a control group of children free of any disturbances of the amino-acid metabolism (n — 44). A method of qualitative chromatography on silica gel was used for separation of aminoacids, while the proportions of each individual aminoacid were determined by a densitometer. The content of total salivary proteins was assessed by the method of Lowry, and the concentration of lysozyme by the method of Prockop. Differences in particular proportions of aminoacids, and an increase in the total protein value as well as in the lysozyme activity, could be taken as the factors of predisposition or resistance to caries.Budući da djeca oboljela od fenilketonurije imaju malu incidenciju karijesa, željeli smo ispitati promjene u sastavu aminokiselina, proteina i fermenata, koje bi mogle — kao biokemijski indikatori — biti predispozicijski činioci za razvoj karijesa. U tu svrhu analizirana je nativna slina sublingvalnog područja u uzorcima djece s kasno otkrivenom fenilketonurijom (n — 16), djece s rano otkrivenom bolešću u sistematskom traganju za fenilketonurijom primjenom Guthrie testa (n — 7) te djece kontrolne skupine bez poremećaja u metabolizmu aminokiselina. Aminokiseliine su razdvajane metodom tankoslojne kromatografije na silika gelu, a proporcije pojedinih aminokiselina određene su denzitometrijski. Sadržaj ukupnih proteina sline određen je po Lowryevoj metodi u mg/dl sline. Za određivanje lizozima korištena je metoda po Prockopu. Razlike u pojedinim proporcijama aminokiselina, kao i povišeni ukupni proteini i povećana aktvnost lizozima, mogle bi se označiti kao faktor sklonosti, odnosno rezistencije prema karijesu

Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency

a b s t r a c t Specific mutations in the gene encoding phenylalanine hydroxylase (PAH), located on chromosome 12q22-24.1, are linked to tetrahydrobiopterin (BH 4 ; sapropterin)-responsive phenylketonuria (PKU). Diagnosis is usually done through the newborn screening for PKU, followed by a BH 4 loading test. So far, more than 60 mutant alleles, presenting with a substantial residual PAH activity (average $47%), were identified in more than 500 patients worldwide. We investigated the predictive value of BH 4 -responsive PAH mutations in Croatian population. From a group of 127 PKU patients, 62 were selected (based on the genotype) as potentially BH 4 -responsive and 39 loaded with BH 4 (20 mg/kg). The overall frequency of BH 4 -responsiveness (>30% blood phenylalanine reduction within 24 h) was 36% (14 out of 39 patients with 23 different genotypes), significantly less than expected. The best responders were patients with mild hyperphenylalaninemia (4/4; 100%), followed by mild PKU (8/9; 89%), and classical PKU (2/26; 8%). The most common BH 4 -responsive genotypes were p.E390G/p.R408W and p.P281L/ p.E390G. These genotypes correspond for approximately >30% residual PAH activity. The p.E390G mutation was 100% associated with BH 4 -responsiveness, regardless of the second allele (p.R408W, p.P281L, p.F55Lfs, p.L249P). With regard to the predicted relative PAH activity of recombinantly expressed mutant alleles, there was a significant (p < 0.002) difference between BH 4 -responders and non-responders. In a general Croatian PKU population, disease-causing mutations were identified on 226 alleles (99%). There were 35 different mutations: 21 missense, 8 splice site, 3 nonsense, 2 single nucleotide deletions

Experiences with galactosemia in Croatia

Cilj našeg rada bio je opis osobitosti bolesnika s klasičnom galaktozemijom iz Hrvatske uz prikaz bolesnika s manjkom galaktokinaze i bolesnika koji je dvostruki heterozigot za mutacije gena galaktoza-1-fosfat- -uridiltransferaze (GALT) i galaktoza-4’-epimeraze (GALE). Istraživanje je obuhvatilo 24 bolesnika s dijagnozom klasične galaktozemije postavljenom u razdoblju od 1977. do 2020. godine. Dijagnoza je postavljana na temelju kliničke slike, koncentracije galaktoze u krvi i urinu, a potvrđivana mjerenjem aktivnost galaktoza-1-fosfat-uridil-transferaze i/ili analizom gena GALT. Simptome u novorođenačkom razdoblju razvilo je 87% bolesnika, a jedan bolesnik je umro. Medijan dobi pri pojavi prvih simptoma bio je četiri dana, a pri početku dijete jedanaest i pol dana. Barem jednu dugoročnu komplikaciju razvilo je 78,3% bolesnika. Među njima su bili poremećaji psihomotoričkog razvoja (68,2%), ponašanja (31,8%) i govora (55,6%), smanjene intelektualne sposobnosti (46,2%), druge neurološke komplikacije (40,9%), katarakta (18,2%) i smanjena mineralna gustoća kostiju (27,8%). Zatajenje jajnika razvilo je 66,7% bolesnica starijih od 10 godina. Uspoređujući bolesnike iz iste obitelji, iako je početak liječenja u drugorođenih bio raniji, čini se da dugoročne komplikacije nisu bile povezane s redoslijedom rođenja. Ova studija pokazuje da većina bolesnika s klasičnom galaktozemijom razvije simptome u novorođenačkom razdoblju i, unatoč strogom pridržavanju dijete, dugoročne komplikacije. Mnogi su još nepoznati čimbenici koji utječu na patogenezu i klinički tijek bolesti, zbog čega su potrebna daljnja istraživanja klasične galaktozemije.The aim of our study was to describe the characteristics of patients with classical galactosemia in Croatia, with the description of patients with galactokinase deficiency and a patient who was a double heterozygote for mutations of the galactose-1-phosphate uridyl transferase (GALT), and galactose-4’-epimerase (GALE) genes. The study included 24 patients who were diagnosed with classic galactosemia from 1977 to 2020. Diagnosis was based on clinical presentation and galactose concentrations in blood and urine, and confirmed by measuring galactose-1-phosphate-uridyl-transferase activity and/or GALT gene analysis. Acute manifestations of the disease developed in 87% of patients in the newborn period, and one patient died. The median age at the onset of first symptoms was four days and for onset of therapy 11.5 days. At least one long-term complication occured in 78.3% of patients, including developmental disorders (68.2%), behavioral disorders (31.8%), speech disorders (55.6%), impaired intellectual abilities (46.2%), other neurological complications (40.9%), cataract (18.2%), and decreased bone mineral density (27.8%). Ovarian insufficiency occured in 66.7% of female patients older than 10 years. When comparing siblings, although a galactose-free diet was started earlier in the second-born children with classical galactosemia, the incidence of long-term outcomes did not appear to be related to birth order. In conclusion, this study shows that the vast majority of patients develop symptoms in the neonatal period, as well as long-term complications, despite strict adherence to a galactose-free diet. Many factors that affect the pathogenesis and clinical course of the disease are still unknown, which is why further research into classical galactosemia is needed