Mutational spectrum of the phenylalanine hydroxylase (PAH) deficiency was investigated in 107 families representing 90% of the Slovene phenylketonuria (PKU) population. Altogether, disease-causing mutations were identified with detection rate 97.7%. A spectrum of 36 different disease-causing mutations was identified, among them five novel mutations and two large deletions. 54.2% families were classified as classic PKU, 25.9% as mild PKU and 19.6% as mild hyperphenylalaninemia. Correlations with patients' phenotypes and genotype-based predictions of BH4-responsiveness were assessed. 26 different genotypes (40.6%) were predicted to be BH4-responsive, represented by 38 different families (35.5%).
COBISS.SI-ID: 29876441
BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onsettype 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng permilliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies.Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, twodoses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).
COBISS.SI-ID: 29623769
Background: Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder characterized by palmoplantar keratoderma together with a severe formof generalized aggressive periodontitis and associated with mutations in cathepsin C gene (CTSC). Objective: To investigate the clinical and mutationalcharacteristics of 6 PLS patients from 4 unrelated Slovenian families. Methods:CTSC mutational and functional analyses were performed. Results: In all patients, a novel homozygous substitution, c.-55C)A, in the CTSC 5Ž-untranslated region (UTR) was detected on genomic DNA level and confirmed by mRNA analysis, resulting in the almost complete loss of CTSC mRNAexpression and CTSC activity. In silico analysis revealed the potential ofthe mutation to disrupt putative transcription factor binding sites (TFBSs) for AP-2 and Sp families of transcription factors. Conclusion: Identification of a novel CTSC 5Ž-UTR mutation together with a severe reduction of CTSC mRNA expression and virtually nonexistent CTSC activity was suggestive of a novel mechanism of TFBS dysfunction associated with PLS.
COBISS.SI-ID: 583596