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F Taroni

Publications and source records attributed to F Taroni.

At least 37 records · Page 2Linked to original sources
PubMed2000

Clinical and molecular heterogeneity in very-long-chain acyl-coenzyme A dehydrogenase deficiency.

Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is an increasingly recognized defect of mitochondrial fatty acid beta-oxidation manifesting with episodes of metabolic decompensation or isolated recurrent myoglobinuria. In this report the clinical, biochemical, and molecular studies in a series of five patients (four Italian and one Spanish) with this disorder are discussed. Biochemical studies included the determination of fibroblast substrate oxidation rates and enzyme activity and Western blot analysis of VLCAD protein. Molecular analysis was performed by sequencing the VLCAD gene from the genomic DNA. Clinical features were within the spectrum previously reported. Four patients presented in infancy or childhood with episodes of severe metabolic decompensation and dicarboxylic aciduria. Two exhibited cardiomyopathy. The fifth patient presented with isolated recurrent rhabdomyolysis, with no cardiomyopathy or dicarboxylic aciduria. In all patients a significant loss of VLCAD activity associated with a marked reduction of VLCAD protein levels occurred. Molecular analysis disclosed one novel missense mutation (Cys437Tyr) and four previously reported mutations, including two missense substitutions (Phe418Leu and Arg419Trp), a single amino acid deletion (Lys258del), and one splice site mutation (IVS8-C(-2)), which was present in all four Italian patients. All patients exhibited compound heterozygosity. The phenotypic variability and the high genotypic heterogeneity of this hereditary metabolic disorder is reported.

Acyl-CoA Dehydrogenase↗
PubMed2000

Sensitivity of FRDA lymphoblasts to salts of transition metal ions.

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease resulting from decreased expression of the nuclear-encoded mitochondrial protein, frataxin. FRDA patients have characteristic iron deposits and dysfunction of mitochondrial enzymes in the heart. Inactivation of the frataxin homologue in yeast causes dysregulation of both mitochondrial iron levels and iron export. Previously, we have observed sensitivity of FRDA fibroblasts to FeCl3 and hydrogen peroxide, results consistent with the hypothesis that FRDA cells may experience increased Fenton chemistry. To determine whether the sensitivity of FRDA cells to transition metal ions is a general or specific property, we have compared the sensitivity of lymphoblasts from FRDA patients and healthy controls to the transition metal salts CoCl2, CuSO4 FeCl3 FeSO4, MnCl2, and ZnCl2. FRDA lymphoblasts were significantly more sensitive to FeCl3 and MnCl2 than control cells. However, there were no significant differences observed in sensitivity to CoCl2, CuSO4, FeSO4 and ZnCl2 in the concentration ranges studied. Thus, the sensitivity of FRDA lymphoblasts exposed to transition metals appears to be specific, and could be relevant to the pathophysiological mechanism, which is discussed.

Blotting, Western↗
PubMed2000

Identification concept and the use of probabilities in forensic odontology--an approach by philosophical discussion.

This paper questions the practitioners' deterministic approach(es) in forensic identification and notes the limits of their conclusions in order to encourage a discussion to question current practices. With this end in view, a hypothetical discussion between an expert in dentistry and an enthusiastic member of a jury, eager to understand the scientific principles of evidence interpretation, is presented. This discussion will lead us to regard any argument aiming at identification as probabilistic.

Bites, Human↗
PubMed1999

Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase.

Frataxin is a nuclear-encoded mitochondrial protein which is deficient in Friedreich's ataxia, a hereditary neurodegenerative disease. Yeast mutants lacking the yeast frataxin homologue (Yfh1p) show iron accumulation in mitochondria and increased sensitivity to oxidative stress, suggesting that frataxin plays a critical role in mitochondrial iron homeostasis and free radical toxicity. Both Yfh1p and frataxin are synthesized as larger precursor molecules that, upon import into mitochondria, are subject to two proteolytic cleavages, yielding an intermediate and a mature size form. A recent study found that recombinant rat mitochondrial processing peptidase (MPP) cleaves the mouse frataxin precursor to the intermediate but not the mature form (Koutnikova, H., Campuzano, V., and Koenig, M. (1998) Hum. Mol. Gen. 7, 1485-1489), suggesting that a different peptidase might be required for production of mature size frataxin. However, in the present study we show that MPP is solely responsible for maturation of yeast and human frataxin. MPP first cleaves the precursor to intermediate form and subsequently converts the intermediate to mature size protein. In this way, MPP could influence frataxin function and indirectly affect mitochondrial iron homeostasis.

Amino Acid Sequence↗
PubMed1999

Medium-chain triglyceride loading test in carnitine-acylcarnitine translocase deficiency: insights on treatment.

The results of a medium-chain triglyceride loading test in a patient with severe carnitine-acylcarnitine translocase deficiency clearly demonstrated impaired in vivo utilization of medium-chain triglycerides. The loading test was performed at the ages of 7 and 36 months. The diet was adjusted accordingly. The clinical course has been favourable and the child is now in very good condition at age 4 years. We conclude that the utilization of medium-chain triglycerides is only partial in carnitine-acylcarnitine translocase deficiency and cannot reasonably be considered an optimal source of energy for these patients. Careful adjustment of dietetic treatment may help to improve prognosis.

3-Hydroxybutyric Acid↗
PubMed1999

The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis.

Expansions of an intronic GAA repeat reduce the expression of frataxin and cause Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease. Frataxin is a mitochondrial protein, and disruption of a frataxin homolog in yeast results in increased sensitivity to oxidant stress, increased mitochondrial iron and respiration deficiency. These previous data support the hypothesis that FRDA is a disease of mitochondrial oxidative stress, a hypothesis we have tested in cultured cells from FRDA patients. FRDA fibroblasts were hypersensitive to iron stress and significantly more sensitive to hydrogen peroxide than controls. The iron chelator deferoxamine rescued FRDA fibroblasts more than controls from oxidant-induced death, consistent with a role for iron in the differential kinetics of death; however, mean mitochondrial iron content in FRDA fibroblasts was increased by only 40%. Treatment of cells with the intracellular Ca2+chelator BAPTA-AM rescued both FRDA fibroblasts and controls from oxidant-induced death. Treatment with apoptosis inhibitors rescued FRDA but not control fibroblasts from oxidant stress, and staurosporine-induced caspase 3 activity was higher in FRDA fibroblasts, consistent with the possibility that an apoptotic step upstream of caspase 3 is activated in FRDA fibroblasts. These results demonstrate that FRDA fibroblasts are sensitive to oxidant stress, and may be a useful model in which to elucidate the FRDA mechanism and therapeutic strategies.

Apoptosis↗
PubMed1998

Detection of hereditary neuropathy with liability to pressure palsies among patients with acute painless mononeuropathy or plexopathy.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies or brachial plexopathies, commonly associated with a chromosome 17p11.2-12 deletion encompassing the peripheral myelin protein-22 (PMP22) gene. We tried to identify criteria distinguishing HNPP among patients with acute painless mononeuropathy/plexopathy. We investigated by pulsed-field gel electrophoresis the presence of the deletion in 27 patients with isolated or recurrent acute painless mononeuropathy or brachial plexopathy, and no obvious cause of neuropathy. Eight patients carried the deletion, whereas 19 had neither the deletion nor mutations in the PMP22 gene. Age at onset, presenting modality, precipitating events, and rate of recovery did not significantly differ in the two groups. Family history was informative for HNPP diagnosis in 3 cases only. HNPP patients more often showed recurrent episodes, brachial plexopathy, and clinical or electrophysiologic involvement of other nerves. Non-HNPP patients more frequently had peroneal palsy, recent weight loss, and normal electrophysiologic examination in other nerves. Signs of generalized neuropathy and evidence of disease in other family member are often subtle in HNPP and must be thoroughly investigated in patients with acute painless mononeuropathy/plexopathy.

Action Potentials↗
PubMed1998

Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: functional analysis and association with polymorphic haplotypes and two clinical phenotypes.

Carnitine palmitoyltransferase II (CPT II) deficiency manifests as two different clinical phenotypes: a muscular form and a hepatic form. We have investigated three nonconsanguineous Japanese patients with CPT II deficiency. Molecular analysis revealed two missense mutations, a glutamate (174)-to-lysine substitution (E174K) and a phenylalanine (383)-to-tyrosine substitution (F383Y) in the CPT II cDNA. Transfection experiments in COS-1 cells demonstrated that the two mutations markedly decreased the catalytic activity of mutant CPT II. Case 1 (hepatic form) was homozygous for the F383Y mutation, whereas case 3 (muscular form) was homozygous for the E174K mutation. Case 2 and her brother, who were compound heterozygotes for E174K and F383Y, exhibited the hepatic phenotype. We also identified a novel polymorphism in the CPT2 gene, a phenylalanine (352)-to-cysteine substitution (F352C), which did not alter CPT II activity in transfected cells. It was present in 21 out of 100 normal alleles in the Japanese population, but absent in Caucasian populations. Genotyping with the F352C polymorphism and the two previously reported polymorphisms, V368I and M647V, allowed normal Japanese alleles to be classified into five haplotypes. In all three families with CPT II deficiency, the E174K mutation resided only on the F1V1M1 allele, whereas the F383Y mutation was observed on the F2V2M1 allele, suggesting a single origin for each mutation.

Adult↗
PubMed1998

Very-long-chain acyl-coenzyme A dehydrogenase deficiency in a child with recurrent myoglobinuria.

A 9-year-old boy had recurrent episodes of myoglobinuria and normal urinary organic acid profile. Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency was detected biochemically in cultured skin fibroblasts and confirmed by Western blot analysis. The patient had a distinctive plasma fatty-acid profile, which was present even between attacks. Early diagnosis of this disorder is important because of the apparently protective effect of an appropriate dietary regimen.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1998

The health care reform in Italy: transition or turmoil.

Health care reform in Italy is transforming its centrally planned, vertically integrated National Health Service into a market-oriented system in which public funders contract directly with individual providers. A model is envisaged in which a plurality of public and private care providers compete for contracts with capitated health agencies responsible for assuring uniform levels of services for geographically defined populations. The ultimate goal of the reform is to guarantee universal coverage and secure global spending limits while, at the same time, promoting efficiency in the delivery of care and enhancing responsiveness to consumers. The emphasis upon incentives for the individual provider which will be introduced should, however, be considered against the quest for equity in health care which was the central tenet of the 1978 reform and is yet to be attained. The fragmentation of the National Health Service into many separate, competing delivery units might well damage the ability to plan strategically for addressing the substantial inequities in health status, health care utilization, and health service availability which still exist across the country. Competition between a plurality of providers and fee-for-service payment schemes add additional concerns about unnecessary care and supplier-induced demand. It creates the need for developing rules to make competition manageable and providing sound clinical and financial information that make enforcement possible. The poor record scored in managing the contractual relationships between the LHUs and the strong private health sector suggests that massive investment in promoting managerial skills and developing appropriate clinical and financial information systems are required. Careful experimentation in implementing the reform and continuous monitoring of its impact on the health care system are, therefore, the imperatives of the next two years.

Capitation Fee↗
PubMed1997

Characterisation of carnitine palmitoyltransferases in patients with a carnitine palmitoyltransferase deficiency: implications for diagnosis and therapy.

OBJECTIVES: Carnitine palmitoyltransferase (CPT) deficiency is one of the most common defects of mitochondrial fatty acid oxidation. Two different enzymes (CPT-I and CPT-II) are involved. Due to problems in measuring enzyme activity, relatively little is known about the substrate specificity of each of the human enzymes. This is of considerable importance in the treatment of patients. The objectives were to establish a reliable method for the measurement of CPT activity in whole cells, to use this to characterise the substrate specificity of each enzyme, and finally, to determine if medium chain triglycerides would be of benefit in the treatment of deficient patients. METHODS: A simple permeabilisation technique was used which allows the measurement of CPT activity in a small amount of cultured skin fibroblasts or peripheral blood cells. Using this technique three patients were identified with CPT deficiency. In two of these patients, one with CPT-I deficiency and one with CPT-II deficiency, a complete substrate specificity profile of the mitochondrial carnitine acyltransferases was established for all saturated even chain acyl-CoA esters. RESULTS: For both enzymes the highest CPT activity was with C12-CoA. About 70% of total cellular carnitine octanoyltransferase activity was due to mitochondrial CPT. As CPT is involved in the transport of medium chain fatty acids the metabolic response of a patient with CPT-II deficiency to dietary medium chain triglycerides was assessed. Despite the normal production of ketone bodies there was a significant medium chain dicarboxylic aciduria in the patient, indicating a limited capacity of the CPT independent mitochondrial uptake of medium chain fatty acids. CONCLUSIONS: CPT deficiency can easily be diagnosed in permeabilised cultured skin fibroblasts. Both CPT-I and CPT-II are more active with medium chain length substrates than previously assumed. Care should therefore be taken in the treatment of these patients with medium chain triglycerides.

Adult↗
PubMed1997

Variation in hospital use and avoidable patient morbidity.

OBJECTIVES: To determine whether geographical areas with relatively low overall hospitalization rates have higher population-based rates of admission of patients with advanced stages of disease. METHODS: Age- and sex-standardized hospital admission rate were calculated for the residents of the 80 Local Health Units in Lombardia, Italy. Using the Disease Staging classification, advanced stage admissions were identified for six common medical and surgical conditions, which it was presumed would reflect untimely hospital admission. Standardized rates of advanced stage admissions were compared in areas with overall high hospitalization rates (high-use areas). RESULTS: Hospitalization at advanced stages of disease in the low-use areas were significantly higher for the six conditions combined (55.9 vs 43.0 per 100,000; P = 0.005), and for external hernia, appendicitis and uterine fibroma, but not for bacterial pneumonia, diverticular disease and peptic ulcer. For the six study conditions combined, residents of overall low-use area were 30% more likely to be admitted with advanced stages of disease. CONCLUSION: Low overall hospitalization rates were found to be associated with greater severity of illness at hospitalization and potentially avoidable morbidity for some conditions. Policies aimed at curbing unnecessary hospital admission should consider preserving access for appropriate treatment.

Acute Disease↗
PubMed1997

Gene dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies.

A duplication of a 1.5-Megabase genomic region encompassing the gene for the peripheral myelin protein 22 (PMP22) is found on chromosome 17p11.2-12 in Charcot-Marie-Tooth disease type 1A (CMT1A), whereas the reciprocal deletion is associated with hereditary neuropathy with liability to pressure palsies (HNPP). Since most CMT1A patients harbor three copies of the PMP22 gene, and most HNPP patients carry only a single copy, a gene dosage effect has been proposed as a mechanism for both diseases. We have analyzed the steady-state expression of PMP22 protein in sural nerve biopsies from three CMT1A and four HNPP patients. Quantitative immunohistochemical determination showed that PMP22 protein expression relative to that of myelin protein zero and myelin basic protein was increased in all CMT1A patients and reduced in all HNPP patients, as compared with biopsy samples of patients with normal PMP22 gene expression. These data demonstrate that both neuropathies result from an imbalance of PMP22 protein expression.

Adolescent↗