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1.
Rev Neurol (Paris) ; 172(3): 231-41, 2016 Mar.
Article in English | MEDLINE | ID: mdl-27038534

ABSTRACT

INTRODUCTION: Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare, treatable, beta-oxidation disorder responsible for neuromuscular symptoms in adults. This case series describes the clinical and biochemical features of 13 French patients with late-onset MADD. METHODS AND RESULTS: Thirteen ambulant patients (eight women, five men), with a median age at onset of 27 years, initially experienced exercise intolerance (n=9), isolated muscle weakness (n=1) and a multisystemic pattern with either central nervous system or hepatic dysfunction (n=3). During the worsening period, moderate rhabdomyolysis (n=5), a pseudomyasthenic pattern (n=5) and acute respiratory failure (n=1) have been observed. Weakness typically affected the proximal limbs and axial muscles, and there was sometimes facial asymmetry (n=3). Moderate respiratory insufficiency was noted in one case. Median baseline creatine kinase was 190IU/L. Lactacidemia was sometimes moderately increased at rest (3/10) and after exercise (1/3). The acylcarnitine profile was characteristic, with increases in all chain-length acylcarnitine species. Electromyography revealed a myogenic pattern, while muscle biopsy showed lipidosis, sometimes with COX-negative fibers (n=2). The mitochondrial respiratory chain was impaired in five cases, with coenzyme Q10 decreased in two cases. All patients harbored mutations in the ETFDH gene (four homozygous, seven compound heterozygous, two single heterozygous), with nine previously unidentified mutations. All patients were good responders to medical treatment, but exercise intolerance and/or muscular weakness persisted in 11 of them. CONCLUSION: Late-onset forms of MADD may present as atypical beta-oxidation disorders. Acylcarnitine profiling and muscle biopsy remain the most decisive investigations for assessing the diagnosis. These tests should thus probably be performed more widely, particularly in unexplained cases of neuromuscular and multisystemic disorders.


Subject(s)
Lipid Metabolism, Inborn Errors/enzymology , Lipid Metabolism, Inborn Errors/therapy , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/complications , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/genetics , Neuromuscular Diseases/enzymology , Neuromuscular Diseases/therapy , Adult , Age of Onset , Biopsy , Carnitine/analogs & derivatives , Carnitine/metabolism , Electromyography , Electron-Transferring Flavoproteins/genetics , Exercise , Female , France , Humans , Iron-Sulfur Proteins/genetics , Lipid Metabolism, Inborn Errors/genetics , Male , Middle Aged , Muscle, Skeletal/enzymology , Muscle, Skeletal/pathology , Mutation/genetics , Neuromuscular Diseases/genetics , Oxidation-Reduction , Oxidoreductases Acting on CH-NH Group Donors/genetics , Rhabdomyolysis/etiology , Young Adult
2.
Mol Genet Metab ; 104(4): 507-16, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21914562

ABSTRACT

BACKGROUND: Pyruvate dehydrogenase complex (PDHc) deficiencies are an important cause of primary lactic acidosis. Most cases result from mutations in the X-linked gene for the pyruvate dehydrogenase E1α subunit (PDHA1) while a few cases result from mutations in genes for E1ß (PDHB), E2 (DLAT), E3 (DLD) and E3BP (PDHX) subunits or PDH-phosphatase (PDP1). AIM: To report molecular characterization of 82 PDHc-deficient patients and analyze structural effects of novel missense mutations in PDHA1. METHODS: PDHA1 variations were investigated first, by exon sequencing using a long range PCR product, gene dosage assay and cDNA analysis. Mutation scanning in PDHX, PDHB, DLAT and DLD cDNAs was further performed in unsolved cases. Novel missense mutations in PDHA1 were located on the tridimensional model of human E1 protein to predict their possible functional consequences. RESULTS: PDHA1 mutations were found in 30 girls and 35 boys. Three large rearrangements, including two contiguous gene deletion syndrome were identified. Novel missense, frameshift and splicing mutations were also delineated and a nonsense mutation in a mosaic male. Mutations p.Glu75Ala, p.Arg88Ser, p.Arg119Trp, p.Gly144Asp, p.Pro217Arg, p.Arg235Gly, p.Tyr243Cys, p.Tyr243Ser, p.Arg245Gly, p.Pro250Leu, p.Gly278Arg, p.Met282Val, p.Gly298Glu in PDHA1 were predicted to impair active site channel conformation or subunit interactions. Six out of the seven patients with PDHB mutations displayed the recurrent p.Met101Val mutation; 9 patients harbored PDHX mutations and one patient DLD mutations. CONCLUSION: We provide an efficient stepwise strategy for mutation screening in PDHc genes and expand the growing list of PDHA1 mutations analyzed at the structural level.


Subject(s)
Amino Acid Substitution , Pyruvate Dehydrogenase (Lipoamide)/genetics , Pyruvate Dehydrogenase Complex Deficiency Disease/genetics , Adolescent , Base Sequence , Catalytic Domain , Cells, Cultured , Child , Child, Preschool , Female , Fibroblasts/enzymology , Fibroblasts/metabolism , Gene Dosage , Humans , Hydrogen Bonding , INDEL Mutation , Infant , Infant, Newborn , Male , Molecular Sequence Data , Pyruvate Dehydrogenase Complex/chemistry , Pyruvate Dehydrogenase Complex/genetics , Pyruvate Dehydrogenase Complex/metabolism , Sequence Analysis, DNA
3.
Mol Genet Metab ; 103(4): 341-8, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21549624

ABSTRACT

BACKGROUND: Deficiency of mitochondrial trifunctional protein (MTP) is caused by mutations in the HADHA and HADHB genes, which have been mostly delineated at the genomic DNA level and have not been always elucidated. AIM: To identify mutations in a French cohort of 52 MTP deficient patients and the susceptibility of mutations generating premature termination codons (PTCs) to the nonsense mRNA mediated decay (NMD). METHODS: Mutation screening in fibroblasts was performed at the cDNA level and real-time RT-PCR was used to compare the levels of the different PTC-bearing mRNAs before and after a treatment of fibroblasts by emetine, a translation inhibitor. RESULTS: A mutation detection rate of 100% was achieved. A total of 22 novel mutations were identified, including a large-sized genomic deletion in HADHB gene. A high proportion of all identified mutations were non-sense, frameshift and splicing mutations, generating (PTCs), distributed essentially on HADHA coding regions. We could demonstrate that the majority of mutations resulting in PTCs conform to the established rules governing the susceptibility to NMD. CONCLUSION: Our results emphasize the value of cDNA analysis in the characterization of HADHA and HADHB mutations and further strengthen the model of haploinsufficiency as a major pathomechanism in MTP defects.


Subject(s)
DNA, Complementary/genetics , Lipid Metabolism Disorders/genetics , Mitochondrial Diseases/genetics , Mitochondrial Proteins/genetics , Multienzyme Complexes/genetics , Mutation , Base Sequence , Cohort Studies , Female , France , Haploinsufficiency , Humans , Male , Mitochondrial Trifunctional Protein , Mitochondrial Trifunctional Protein, alpha Subunit , Mitochondrial Trifunctional Protein, beta Subunit , Molecular Sequence Data , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA
4.
Rev Neurol (Paris) ; 166(3): 289-94, 2010 Mar.
Article in French | MEDLINE | ID: mdl-19592060

ABSTRACT

INTRODUCTION: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare genetic disease involving fatty acid oxidation. It is due to the deficiency of one of the two electron transporters: electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxydoreductase (ETF-QO). Symptoms begin more often in childhood or in young adulthood with a multisystemic disease with encephalopathy or muscular weakness. CASE REPORTS: We report here two adult cases with ETF-QO deficiency, confirmed by mutation analysis (ETFDH gene), revealed by a muscular weakness associated with muscle lipidosis. One of our patients presented an acute encephalopathy with vomiting ten years before the onset of muscular symptoms. The second patient exhibited a slowly progressive pelvic girdle muscle weakness. Diagnosis was established by characteristic abnormalities of acylcarnitine profile by tandem mass spectrometry. For both patients, a dramatic clinical improvement was observed under treatment with riboflavine and L-carnitine. CONCLUSION: Since it is a treatable disorder, this diagnosis must be considered by performing an acylcarnitine profile in all patients presenting with an unexplained muscular weakness.


Subject(s)
Acyl-CoA Dehydrogenases/deficiency , Lipid Metabolism, Inborn Errors/enzymology , Lipid Metabolism, Inborn Errors/genetics , Lipidoses/drug therapy , Lipidoses/genetics , Adult , Biopsy , Brain Diseases, Metabolic/genetics , Carnitine/analogs & derivatives , Carnitine/analysis , Carnitine/metabolism , Coloring Agents , DNA Mutational Analysis , Electron Transport/genetics , Electron-Transferring Flavoproteins/genetics , Electron-Transferring Flavoproteins/metabolism , Female , Humans , Lipid Metabolism, Inborn Errors/pathology , Lipidoses/pathology , Male , Middle Aged , Muscle Weakness/etiology , Muscle Weakness/genetics , Muscle, Skeletal/pathology , Riboflavin/metabolism , Tandem Mass Spectrometry , Young Adult
6.
Mol Genet Metab ; 93(3): 323-30, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18023225

ABSTRACT

BACKGROUND: Synonymous mutations within exons may cause aberrant splicing by disrupting exonic splicing enhancer (ESE) motifs in the vicinity of non consensus splice sites. Mutational analysis of PDHA1 revealed only one silent single nucleotide substitution in exon 5 in two unrelated boys and a girl (c.483C>T and c.498C>T variants, respectively). For both patients, pyruvate dehydrogenase complex activity was low and the immunoreactive E1alpha protein was defective in cultured fibroblasts. METHODS AND RESULTS: One of the boys was a somatic mosaic for the c.483C>T variant, as shown by the variable ratio of mutant to normal alleles in fibroblast, lymphocyte and single hair root DNA. Transcript analysis in fibroblasts from the three patients revealed the presence of both normal and truncated cDNAs, with the splicing out of exon 5 predicted to result in a frame shift and premature termination (p.Arg141AlafsX11). The treatment of fibroblasts with emetine before harvesting to prevent nonsense mRNA-mediated decay increased the amount of mutant mRNA. In silico analysis revealed that each variant disrupted a putative SRp55 binding site and that the intron 5 donor splice site (5'ss) contained a weak splicing signal. Transient transfection of COS-7 or Hela cells with hybrid minigene constructs containing wild-type or mutant PDHA1 exon 5, followed by RT-PCR demonstrated that each variant resulted in the incomplete inclusion of PDHA1 exon 5, and that this defect was corrected following the restoration of a perfect consensus sequence for the 5' splice site by site-directed mutagenesis. CONCLUSION: These two synonymous mutations expand the spectrum of rare PDHA1 splicing mutations, all of which are located in non canonical splice sites.


Subject(s)
Pyruvate Dehydrogenase (Lipoamide)/genetics , RNA Splicing , Animals , Binding Sites , Cell Line , Child , Child, Preschool , Enhancer Elements, Genetic , Exons , Female , Humans , Male , Mutation
8.
Mol Genet Metab ; 86(4): 462-5, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16263314

ABSTRACT

The activity of deoxyguanosine kinase (DGUOK), a mitochondrial enzyme involved in the anabolism of mitochondrial (mt) deoxyribonucleotides, governs the maintenance of the mtDNA. Deleterious mutations of the DGUOK gene are thus associated with mtDNA depletion and result in combined deficiencies of mtDNA-encoded respiratory chain enzymes. With the aim to estimate the prevalence of DGUOK mutations in a cohort of 30 patients with hepatocerebral disease and combined respiratory chain deficiencies, we studied the DGUOK gene and identified previously unreported mutations in five families. Two patients and their affected sibs, born to non-consanguineous parents, were homozygous for a missense mutation (M1T, and L250S, respectively). One patient presented a homozygous 4 pb insertion (796 insTGAT) and two other patients, and their affected sibs, were compound heterozygous (E165V/L266R and E211G/L266R, respectively). These findings allowed us to propose prenatal diagnosis in two families. In conclusion, we observed a high prevalence of DGUOK mutations (17%) in patients with hepatic involvement and combined respiratory chain deficiencies with hepatic involvement.


Subject(s)
Mitochondrial Diseases/enzymology , Mitochondrial Diseases/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics , Amino Acid Sequence , Base Sequence , DNA/genetics , DNA Mutational Analysis , DNA, Mitochondrial/metabolism , Female , Humans , Infant , Liver/physiopathology , Male , Mitochondrial Diseases/physiopathology , Molecular Sequence Data , Mutation , Sequence Homology, Amino Acid
9.
Arch Pediatr ; 12(2): 160-2, 2005 Feb.
Article in French | MEDLINE | ID: mdl-15694540

ABSTRACT

Congenital galactosaemia reveals usually in the second and third weeks of life with a severe liver dysfunction. We report on a case of congenital galactosaemia with, on the one hand, an early onset liver failure, without any free interval, and on the other hand, an hemophagocytic syndrome as a severe secondary outbreak with pulmonary haemorrhage. Appropriate diet led to normalisation of liver function. Hemophagocytosis, probably linked to an associated Klebsiella Pneumoniae sepsis, had a favourable outcome after antibiotic and corticosteroid therapy.


Subject(s)
Galactosemias/pathology , Hemorrhage/etiology , Liver Failure/etiology , Lung Diseases/etiology , Galactosemias/therapy , Humans , Infant, Newborn , Klebsiella Infections/complications , Klebsiella pneumoniae , Liver Failure/diet therapy , Male , Phagocytosis , Sepsis/complications , Treatment Outcome
10.
Mol Genet Metab ; 78(3): 186-92, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12649063

ABSTRACT

The patient was the first child of healthy consanguineous parents. She presented at birth with hypotonia, mild facial dysmorphism, periventricular cysts, marked metabolic acidosis, hyperlactacidemia with normal lactate/pyruvate molar ratios, normoglycemia, and normal ammonia. Hyperlactacidemia was severe (5-14 mmol/l) and not corrected with bicarbonate, thiamine (10 mg/d), 2-chloropropionate (100 mg/kg/d) and a ketogenic diet. Pyruvate dehydrogenase (PDHC) activity was normal in lymphocytes and fibroblasts. Functional assays were performed in digitonin-permeabilized fibroblasts to measure oxidation rates from radiolabeled pyruvate and malate. The production of [14C]acetylcarnitine or [14C]citric cycle intermediates derived from [2-14C]pyruvate as well as the release of 14CO(2) from [1-14C]pyruvate was severely impaired, whereas decarboxylation of [U-14C]malate was normal. With increasing concentrations of [1-14C]pyruvate, the patient's fibroblasts behave like control fibroblasts incubated in the presence of alpha-cyano-4-hydroxycinnamate, a specific inhibitor of mitochondrial pyruvate uptake: a progressive increase in 14CO(2) production was observed, likely due to passive diffusion of [1-14C]pyruvate through the mitochondrial membranes. Our results are consistent with a defect of mitochondrial pyruvate transport in the patient. Mutational analysis was precluded as the cDNA sequence of the pyruvate carrier has not been identified as yet in any organism. An affected fetus was recognized in a subsequent dichorionic twin pregnancy using the coupled assay measuring [2-14C]pyruvate oxidation rates on digitonin-permeabilized trophoblasts. After selective feticide, the pregnancy was uncomplicated with delivery at 37w of a healthy female, who is currently 2-month old.


Subject(s)
Diseases in Twins , Fetal Diseases/metabolism , Fetus/metabolism , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Prenatal Diagnosis , Pyruvic Acid/metabolism , Algeria , Biological Transport , Cell Membrane Permeability , Cells, Cultured , Consanguinity , Digitonin , Diseases in Twins/prevention & control , Female , Fetal Diseases/diagnosis , Fibroblasts/metabolism , Genetic Predisposition to Disease , Humans , Infant, Newborn , Lymphocytes/metabolism , Mitochondrial Diseases/diagnosis , Pregnancy , Pyruvate Dehydrogenase Complex/metabolism , Risk Assessment
11.
Mol Genet Metab ; 78(1): 68-73, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12559850

ABSTRACT

Carnitine-acylcarnitine translocase (CAC) deficiency is a rare autosomal recessive disorder of long-chain fatty acid oxidation with a severe outcome. We report mutation analysis in a cohort of 12 patients. Twelve mutations were identified of which 9 have not been reported so far (G28C, D32N, R178Q, P230R, D231H, 179delG, 802delG, 69-70insTGTGC, and 609-1g>a). Altogether, including our results, 22 mutations of the CAC gene have been published to date in 23 patients demonstrating the allelic heterogeneity of CAC deficiency. DNA-based prenatal diagnosis was performed for the first time in pregnancies at risk for CAC deficiency. Two fetuses were affected and one pregnancy was terminated by family decision. Two other fetuses had normal genotype and five others were heterozygotes. All the offspring of these seven pregnancies are alive and apparently healthy.


Subject(s)
Carnitine Acyltransferases/genetics , DNA/genetics , Prenatal Diagnosis/methods , Amniotic Fluid/cytology , Carnitine Acyltransferases/deficiency , Carnitine Acyltransferases/metabolism , Cell Line , DNA/chemistry , DNA Mutational Analysis , Fatty Acids/metabolism , Female , Humans , Mutation , Oxidation-Reduction
12.
J Inherit Metab Dis ; 25(5): 379-84, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12408187

ABSTRACT

A North African boy, the son of consanguineous parents, presented at 8 years of age with hypophosphataemic rickets due to De Toni-Debré-Fanconi syndrome. Hepatomegaly and abnormalities of carbohydrate metabolism were suggestive of Fanconi-Bickel syndrome. This was confirmed by the detection of a mutation within GLUT2, the gene encoding the liver-type facilitative glucose transporter. The study of the respiratory chain revealed a deficiency of complexes I, III and IV in muscle. Mechanisms responsible for an impairment ofmitochondrial function, which we interpret as a secondary phenomenon, are discussed.


Subject(s)
Electron Transport/genetics , Fanconi Syndrome/genetics , Monosaccharide Transport Proteins/genetics , Biopsy , Child , Cytochrome-c Oxidase Deficiency/diagnosis , Cytochrome-c Oxidase Deficiency/genetics , Electron Transport Complex III/deficiency , Fanconi Syndrome/diagnosis , Fanconi Syndrome/metabolism , Glucose Transporter Type 2 , Humans , Liver/enzymology , Male , Mitochondria, Muscle/genetics , Muscles/enzymology , NAD(P)H Dehydrogenase (Quinone)/deficiency
13.
Acta Paediatr ; 91(6): 719-22, 2002.
Article in English | MEDLINE | ID: mdl-12162610

ABSTRACT

UNLABELLED: A cholestatic 6-mo-old girl was admitted to our department because she recently presented with hypotonia and lethargy, apparently due to moderate and transient hypoglycaemia. Her urine contained 3-hydroxy-dicarboxylic acids of 12 to 14 carbons in length and her plasma acylcarnitine profile was consistent with long-chain 3-hydroxyacylCoA dehydrogenase deficiency. This diagnosis was confirmed by enzyme studies. This deficiency was due to a G1528C mutation on the paternal allele (mutation on the maternal allele as yet not identified). The patient improved dramatically with medium-chain triglyceride supplementation. CONCLUSION: Early cholestasis and hepatic fibrosis must lead to search for long-chain 3-hydroxyacylCoA dehydrogenase deficiency, particularly when hypoketotic hypoglycaemia is present.


Subject(s)
Cholestasis/etiology , Fatty Acid Desaturases/deficiency , Fatty Acid Desaturases/metabolism , Lipid Metabolism, Inborn Errors/complications , Lipid Metabolism, Inborn Errors/diagnosis , Liver Cirrhosis/etiology , Acyl-CoA Dehydrogenase, Long-Chain , Biopsy, Needle , Cholestasis/pathology , Female , Follow-Up Studies , Humans , Infant , Lipid Metabolism, Inborn Errors/diet therapy , Liver Cirrhosis/pathology , Risk Assessment , Severity of Illness Index
14.
Arch Pediatr ; 9(6): 581-6, 2002 Jun.
Article in French | MEDLINE | ID: mdl-12108311

ABSTRACT

UNLABELLED: Idiopathic Reye syndrome is a rare disease revealed by unexplained encephalopathy and microvesicular liver steatosis. Some clinical and epidemiological studies mainly performed in English speaking countries questioned the reality of Reye syndrome because numerous know inherited metabolic diseases, and some of them unrecognized, could mimick this disorder. We focused in our study on severe forms of Reye syndrome admitted to a pediatric intensive care unit. METHODS: Retrospective study over the last eleven years (1991-2001) included all the pediatric patients admitted to our tertiary referral center with the classical American Reye syndrome criteria (e.g. CDC). Extensive metabolic screening was performed in all cases, except for the ultimately dead patients. RESULT: Fourteen patients (mean age 52 months) were included. Fever always occurred before their admission and aspirin (n = 12) or acetaminophen (n = 7) was prescribed. Median Glasgow scale was 7 on admission. Mean amoniac plasma level was 320 mumol/L and alanine-aminotransferase peak plasma level 1475 +/- 1387 IU/L. Mechanical ventilation was started in ten children and six of them underwent continuous venovenous hemofiltration. Three patients ultimately died and 11 survived with a mean five years follow-up without relapses or neurological impairment. Any of them demonstrated inherited metabolic disease except for one infant with hereditary fructose intolerance. CONCLUSION: Unlike widespread opinion, severe Reye syndrome without identified metabolic disorders seems to not disappear in our country. Reye syndrome remains a potentially life threatening disease and raises for aggressive treatment of brain edema. If aspirin and Reye syndrome association are not formally documented in France, cautiousness must be kept in mind and all the aspirin adverse effects notifications should be addressed to the public drugs survey network.


Subject(s)
Acetaminophen/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Aspirin/adverse effects , Brain Edema/etiology , Reye Syndrome/pathology , Acetaminophen/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Aspirin/therapeutic use , Child , Child, Preschool , Fatal Outcome , Female , Fever/drug therapy , Humans , Infant , Infant, Newborn , Male , Patient Admission , Prognosis , Recurrence , Reye Syndrome/etiology , Risk Factors , Severity of Illness Index
15.
J Inherit Metab Dis ; 24(4): 507-8, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11596654

ABSTRACT

Bromocriptine combined with galactose restriction in the matenal diet seems to be partially effective in decreasing endogenous lactose and galactose synthesis, monitored in a pregnant woman heterozygous for galactosaemia at risk of producing a homozygous infant.


Subject(s)
Bromocriptine/therapeutic use , Galactose/biosynthesis , Galactosemias/genetics , Heterozygote , Lactose/biosynthesis , Pregnancy Complications , Diet , Female , Galactose/administration & dosage , Galactosemias/drug therapy , Humans , Pregnancy
16.
Mol Genet Metab ; 73(1): 64-70, 2001 May.
Article in English | MEDLINE | ID: mdl-11350184

ABSTRACT

The neonatal phenotype of carnitine-acylcarnitine translocase (CACT) deficiency is one of the most severe and usually lethal mitochondrial fat oxidation disorders characterized by hypoketotic hypoglycemia, hyperammonemia, cardiac abnormalities, and early death. In this study, the proband was the daughter of consanguineous Hispanic parents. At 36 h of life, she had bradycardia and died at 4 days of age without a specific diagnosis. In a subsequent pregnancy, prenatal counseling and amniocentesis were provided. Incubation of the amniocytes from this pregnancy and fibroblasts (from the dead proband) with [16-(2)H(3)]palmitic acid and analysis by tandem mass spectrometry revealed an increasedconcentration of [16-(2)H(3)]palmitoylcarnitine, suggesting the diagnoses of either CACT or carnitine palmitoyltransferase II (CPT-II) deficiency. CACT enzyme activity was absent in both cell lines. Molecular investigation of cDNA from the dead proband and her affected sibling revealed aberrant CACT cDNA species, including exon 3 skipping, both exon 3 and 4 skipping, and a 13-bp insertion at cDNA position 388. Investigation of these cell lines for mutations affecting CACT RNA processing by analysis of CACT gene sequences, including intron and exon boundaries, revealed a single nucleotide G deletion at the donor site in intron 3 which resulted in exon skipping and a 13-bp insertion. The proband and her affected sibling were homozygous for this deletion.


Subject(s)
Carnitine Acyltransferases/deficiency , Carnitine Acyltransferases/genetics , Base Sequence , Carnitine Acyltransferases/metabolism , DNA/chemistry , DNA/genetics , DNA/metabolism , DNA Mutational Analysis , DNA Restriction Enzymes/metabolism , Exons/genetics , Family Health , Fatal Outcome , Humans , Infant, Newborn , Male , Mitochondria/metabolism , Mutation , Oxidation-Reduction , Phenotype , Polymerase Chain Reaction , Prenatal Diagnosis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sequence Deletion
18.
Neuromuscul Disord ; 10(3): 200-5, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10734268

ABSTRACT

Carnitine palmitoyl transferase II deficiency, an inherited disorder of long-chain fatty acid oxidation, may result in either a mild form (muscle disease in adults) or a severe form (hepatocardiomuscular syndrome in infants). The difference in severity between these two forms is related to a difference in levels of residual carnitine palmitoyl transferase II activity and long-chain fatty acid oxidation and in genotypes. Few data are, however, available regarding compound heterozygotes for a 'mild' and a 'severe' carnitine palmitoyl transferase II mutation. We report on such a patient carrying both the 'mild' S113L substitution and the 'severe' Y628S mutation. The patient's clinical picture (cardiac arrest at 6 years) was markedly more serious than usually observed in S113L homozygotes, and suggested that 'mild'/'severe' compound heterozygosity makes patients at risk from life-threatening events. Palmitate oxidation and carnitine palmitoyl transferase II activity were lower in lymphocytes from the S113L/Y628S patient than in those from a S113L homozygote. Thus, assessment of carnitine palmitoyl transferase II mutations, long-chain fatty acid oxidation, and carnitine palmitoyl transferase II activity, may help in predicting the potential severity of the muscular form of carnitine palmitoyl transferase II deficiency.


Subject(s)
Carnitine O-Palmitoyltransferase/deficiency , Carnitine O-Palmitoyltransferase/genetics , Genotype , Mitochondrial Myopathies/genetics , Phenotype , Child , Female , Humans , Polymerase Chain Reaction
20.
Eur J Pediatr ; 159(1-2): 82-5, 2000.
Article in English | MEDLINE | ID: mdl-10653336

ABSTRACT

UNLABELLED: A patient with a severe phenotype of carnitine-acylcarnitine translocase deficiency (CATR)(McKusick 212138) is reported. Prior to birth, a defect in beta-oxidation was suspected because of neonatal death of six siblings. Dietary treatment during neonatal adaptation and the subsequent six months of life and a trial of carnitine supplementation are reported. The rapidity with which long chain fatty acid metabolites can accumulate and induce secondary carnitine deficiency within a few hours after birth in an infant with CATR is noteworthy. CONCLUSION: High rates of glucose suppressed neonatal lipolysis in this infant, but did not seem sufficient to avoid secondary carnitine deficiency as in severe forms of CATR. Therefore simultaneous use of insulin and glucose may be necessary to control neonatal lipolysis. Carnitine supplementation and the possible adverse effects of MCT systematically administrated, should be further assessed in patients with CATR.


Subject(s)
Carnitine Acyltransferases/deficiency , Lipid Metabolism, Inborn Errors/genetics , Sudden Infant Death/genetics , Carnitine/therapeutic use , Dietary Supplements , Fatal Outcome , Female , Humans , Infant, Newborn , Lipolysis , Phenotype
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