Rezultati metaboličkog probira u Hrvatskoj

Novorođenački skrining je postupak u okviru preventivne medicine kojemu je svrha sustavno otkrivanje bolesne novorođenčadi kod koje će pravodobna dijagnoza i liječenje dovesti do značajnog smanjenja smrtnosti, morbiditeta i invalidnosti. Etička načela i kriteriji za uvrštenje neke bolesti u program sustavnog pretraživanja nisu se mnogo mijenjali od početaka organiziranja takvih programa. Skrining na fenilketonuriju i konatalnu hipotireozu su općenito svugdje prihvaćeni. U radu se opisuje sadašnje stanje novorođenačkog skrininga u Hrvatskoj i u svijetu.

Hypophosphatasia: Phenotypic Variability and Possible Croatian Origin of the c.1402G>A Mutation of TNSALP Gene

Hypophosphatasia is a metabolic bone disease characterized by bone and teeth hypomineralization due to defective function of tissue-nonspecific alkaline phosphatase (TNSALP). The disorder is caused by various mutations in the TNSALP gene localized on short arm of chromosome 1. Infantile hypophosphatasia is a severe form of the disease inherited as an autosomal recessive trait which presents before age of six months and often has fatal outcome. We report a patient with typical clinical course for infantile hypophosphatasia who was homozygous for the c.1402G>A mutation. The same mutation has been previously associated with a more severe perinatal form also in a Croatian family what indicates a possible common ancestral origin and phenotypic variability potential of c.1402G>A mutation of TNSALP gene

Pallister Killian Syndrome: Unusual Significant Postnatal Overgrowth in a Girl with otherwise Typical Presentation

Pallister Killian syndrome (PKS) is a rare genetic disorder caused by tetrasomy of the short arm of chromosome 12, revealed usually in mosaic distribution of an extra i(12)(p10) chromosome in fibroblasts. The syndrome presents with a recognizable pattern of findings including pigmentary skin changes, coarse face, high forehead, sparse anterior scalp hair, hypertelorism, seizures and progressive psychomotor developmental delay. It was first described independently by Pallister in 1977 and by Killian and Teschler-Nikola in 19811,2. We report a case of 21 month old girl with PKS and significant overgrowth. Cytogenetic analysis was performed using the GTG banding technique. The karyotype of cultured lymphocytes was normal. The karyotype from skin fibroblasts was established as mosaic tetrasomy of 12p 47,XX,+i(12) (p10)/46,XX. The origin of the extra marker chromosome was determinated by fluorescence in situ hybridization with chromosome 12 specific DNA probes confirming that supernumerary marker is chromosome i(12p) in 68% of cells. Despite the excessive postnatal growth we found low serum growth hormone levels and reduced response to pharmacological stimulation test. This is also the first report of a postnatal patient in our country

A path towards a cultured skin fi broblast biobank of patients with inherited errors of metabolism in Croatia

Rijetke bolesti etiološki su heterogena skupina najčešće nasljednih, kroničnih i degenerativnih bolesti s pojavnošću manjom od 5 na 10 000 osoba. Poznato je više od 7000 rijetkih bolesti od kojih više od 600 ima osobitosti nasljednih metaboličkih poremećaja. Zbog velike kliničke heterogenosti i zahtjevnih dijagnostičkih testova put do konačne dijagnoze je često dug te uključuje i obradu u ino zemnim laboratorijima. Unatoč tome, dio bolesnika ostaje bez konačne dijagnoze. U situacijama kad je bolesnik vitalno ugrožen uz mogućnost letalnog ishoda i pri sumnji na nasljednu metaboličku bolest, biopsija kože je dio standardnog postupka. Posljednjih godina sve je više dostupnih mogućnosti liječenja za širok spektar nasljednih metaboličkih bolesti. Osnovni preduvjet za njihovu djelotvornost je pravodobna dijagnoza. Kultivirani kožni fi broblasti pohranjeni u biobanke vrijedan su biološki materijal. Osim za postavljanje dijagnoze, mogu se primijeniti i za provjeru djelotvornosti novih pristupa liječenju kao što su male molekule pratitelji. Sve navedeno upućuje na značenje organiziranja biobanke fi broblasta prema međunarodno prihvaćenim standardima.Rare diseases are an etiologically heterogeneous group of hereditary, chronic and degenerative disorders with the incidence lower than 5 per 10,000 individuals. More than 7,000 rare diseases have been identifi ed so far, and more than 600 of them have the characteristics of hereditary metabolic disorders. Due to the high clinical heterogeneity and demanding diagnostic tests, the path to fi nal diagnosis is often long and may also involve tests performed in laboratories abroad. Despite this, a number of patients remain without fi nal diagnosis. In life-threatening situations for the patient and in case of suspected hereditary metabolic disease, skin biopsy is part of the routinely performed standard procedure. Recent years have seen an increasing availability of treatment options for a broad range of hereditary metabolic diseases. The basic precondition for therapy effi cacy is timely diagnosis. Cultured skin fi broblasts that are stored in biobanks are a valuable biological material. Except for making diagnosis, they may be used to verify the effi cacy of novel approaches to treatment, e.g., small chaperon molecules. All of the above indicates the signifi cance of establishing a fi broblast biobank according to the internationally accepted standards

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

Manjak lizosomske kisele lipaze u djece: vlastita iskustva i nova mogućnost enzimskoga nadomjesnog liječenja [Lysosomal acid lipase deficiency in children: our experience and a novel possibility of enzyme replacement therapy]

Lysosomal acid lipase deficiency is an autosomal recessive disorder with two distinct clinical phenotypes. Wolman disease is rapidly progressive with onset in early infancy. Complete enzyme deficiency results in massive accumulation of cholesterol esters and triglycerides in intestines, liver, spleen and other monocyte-macrophage system cells causing malabsorption, hepatosplenomegaly, liver failure and death in early infancy. Cholesterol ester storage disease may be diagnosed in childhood or later in life. It is characterized by chronic course and variable progression. Main features are variously expressed hepatopathy, including cirrhosis and liver failure, hypercholesterolemia and premature atherosclerosis. Characteristic is pathohistological finding of microvesicular steatosis and fibrosis and patognomonic are typical cholesterol ester crystals. Diagnosis is confirmed by enzyme assay and/or gene analysis. Until recently treatment was symptomatic. Ongoing clinical trials of enzyme replacement therapy have shown very promising results. We are presenting an infant with Wolman disease and two children with cholesterol ester storage disease with the aim to raise awareness about this disease and to start optimal care early