Carnitine-acylcarnitine translocase deficiency with severe hypoglycemia and auriculo ventricular block. Translocase assay in permeabilized fibroblasts.

Pande, Shri V.; Brivet, M.; Slama, Abdelhamid; Demaugre, F.; Aufrant, C; Saudubray, Jean‐Marie

doi:10.1172/jci116288

Cited by 99 publications

(53 citation statements)

References 23 publications

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“…Thirty-one articles describing clinical reports of CACT deficiency were found by searching the PubMed database (Al Aqeel et al 2003;Al-Sannaa and Cheriyan 2010;Brivet et al 1996;Chalmers et al 1997;Costa et al 1999;Costa et al 2003;Fearing et al 2011;Fukushima et al 2013;Galron et al 2004;Geven et al 2007;Huizing et al 1997Huizing et al , 1998Iacobazzi et al 2004a;Iacobazzi et al 2004b;Korman et al 2006;Lee et al 2007;Lopriore et al 2001;Morris et al 1998;Niezen-Koning et al 1995;Nuoffer et al 2000;Ogawa et al 2000;Ogier de Baulny et al 1995;Olpin et al 1997;Pande et al 1993;Parini et al 1999;Pierre et al 2007;Roschinger et al 2000;Rubio-Gozalbo et al 2003;RubioGozalbo et al 2004;Stanley et al 1992;Wang et al 2011;Yang et al 2001). Data from the literature were compiled, compared with the cases reported here, and discussed.…”

Section: Resultsmentioning

confidence: 99%

Carnitine-Acylcarnitine Translocase Deficiency: Experience with Four Cases in Spain and Review of the Literature

Vitoria¹,

Martín‐Hernández

Quintana

et al. 2014

JIMD Reports

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Background: Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive disease in the mitochondrial transport of long-chain fatty acids. Despite early diagnosis and treatment, the disease still has a high mortality rate.Methods: Clinical symptoms, long-term follow-up, and biochemical and molecular results of four cases are described and compared with the reviewed literature data of 55 cases.Results: Two cases with neonatal onset, carrying in homozygosity the novel variant sequences p.Gly20Asp (c.59G>A) and p.Arg179Gly (c.536A>G), died during an intercurrent infectious process in the first year of life despite adequate dietetic treatment (frequent feeding, highcarbohydrate/low-fat diet, MCT, carnitine). The other two cases, one with infantile onset and the other diagnosed in the newborn period after a previous affected sibling, show excellent development at 4 and 16 years of age under treatment. The review shows that the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress. The onset of symptoms is predominantly neonatal in 82% and infantile in 18%. The mortality rate is high (65%), most in the first year of life due to myocardiopathy or sudden death. Outcomes seem to correlate better with the absence of cardiac disease and with a higher long-chain fatty acid oxidation rate in cultured fibroblasts than with residual enzyme activity.Conclusion: Diagnosis before the occurrence of clinical symptoms by tandem MS-MS and very early therapeutic intervention together with good dietary compliance could lead to a better prognosis, especially in milder clinical cases.

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Section: Resultsmentioning

confidence: 99%

Carnitine-Acylcarnitine Translocase Deficiency: Experience with Four Cases in Spain and Review of the Literature

Vitoria¹,

Martín‐Hernández

Quintana

et al. 2014

JIMD Reports

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“…Rare case reports noticed conduction anomalies or ventricular arrhythmias as a major feature of these defects. Pande et al 9 reported the first case of carnitineacylcarnitine translocase deficiency in a newborn infant with severe hypoglycemia and atrioventricular block (patient 1, Table). de Lonlay-Debeney et al 19 reported the case of a 9-month-old child with VLCAD deficiency who presented with severe heart failure and polymorphic ventricular tachycardia masquerading as fulminant myocarditis.…”

Section: Discussionmentioning

confidence: 99%

“…8 In addition, arrhythmias and conduction defects, in association with hepatomuscular symptoms, have been previously mentioned in isolated cases of fatty acid oxidation disorders. 9 Severe ventricular arrhythmias are suspected as the cause of sudden infant death syndrome or unexpected death in young children harboring these defects. 10,11 Although neonatal ventricular or atrial tachycardias in infants with a structurally and functionally normal heart are usually considered idiopathic, we report a series of 24 children in whom arrhythmias or conduction defects were the predominant presenting symptom of various fatty acid oxidation disorders.…”

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confidence: 99%

Arrhythmias and Conduction Defects as Presenting Symptoms of Fatty Acid Oxidation Disorders in Children

et al. 1999

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Background —The clinical manifestations of inherited disorders of fatty acid oxidation vary according to the enzymatic defect. They may present as isolated cardiomyopathy, sudden death, progressive skeletal myopathy, or hepatic failure. Arrhythmia is an unusual presenting symptom of fatty acid oxidation deficiencies. Methods and Results —Over a period of 25 years, 107 patients were diagnosed with an inherited fatty acid oxidation disorder. Arrhythmia was the predominant presenting symptom in 24 cases. These 24 cases included 15 ventricular tachycardias, 4 atrial tachycardias, 4 sinus node dysfunctions with episodes of atrial tachycardia, 6 atrioventricular blocks, and 4 left bundle-branch blocks in newborn infants. Conduction disorders and atrial tachycardias were observed in patients with defects of long-chain fatty acid transport across the inner mitochondrial membrane (carnitine palmitoyl transferase type II deficiency and carnitine acylcarnitine translocase deficiency) and in patients with trifunctional protein deficiency. Ventricular tachycardias were observed in patients with any type of fatty acid oxidation deficiency. Arrhythmias were absent in patients with primary carnitine carrier, carnitine palmitoyl transferase I, and medium chain acyl coenzyme A dehydrogenase deficiencies. Conclusions —The accumulation of arrhythmogenic intermediary metabolites of fatty acids, such as long-chain acylcarnitines, may be responsible for arrhythmias. Inborn errors of fatty acid oxidation should be considered in unexplained sudden death or near-miss in infants and in infants with conduction defects or ventricular tachycardia. Diagnosis can be easily ascertained by an acylcarnitine profile from blood spots on filter paper.

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“…In some experiments, the culture medium was supplemented with 5 mM DCA for 3 d before plating and throughout the 48-h period of cell culture in the 25-cm 2 flasks. Cells were incubated with 14 C-labeled substrates for 45 min at 37°C, in 1 mL of respiratory medium (225 mM mannitol, 25 mM HEPES, 50 M EDTA (pH 7.5), 5 mM potassium phosphate, 3 mM ADP) supplemented with 2 mg/mL BSA and 20 g/mL digitonin (20). The production of 14 Figure 1.…”

Section: Case Reportsmentioning

confidence: 99%

Differential Effect of DCA Treatment on the Pyruvate Dehydrogenase Complex in Patients with Severe PDHC Deficiency

et al. 2003

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Dichloroacetate (DCA) is a structural analog of pyruvate that has been recommended for the treatment of primary lactic acidemia, particularly in patients with pyruvate dehydrogenase (PDHC) deficiency. Recent reports have demonstrated that the response to DCA may depend on the type of molecular abnormality. In this study, we investigated the response to DCA in various PDHC-deficient cell lines and tried to determine the mechanism involved. The effect of chronic 3-d DCA treatment on PDHC activity was assessed in two PDHC-deficient cell lines, each with a different point mutation in the E1␣ subunit gene (R378C and R88C), and one cell line in which an 8-bp tandem repeat was deleted (W383 del). Only two (R378C and R88C) of the three PDHC-deficient cell lines with very low levels of PDHC activity and unstable polypeptides were sensitive to chronic DCA treatment. In these cell lines, DCA treatment resulted in an increase in PDHC activity by 125 and 70%, respectively, with concomitant increases of 121 and 130% in steady-state levels of immunoreactive E1␣. DCA treatment reduced the turnover of the E1␣ subunit in R378C and R88C mutant cells with no significant effect on the E1␤ subunit. Chronic DCA treatment significantly improved the metabolic function of PDHC in digitonin-permeabilized R378C and R88C fibroblasts. The occurrence of DCA-sensitive mutations suggests that DCA treatment is potentially useful as an adjuvant to ketogenic and vitamin treatment in PDHC-deficient patients. PDHC deficiency is a nuclear-encoded mitochondrial disorder and a major recognized cause of neonatal encephalopathies associated with primary lactic acidosis (1). This multienzyme complex plays an important role in the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA. E1, one of the subunits of the complex, is a thiamine pyrophosphatedependent pyruvate decarboxylase. It is a tetramer composed of two ␣ and two ␤ subunits, the ␣ subunit containing the thiamine pyrophosphate binding sites. E2 is a dihydrolipoamide acetyl transferase. E3 is a dihydrolipoamide dehydrogenase, and E3BP or protein X mediates the interaction between E2 and E3. Two elements regulate the complex: an E1 kinase and a phospho-E1 phosphatase, which phosphorylate and dephosphorylate, respectively, three serine residues in the E1 ␣ subunit, resulting in the deactivation and activation, respectively, of the complex (2).Defects in the PDHC are frequently attributed to deficiencies in the E1 ␣ component (3), encoded by chromosome X (Xp22.1-22.2) (4, 5). Considerable phenotypic and allelic heterogeneity has been observed for this defect. Previous studies have reported that a decrease in the stability of the E1 ␣ immunoreactive subunit may contribute to the expression of many E1 ␣ mutations (6, 7); very few studies to distinguish mutations that impair polypeptide stability from those impairing catalytic efficiency have been carried out to date (8).DCA is a structural analog of pyruvate that has been recommended for the treatment of primary lactic acidemia, particular...

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Carnitine-acylcarnitine translocase deficiency with severe hypoglycemia and auriculo ventricular block. Translocase assay in permeabilized fibroblasts.

Cited by 99 publications

References 23 publications

Carnitine-Acylcarnitine Translocase Deficiency: Experience with Four Cases in Spain and Review of the Literature

Carnitine-Acylcarnitine Translocase Deficiency: Experience with Four Cases in Spain and Review of the Literature

Arrhythmias and Conduction Defects as Presenting Symptoms of Fatty Acid Oxidation Disorders in Children

Differential Effect of DCA Treatment on the Pyruvate Dehydrogenase Complex in Patients with Severe PDHC Deficiency

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