1,222 research outputs found
Rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of multiple sulfatase deficiency
Get PDFSchlotawa L, Radhakrishnan K, Baumgartner M, et al. Rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of multiple sulfatase deficiency. European Journal Of Human Genetics. 2013;21(9):1020-1023.Multiple sulfatase deficiency (MSD) is a rare inborn error of metabolism affecting posttranslational activation of sulfatases by the formylglycine generating enzyme (FGE). Due to mutations in the encoding SUMF1 gene, FGE's catalytic capacity is impaired resulting in reduced cellular sulfatase activities. Both, FGE protein stability and residual activity determine disease severity and have previously been correlated with the clinical MSD phenotype. Here, we report a patient with a late infantile severe course of disease. The patient is compound heterozygous for two so far undescribed SUMF1 mutations, c.156delC (p.C52fsX57) and c.390A>T (p.E130D). In patient fibroblasts, mRNA of the frameshift allele is undetectable. In contrast, the allele encoding FGE-E130D is expressed. FGE-E130D correctly localizes to the endoplasmic reticulum and has a very high residual molecular activity in vitro (55% of wildtype FGE); however, it is rapidly degraded. Thus, despite substantial residual enzyme activity, protein instability determines disease severity, which highlights that potential MSD treatment approaches should target protein folding and stabilization mechanisms
Successful pregnancy in a woman with maple syrup urine disease: case report
No full textWe present the positive outcome of a pregnancy in a woman with severe classic maple syrup urine disease (MSUD). Maintaining the maternal plasma levels of leucine between 200 and 300 μmol/L allowed normal development of the foetus. Tolerance of protein and leucine increased continuously from the 16th gestational week until delivery. The patient was able to increase protein and leucine intake from 5 g to nearly 30 g and 300-3,000 mg/day, respectively. Weekly measurement of branched-chain amino acid (BCAA) concentrations and the assessment of dietary intake were used to adjust protein intake. After 41 weeks of pregnancy, she gave birth to a healthy baby girl and was able to breastfeed her daughter for 6 months during which time, the protein and leucine intake were lower than during pregnancy, but higher than with her usual pre-pregnancy diet. The development of the girl is normal at the age of 3 years
Molecular basis and functional characterization of human 3-methylcrotonyl-CoA carboxylase deficiency
Get PDF3-Methylcrotonyl-CoA carboxylase (MCC) deficiency is a rare disorder of leucine catabolism inherited as an autosomal recessive trait. The phenotypic expression of the disease is highly variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. Most patients, however, are asymptomatic until an episode of acute metabolic decompensation following intercurrent illness leads to the diagnosis. The metabolic phenotype of MCC deficiency includes a characteristic organic aciduria with greatly increased excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine and elevated blood levels of 3-hydroxyisovalerylcarnitine, usually in combination with severe secondary carnitine deficiency due to urinary loss of carnitine esters. Introduction of tandem mass spectrometry (TMS) to newborn screening has revealed an unexpectedly high incidence of MCC deficiency and indicates that this disorder is the most frequent organic aciduria.
MCC is one of the four biotin-dependent carboxylases present in humans. MCC is a mitochondrial enzyme composed of biotin containing subunits and smaller subunits, encoded by MCCA and MCCB, respectively. In order to understand the molecular biology of human MCC, including the molecular defects causing MCC deficiency and their functional consequences, MCC-deficient patients were studied and attempts were made to correlate molecular defects with the phenotypic variability in our patient population.
In this thesis mutation analysis is described in 30 MCC-deficient probands, of whom 10 came to attention because of clinical symptoms, 18 were asymptomatic newborns detected by TMS based newborn screening, and 2 were affected but asymptomatic mothers diagnosed by abnormal metabolites in the neonatal screening samples of their healthy babies. Among these 30 probands, 11 have mutations in MCCA, and 19 in MCCB. We identified 10 novel MCCA and 14 novel MCCB mutant alleles including missense, nonsense, frameshift and splice site mutations.
In order to confirm the functional consequences of MCCA and MCCB missense mutations, we used transient transfection of SV40T-transformed MCCA and MCCB deficient skin fibroblasts to express 1 MCCA and 3 MCCB missense alleles. The MCCB missense alleles expressed showed no or very low residual activity, whereas the MCCA missense allele had 26% residual activity of wild type, thus confirming that 3 out of 4 missense alleles expressed have a deleterious effect on enzyme activity. The apparent severity of MCC mutations contrasts with the variety of clinical phenotypes found in MCC-deficient patients. Our data demonstrate no clear correlation between genotype and phenotype suggesting that factors other than the genotype at the MCC loci have a major influence on the phenotype of MCC deficiency.
To analyse the MCC polypeptides under steady-state condition in fibroblasts of MCCA deficient patients, we carried out Western blot analysis. Our results demonstrate that the MCC protein was absent in 5 patients homozygous or compound heterozygous for nonsense or frameshift mutations that are expected to result in a truncated protein. The MCC protein was also absent in 2 further compound heterozygous patients in whom only one missense allele could be identified in the RT-PCR products. The second allele could not be detected because presumably this mutant allele is unstable and degraded by the mechanisms of nonsense-mediated mRNA decay. In contrast, Western blot analysis of the MCC protein was normal in amount and size in 4 patients carrying MCCA-p.R385S. This is in agreement with previous studies, which show that the protein product of this allele is stable.
Finally, we provide evidence that the missense mutation MCCA-p.R385S has a dominant negative effect on the activity of wild type. Biotin can partially reverse this negative effect and result in biotin responsiveness in vivo. This is the first example of biotin responsiveness for an isolated partial deficiency of any of the biotin-dependent carboxylases, suggesting that therapeutic trials with biotin in patients carrying this mutant allele are warranted
Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise
Get PDFOrganic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work‐up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence‐based recommendations have improved neonatal survival and short‐term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post‐translational short‐chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short‐chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising
The PRO-AGE study: an international randomised controlled study of health risk appraisal for older persons based in general practice
Get PDFBackground: This paper describes the study protocol, the recruitment, and base-line data for evaluating the success of randomisation of the PRO-AGE (PRevention in Older people-Assessment in GEneralists' practices) project.Methods/Design: A group of general practitioners (GPs) in London (U.K.), Hamburg (Germany) and Solothurn (Switzerland) were trained in risk identification, health promotion, and prevention in older people. Their non-disabled older patients were invited to participate in a randomised controlled study. Participants allocated to the intervention group were offered the Health Risk Appraisal for Older Persons (HRA-O) instrument with a site-specific method for reinforcement (London: physician reminders in electronic medical record; Hamburg: one group session or two preventive home visits; Solothurn: six-monthly preventive home visits over a two-year period). Participants allocated to the control group received usual care. At each site, an additional group of GPs did not receive the training, and their eligible patients were invited to participate in a concurrent comparison group. Primary outcomes are self-reported health behaviour and preventative care use at one-year follow-up. In Solothurn, an additional follow-up was conducted at two years. The number of older persons agreeing to participate (% of eligible persons) in the randomised controlled study was 2503 (66.0%) in London, 2580 (53.6%) in Hamburg, and 2284 (67.5%) in Solothurn. Base-line findings confirm that randomisation of participants was successful, with comparable characteristics between intervention and control groups. The number of persons (% of eligible) enrolled in the concurrent comparison group was 636 (48.8%) in London, 746 (35.7%) in Hamburg, and 1171 (63.0%) in Solothurn.Discussion: PRO-AGE is the first large-scale randomised controlled trial of health risk appraisal for older people in Europe. Its results will inform about the effects of implementing HRA-O with different methods of reinforcement
Living with intoxication-type inborn errors of metabolism: a qualitative analysis of interviews with paediatric patients and their parents
No full textINTRODUCTION Progress in diagnosis and treatment of patients with intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders, organic acidurias or maple syrup urine disease is resulting in a growing number of long-term survivors. Consequently, health-related quality of life (HrQoL) of patients is increasingly regarded as a meaningful outcome parameter. To develop the first validated, disease-specific HrQoL questionnaire for IT-IEM, patients and parents were interviewed as content experts to identify major physical and psychosocial constraints and resources. METHODS Focus group interviews with 19 paediatric IT-IEM patients and 26 parents were conducted in four metabolic centres in Austria, Germany and Switzerland. Disease-specific HrQoL categories were established by qualitative content analysis. RESULTS Fourteen disease-specific topics related to the three well-established generic HrQoL dimensions of physical, mental and social functioning were derived from the interview transcripts. Both patients and parents perceived dietary restrictions and social stigmatisation as major burdens. Dietary restrictions and emotional burdens were more important for young (<8 years) patients, whereas cognition, fatigue and social issues were more relevant to older patients (≥8 years). Treatment-related topics had a significant effect on social and emotional HrQoL. DISCUSSION By exploring patients' and parents' perspectives, 14 HrQoL categories were identified. These new categories will allow the development of a disease-specific, standardised questionnaire to assess HrQoL in paediatric IT-IEM patients. Age-appropriate information on the disease and psychosocial support targeted to patients' individual burdens are essential to the delivery of personalised care that takes account of physical, mental and social dimensions of HrQoL
Bilanz und Perspektiven zum Berufsschulsport in Deutschland
No full textArndt M, Baumgartner M, Leineweber H, Meier S, Wegener M. Bilanz und Perspektiven zum Berufsschulsport in Deutschland. In: Gogoll A, Messmer R, eds. Sportpädagogik zwischen Stillstand und Beliebigkeit. Bern & Magglingen: BASPO; 2013: 178-193
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