Biomedical subjects

Roser Pons

Publications and source records attributed to Roser Pons.

4 recordsLinked to original sources

PubMed2004

Molecular and functional analysis of SLC25A20 mutations causing carnitine-acylcarnitine translocase deficiency.

The enzyme carnitine-acylcarnitine translocase (CACT) is involved in the transport of long-chain fatty acids into mitochondria. CACT deficiency is a life-threatening, recessively inherited disorder of lipid beta-oxidation which manifests in early infancy with hypoketotic hypoglycemia, cardiomyopathy, liver failure, and muscle weakness. We report here the clinical, biochemical, and molecular features of six CACT-deficient patients from Italy, Spain, and North America who exhibited significant clinical heterogeneity. In five patients (Patients 1, 2, 4, 5, and 6) the disease manifested in the neonatal period, while the remaining patient (Patient 3), the younger sibling of an infant who had died with clinical suspicion of fatty acid oxidation defect, has been treated since birth and was clinically asymptomatic at 4.5 years of age. Patients 1 and 4 were deceased within 6 months from the onset of this study, while the remaining four are still alive at 8, 4.5, 3.5, and 2 years, respectively. Sequence analysis of the CACT gene (SLC25A20) disclosed five novel mutations and three previously reported mutations. Three patients were homozygous for the identified mutations. Two of the novel mutations (c.718+1G>C and c.843+4_843+50del) altered the donor splice site of introns 7 and 8, respectively. The 47-nt deletion in intron 8 caused both skipping of exon 8 only and skipping of exons 6-8. Four mutations [[c.159dupT;c.163delA] ([p.Gly54Trp;p.Thr55Ala]) c.397C>T (p.Arg133Trp), c.691G>C (p.Asp231His), and c.842C>T (p.Ala281Val)] resulted in amino acid substitutions affecting evolutionarily conserved regions of the protein. Interestingly, one of these exonic mutations (p.Ala281Val) was associated with a splicing defect also characterized by skipping of exons 6-8. The deleterious effect of the p.Arg133Trp substitution was demonstrated by measuring CACT activity upon expression of the normal and the mutant protein in E. coli and functional reconstitution into liposomes. Combined analysis of clinical, biochemical, and molecular data failed to indicate a correlation between the phenotype and the genotype.

Amino Acid Sequence↗

PubMed2004

Mitochondrial DNA abnormalities and autistic spectrum disorders.

OBJECTIVES: To further characterize mtDNA defects associated with autistic features, especially the A3243G mtDNA mutation and mtDNA depletion.Study design Five patients with autistic spectrum disorders and family histories of mitochondrial DNA diseases were studied. We performed mtDNA analysis in all patients and magnetic resonance spectroscopy in three. RESULTS: Three patients manifested isolated autistic spectrum features and two had additional neurologic symptoms. Two patients harbored the A3243G mutation. In two others, the A3243G mutation was not found in accessible tissues but was present in tissues from their mothers. The fifth patient had 72% mtDNA depletion in skeletal muscle. CONCLUSIONS: Autistic spectrum disorders with or without additional neurologic features can be early presentations of the A3243G mtDNA mutation and can be a prominent clinical manifestation of mtDNA depletion. Mitochondrial dysfunction should be considered in patients who have autistic features and associated neurologic findings or who have evidence of maternal inheritance.

Adolescent↗

PubMed2003

Neonatal blood carnitine concentrations: normative data by electrospray tandem mass spectometry.

Despite a number of published reports, there is limited information about carnitine metabolism in the newborn. To establish normative data, we analyzed whole-blood carnitine concentrations in 24,644 newborns at age 1.85 +/- 0.95 d and umbilical cord whole blood and plasma carnitine concentrations in 50 full-term newborns. Total carnitine (TC), free carnitine (FC), and acylcarnitine (AC) were measured by electrospray tandem mass spectrometry. AC/FC ratios were derived from these measurements. The entire cohort was stratified according to TC values into a middle TC group representing 90% of the population and lower and upper TC groups representing 5% of the population, respectively. Normative data were derived from the middle TC group of full-term infants (N = 19,595). TC was 72.42 +/- 20.75 microM, FC was 44.94 +/- 14.99 microM, AC was 27.48 +/- 8.05 microM, and AC/FC ratio was 0.64 +/- 0.19 (+/-SD). These values differed significantly from umbilical cord whole blood TC values of 31.27 +/- 10.54 microM determined in 50 samples. No meaningful correlation was found between TC and gestational age or birth weight in any group. In controlled analyses, prematurity was not associated with TC levels, whereas low birth weight (<2500 g) and male sex were significantly associated with higher TC levels. The association of low birth weight with higher TC values may be related to decreased tissue carnitine uptake. The sex effect may be related to hormonal influences on carnitine metabolism. Our study provides normative data of carnitine values measured by the highly precise method of electrospray tandem mass spectrometry in a large cohort of newborns and provides the basis for future studies of carnitine metabolism in health and disease states during the neonatal period.

Carnitine↗

PubMed2001

Mitochondrial Disease.

Mitochondrial diseases are disorders of energy metabolism that include defects of pyruvate metabolism, Krebs cycle, respiratory chain (RC), and fatty acid oxidation (FAO). Treatment of pyruvate metabolism, Krebs cycle, and RC disorders is, in general, disappointing. Therapeutic approaches consist of electron acceptors, enzyme activators, vitamins, coenzymes, free-radical scavengers, dietary measures, and supportive therapy. These treatment assumptions are based on current understanding of the pathophysiology, on anecdotal clinical reports, and on a few controlled clinical trials, which have not been encouraging. Although it is difficult to perform clinical trials in these conditions due to their rarity and genotypic and phenotypic heterogeneity, there is a great need for well-performed double-blind placebo- controlled clinical trials with comparable groups of patients and with sufficient follow-up periods. Treatment options for FAO disorders are, in general, satisfactory and are mainly based on diet, lifestyle recommendations, and administration of L-carnitine and, in some cases, riboflavin. Special conditions that involve primary deficiencies of L-carnitine, coenzyme Q(10), and cofactor- and vitamin-responsive enzyme defects must be systematically considered, because supplementation with these substances may be curative or produce dramatic improvements. While awaiting more specific therapies for mitochondrial disorders, it is useful to reach a consensus regarding the management of these patients. The expected outcome is a slowing of the disease process and stabilization of the clinical syndrome. More definitive treatments hopefully will follow in the near future.

Journal Article↗