The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes

Background: The high variability in clinical outcome of patients with Classical Galactosemia (CG) is poorly understood and underlines the importance of prognostic biomarkers, which are currently lacking. The aim of this study was to investigate if residual galactose metabolism capacity is associated with clinical and biochemical outcomes in CG patients with varying geno- and phenotypes. Methods: Galactose Metabolite Profiling (GMP) was used to determine residual galactose metabolism in fibroblasts of CG patients. The association between the galactose index (GI) defined as the ratio of the measured metabolites [U13C]Gal-1-P/ [13C6]UDP-galactose, and both intellectual and neurological outcome and galactose-1-phosphate (Gal-1-P) levels was investigated. Results: GMP was performed in fibroblasts of 28 patients and 3 control subjects. The GI of the classical phenotype patients (n = 22) was significantly higher than the GI of four variant patients detected by newborn screening (NBS) (p = .002), two homozygous p.Ser135Leu patients (p = .022) and three controls (p = .006). In the classical phenotype patients, 13/18 (72%) had a poor intellectual outcome (IQ < 85) and 6/12 (50%) had a movement disorder. All the NBS detected variant patients (n = 4) had a normal intellectual outcome (IQ ≥ 85) and none of them has a movement disorder. In the classical phenotype patients, there was no significant difference in GI between patients with a poor and normal clinical outcome. The NBS detected variant patients had significantly lower GI levels and thus higher residual galactose metabolism than patients with classical phenotypes. There was a clear correlation between Gal-1-P levels in erythrocytes and the GI (p = .001). Conclusions: The GI was able to distinguish CG patients with varying geno- and phenotypes and correlated with Gal-1-P. The data of the NBS detected variant patients demonstrated that a higher residual galactose metabolism may result in a more favourable clinical outcome. Further research is needed to enable individual prognostication and treatment in all CG patients

Genetic basis of hyperlysinemia

Background: Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia. Methods. We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features. Results: We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1. Conclusions: Hyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient

Wpływ rolniczego użytkowania na właściwości fizyczno-wodne gleb w katenie moreny dennej Pojezierza Mazurskiego

A study was carried out in the soil used for agricultural purposes in a rolling bottom moraine of the Mazurian Lakeland. Deluvial and muck soils were found in the depression and lessive soils covered the surrounding slopes. The examined soils were analysed for granulometric composition, bulk and proper density, total porosity, ash content and organic carbon content as well as water sorption curves. Agricultural use of soils accelerates and amplifies deluvial processes that modify both the morphology and physical and water properties of soil. The soil material migration down the slope was observed in the studied soils. In the deluvial and muck soil the content of clay fraction was 2–9 times as high as in the surface layer of lessive soil. Progressing anthropogenic denudation processes resulted in covering the organic layers (muck and peat) with deluvial silt of the thickness of 10–30 cm (mucky soils) and above 30 cm (deluvial soils). Deluvial silt exhibits 2–3-fold greater density and significantly lower porosity (about 20%) than the deeper layers of silted peat muck and lessive peat. The content of macropores and mezopores in the surface layers of deluvial and mucky soils is twice as big as in the deeper silted muck and peat. The content of macropores in the surface layers of deluvial soil is 2–4 times fold low as in the deeper silted alder wood peat. In mucky soil level, a greater content of micropores was characteristic of silted peat muck. In the lessive soil occurring in the vicinity of the depression, a greater content of macropores and a lower content of mezopores and micropores was found. Anthropogenic denudation processes caused by agricultural use of mid-morain depressions soil leads to an increase in the content of mezo- and micropores and a decrease in the content of macropores in the total porosity of the examined soils

Bezafibrate increases very-long-chain acyl-CoA dehydrogenase protein and mRNA expression in deficient fibroblasts and is a potential therapy for fatty acid oxidation disorders

International audienceInherited defect in very-long-chain acyl-CoA dehydrogenase (VLCAD), a mitochondrial enzyme catalyzing the initial step of long-chain fatty acid beta-oxidation (FAO), is one of the most frequent FAO enzyme defects. VLCAD deficiency is associated with clinical manifestations varying in severity, tissue involvement and age of onset. The molecular basis of VLCAD deficiency has been elucidated but therapeutic approaches are quite limited. In this study, we tested the hypothesis that fibrates, acting as agonist of peroxisome proliferator-activated receptors (PPARs), might stimulate FAO in VLCAD-deficient cells. We demonstrate that addition of bezafibrate or fenofibric acid in the culture medium induced a dose-dependent (up to 3-fold) increase in palmitate oxidation capacities in cells from patients with the myopathic form of VLCAD deficiency, but not in cells from severely affected patients. Complete normalization of cell FAO capacities could be achieved after exposure to 500 microm bezafibrate for 48 h. Cell therapy of VLCAD deficiency was related to drug-induced increases in VLCAD mRNA (+44 to +150%; P<0.001), protein (1.5-2-fold) and residual enzyme activity (up to 7.7-fold) in patient cells. Bezafibrate also diminished the production of toxic long-chain acylcarnitines by 90% in cells harboring moderate VLCAD deficiency. Finally, real-time PCR studies indicated that bezafibrate potentially stimulated gene expression of other enzymes in the beta-oxidation pathway. These data highlight the potential of fibrates in the correction of inborn FAO defects, as most mutations associated with these defects are compatible with the synthesis of a mutant protein with variable levels of residual enzyme activity