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

Expanding the phenotype in aminoacylase 1 (ACY1) deficiency: characterization of the molecular defect in a 63-year-old woman with generalized dystonia

Aminoacylase 1 (ACY1) deficiency is an organic aciduria due to mutations in the ACY1 gene. It is considered much underdiagnosed. Most individuals known to be affected by ACY1 deficiency have presented with neurologic symptoms. We report here a cognitively normal 63-year-old woman who around the age of 12 years had developed dystonic symptoms that gradually evolved into generalized dystonia. Extensive investigations, including metabolic diagnostics and diagnostic exome sequencing, were performed to elucidate the cause of dystonia. Findings were only compatible with a diagnosis of ACY1 deficiency: the urinary metabolite pattern with N-acetylated amino acids was characteristic, there was decreased ACY1 activity in immortalized lymphocytes, and two compound heterozygous ACY1 mutations were detected, one well-characterized c.1057C>T (p.Arg353Cys) and the other novel c.325A>G (p.Arg109Gly). Expression analysis in HEK293 cells revealed high residual activity of the enzyme with the latter mutation. However, following co-transfection of cells with stable expression of the c.1057C>T variant with either wild-type ACY1 or the c.325A>G mutant, only the wild-type enhanced ACY1 activity and ACY1 presence in the Western blot, suggesting an inhibiting interference between the two variants. Our report extends the clinical spectrum of ACY1 deficiency to include dystonia and indicates that screening for organic acidurias deserves consideration in patients with unexplained generalized dystonia

Levels Of Selected Persistent Organic Pollutants In Blood From Delivering Women In Seven Selected Areas Of São Paulo State, Brazil

Persistent organic pollutants (POPs) present in the living environment are thought to have detrimental health effects on the population, with pregnant women and the developing foetus being at highest risk. We report on the levels of selected POPs in maternal blood of 155 delivering women residing in seven regions within the São Paulo State, Brazil.The following selected POPs were measured in the maternal whole blood: 12 polychlorinated biphenyls (PCBs) congeners (IUPAC Nos. 99, 101, 118, 138, 153, 156, 163, 170, 180, 183, 187, 194); dichlordiphenyltrichloroethane p,p'-DDT, diphenyldichloroethylene p,p'-DDE and other pesticides such as hexachlorocyclohexanes (α-HCH, β-HCH, γ-HCH), hexachlorobenzene (HCB), chlordane derivatives cis-chlordane, trans-chlordane, oxy-chlordane, cis-nonachlor and trans-nonachlor.Statistical comparisons between regions were performed only on compounds having concentrations above LOD in 70% of the samples. PCB118 congener was found to be highest in the industrial site (mean 4.97. ng/g lipids); PCB138 congener concentration was highest in the Urban 3 site (mean 4.27. ng/g lipids) and congener PCB153 was highest in the industrial and Urban 3 sites with mean concentration of 7.2. ng/g lipids and 5.89. ng/g lipids respectively. Large differences in levels of p,p'-DDE between regions were observed with the Urban 3 and industrial sites having the highest concentrations of 645. ng/g lipids and 417. ng/g lipids, respectively; β-HCH was found to be highest in the Rural 1 site; the γ-HCH in Rural 1 and industrial; the HCB in the Rural 1 and industrial sites and oxy-chlordane and t-NC in the Rural 2 sites. 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Toxic And Essential Elements In Blood From Delivering Women In Selected Areas Of São Paulo State, Brazil

This study was designed to evaluate the degree of environmental contamination and possible exposure of pregnant women to toxic elements in seven selected areas of São Paulo State, Brazil. The overall median concentration of Mo in maternal blood was 0.53 μg L -1, highly significant differences found between sites (p < 0.0001). Cd was found to be low overall - 0.09 μg L -1 (0.01-0.58 μg L -1) - with mothers from the Coastal and Rural 1 sites having the highest levels (p < 0.016). Median Hg concentration was 0.60 μg L -1 (0.06 μg L -1-4.35 μg L -1); median Pb level was 16.2 μg L -1 (3.5-57.7 μg L -1) and no differences between sites were observed for both metals. Median Mn level was 16.7 μg L -1 (7.0-39.7 μg L -1), being highest in Urban 2 site (p<0.016). Concentrations of maternal Co were found to range between 0.06 μg L -1 and 1.1 μg L -1 (median 0.25 μg L -1) and As level was 0.60 μg L -1 (0.10-3.8 μg L -1) overall, with no statistical significance between sites for Co and As. Median Se concentrations were found to be 64 μg L -1 (36-233 μg L -1), with the highest median levels found in Urban 3 site; site differences were statistically significant (p < 0.0001). Correlation for each element (between paired maternal and cord blood) was measured only in Rural site 1; significant correlation was shown for Hg, Pb, Mn and Co (p<0.05). These findings may be interpreted as indicating low environmental contamination in São Paulo State, Brazil. These findings could also indicate that pregnant women have little or no contact with pollutants, possibly due to awareness campaigns carried out by public health practitioners. © 2011 The Royal Society of Chemistry.133563571Jarup, L., (2003) Br. Med. Bull., 68, pp. 167-182Mathee, A., Röllin, H., Von Schirnding, Y., Levin, J., Naik, I., (2006) Environ. Res., 100, pp. 319-322Odland, J.O., Nieboer, E., Romanova, N., Thomassen, Y., (2004) Int. J. 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Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA)

Item does not contain fulltextWe used exome sequencing of blood DNA in four unrelated patients to identify the genetic basis of metaphyseal chondromatosis with urinary excretion of D-2-hydroxy-glutaric acid (MC-HGA), a rare entity comprising severe chondrodysplasia, organic aciduria, and variable cerebral involvement. No evidence for recessive mutations was found; instead, two patients showed mutations in IDH1 predicting p.R132H and p.R132S as apparent somatic mosaicism. Sanger sequencing confirmed the presence of the mutation in blood DNA in one patient, and in blood and saliva (but not in fibroblast) DNA in the other patient. Mutations at codon 132 of IDH1 change the enzymatic specificity of the cytoplasmic isocitrate dehydrogenase enzyme. They result in increased D-2-hydroxy-glutarate production, alpha-ketoglutarate depletion, activation of HIF-1alpha (a key regulator of chondrocyte proliferation at the growth plate), and reduction of N-acetyl-aspartyl-glutamate level in glial cells. Thus, somatic mutations in IDH1 may explain all features of MC-HGA, including sporadic occurrence, metaphyseal disorganization, and chondromatosis, urinary excretion of D-2-hydroxy-glutaric acid, and reduced cerebral myelinization

Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3)

Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14-16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3-1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considere