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1.
Mol Genet Metab ; 92(1-2): 109-14, 2007.
Article in English | MEDLINE | ID: mdl-17689999

ABSTRACT

A newborn female presented on the first day of life with clinical and biochemical findings consistent with multiple acyl-CoA dehydrogenase deficiency (MADD). Riboflavin supplementation corrected the biochemical abnormalities 24 h after commencing the vitamin. In vitro acylcarnitine profiling in intact fibroblasts both in normal and riboflavin depleted media showed normal oxidation of fatty acids excluding defects in electron transfer flavoprotein (ETF), or ETF ubiquinone oxidoreductase (ETF:QO), or a genetic abnormality in flavin metabolism. In addition, sequencing of the genes encoding ETF and ETF:QO in the proband did not reveal any pathogenic mutations. Determination of the maternal riboflavin status after delivery showed that the mother was riboflavin deficient. Repeat testing done two years after the infant's birth and while on a normal diet showed that the mother was persistently riboflavin deficient and showed a typical MADD profile on plasma acylcarnitine testing. A possible genetic defect in riboflavin transport of metabolism in the mother is postulated to be the cause of the transient MADD seen in the infant. Sequencing of the SLC16A12, RFK and FLAD1 genes encoding key enzymes in riboflavin transport of metabolism in the mother did not identify any pathogenic mutations. The underlying molecular basis of the mother's defect in riboflavin metabolism remains to be established.


Subject(s)
Acyl-CoA Dehydrogenase/deficiency , Lipid Metabolism, Inborn Errors/diagnosis , Riboflavin Deficiency/genetics , Carnitine/analogs & derivatives , Carnitine/blood , Electron-Transferring Flavoproteins/genetics , Female , Fibroblasts/cytology , Fibroblasts/enzymology , Fibroblasts/pathology , Humans , Infant, Newborn , Lipid Metabolism, Inborn Errors/genetics , Malnutrition , Monocarboxylic Acid Transporters/genetics , Monocarboxylic Acid Transporters/metabolism , Mothers , Oxidation-Reduction , Riboflavin Deficiency/metabolism , Riboflavin Deficiency/pathology , Skin/enzymology , Skin/pathology , Symporters , Vitamins/administration & dosage
2.
J Inherit Metab Dis ; 28(4): 533-44, 2005.
Article in English | MEDLINE | ID: mdl-15902556

ABSTRACT

General mitochondrial trifunctional protein (TFP) deficiency leads to a wide clinical spectrum of disease ranging from severe neonatal/infantile cardiomyopathy and early death to mild chronic progressive sensorimotor poly-neuropathy with episodic rhabdomyolysis. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency resulting from the common Glu510Gln mutation usually gives rise to a moderately severe phenotype with multiorgan involvement with high morbidity and mortality. However, isolated LCHAD deficiency can also be consistent with long-term survival in patients identified and treated from an early age. We present biochemical, clinical and mutation data in 9 patients spanning the full spectrum of disease. Fibroblast acylcarnitine profiling shows good correlation with clinical phenotype using the ratio C18(OH)/(C14(OH)+C12(OH)). This ratio shows a gradation of values, from high in four patients with severe neonatal disease (2.5+/-0.8), to low in two neuromyopathic patients (0.35, 0.2). Fibroblast fatty acid oxidation flux assays also show correlation with the patient phenotype, when expressed either as percentage residual activity with palmitate or as a ratio of percentage activity of myristate/oleate (M/O ratio). Fibroblasts from four patients with severe neonatal disease gave an M/O ratio of 4.0+/-0.6 compared to 1.97 and 1.62 in two neuromyopathic patients. Specific enzyme assay of LCHAD and long-chain 3-ketothiolase activity in patient cells shows lack of correlation with phenotype. These results show that measurements in intact cells, which allow all determinative and modifying cellular factors to be present, better reflect patient phenotype. Mutation analysis reveals a number of alpha- and beta-subunit mutations. Peripheral sensorimotor polyneuropathy, often as the initial major presenting feature but usually later accompanied by episodic rhabdomyolysis, is a manifestation of mild TFP protein deficiency. The mild clinical presentation and relative difficulty in diagnosis suggest that this form of TFP is probably underdiagnosed.


Subject(s)
Acyl-CoA Dehydrogenase, Long-Chain/deficiency , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/genetics , Mitochondria/pathology , Multienzyme Complexes/deficiency , Cardiomyopathies/diagnosis , Cardiomyopathies/genetics , Carnitine/analogs & derivatives , Carnitine/metabolism , Exons , Fatty Acids/metabolism , Fibroblasts/metabolism , Homozygote , Humans , Male , Mitochondrial Trifunctional Protein , Mutation , Phenotype , Polyneuropathies/diagnosis , Polyneuropathies/genetics , Prognosis , Rhabdomyolysis/diagnosis , Rhabdomyolysis/genetics
3.
J Inherit Metab Dis ; 27(5): 671-8, 2004.
Article in English | MEDLINE | ID: mdl-15669683

ABSTRACT

We report a patient with lipid-storage myopathy due to multiple acyl-CoA dehydrogenation deficiency (MADD). Molecular genetic analysis showed that she was compound heterozygous for mutations in the gene for electron transfer flavoprotein:ubiquinone oxidoreductase (ETFQO). Despite a good initial response to treatment, she developed respiratory insufficiency at age 14 years and has required long-term overnight ventilation. Thus, MADD is one of the few conditions that can cause a myopathy with weakness of the respiratory muscles out of proportion to the limb muscles.


Subject(s)
Acyl-CoA Dehydrogenases/genetics , Electron-Transferring Flavoproteins/genetics , Iron-Sulfur Proteins/genetics , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism , Muscular Diseases/genetics , Mutation , Oxidoreductases Acting on CH-NH Group Donors/genetics , Acyl-CoA Dehydrogenases/deficiency , Adolescent , Age of Onset , Base Sequence , Blotting, Western , DNA Mutational Analysis , DNA, Complementary/metabolism , Electron Transport Complex I/deficiency , Electron Transport Complex I/genetics , Electron-Transferring Flavoproteins/metabolism , Female , Fibroblasts/metabolism , Heterozygote , Humans , Models, Genetic , Molecular Sequence Data , Muscular Diseases/diagnosis , Phenotype , Respiration, Artificial
4.
Mol Genet Metab ; 78(4): 247-9, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12706375

ABSTRACT

Multiple acyl-CoA-dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) are a group of metabolic disorders due to deficiency of either electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO). We report the clinical features and biochemical and molecular genetic analyses of a patient with a mild late-onset form of GAII due to beta-ETF deficiency. Biochemical data showed an abnormal urine organic acid profile, low levels of free carnitine, increased levels of C(10:1n-6), and C(14:1n-9) in plasma, and decreased oxidation of [9,10-3H]palmitate and [9,10-3H]myristate in fibroblasts, suggesting MAD deficiency. In agreement with these findings, mutational analysis of the ETF/ETFDH genes demonstrated an ETFB missense mutation 124T>C in exon 2 leading to replacement of cysteine-42 with arginine (C42R), and a 604_606AAG deletion in exon 6 in the ETFB gene resulting in the deletion of lysine-202 (K202del). The present report delineates further the phenotype of mild beta-ETF deficiency and illustrates that the differential diagnosis of GAII is readily achieved by mutational analysis.


Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/genetics , Electron-Transferring Flavoproteins/deficiency , Electron-Transferring Flavoproteins/genetics , Electrons , Iron-Sulfur Proteins/deficiency , Iron-Sulfur Proteins/genetics , Oxidoreductases Acting on CH-NH Group Donors/deficiency , Oxidoreductases Acting on CH-NH Group Donors/genetics , Arginine/chemistry , Carnitine/blood , Cysteine/chemistry , DNA Mutational Analysis , Exons , Female , Fibroblasts/metabolism , Gas Chromatography-Mass Spectrometry , Gene Deletion , Glutarates/urine , Humans , Infant, Newborn , Lysine/chemistry , Mutation, Missense , Oxygen/metabolism , Phenotype
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