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Biomedical subjects

Kevin Carpenter

Publications and source records attributed to Kevin Carpenter.

9 recordsLinked to original sources
PubMed2005

Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations.

The fatty acid oxidation disorder most commonly identified by tandem mass spectrometry newborn screening is the potentially fatal medium-chain acyl-CoA dehydrogenase deficiency (MCAD). In clinically presenting cases, 80% are homozygous for the common mutation, c.985A > G and 18% heterozygous. We screened 592,785 babies and identified 34 with MCAD, 17 homozygous for c.985A > G, 14 with one copy, and 3 with no copy. We sequenced the exons of 19 patients, the 17 carrying one or no copy of c.985A > G, and two with marginal findings, and examined correlations between groups of mutations and biochemical markers. We found two known or putative pathogenic mutations in 18 of the 19 patients. Two mutations appeared more than once: c.199T > C, not recorded in clinically presenting cases (n = 4), and c.583G > A (n = 2). Patients homozygous for c.985A > G had the highest levels of neonatal octanoylcarnitine, plasma octanoylcarnitine when asymptomatic, and urinary acylglycines. Compound heterozygotes of c.985A > G and other mutations had intermediate levels, and those without c.985A > G, or heterozygous for that and c.199T > C had the lowest levels of these analytes. There was overlap in all values. The c.985A > G and c.583G > A mutations appear to have functional effects towards the severe end of the spectrum, and the c.199T > C mutation a smaller effect, as has been previously postulated. If these results are confirmed and extended, this could influence the advice given to parents of babies with MCAD detected by newborn screening, and make management more specific. In the meantime, all MCAD patients identified by newborn screening have, by definition, a functional defect and require careful clinical management.

Acyl-CoA Dehydrogenase↗
PubMed2003

D-2-hydroxyglutaric aciduria: a case with an intermediate phenotype and prenatal diagnosis of two affected fetuses.

D-2-hydroxyglutaric aciduria (D2HGA) is a rare autosomal recessive disorder with variable clinical expression. The biochemical defect is unknown at present. Previously reported cases have either followed a severe clinical course characterized by neonatal epileptic encephalopathy, cortical blindness, and profound developmental delay, or a mild course characterized by mild developmental delay, manageable epilepsy, and mild hypotonia. To date there has been a clear distinction between these two groups. We report the second case of a child with D2HGA who has followed an intermediate course. She presented in infancy with hypotonia, manageable epilepsy and developed moderate to severe developmental delay, and cortical visual impairment. The proposita had a coarse facial appearance, flat face, broad nasal bridge, up-turned nose, and simple, anteverted ears. These facial anomalies have been noted in other children with D2HGA and this case strengthens the proposed association between this facial phenotype and D2HGA. We also report the third and fourth instances of prenatal diagnosis for D2HGA. At each prenatal diagnosis, an affected fetus was diagnosed on the basis of markedly increased levels of D-2-hydroxyglutaric acid in amniotic fluid.

Adult↗
PubMed2003

Screening newborns for inborn errors of metabolism by tandem mass spectrometry.

BACKGROUND: The recent development of electrospray tandem mass spectrometry makes it possible to screen newborns for many rare inborn errors of metabolism, but the efficacy and outcomes of screening remain unknown. We examined the effect of the screening of newborns by tandem mass spectrometry on the rates of diagnosis of 31 disorders. METHODS: We compared the rates of detection of 31 inborn errors affecting the metabolism of the urea cycle, amino acids, and organic acids and fatty-acid oxidation among 362,000 newborns screened by tandem mass spectrometry over a four-year period (April 1998 through March 2002) with the rates in six preceding four-year birth cohorts in New South Wales and the Australian Capital Territory, Australia, where screening, diagnostic, and clinical services were centralized. RESULTS: The overall prevalence of disorders during the periods when clinical diagnosis was used did not vary between 1982 and 1998. In the cohort screened with tandem mass spectrometry, the prevalence of inborn errors, excluding phenylketonuria, was 15.7 per 100,000 births (95 percent confidence interval, 11.9 to 20.4), as compared with adjusted rates of 8.6 to 9.5 per 100,000 births in the four preceding four-year cohorts. Of the 57 cases diagnosed after the introduction of newborn screening, 15 were diagnosed clinically; 7 of the 15 newborns had a normal result on screening. The rate of detection was increased specifically for medium-chain acyl-coenzyme A dehydrogenase deficiency (P<0.001) and other disorders of fatty-acid oxidation (P=0.007), as compared with the 16-year period before the implementation of neonatal screening for these disorders. CONCLUSIONS: More cases of inborn errors of metabolism are diagnosed by screening with tandem mass spectrometry than are diagnosed clinically. It is not yet clear which patients with disorders diagnosed by such screening would have become symptomatic if screening had not been performed.

Australian Capital Territory↗
PubMed2003

Mutations in the AUH gene cause 3-methylglutaconic aciduria type I.

The conversion of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA is the only step in leucine catametabolism yet to be characterized at enzyme and DNA levels. The deficiency of the putative mitochondrial enzyme 3-methylglutaconyl-CoA hydratase associates with the rare organic aciduria 3-methylglutaconic aciduria type I (MGA1), but neither the enzyme nor its gene have been described in any organism. Here we report that human 3-methylglutaconyl-CoA hydratase is identical with a previously described RNA-binding protein (designated AUH) possessing enoyl-CoA hydratase activity. Molecular analyses in five patients from four independent families revealed homozygosity or compound heterozygosity for mutations in the AUH gene; most mutations are predicted to completely abolish protein function. Mutations identified include c.80delG, R197X, IVS8-1G>A, A240V, and c.613_614insA. Clinical severity of MGA1 in published patients has been quite variable. Included in the present study is an additional patient with MGA1 who was detected by neonatal screening and has remained asymptomatic up to his present age of 2 years. The boy is homozygous for an N-terminal frameshift mutation in the AUH gene. Complete absence of 3-methylglutaconyl-CoA hydratase/AUH appears to be compatible with normal development in some cases. Further work is required to identify external or genetic factors associated with development of clinical problems in patients with MGA1.

Amino Acid Metabolism, Inborn Errors↗
PubMed2003

Information overload--new technologies, can we store the data?

Computerization within newborn screening programs is a developing issue. To date two basic approaches to data storage have been used: (1) a storage system for babies diagnosed with a disorder, (2) a comprehensive system with long-term details for all patient samples, tests performed, test results and interpretations. It usually provides efficient real-time reports for various clinical and quality control requirements and easy access to an inborn errors registry. Within the last decade there have been two new technologies adapted to routine use in newborn screening laboratories: (1) tandem mass spectrometry for selected amino acids and acyl carnitine, and (2) DNA mutational analysis of PCR products. Both technologies present data storage challenges. Both are capable of providing large files of information for a sample. Consideration must be given to how these data are stored, whether all results including a graphical representation or DNA sequence data are kept or whether only final results for specific analytes are stored. Many new analytical technologies can only be incorporated into routine programs as a result of advances in hardware and software allowing better access to, and storage of, data.

Australia↗
PubMed2003

Newborn screening--is it really that simple?

The incorporation of tandem mass spectrometry (MSMS) into an existing newborn screening program is an evolving process. Limited worldwide experience has ensured that all stages of reliability testing need to be followed. These include a literature review to establish methodology and analytes/disorders for testing and a pilot screening project including assaying archival samples from subjects with proven target disorders. Algorithms used for analyte concentrations and the relationships of various analytes to one another for resample criteria need to be continually reassessed to maximise screening specificity, sensitivity and positive predictive value. Since 1st of April 1998, the NSW Newborn Screening Program has screened 320, 848 babies using electrospray MSMS for selected amino acids and acyl camitines. Screening for amino acids has led to requests for 415 repeat samples with 94 babies referred for further testing. Of these 73 had a disorder of amino acid metabolism, including 43 with persistent hyperphenylalaninemia (36 of whom had PKU, 2 had a pterin pathway defect, 5 HPAA). Screening for acyl carnitines has led to requests for 245 repeat samples with 63 babies referred for further investigation. Of these 44 had a diagnosed disorder, including 15 with medium chain acyl CoA dehydrogenase deficiency. Five babies with confirmed disorders detectable with MS/MS had negative test results. The cost of screening using MSMS was only $A0.50 more than the method for screening for PKU and homocystinuria alone (ie the bacterial inhibition assays) and has allowed detection of an additional 74 babies at least 48 of whom have a diagnosis for which early treatment seems clearly beneficial. MSMS has shown a sensitivity of 95.9% and specificity of 99.8% in our laboratory with a positive predictive value of 18%.

Acyl-CoA Dehydrogenase↗
PubMed2002

Quantitative fibroblast acylcarnitine profiles in mitochondrial fatty acid beta-oxidation defects: phenotype/metabolite correlations.

Mitochondrial fatty acid beta-oxidation (FAO) disorders are clinically and biochemically heterogeneous diseases mainly associated with intolerance to catabolic stress. These disorders can now be detected pre-symptomatically by newborn screening, and thus the clinical phenotype in an individual patient may be unclear. Correlation of clinical severity with concentrations of acylcarnitine species was investigated in fibroblasts from FAO-deficient patients presenting with various phenotypes and asymptomatic neonates detected by newborn screening. Intact cells were incubated in medium containing deuterium-labelled hexadecanoic acid and L-carnitine for 72h, and the accumulated acylcarnitines in the culture medium analysed using electrospray tandem mass spectrometery. Fibroblasts from patients with long-chain FAO disorders presenting at an early age and with poor clinical outcomes accumulated higher concentrations of long-chain acylcarnitine species compared with those from patients with milder phenotypes. This suggests that the in vitro quantitative acylcarnitine profiling could perhaps predict the prognosis of some FAO defects. This would be particularly useful information for the asymptomatic/pre-symptomatic FAO-deficient infant detected by the expanded newborn screening program, in whom the risk of developing symptoms later in life is not known.

Acyl-CoA Dehydrogenase↗
PubMed2002

Acylcarnitine profiles in fibroblasts from patients with respiratory chain defects can resemble those from patients with mitochondrial fatty acid beta-oxidation disorders.

Mitochondrial fatty acid beta-oxidation (FAO) is coupled to the respiratory chain (RC). Functional defects of one pathway may lead to secondary alteration in flux through the other. We investigated the acylcarnitine profiles in cultured fibroblasts obtained from 14 healthy subjects, 31 patients with 8 different primary enzyme deficiencies of FAO, and 16 patients with primary RC defects including both isolated and multiple enzyme complex defects. Intact cells were incubated in media containing deuterium-labeled hexadecanoic acid and L-carnitine, and the acylcarnitines analysed using an electrospray tandem mass spectrometer. All FAO-deficient cell lines revealed disease-specific acylcarnitine profiles related to the sites of defects. Some cell lines from patients with RC defects showed profiles similar to those of controls, whereas others had abnormal profiles mimicking those found in FAO disorders. The acylcarnitine profiles of patients with RC enzyme defects were not predictable, and in some patients defects caused by mutations in either nuclear-encoded or mitochondrial DNA were associated with acylcarnitine abnormalities. While in vitro acylcarnitine profiling is useful for the diagnosis of FAO deficiencies, abnormal profiles do not exclusively indicate these disorders, and primary defects of the RC remain a possibility. Awareness of this diagnostic pitfall will aid in the selection of subsequent confirmatory tests and therapeutic options.

Carnitine↗