The Experts below are selected from a list of 15735 Experts worldwide ranked by ideXlab platform
Jerry Vockley - One of the best experts on this subject based on the ideXlab platform.
-
different spectrum of mutations of isovaleryl coa Dehydrogenase ivd gene in korean patients with isovaleric acidemia
Molecular Genetics and Metabolism, 2007Co-Authors: Yong-wha Lee, Jerry Vockley, Dong Hwan Lee, Nam-doo Kim, You Kyoung LeeAbstract:Isovaleric acidemia (IVA) is an autosomal recessive inborn error of the leucine metabolism that is caused by a deficiency of Isovaleryl-CoA Dehydrogenase (IVD). Recent application of tandem mass spectrometry to newborn screening has allowed a significant expansion of the recognition of individuals with IVD deficiency. Although many patients have been reported worldwide, there are no genetically confirmed patients in Korea. This study characterizes IVD mutations in seven Korean IVA patients from six unrelated families. Bi-directional sequencing analysis identified two novel variations affecting consensus splice sites (c.144+1G>T in intron 1 and c.457-3_2CA>GG in intron 4) and three novel variations altering coding sequences (c.149G>T; Arg21Leu, c.832A>G; Ser249Gly, and c.1135T>G; Phe350Val). Five patients from four families were found to be compound heterozygotes while two unrelated patients were homozygous for the c.457-3_2CA>GG variation. Reverse-transcription polymerase chain reaction confirmed that both intron variations cause aberrant splicing. Furthermore, analysis of cultured lymphocyte extracts of the seven patients showed no detectable enzyme activity and reduced levels of IVD protein (<10.0% of control) in all samples. These results confirm IVD mutations in Korean patients with IVA and reveal that the mutation spectrum is different from previously reported patients.
-
isovaleric acidemia new aspects of genetic and phenotypic heterogeneity
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2006Co-Authors: Jerry Vockley, Regina EnsenauerAbstract:Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme Isovaleryl-CoA Dehydrogenase (IVD) resulting in the accumulation of derivatives of Isovaleryl-CoA. It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra- and interfamilial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of Isovaleryl-CoA to 3methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years. 2006 Wiley-Liss, Inc.
-
Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2006Co-Authors: Jerry Vockley, Regina EnsenauerAbstract:Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme Isovaleryl-CoA Dehydrogenase (IVD) resulting in the accumulation of derivatives of Isovaleryl-CoA. It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra- and interfamilial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of Isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years.
-
Exon Skipping in IVD RNA Processing in Isovaleric Acidemia Caused by Point Mutations in the Coding Region of the IVD Gene
American Journal of Human Genetics, 2000Co-Authors: Jerry Vockley, Bambi D. Anderson, Peter K. Rogan, Jan Willard, Ratnam S. Seelan, David I. SmithAbstract:Summary Isovaleric acidemia (IVA) is a recessive disorder caused by a deficiency of Isovaleryl-CoA Dehydrogenase (IVD). We have reported elsewhere nine point mutations in the IVD gene in fibroblasts of patients with IVA, which lead to abnormalities in IVD protein processing and activity. In this report, we describe eight IVD gene mutations identified in seven IVA patients that result in abnormal splicing of IVD RNA. Four mutations in the coding region lead to aberrantly spliced mRNA species in patient fibroblasts. Three of these are amino acid altering point mutations, whereas one is a single-base insertion that leads to a shift in the reading frame of the mRNA. Two of the coding mutations strengthen pre-existing cryptic splice acceptors adjacent to the natural splice junctions and apparently interfere with exon recognition, resulting in exon skipping. This mechanism for missplicing has not been reported elsewhere. Four other mutations alter either the conserved gt or ag dinucleotide splice sites in the IVD gene. Exon skipping and cryptic splicing were confirmed by transfection of these mutations into a Cos-7 cell line model splicing system. Several of the mutations were predicted by individual information analysis to inactivate or significantly weaken adjacent donor or acceptor sites. The high frequency of splicing mutations identified in these patients is unusual, as is the finding of missplicing associated with missense mutations in exons. These results may lead to a better understanding of the phenotypic complexity of IVA, as well as provide insight into those factors important in defining intron/exon boundaries in vivo.
-
characterization of molecular defects in isovaleryl coa Dehydrogenase in patients with isovaleric acidemia
Biochemistry, 1998Co-Authors: Alwalid Mohsen, Samuel L Volchenboum, Kevin P Battaile, Karen Tiffany, David D Roberts, Jungja P Kim, Bambi D. Anderson, Jerry VockleyAbstract:Isovaleryl-CoA Dehydrogenase (IVD) is a homotetrameric mitochondrial flavoenzyme which catalyzes the conversion of Isovaleryl-CoA to 3-methylcrotonyl-CoA. PCR of IVD genomic and complementary DNA was used to identify mutations occurring in patients with deficiencies in IVD activity. Western blotting, in vitro mitochondrial import, prokaryotic expression, and kinetic studies of IVD mutants were conducted to characterize the molecular defects caused by the amino acid replacements. Mutations leading to Arg21Pro, Asp40Asn, Ala282Val, Cys328Arg, Val342Ala, Arg363Cys, and Arg382Leu replacements were identified. Western blotting of fibroblast extracts and/or in vitro mitochondrial import experiments indicate that the seven precursor IVD mutant peptides, and a previously identified IVD Leu13Pro mutant, are synthesized and imported into mitochondria. While the IVD Leu13Pro, Arg21Pro, and Cys328Arg mutant peptides are rapidly degraded following mitochondrial import, the other mutant peptides exhibit greater mitocho...
Arie B Vaandrager - One of the best experts on this subject based on the ideXlab platform.
-
equine biochemical multiple acyl coa Dehydrogenase deficiency madd as a cause of rhabdomyolysis
Molecular Genetics and Metabolism, 2007Co-Authors: C M Westermann, J. P. Koeman, M G M De Sainvan Der Velden, J H Van Der Kolk, Ruud Berger, I D Wijnberg, R J A Wanders, Johannes A Lenstra, N Testerink, Arie B VaandragerAbstract:Two horses (a 7-year-old Groninger warmblood gelding and a six-month-old Trakehner mare) with pathologically confirmed rhabdomyolysis were diagnosed as suffering from multiple acyl-CoA Dehydrogenase deficiency (MADD). This disorder has not been recognised in animals before. Clinical signs of both horses were a stiff, insecure gait, myoglobinuria, and finally recumbency. Urine, plasma, and muscle tissues were investigated. Analysis of plasma showed hyperglycemia, lactic acidemia, increased activity of muscle enzymes (ASAT, LDH, CK), and impaired kidney function (increased urea and creatinine). The most remarkable findings of organic acids in urine of both horses were increased lactic acid, ethylmalonic acid (EMA), 2-methylsuccinic acid, butyrylglycine (iso)valerylglycine, and hexanoylglycine. EMA was also increased in plasma of both animals. Furthermore, the profile of acylcarnitines in plasma from both animals showed a substantial elevation of C4-, C5-, C6-, C8-, and C5-DC-carnitine. Concentrations of acylcarnitines in urine of both animals revealed increased excretions of C2-, C3-, C4-, C5-, C6-, C5-OH-, C8-, C10:1-, C10-, and C5-DC-carnitine. In addition, concentrations of free carnitine were also increased. Quantitative biochemical measurement of enzyme activities in muscle tissue showed deficiencies of short-chain acyl-CoA Dehydrogenase (SCAD), medium-chain acyl-CoA Dehydrogenase (MCAD), and Isovaleryl-CoA Dehydrogenase (IVD) also indicating MADD. Histology revealed extensive rhabdomyolysis with microvesicular lipidosis predominantly in type 1 muscle fibers and mitochondrial damage. However, the ETF and ETF-QO activities were within normal limits indicating the metabolic disorder to be acquired rather than inherited. To our knowledge, these are the first cases of biochemical MADD reported in equine medicine.
R J A Wanders - One of the best experts on this subject based on the ideXlab platform.
-
Clinical variability of isovaleric acidemia in a genetically homogeneous population
Journal of inherited metabolic disease, 2012Co-Authors: Marinus Duran, L J Mienie, C J Reinecke, Lodewijk Ijlst, Jos P.n. Ruiter, Hans R. Waterham, R J A WandersAbstract:Isovaleric acidemia (IVA) is one of the most common organic acidemias found in South Africa. Since 1983, a significant number of IVA cases have been identified in approximately 20,000 Caucasian patients screened for metabolic defects. IVA is caused by an autosomal recessive deficiency of Isovaleryl-CoA Dehydrogenase (IVD) resulting in the accumulation of Isovaleryl-CoA and its metabolites. In total, 10 IVA patients and three carriers were available for phenotypic and genotypic investigation in this study. All patients were found to be homozygous for a single c.367 G > A (p.G123R) mutation. The amino acid substitution of a glycine to arginine resulted in a markedly reduced steady-state level of the IVD protein, which explains the nearly complete lack of IVD enzyme activity as assessed in fibroblast homogenates. Despite the genetic homogeneity of this South African IVA group, the clinical presentation varied widely, ranging from severe mental handicap and multiple episodes of metabolic derangement to an asymptomatic state. The variation may be due to poor dietary intervention, delayed diagnosis or even epigenetic and polygenetic factors of unknown origin.
-
equine biochemical multiple acyl coa Dehydrogenase deficiency madd as a cause of rhabdomyolysis
Molecular Genetics and Metabolism, 2007Co-Authors: C M Westermann, J. P. Koeman, M G M De Sainvan Der Velden, J H Van Der Kolk, Ruud Berger, I D Wijnberg, R J A Wanders, Johannes A Lenstra, N Testerink, Arie B VaandragerAbstract:Two horses (a 7-year-old Groninger warmblood gelding and a six-month-old Trakehner mare) with pathologically confirmed rhabdomyolysis were diagnosed as suffering from multiple acyl-CoA Dehydrogenase deficiency (MADD). This disorder has not been recognised in animals before. Clinical signs of both horses were a stiff, insecure gait, myoglobinuria, and finally recumbency. Urine, plasma, and muscle tissues were investigated. Analysis of plasma showed hyperglycemia, lactic acidemia, increased activity of muscle enzymes (ASAT, LDH, CK), and impaired kidney function (increased urea and creatinine). The most remarkable findings of organic acids in urine of both horses were increased lactic acid, ethylmalonic acid (EMA), 2-methylsuccinic acid, butyrylglycine (iso)valerylglycine, and hexanoylglycine. EMA was also increased in plasma of both animals. Furthermore, the profile of acylcarnitines in plasma from both animals showed a substantial elevation of C4-, C5-, C6-, C8-, and C5-DC-carnitine. Concentrations of acylcarnitines in urine of both animals revealed increased excretions of C2-, C3-, C4-, C5-, C6-, C5-OH-, C8-, C10:1-, C10-, and C5-DC-carnitine. In addition, concentrations of free carnitine were also increased. Quantitative biochemical measurement of enzyme activities in muscle tissue showed deficiencies of short-chain acyl-CoA Dehydrogenase (SCAD), medium-chain acyl-CoA Dehydrogenase (MCAD), and Isovaleryl-CoA Dehydrogenase (IVD) also indicating MADD. Histology revealed extensive rhabdomyolysis with microvesicular lipidosis predominantly in type 1 muscle fibers and mitochondrial damage. However, the ETF and ETF-QO activities were within normal limits indicating the metabolic disorder to be acquired rather than inherited. To our knowledge, these are the first cases of biochemical MADD reported in equine medicine.
C M Westermann - One of the best experts on this subject based on the ideXlab platform.
-
equine biochemical multiple acyl coa Dehydrogenase deficiency madd as a cause of rhabdomyolysis
Molecular Genetics and Metabolism, 2007Co-Authors: C M Westermann, J. P. Koeman, M G M De Sainvan Der Velden, J H Van Der Kolk, Ruud Berger, I D Wijnberg, R J A Wanders, Johannes A Lenstra, N Testerink, Arie B VaandragerAbstract:Two horses (a 7-year-old Groninger warmblood gelding and a six-month-old Trakehner mare) with pathologically confirmed rhabdomyolysis were diagnosed as suffering from multiple acyl-CoA Dehydrogenase deficiency (MADD). This disorder has not been recognised in animals before. Clinical signs of both horses were a stiff, insecure gait, myoglobinuria, and finally recumbency. Urine, plasma, and muscle tissues were investigated. Analysis of plasma showed hyperglycemia, lactic acidemia, increased activity of muscle enzymes (ASAT, LDH, CK), and impaired kidney function (increased urea and creatinine). The most remarkable findings of organic acids in urine of both horses were increased lactic acid, ethylmalonic acid (EMA), 2-methylsuccinic acid, butyrylglycine (iso)valerylglycine, and hexanoylglycine. EMA was also increased in plasma of both animals. Furthermore, the profile of acylcarnitines in plasma from both animals showed a substantial elevation of C4-, C5-, C6-, C8-, and C5-DC-carnitine. Concentrations of acylcarnitines in urine of both animals revealed increased excretions of C2-, C3-, C4-, C5-, C6-, C5-OH-, C8-, C10:1-, C10-, and C5-DC-carnitine. In addition, concentrations of free carnitine were also increased. Quantitative biochemical measurement of enzyme activities in muscle tissue showed deficiencies of short-chain acyl-CoA Dehydrogenase (SCAD), medium-chain acyl-CoA Dehydrogenase (MCAD), and Isovaleryl-CoA Dehydrogenase (IVD) also indicating MADD. Histology revealed extensive rhabdomyolysis with microvesicular lipidosis predominantly in type 1 muscle fibers and mitochondrial damage. However, the ETF and ETF-QO activities were within normal limits indicating the metabolic disorder to be acquired rather than inherited. To our knowledge, these are the first cases of biochemical MADD reported in equine medicine.
Westermann C. M. - One of the best experts on this subject based on the ideXlab platform.
-
Acquired multiple Acyl-CoA Dehydrogenase deficiency in 10 horses with atypical myopathy
2008Co-Authors: Westermann C. M., De Sain-van Der Velden M. G. M., Berger R., Wijnberg I. D., Wanders R. J. A., Testerink N., Dorland L., Spliet W. G. M., Votion D. M., Ruiter J. P. N.Abstract:The aim of the current study was to assess lipid metabolism in horses with atypical myopathy. Urine samples from 10 cases were subjected to analysis of organic acids, glycine conjugates, and acylcarnitines revealing increased mean excretion of lactic acid, ethylmalonic acid, 2-methylsuccinic acid, butyrylglycine, (iso)valerylglycine, hexanoylglycine, free carnitine, C2-, C3-, C4-, C5-, C6-, C8-, C8:1-, C10:1-, and C10:2-carnitine as compared with 15 control horses (12 healthy and three with acute myopathy due to other causes). Analysis of plasma revealed similar results for these predominantly short-chain acylcarnitines. Furthermore, measurement of Dehydrogenase activities in lateral vastus muscle from one horse with atypical myopathy indeed showed deficiencies of short-chain acyl-CoA Dehydrogenase (0.66 as compared with 2.27 and 2.48 in two controls), medium-chain acyl-CoA Dehydrogenase (0.36 as compared with 4.31 and 4.82 in two controls) and Isovaleryl-CoA Dehydrogenase (0.74 as compared with 1.43 and 1.61 nmol min(-1) mg(-1) in two controls). A deficiency of several mitochondrial Dehydrogenases that utilize flavin adenine dinucleotide as cofactor including the acyl-CoA Dehydrogenases of fatty acid beta-oxidation, and enzymes that degrade the CoA-esters of glutaric acid, isovaleric acid, 2-methylbutyric acid, isobutyric acid, and sarcosine was suspected in 10 out of 10 cases as the possible etiology for a highly fatal and prevalent toxic equine muscle disease similar to the combined metabolic derangements seen in human multiple acyl-CoA Dehydrogenase deficiency also known as glutaric acidemia type I
-
Acquired multiple Acyl-CoA Dehydrogenase deficiency in 10 horses with atypical myopathy.
2008Co-Authors: Westermann C. M., De Sain-van Der Velden M. G. M., Berger R., Wijnberg I. D., Wanders R. J. A., Testerink N., Dorland L., Votion Dominique, Spliet W. G. M., Ruiter J. P. N.Abstract:The aim of the current study was to assess lipid metabolism in horses with atypical myopathy. Urine samples from 10 cases were subjected to analysis of organic acids, glycine conjugates, and acylcarnitines revealing increased mean excretion of lactic acid, ethylmalonic acid, 2-methylsuccinic acid, butyrylglycine, (iso)valerylglycine, hexanoylglycine, free carnitine, C2-, C3-, C4-, C5-, C6-, C8-, C8:1-, C10:1-, and C10:2-carnitine as compared with 15 control horses (12 healthy and three with acute myopathy due to other causes). Analysis of plasma revealed similar results for these predominantly short-chain acylcarnitines. Furthermore, measurement of Dehydrogenase activities in lateral vastus muscle from one horse with atypical myopathy indeed showed deficiencies of short-chain acyl-CoA Dehydrogenase (0.66 as compared with 2.27 and 2.48 in two controls), medium-chain acyl-CoA Dehydrogenase (0.36 as compared with 4.31 and 4.82 in two controls) and Isovaleryl-CoA Dehydrogenase (0.74 as compared with 1.43 and 1.61 nmol min(-1) mg(-1) in two controls). A deficiency of several mitochondrial Dehydrogenases that utilize flavin adenine dinucleotide as cofactor including the acyl-CoA Dehydrogenases of fatty acid beta-oxidation, and enzymes that degrade the CoA-esters of glutaric acid, isovaleric acid, 2-methylbutyric acid, isobutyric acid, and sarcosine was suspected in 10 out of 10 cases as the possible etiology for a highly fatal and prevalent toxic equine muscle disease similar to the combined metabolic derangements seen in human multiple acyl-CoA Dehydrogenase deficiency also known as glutaric acidemia type II.Peer reviewe
-
Acquired multiple Acyl-CoA Dehydrogenase deficiency in 10 horses with atypical myopathy.
'Elsevier BV', 2008Co-Authors: Westermann C. M., De Sain-van Der Velden M. G. M., Berger R., Wijnberg I. D., Wanders R. J. A., Testerink N., Dorland L., Votion Dominique, Spliet W. G. M., Ruiter J. P. N.Abstract:peer reviewedaudience: researcherThe aim of the current study was to assess lipid metabolism in horses with atypical myopathy. Urine samples from 10 cases were subjected to analysis of organic acids, glycine conjugates, and acylcarnitines revealing increased mean excretion of lactic acid, ethylmalonic acid, 2-methylsuccinic acid, butyrylglycine, (iso)valerylglycine, hexanoylglycine, free carnitine, C2-, C3-, C4-, C5-, C6-, C8-, C8:1-, C10:1-, and C10:2-carnitine as compared with 15 control horses (12 healthy and three with acute myopathy due to other causes). Analysis of plasma revealed similar results for these predominantly short-chain acylcarnitines. Furthermore, measurement of Dehydrogenase activities in lateral vastus muscle from one horse with atypical myopathy indeed showed deficiencies of short-chain acyl-CoA Dehydrogenase (0.66 as compared with 2.27 and 2.48 in two controls), medium-chain acyl-CoA Dehydrogenase (0.36 as compared with 4.31 and 4.82 in two controls) and Isovaleryl-CoA Dehydrogenase (0.74 as compared with 1.43 and 1.61 nmol min(-1) mg(-1) in two controls). A deficiency of several mitochondrial Dehydrogenases that utilize flavin adenine dinucleotide as cofactor including the acyl-CoA Dehydrogenases of fatty acid beta-oxidation, and enzymes that degrade the CoA-esters of glutaric acid, isovaleric acid, 2-methylbutyric acid, isobutyric acid, and sarcosine was suspected in 10 out of 10 cases as the possible etiology for a highly fatal and prevalent toxic equine muscle disease similar to the combined metabolic derangements seen in human multiple acyl-CoA Dehydrogenase deficiency also known as glutaric acidemia type II
-
Equine biochemical multiple acyl-CoA Dehydrogenase deficiency (MADD) as a cause of rhabdomyolysis
2007Co-Authors: Westermann C. M., De Sain-van Der Velden M. G. M., Van Der Kolk J. H., Berger R., Wijnberg I. D., Koeman J. P., Wanders R. J. A., Lenstra J. A., Testerink N., Vaandrager A. B.Abstract:Two horses (a 7-year-old Groninger warmblood gelding and a six-month-old Trakehner mare) with pathologically confirmed rhabdomyolysis were diagnosed as suffering from multiple acyl-CoA Dehydrogenase deficiency (MADD). This disorder has not been recognised in animals before. Clinical signs of both horses were a stiff, insecure gait, myoglobinuria, and finally recumbency. Urine, plasma, and muscle tissues were investigated. Analysis of plasma showed hyperglycemia, lactic acidemia, increased activity of muscle enzymes (ASAT, LDH, CK), and impaired kidney function (increased urea and creatinine). The most remarkable findings of organic acids in urine of both horses were increased lactic acid, ethylmalonic acid (EMA), 2-methylsuccinic acid, butyrylglycine (iso)valerylglycine, and hexanoylglycine. EMA was also increased in plasma of both animals. Furthermore, the profile of acylcarnitines in plasma from both animals showed a substantial elevation of C4-, C5-, C6-, C8-, and C5-DC-carnitine. Concentrations of acylcarnitines in urine of both animals revealed increased excretions of C2-, C3-, C4-, C5-, C6-, C5-OH-, C8-, C10:1-, C10-, and C5-DC-carnitine. In addition, concentrations of free carnitine were also increased. Quantitative biochemical measurement of enzyme activities in muscle tissue showed deficiencies of short-chain acyl-CoA Dehydrogenase (SCAD), medium-chain acyl-CoA Dehydrogenase (MCAD), and Isovaleryl-CoA Dehydrogenase (IVD) also indicating MADD. Histology revealed extensive rhabdomyolysis with microvesicular lipidosis predominantly in type 1 muscle fibers and mitochondrial damage. However, the ETF and ETF-QO activities were within normal limits indicating the metabolic disorder to be acquired rather than inherited. To our knowledge, these are the first cases of biochemical MADD reported in equine medicin
