Materiały źródłowe

• #1 Isovaleric Acidemia — New England Consortium of Metabolic Programs

  https://www.newenglandconsortium.org/isova

  Isovaleric acidemia (IVA,) also known as the sweaty foot syndrome, is an autosomal recessively inherited organic acid disorder due to a defect in the mitochondrial FAD-dependent enzyme isovaleryl-CoA dehydrogenase. This enzyme catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA. Since leucine is the amino acid precursor of isovaleryl-CoA, treatment of IVA includes control of leucine, an essential amino acid. […] In acute illness in IVA, isovaleric acid and its derivatives accumulate and profound metabolic acidosis (due to ketone body production and organic acid accumulation), hypoglycemia, and hyperammonemia ensue. […] The immediate metabolic precursor of isovaleryl-CoA is -ketocaproate, which is produced from leucine. In normal metabolism, -ketocaproate is catabolized to isovaleryl-CoA at which point isovaleryl-CoA dehydrogenase would catalyze further conversion to -methylcrotonyl-CoA. In isovaleric acidemia, deficient activity of isovaleryl-CoA dehydrogenase prevents this conversion, as shown in this figure:

• #2 Frontiers | Analysis of the genotype–phenotype correlation in isovaleric acidaemia: A case report of long-term follow-up of a chinese patient and literature review

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.928334/full

  Background: Isovaleric acidaemia (IVA), characterized by an acute metabolic crisis and psychomotor delay, is a rare inherited metabolic disease caused by a deficiency in isovaleryl-CoA dehydrogenase (IVD). […] Isovaleric acidaemia (IVA) is a rare inherited metabolic disease caused by a deficiency in isovaleryl-CoA dehydrogenase (IVD) (1), which catalyses the oxidation of isovaleryl-CoA to 3-methylcrotonyl-CoA during the third step of leucine catabolism (2). […] IVD catalyses the oxidation of isovaleryl-CoA to 3-methylcrotonyl-CoA during the third step of leucine catabolism. IVD deficiency disrupts leucine metabolism, leading to the accumulation of upstream isovaleric acid and its metabolites 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine, and isovalerylglycine (11), resulting in the metabolic acidosis and functional impairment of the brain, liver, kidneys, bone marrow, and other organs.

• #3 Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2652706/

  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. […] IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. […] Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. […] One missense mutation, 932CT (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.

• #4 Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2652706/

  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. […] The reaction catalyzed by IVD is initiated upon acyl-CoA substrate binding. […] The molecular mechanism of the oxidative half-reaction and the order of binding of the substrates have not been elucidated. […] Molecular cloning of the IVD gene showed it to be located on chromosome 15q1415, consisting of 12 exons that span ~15 kb of genomic DNA. […] Molecular analysis of the IVD gene in patients with symptomatic IVA has identified numerous point mutations in the protein coding region that lead to the production of an inactive or unstable protein. […] Some of these have been shown to cause only a mild alteration in enzyme function, correlating to some extent with a mild clinical phenotype in patients.

• #5 Classic Isovaleric Acidemia – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK601614/

  Biallelic IVD pathogenic variants result in reduced enzyme activity in the mitochondrial isovaleryl-conenzyme A dehydrogenase and, subsequently, in accumulation of isovaleryl-conenzyme A and its metabolites. […] Mechanism of disease causation. Loss of function.

• #6 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-is-Isovaleric-Acidemia.aspx

  A hereditary deficit of the enzyme isovaleryl-CoA dehydrogenase (IVD), which catalyzes the third stage in leucine catabolism, causes IVA. […] Isovaleric acidemia is caused by IVD (isovaleryl-CoA dehydrogenase) gene mutations. […] The body cannot adequately break down leucine if a mutation in the IVD gene decreases or eliminates the activity of this enzyme. […] As a result, hazardous levels of an organic acid called isovaleric acid and related chemicals build up in the body. […] The brain and nerve system are damaged due to this buildup, resulting in major health issues. […] Isovaleric acidemia has an autosomal recessive inheritance pattern. […] IVA treatment focuses on symptom management and avoiding a metabolic crisis. […] A better outcome is linked to early diagnosis and treatment. […] A particular protein-restricted diet and drugs are used to minimize the amount of isovaleric acid in the body.

• #7 Isovaleric acidemia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/isovaleric-acidemia/

  Isovaleric acidemia is a rare disorder in which the body is unable to properly break down a particular protein building block (amino acid). The condition is classified as an organic acid disorder, which is a condition that leads to an abnormal buildup of particular acids known as organic acids. Abnormal levels of organic acids in the blood (organic acidemia), urine (organic aciduria), and tissues can be toxic and can cause serious health problems. […] People with isovaleric acidemia have inadequate levels of an enzyme that helps break down a particular amino acid called leucine. […] Mutations in the IVD gene cause isovaleric acidemia. The IVD gene provides instructions for making an enzyme that plays an essential role in breaking down proteins from the diet. Specifically, this enzyme helps process the amino acid leucine, which is part of many proteins. If a mutation in the IVD gene reduces or eliminates the activity of this enzyme, the body is unable to break down leucine properly. As a result, an organic acid called isovaleric acid and related compounds build up to harmful levels in the body. This buildup damages the brain and nervous system, causing serious health problems.

• #8 Isovaleric acidemia – Wikipedia

  https://en.wikipedia.org/wiki/Isovaleric_acidemia

  Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia. […] The enzyme encoded by IVD, isovaleric acid-CoA dehydrogenase (EC 1.3.99.10), plays an essential role in breaking down proteins from the diet. Specifically, the enzyme is responsible for the third step in processing leucine, an essential amino acid. If a mutation in the IVD gene reduces or eliminates the activity of this enzyme, the body is unable to break down leucine properly. As a result, isovaleric acid and related compounds build up to toxic levels, damaging the brain and nervous system.

• #9 Isovaleric Acidemia — New England Consortium of Metabolic Programs

  https://www.newenglandconsortium.org/isova

  Isovaleric acidemia (IVA,) also known as the sweaty foot syndrome, is an autosomal recessively inherited organic acid disorder due to a defect in the mitochondrial FAD-dependent enzyme isovaleryl-CoA dehydrogenase. This enzyme catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA. Since leucine is the amino acid precursor of isovaleryl-CoA, treatment of IVA includes control of leucine, an essential amino acid. […] In acute illness in IVA, isovaleric acid and its derivatives accumulate and profound metabolic acidosis (due to ketone body production and organic acid accumulation), hypoglycemia, and hyperammonemia ensue. […] The immediate metabolic precursor of isovaleryl-CoA is -ketocaproate, which is produced from leucine. In normal metabolism, -ketocaproate is catabolized to isovaleryl-CoA at which point isovaleryl-CoA dehydrogenase would catalyze further conversion to -methylcrotonyl-CoA. In isovaleric acidemia, deficient activity of isovaleryl-CoA dehydrogenase prevents this conversion, as shown in this figure:

• #10 Isovaleric Acidemia — New England Consortium of Metabolic Programs

  https://www.newenglandconsortium.org/isova

  Catabolic stress such as normal perinatal catabolism or an acute illness (e.g. in the setting of infection, injury, surgery, febrile illness) produces endogenous protein breakdown leading to the liberation of amino acids, including leucine. Normal or certainly excessive protein ingestion may produce a similar increase in leucine. In IVA, the leucine leads to the accumulation of isovaleryl-CoA and then isovaleric acid, as well as the metabolites hydroxyisovalerate and isovalerylglycine, with primary and secondary consequences noted here: […] The ketoacidosis, hyperammonemia, and hypoglycemia can explain the lethargy and obtundation that are sometimes seen in IVA patients in acute crisis. The ketoacidosis also produces vomiting. Release of free fatty acids from body fat into the liver produces a fatty liver. Prolonged metabolic decompensation can lead to bone marrow suppression with resulting neutropenia or pancytopenia.

• #11 Aspects of Newborn Screening in Isovaleric Acidemia

  https://www.mdpi.com/2409-515X/4/1/7

  Isovaleric acidemia (IVA), an inborn error of leucine catabolism, is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene, resulting in the accumulation of derivatives of isovaleryl-CoA including isovaleryl (C5)-carnitine, the marker metabolite used for newborn screening (NBS). […] The pathogenesis of the disease is still not fully understood. Mechanisms thought to be involved include the induction of oxidative stress through accumulating metabolites as seen in the rat brain cortex, the reduction of Na+, K+-ATPase activity by free isovaleric acid as shown in synaptic membranes from the cerebral cortex in young rats, and abnormal cellular growth signaling through activation of the mammalian target of rapamycin complex 1 (mTORC1), as suggested from studies with human IVD deficient cells. […] Deficiency of IVD results in an accumulation of derivatives of isovaleryl-coenzyme A (CoA), the metabolite before the block, such as isovaleric acid, 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine, and isovalerylglycine (IVG).

• #12 Isovaleric acidemia | MedLink Neurology

  https://www.medlink.com/articles/isovaleric-acidemia

  Isovaleric acidemia is an inborn error of leucine metabolism that results from a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase, which is caused by a homozygous mutation in the isovaleryl-CoA dehydrogenase gene on chromosome 15q15.1. […] Isovaleric acidemia is transmitted as an autosomal recessive trait. […] Due to the metabolic block, isovaleryl-CoA accumulates, and the pathognomonic metabolite isovalerylglycine is formed by conjugation of isovaleryl-CoA to the amino group of glycine. […] The mechanism of isovaleric acid toxicity remains unclear, though it is likely to be multifactorial. Some findings point to an inhibition of mitochondrial energy metabolism. […] The catabolic pathway is challenged by increased protein intake or increased endogenous protein degradation. […] The other important therapy principle is to increase the excretion of isovaleric acid as nontoxic glycine and carnitine conjugates.

• #13 Clinical and neurocognitive outcome in symptomatic isovaleric acidemia | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-9

  Isovaleric acidemia (IVA) is known as one of the „classical” organic acidemias/acidurias. It is caused by a genetic deficiency of isovaleryl-CoA dehydrogenase (IVD) catalyzing the third step in leucine catabolism. The enzyme defect results in the accumulation of derivatives of isovaleryl-CoA including free isovaleric acid, 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine, and isovalerylglycine (IVG) which partly may exert neurotoxicity. […] The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening. […] The underlying pathophysiologic mechanisms leading to cerebral damage are still not fully elucidated. Based on studies in rats it can be presumed that metabolites accumulating in IVA induce oxidative stress in the brain cortex and that oxidative damage may be at least in part involved in the neuropathology of IVA.

• #14 Aspects of Newborn Screening in Isovaleric Acidemia

  https://www.mdpi.com/2409-515X/4/1/7

  Isovaleric acidemia (IVA), an inborn error of leucine catabolism, is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene, resulting in the accumulation of derivatives of isovaleryl-CoA including isovaleryl (C5)-carnitine, the marker metabolite used for newborn screening (NBS). […] The pathogenesis of the disease is still not fully understood. Mechanisms thought to be involved include the induction of oxidative stress through accumulating metabolites as seen in the rat brain cortex, the reduction of Na+, K+-ATPase activity by free isovaleric acid as shown in synaptic membranes from the cerebral cortex in young rats, and abnormal cellular growth signaling through activation of the mammalian target of rapamycin complex 1 (mTORC1), as suggested from studies with human IVD deficient cells. […] Deficiency of IVD results in an accumulation of derivatives of isovaleryl-coenzyme A (CoA), the metabolite before the block, such as isovaleric acid, 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine, and isovalerylglycine (IVG).

• #15 Aspects of Newborn Screening in Isovaleric Acidemia

  https://www.mdpi.com/2409-515X/4/1/7

  Isovaleric acidemia (IVA), an inborn error of leucine catabolism, is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene, resulting in the accumulation of derivatives of isovaleryl-CoA including isovaleryl (C5)-carnitine, the marker metabolite used for newborn screening (NBS). […] The pathogenesis of the disease is still not fully understood. Mechanisms thought to be involved include the induction of oxidative stress through accumulating metabolites as seen in the rat brain cortex, the reduction of Na+, K+-ATPase activity by free isovaleric acid as shown in synaptic membranes from the cerebral cortex in young rats, and abnormal cellular growth signaling through activation of the mammalian target of rapamycin complex 1 (mTORC1), as suggested from studies with human IVD deficient cells. […] Deficiency of IVD results in an accumulation of derivatives of isovaleryl-coenzyme A (CoA), the metabolite before the block, such as isovaleric acid, 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine, and isovalerylglycine (IVG).

• #16 Isovaleric acidemia | MedLink Neurology

  https://www.medlink.com/articles/isovaleric-acidemia

  Isovaleric acidemia is an inborn error of leucine metabolism that results from a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase, which is caused by a homozygous mutation in the isovaleryl-CoA dehydrogenase gene on chromosome 15q15.1. […] Isovaleric acidemia is transmitted as an autosomal recessive trait. […] Due to the metabolic block, isovaleryl-CoA accumulates, and the pathognomonic metabolite isovalerylglycine is formed by conjugation of isovaleryl-CoA to the amino group of glycine. […] The mechanism of isovaleric acid toxicity remains unclear, though it is likely to be multifactorial. Some findings point to an inhibition of mitochondrial energy metabolism. […] The catabolic pathway is challenged by increased protein intake or increased endogenous protein degradation. […] The other important therapy principle is to increase the excretion of isovaleric acid as nontoxic glycine and carnitine conjugates.

• #17 Isovaleric Acidaemia – Metabolic Support UKAccessibility ToolsIncrease TextDecrease TextGrayscaleHigh ContrastNegative ContrastLight BackgroundLinks UnderlineReadable FontReset

  https://metabolicsupportuk.org/condition/isovaleric-acidaemia/

  Isovaleric Acidaemia is caused by a problem in the IVD gene. This gene produces an enzyme which breaks down an amino acid called leucine. This process is needed because leucine is a part of many proteins which helps to provide energy to your body. […] If you have a problem in the IVD gene, you will not produce enough of this enzyme. Therefore, you will be unable to break down leucine properly and this causes its compounds to build up to toxic levels. This can damage your brain and your nervous system, leading to a number of serious health issues. […] There is no cure for Isovaleric Acidaemia, however there are a range of ways that the disorder can be managed successfully, and plans can be put in place to reduce the chances of the disorder getting worse. […] One of the most important ways to manage the disorder is through following a specific diet. It is recommended that you follow a low-protein diet, as people with Isovaleric Acidaemia are unable to process protein properly.

• #18 | Myriad Prequel® Prenatal Screen

  https://myriad.com/womens-health/diseases/isovaleric-acidemia/

  Isovaleric Acidemia (IVA), caused by mutations in the IVD gene, is an inherited disorder in which an enzyme that breaks down the amino acid leucine does not function properly resulting in accumulation isovaleric acid in the blood. High levels of isovaleric acid in the blood can be toxic and result in damage to the brain and nervous system. […] Without early diagnosis and treatment, individuals with IVA may have damage to the brain and nervous system, intellectual and developmental disability, or in severe cases, death. If a person with IVA receives treatment, they are more likely to reach normal levels of growth, development, and intellectual ability. However, some individuals may experience a reduction in growth and development, learning disabilities, or even death, due to periodic episodes of high levels of isovaleric acid, primarily in response to stress. […] Individuals with IVA need close monitoring by a physician during times of illness and may need to ensure adequate hydration and adopt a diet high in carbohydrates. Symptoms such as vomiting, diarrhea, and illness with a fever may require prompt treatment.

• #19

  https://omim.org/entry/243500?search=isovaleric%20acidemia&highlight=acidaemia%20acidemia%20isovaleric

  The phenotypic abnormalities in this disorder result from an accumulation of isovaleric acid, which is toxic to the central nervous system. An alternative pathway through glycine-N-acylase (EC 2.3.1.13) allows detoxification by producing isovalerylglycine, which is excreted. […] Rhead and Tanaka (1980) demonstrated a specific deficiency of mitochondrial isovaleryl-CoA dehydrogenase activity in skin fibroblasts from patients with IVA. Mitochondrial butyryl-CoA dehydrogenase activity was maintained at normal levels. Although clinical heterogeneity is observed, cell-fusion studies (Dubiel et al., 1983) involving 12 cell lines, each from a different patient and representing a variety of clinical presentation, showed no complementation. Complementation was observed when IVA cells were fused with those from glutaric aciduria IIB (231680). The authors concluded that the same gene, coding for isovaleryl CoA dehydrogenase, was mutated in all cell lines.

• #20

  https://omim.org/entry/243500?search=isovaleric%20acidemia&highlight=acidaemia%20acidemia%20isovaleric

  The phenotypic abnormalities in this disorder result from an accumulation of isovaleric acid, which is toxic to the central nervous system. An alternative pathway through glycine-N-acylase (EC 2.3.1.13) allows detoxification by producing isovalerylglycine, which is excreted. […] Rhead and Tanaka (1980) demonstrated a specific deficiency of mitochondrial isovaleryl-CoA dehydrogenase activity in skin fibroblasts from patients with IVA. Mitochondrial butyryl-CoA dehydrogenase activity was maintained at normal levels. Although clinical heterogeneity is observed, cell-fusion studies (Dubiel et al., 1983) involving 12 cell lines, each from a different patient and representing a variety of clinical presentation, showed no complementation. Complementation was observed when IVA cells were fused with those from glutaric aciduria IIB (231680). The authors concluded that the same gene, coding for isovaleryl CoA dehydrogenase, was mutated in all cell lines.

• #21 Problem 5 Therapeutic glycine. Isovaleric … [FREE SOLUTION] | Vaia

  https://www.vaia.com/en-us/textbooks/chemistry/biochemistry-6-edition/chapter-24/problem-5-therapeutic-glycine-isovaleric-acidemia-is-an-inhe/

  Glycine conjugates with toxic isovaleric acid to form isovalerylglycine, reducing toxicity and improving clinical outcomes. […] In isovaleric acidemia, excess isovaleric acid can conjugate with glycine to form isovalerylglycine. This conjugation reduces the level of toxic isovaleric acid in the body, as isovalerylglycine is less harmful and can be more easily excreted in urine, leading to clinical improvement. […] By lowering the levels of toxic isovaleric acid through conjugation with glycine, symptoms of toxicity may be alleviated, ensuring a better clinical outcome for infants affected by isovaleric acidemia. […] Glycine plays an essential therapeutic role by binding to excess isovaleric acid. This process creates isovalerylglycine, a much less toxic compound compared to free isovaleric acid. […] This reduction in toxic levels leads to clinical improvements.

• #22 Long Term Follow-Up of Polish Patients with Isovaleric Aciduria. Clinical and Molecular Delineation of Isovaleric Aciduria

  https://www.mdpi.com/2075-4418/10/10/738

  Additionally, carnitine and/or glycine is administered to enhance the conversion of potentially neurotoxic products (free isovaleric acid) into non-toxic carnitine and glycine conjugates which are easily excreted in the urine. […] In 2014, the web-based E-IMD IVA Guidelines were published, which stated that natural protein intake should be restricted to reduce the isovaleric acid burden but should satisfy at least the WHO/FAO/UNU 2007 safe levels of protein intake. […] Given the genotype-phenotype correlation, 89 pathogenic variants in the IVD gene have been reported so far. The relationship regarding IVA manifestation is, however, lacking, and the distribution of hotspot varies among populations. […] In our IVA cohort, patients did well on lower doses of both glycine and carnitine comparing to the literature. This suggests that a mild form of the disease is predominant in the Polish population. […] Therefore, it seems that there is another factor that influences the course of the disease, such as IVA accumulation, which is partly dependent on the endogenous production of glycine (Gly).

• #23 Isovaleric acidaemia – Genomics Education Programme

  http://www.genomicseducation.hee.nhs.uk/documents/isovaleric-acidaemia/

  Isovaleric acidaemia (IVA) is an autosomal recessive disorder caused by the deficiency of the enzyme isovaleryl-CoA dehydrogenase (IVD). […] IVD is responsible for the dehydrogenation of isovaleryl-CoA to produce 3-methylcrotonyl-CoA, and is involved in the metabolism of the amino acid, leucine. […] IVA is an autosomal recessive condition caused by mutations in the IVD gene. […] The IVD gene encodes the enzyme isovaleryl-CoA dehydrogenase. […] The main goal of management is to reduce the production and increase the excretion of isovaleryl-CoA. […] Patients may also be supplemented with carnitine and/or glycine. Carnitine and glycine are used to reduce isovaleric acid levels by the formation of the isovaleryl-CoA conjugates, which can then be excreted in the urine.

• #24 Isovaleric acidemia | MedLink Neurology

  https://www.medlink.com/articles/isovaleric-acidemia

  Isovaleric acidemia is an inborn error of leucine metabolism that results from a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase, which is caused by a homozygous mutation in the isovaleryl-CoA dehydrogenase gene on chromosome 15q15.1. […] Isovaleric acidemia is transmitted as an autosomal recessive trait. […] Due to the metabolic block, isovaleryl-CoA accumulates, and the pathognomonic metabolite isovalerylglycine is formed by conjugation of isovaleryl-CoA to the amino group of glycine. […] The mechanism of isovaleric acid toxicity remains unclear, though it is likely to be multifactorial. Some findings point to an inhibition of mitochondrial energy metabolism. […] The catabolic pathway is challenged by increased protein intake or increased endogenous protein degradation. […] The other important therapy principle is to increase the excretion of isovaleric acid as nontoxic glycine and carnitine conjugates.

• #25 Isovaleric Acidemia — New England Consortium of Metabolic Programs

  https://www.newenglandconsortium.org/isova

  Catabolic stress such as normal perinatal catabolism or an acute illness (e.g. in the setting of infection, injury, surgery, febrile illness) produces endogenous protein breakdown leading to the liberation of amino acids, including leucine. Normal or certainly excessive protein ingestion may produce a similar increase in leucine. In IVA, the leucine leads to the accumulation of isovaleryl-CoA and then isovaleric acid, as well as the metabolites hydroxyisovalerate and isovalerylglycine, with primary and secondary consequences noted here: […] The ketoacidosis, hyperammonemia, and hypoglycemia can explain the lethargy and obtundation that are sometimes seen in IVA patients in acute crisis. The ketoacidosis also produces vomiting. Release of free fatty acids from body fat into the liver produces a fatty liver. Prolonged metabolic decompensation can lead to bone marrow suppression with resulting neutropenia or pancytopenia.

• #26 Isovaleric Acidemia — New England Consortium of Metabolic Programs

  https://www.newenglandconsortium.org/isova

  Catabolic stress such as normal perinatal catabolism or an acute illness (e.g. in the setting of infection, injury, surgery, febrile illness) produces endogenous protein breakdown leading to the liberation of amino acids, including leucine. Normal or certainly excessive protein ingestion may produce a similar increase in leucine. In IVA, the leucine leads to the accumulation of isovaleryl-CoA and then isovaleric acid, as well as the metabolites hydroxyisovalerate and isovalerylglycine, with primary and secondary consequences noted here: […] The ketoacidosis, hyperammonemia, and hypoglycemia can explain the lethargy and obtundation that are sometimes seen in IVA patients in acute crisis. The ketoacidosis also produces vomiting. Release of free fatty acids from body fat into the liver produces a fatty liver. Prolonged metabolic decompensation can lead to bone marrow suppression with resulting neutropenia or pancytopenia.

• #27 Isovaleric acidemia: Symptoms, causes, treatments, and more

  https://www.medicalnewstoday.com/articles/isovaleric-acidaemia

  Isovaleric acidemia (IVA) is a rare condition that children can inherit from both their biological parents. It can cause serious problems with how the body breaks down proteins. […] IVA occurs when there is a mutation in the gene coding for an enzyme called isovaleryl-CoA dehydrogenase (IVD), resulting in a deficiency of typical IVD. […] Several factors may trigger IVA episodes, including infections and a large intake of food that is high in protein. […] Treatment for IVA involves managing the diet, taking medications that promote the breakdown of excess isovaleric acid, and managing metabolic crises with emergency treatment. […] People with IVA need to avoid eating high protein foods, including eggs, fish, meat, milk and dairy products, nuts, and pulses, such as lentils, peas, and beans.

• #28 Isovaleric Acidemia — New England Consortium of Metabolic Programs

  https://www.newenglandconsortium.org/isova

  Isovaleric acidemia (IVA,) also known as the sweaty foot syndrome, is an autosomal recessively inherited organic acid disorder due to a defect in the mitochondrial FAD-dependent enzyme isovaleryl-CoA dehydrogenase. This enzyme catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA. Since leucine is the amino acid precursor of isovaleryl-CoA, treatment of IVA includes control of leucine, an essential amino acid. […] In acute illness in IVA, isovaleric acid and its derivatives accumulate and profound metabolic acidosis (due to ketone body production and organic acid accumulation), hypoglycemia, and hyperammonemia ensue. […] The immediate metabolic precursor of isovaleryl-CoA is -ketocaproate, which is produced from leucine. In normal metabolism, -ketocaproate is catabolized to isovaleryl-CoA at which point isovaleryl-CoA dehydrogenase would catalyze further conversion to -methylcrotonyl-CoA. In isovaleric acidemia, deficient activity of isovaleryl-CoA dehydrogenase prevents this conversion, as shown in this figure:

• #29 Isovaleric Acidemia — New England Consortium of Metabolic Programs

  https://www.newenglandconsortium.org/isova

  Catabolic stress such as normal perinatal catabolism or an acute illness (e.g. in the setting of infection, injury, surgery, febrile illness) produces endogenous protein breakdown leading to the liberation of amino acids, including leucine. Normal or certainly excessive protein ingestion may produce a similar increase in leucine. In IVA, the leucine leads to the accumulation of isovaleryl-CoA and then isovaleric acid, as well as the metabolites hydroxyisovalerate and isovalerylglycine, with primary and secondary consequences noted here: […] The ketoacidosis, hyperammonemia, and hypoglycemia can explain the lethargy and obtundation that are sometimes seen in IVA patients in acute crisis. The ketoacidosis also produces vomiting. Release of free fatty acids from body fat into the liver produces a fatty liver. Prolonged metabolic decompensation can lead to bone marrow suppression with resulting neutropenia or pancytopenia.

• #30 Isovaleric Acidemia — New England Consortium of Metabolic Programs

  https://www.newenglandconsortium.org/isova

  Catabolic stress such as normal perinatal catabolism or an acute illness (e.g. in the setting of infection, injury, surgery, febrile illness) produces endogenous protein breakdown leading to the liberation of amino acids, including leucine. Normal or certainly excessive protein ingestion may produce a similar increase in leucine. In IVA, the leucine leads to the accumulation of isovaleryl-CoA and then isovaleric acid, as well as the metabolites hydroxyisovalerate and isovalerylglycine, with primary and secondary consequences noted here: […] The ketoacidosis, hyperammonemia, and hypoglycemia can explain the lethargy and obtundation that are sometimes seen in IVA patients in acute crisis. The ketoacidosis also produces vomiting. Release of free fatty acids from body fat into the liver produces a fatty liver. Prolonged metabolic decompensation can lead to bone marrow suppression with resulting neutropenia or pancytopenia.

• #31

  https://www.gov.uk/government/publications/iva-is-suspected-description-in-brief/isovaleric-acidaemia-iva-mild-iva

  Isovaleric acidaemia (pronounced iso-val-air-ik acid-ee-mia), or IVA, is a rare but treatable inherited metabolic disorder that prevents the normal breakdown of protein. Babies with IVA inherit two faulty copies of the gene for IVA, one from each parent. […] In IVA, an enzyme called isovaleryl-CoA dehydrogenase is missing, which leads to problems breaking down the amino acid leucine. This causes a harmful substance called isovaleric acid to build up in the body. […] If your baby becomes unwell, they might have an episode known as a metabolic crisis (also known as metabolic decompensation). This is caused by a rapid build-up of isovaleric acid and other related substances in their body, which can make them severely unwell. […] A metabolic crisis can lead to serious illness and long-term brain damage, and can be life-threatening. […] With prompt use of the emergency regimen, the outcome is very good and most children with mild IVA will avoid any long-term health problems.

• #32 Isovaleric acidemia | MedLink Neurology

  https://www.medlink.com/articles/isovaleric-acidemia

  Isovaleric acidemia is an inborn error of leucine metabolism that results from a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase, which is caused by a homozygous mutation in the isovaleryl-CoA dehydrogenase gene on chromosome 15q15.1. […] Isovaleric acidemia is transmitted as an autosomal recessive trait. […] Due to the metabolic block, isovaleryl-CoA accumulates, and the pathognomonic metabolite isovalerylglycine is formed by conjugation of isovaleryl-CoA to the amino group of glycine. […] The mechanism of isovaleric acid toxicity remains unclear, though it is likely to be multifactorial. Some findings point to an inhibition of mitochondrial energy metabolism. […] The catabolic pathway is challenged by increased protein intake or increased endogenous protein degradation. […] The other important therapy principle is to increase the excretion of isovaleric acid as nontoxic glycine and carnitine conjugates.

• #33 Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2652706/

  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. […] The reaction catalyzed by IVD is initiated upon acyl-CoA substrate binding. […] The molecular mechanism of the oxidative half-reaction and the order of binding of the substrates have not been elucidated. […] Molecular cloning of the IVD gene showed it to be located on chromosome 15q1415, consisting of 12 exons that span ~15 kb of genomic DNA. […] Molecular analysis of the IVD gene in patients with symptomatic IVA has identified numerous point mutations in the protein coding region that lead to the production of an inactive or unstable protein. […] Some of these have been shown to cause only a mild alteration in enzyme function, correlating to some extent with a mild clinical phenotype in patients.

• #34 Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2652706/

  A significant proportion of the mutant alleles lead to abnormal splicing of the IVD RNA and subsequent complete lack of IVD protein. […] Studies of the bioprocessing of IVD protein in fibroblasts from patients with IVA have reflected the effects of these mutations but have not provided insight into the clinical variability seen in the disorder. […] In general, genotype and phenotype have not been well correlated.

• #35 Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2652706/

  A significant proportion of the mutant alleles lead to abnormal splicing of the IVD RNA and subsequent complete lack of IVD protein. […] Studies of the bioprocessing of IVD protein in fibroblasts from patients with IVA have reflected the effects of these mutations but have not provided insight into the clinical variability seen in the disorder. […] In general, genotype and phenotype have not been well correlated.

• #36 Neonatal isovaleric acidemia in China: A case report and review of literature

  https://www.wjgnet.com/2307-8960/full/v9/i2/436.htm

  Isovaleric acidemia (IVA) is a rare autosomal recessive inherited organic acidemia caused by a genetic deficiency of isovaleryl-CoA dehydrogenase (IVD). Its morbidity is low, but mortality is high. There is no effective cure for this disease. Early identification of IVA using clinical features can significantly slow disease progression and reduce mortality. […] The clinical presentation of IVA appears to be highly variable ranging from severely affected to asymptomatic patients. Clinical features include poor feeding, vomiting, acidosis, ketosis, progressive alteration of consciousness, seizures and finally deep coma and death without appropriate therapy. The characteristic odor of sweaty feet caused by isovaleric acid is often noted during metabolic crisis. […] The clinical diagnosis of IVA can be confirmed by mutation of the IVD gene. The IVD gene is encoded by the nuclear gene, which is located on chromosome 15q14-15, consisting of 12 exons that span 15 kb of genomic DNA. To date, more than 70 heterogeneous mutations in the IVD gene have been reported in patients with IVA.

• #37 Neonatal isovaleric acidemia in China: A case report and review of literature

  https://www.wjgnet.com/2307-8960/full/v9/i2/436.htm

  The patient had compound heterozygous mutations: c.1193GA (p.Arg398Gln) and c.1208AG (p.Try403Cys). The p.Arg398Gln variant was inherited from his mother, whereas p.Try403Cys was inherited from his father. Both variants were missense mutations in accordance with an autosomal recessive inherited disease, which has been previously reported. […] Plasma isovaleryl carnitine and urine isovaleryl glycine are IVA biomarkers, and the levels of these biomarkers can increase several hundred-fold during acute episodes. […] Molecular genetic analysis helps to further confirm the clinical diagnosis of IVA. To date, more than 70 heterogeneous mutations in the IVD gene have been reported in patients with IVA, including point mutations, frameshift mutations and splice-site mutations. […] Early diagnosis and treatment are necessary to prevent neonatal mortality and improve the neurologic and cognitive outcomes.

• #38 Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2652706/

  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. […] The reaction catalyzed by IVD is initiated upon acyl-CoA substrate binding. […] The molecular mechanism of the oxidative half-reaction and the order of binding of the substrates have not been elucidated. […] Molecular cloning of the IVD gene showed it to be located on chromosome 15q1415, consisting of 12 exons that span ~15 kb of genomic DNA. […] Molecular analysis of the IVD gene in patients with symptomatic IVA has identified numerous point mutations in the protein coding region that lead to the production of an inactive or unstable protein. […] Some of these have been shown to cause only a mild alteration in enzyme function, correlating to some extent with a mild clinical phenotype in patients.

• #39 Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2652706/

  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. […] IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. […] Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. […] One missense mutation, 932CT (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.

• #40 Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2652706/

  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. […] IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. […] Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. […] One missense mutation, 932CT (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.

• #41 Frontiers | Analysis of the genotype–phenotype correlation in isovaleric acidaemia: A case report of long-term follow-up of a chinese patient and literature review

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.928334/full

  The correlation between phenotype and genotype in patients with IVA has been unclear, and siblings carrying the same variant have shown very different phenotypes (17). Therefore, in this study, the data from 155 patients were summarized, and the correlation between phenotype and genotype was further analyzed. The results showed that the two hot regions of the distribution of pathogenic variants in symptomatic patients (including, acute neonatal type and chronic intermittent type) were located in the 123–159 and 356–403 regions, while the distribution in asymptomatic patients was mainly located in the 282–318 region. […] Our patient was identified as having the compound heterozygous variants c.224A>G (p.Asn75Ser) and c.1195G>C (p.Asp399His). Asn75 is located in the α-helical N-terminal domain, whereas Asp399 is located in the α-helical C-terminal domain. All these residues are embedded in the protein and interact with other residues to stabilize the protein structure. When Asn75 is replaced with serine, the hydrogen bond between Asn75 and Asp244 is predicted to be disrupted (Figure 4), thus affecting protein structure and stability. When Asp399 is replaced with histidine, an imidazole ring is added to the side chain, resulting in destroying the hydrogen bond between Asp399 and Met248 (Figure 4), which changes three-dimensional structure and may affect the binding of FAD.

• #42 Frontiers | Analysis of the genotype–phenotype correlation in isovaleric acidaemia: A case report of long-term follow-up of a chinese patient and literature review

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.928334/full

  The correlation between phenotype and genotype in patients with IVA has been unclear, and siblings carrying the same variant have shown very different phenotypes (17). Therefore, in this study, the data from 155 patients were summarized, and the correlation between phenotype and genotype was further analyzed. The results showed that the two hot regions of the distribution of pathogenic variants in symptomatic patients (including, acute neonatal type and chronic intermittent type) were located in the 123–159 and 356–403 regions, while the distribution in asymptomatic patients was mainly located in the 282–318 region. […] Our patient was identified as having the compound heterozygous variants c.224A>G (p.Asn75Ser) and c.1195G>C (p.Asp399His). Asn75 is located in the α-helical N-terminal domain, whereas Asp399 is located in the α-helical C-terminal domain. All these residues are embedded in the protein and interact with other residues to stabilize the protein structure. When Asn75 is replaced with serine, the hydrogen bond between Asn75 and Asp244 is predicted to be disrupted (Figure 4), thus affecting protein structure and stability. When Asp399 is replaced with histidine, an imidazole ring is added to the side chain, resulting in destroying the hydrogen bond between Asp399 and Met248 (Figure 4), which changes three-dimensional structure and may affect the binding of FAD.

• #43 Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia | Journal of Human Genetics

  https://www.nature.com/articles/jhg2016144

  The main goal of treatment is to achieve a state of anabolism to reduce the formation of isovaleryl-CoA from leucine catabolism. Long-term treatment strategies comprise restricted intake of protein or leucine combined with L-carnitine and/or glycine supplementation to enhance the conversion of potentially neurotoxic-free isovaleric acid to non-toxic conjugates excreted in urine. […] The mutations are highly heterogeneous and genotype-phenotype correlations described to date have generally been weak. […] Our data are consistent with this observation, as most patients who were screened at birth had C5 levels 6M and low IVG in urine levels and remained asymptomatic with a protein intake of at least 1.5gkg1perday. IVG in urine at diagnosis is a good biochemical marker of prognosis, and in our series, all the patients with chronic intermittent or acute neonatal forms of IVA had an IVG level 3000mmol per mol creatinine on detection of the disease.

• #44 Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia | Journal of Human Genetics

  https://www.nature.com/articles/jhg2016144

  Incorporation of isovaleric acid into protein, as an indirect measure of IVD activity, also appears to be a good predictor of disease severity. […] Our cohort of patients is genetically heterogeneous. We identified 16 mutations, including 9 novel ones, thereby adding to current knowledge on pathogenic mutations in the IVD gene. […] Some other studies have demonstrated variable clinical presentations for common genotypes, but, although this is a small cohort of IVD patients, their clinical/biochemical findings correlated fairly well with the phenotype predicted by the mutations found.

• #45 Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia | Journal of Human Genetics

  https://www.nature.com/articles/jhg2016144

  Incorporation of isovaleric acid into protein, as an indirect measure of IVD activity, also appears to be a good predictor of disease severity. […] Our cohort of patients is genetically heterogeneous. We identified 16 mutations, including 9 novel ones, thereby adding to current knowledge on pathogenic mutations in the IVD gene. […] Some other studies have demonstrated variable clinical presentations for common genotypes, but, although this is a small cohort of IVD patients, their clinical/biochemical findings correlated fairly well with the phenotype predicted by the mutations found.

• #46 Clinical and neurocognitive outcome in symptomatic isovaleric acidemia | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-9

  Isovaleric acidemia (IVA) is known as one of the „classical” organic acidemias/acidurias. It is caused by a genetic deficiency of isovaleryl-CoA dehydrogenase (IVD) catalyzing the third step in leucine catabolism. The enzyme defect results in the accumulation of derivatives of isovaleryl-CoA including free isovaleric acid, 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine, and isovalerylglycine (IVG) which partly may exert neurotoxicity. […] The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening. […] The underlying pathophysiologic mechanisms leading to cerebral damage are still not fully elucidated. Based on studies in rats it can be presumed that metabolites accumulating in IVA induce oxidative stress in the brain cortex and that oxidative damage may be at least in part involved in the neuropathology of IVA.

• #47 Clinical and neurocognitive outcome in symptomatic isovaleric acidemia | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-9

  However, considering the lack of association between the number of catabolic episodes and cognitive performance (IQ) and the finding that early diagnosis and treatment have a positive impact on the neurocognitive outcome, chronic rather than acute damage might be the predominant factor determining the extent of neuropathology in patients with IVA. […] Within the entity of „classical” organic acidurias which typically result in significant CNS damage, IVA appears to be exceptional considering its milder neuropathologic implications, possibly entirely preventable by treatment.

• #48 Clinical and neurocognitive outcome in symptomatic isovaleric acidemia | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-9

  However, considering the lack of association between the number of catabolic episodes and cognitive performance (IQ) and the finding that early diagnosis and treatment have a positive impact on the neurocognitive outcome, chronic rather than acute damage might be the predominant factor determining the extent of neuropathology in patients with IVA. […] Within the entity of „classical” organic acidurias which typically result in significant CNS damage, IVA appears to be exceptional considering its milder neuropathologic implications, possibly entirely preventable by treatment.

• #49 Isovaleric acidemia: A rare cause of isolated cerebellar atrophy

  https://www.oatext.com/isovaleric-acidemia-a-rare-cause-of-isolated-cerebellar-atrophy.php

  Isovaleric acidemia is a very rare autosomal recessive inborn error of leucine metabolism caused by deficiency of the mitochondrial enzyme isovaleryl-coenzyme A dehydrogenase. […] The disease has two well-known clinical phenotypes: an acute neonatal presentation with severe metabolic crisis and a chronic intermittent form. […] There are only two reports of abnormal neuroimaging features of isovaleric acidemia in the literature, both describing abnormalities of the basal ganglia, as expected with most organic acidurias. […] Our patient was imaged at an older age of 6 years, outside an episode of metabolic crisis, for evaluation of developmental delay, mainly in the form of severe receptive and expressive speech delay. […] As isovaleryl-coenzyme A dehydrogenase is a mitochondrial enzyme and given that mitochondrial disorders are the most common cause of cerebellar atrophy, the finding of cerebellar atrophy in isovaleric acidemia is not surprising.

• #50 Isovaleric acidemia: A rare cause of isolated cerebellar atrophy

  https://www.oatext.com/isovaleric-acidemia-a-rare-cause-of-isolated-cerebellar-atrophy.php

  Isovaleric acidemia is a very rare autosomal recessive inborn error of leucine metabolism caused by deficiency of the mitochondrial enzyme isovaleryl-coenzyme A dehydrogenase. […] The disease has two well-known clinical phenotypes: an acute neonatal presentation with severe metabolic crisis and a chronic intermittent form. […] There are only two reports of abnormal neuroimaging features of isovaleric acidemia in the literature, both describing abnormalities of the basal ganglia, as expected with most organic acidurias. […] Our patient was imaged at an older age of 6 years, outside an episode of metabolic crisis, for evaluation of developmental delay, mainly in the form of severe receptive and expressive speech delay. […] As isovaleryl-coenzyme A dehydrogenase is a mitochondrial enzyme and given that mitochondrial disorders are the most common cause of cerebellar atrophy, the finding of cerebellar atrophy in isovaleric acidemia is not surprising.

• #51 Isovaleric acidemia: A rare cause of isolated cerebellar atrophy

  https://www.oatext.com/isovaleric-acidemia-a-rare-cause-of-isolated-cerebellar-atrophy.php

  Isovaleric acidemia is a very rare autosomal recessive inborn error of leucine metabolism caused by deficiency of the mitochondrial enzyme isovaleryl-coenzyme A dehydrogenase. […] The disease has two well-known clinical phenotypes: an acute neonatal presentation with severe metabolic crisis and a chronic intermittent form. […] There are only two reports of abnormal neuroimaging features of isovaleric acidemia in the literature, both describing abnormalities of the basal ganglia, as expected with most organic acidurias. […] Our patient was imaged at an older age of 6 years, outside an episode of metabolic crisis, for evaluation of developmental delay, mainly in the form of severe receptive and expressive speech delay. […] As isovaleryl-coenzyme A dehydrogenase is a mitochondrial enzyme and given that mitochondrial disorders are the most common cause of cerebellar atrophy, the finding of cerebellar atrophy in isovaleric acidemia is not surprising.

• #52 Isovaleric acidemia: A rare cause of isolated cerebellar atrophy

  https://www.oatext.com/isovaleric-acidemia-a-rare-cause-of-isolated-cerebellar-atrophy.php

  The susceptibility of the cerebellum to selective injury with organic acidurias, such as in particular 3-methylglutaconic aciduria, is another explanation of the cerebellar atrophy seen in our patient. […] Our case demonstrates that isovaleric acidemia is one rare etiology of isolated cerebellar atrophy in children.

• #53 Long Term Follow-Up of Polish Patients with Isovaleric Aciduria. Clinical and Molecular Delineation of Isovaleric Aciduria

  https://www.mdpi.com/2075-4418/10/10/738

  Isovaleric acidemia (IVA) is an autosomal recessive leucine inborn error of metabolism caused by isovaleryl-CoA dehydrogenase deficiency. […] The IVD gene was mapped on chromosome 15q14-q15. It encodes a homonymous protein, IVD enzyme, which catalyses the third step in leucine catabolism. Its deficiency results in the accumulation of isovaleryl-CoA, such as free isovaleric acid, 3-hydroxyisovaleric acid (3-HIVA), isovaleryl (C5)-carnitine, and isovalerylglycine (IVG). Isovaleric acid and IVG are potentially neurotoxic. […] Molecular analysis of the IVD gene has allowed for the identification of different types of pathogenic variants, with no straightforward phenotype–genotype correlation in most cases. […] As far as IVA clinical course is concerned, metabolic decompensations are the most serious complication.

• #54 Isovaleric Acidemia — New England Consortium of Metabolic Programs

  https://www.newenglandconsortium.org/isova

  Catabolic stress such as normal perinatal catabolism or an acute illness (e.g. in the setting of infection, injury, surgery, febrile illness) produces endogenous protein breakdown leading to the liberation of amino acids, including leucine. Normal or certainly excessive protein ingestion may produce a similar increase in leucine. In IVA, the leucine leads to the accumulation of isovaleryl-CoA and then isovaleric acid, as well as the metabolites hydroxyisovalerate and isovalerylglycine, with primary and secondary consequences noted here: […] The ketoacidosis, hyperammonemia, and hypoglycemia can explain the lethargy and obtundation that are sometimes seen in IVA patients in acute crisis. The ketoacidosis also produces vomiting. Release of free fatty acids from body fat into the liver produces a fatty liver. Prolonged metabolic decompensation can lead to bone marrow suppression with resulting neutropenia or pancytopenia.

• #55 :: PGHN :: Pediatric Gastroenterology, Hepatology & Nutrition

  https://www.pghn.org/DOIx.php?id=10.5223/pghn.2017.20.1.61

  Recurrent acute pancreatic attacks is a rare clinical condition (2-5% of all acute pancreatitis) in children and is mainly idiopathic in most cases. […] Isovaleric acidemia (IVA) is a rare autosomal recessive amino acid metabolism disorder associated with isovaleryl coenzyme A dehydrogenase deficiency presenting the clinical findings such metabolic acidosis with increased anion gap, hyperammonemia, ketonemia, hypoglycemia, the odor of sweaty feet, abdominal pain, vomiting, feeding intolerance, shock and coma. […] The pathogenesis of pancreatitis in organic acidemias is still unclear. Factors such as mitochondrial dysfunction due to ATP deficiency, accumulation of toxic metabolites in the pancreatic cell membrane, carnitine deficiency, decreased levels of antioxidant agents such as vitamins C and E, glutathione and selenium and increased free oxygen radicals have been implicated. […] The patients can be diagnosed IVA after recurrent AP attacks or AP attacks can occur during the follow-up of IVA. […] In conclusion; metabolic diseases must be kept in mind in the differential diagnosis of recurrent AP attacks in children even in the absence of metabolic disturbances.

• #56 :: PGHN :: Pediatric Gastroenterology, Hepatology & Nutrition

  https://www.pghn.org/DOIx.php?id=10.5223/pghn.2017.20.1.61

  Recurrent acute pancreatic attacks is a rare clinical condition (2-5% of all acute pancreatitis) in children and is mainly idiopathic in most cases. […] Isovaleric acidemia (IVA) is a rare autosomal recessive amino acid metabolism disorder associated with isovaleryl coenzyme A dehydrogenase deficiency presenting the clinical findings such metabolic acidosis with increased anion gap, hyperammonemia, ketonemia, hypoglycemia, the odor of sweaty feet, abdominal pain, vomiting, feeding intolerance, shock and coma. […] The pathogenesis of pancreatitis in organic acidemias is still unclear. Factors such as mitochondrial dysfunction due to ATP deficiency, accumulation of toxic metabolites in the pancreatic cell membrane, carnitine deficiency, decreased levels of antioxidant agents such as vitamins C and E, glutathione and selenium and increased free oxygen radicals have been implicated. […] The patients can be diagnosed IVA after recurrent AP attacks or AP attacks can occur during the follow-up of IVA. […] In conclusion; metabolic diseases must be kept in mind in the differential diagnosis of recurrent AP attacks in children even in the absence of metabolic disturbances.

• #57 :: PGHN :: Pediatric Gastroenterology, Hepatology & Nutrition

  https://www.pghn.org/DOIx.php?id=10.5223/pghn.2017.20.1.61

  Recurrent acute pancreatic attacks is a rare clinical condition (2-5% of all acute pancreatitis) in children and is mainly idiopathic in most cases. […] Isovaleric acidemia (IVA) is a rare autosomal recessive amino acid metabolism disorder associated with isovaleryl coenzyme A dehydrogenase deficiency presenting the clinical findings such metabolic acidosis with increased anion gap, hyperammonemia, ketonemia, hypoglycemia, the odor of sweaty feet, abdominal pain, vomiting, feeding intolerance, shock and coma. […] The pathogenesis of pancreatitis in organic acidemias is still unclear. Factors such as mitochondrial dysfunction due to ATP deficiency, accumulation of toxic metabolites in the pancreatic cell membrane, carnitine deficiency, decreased levels of antioxidant agents such as vitamins C and E, glutathione and selenium and increased free oxygen radicals have been implicated. […] The patients can be diagnosed IVA after recurrent AP attacks or AP attacks can occur during the follow-up of IVA. […] In conclusion; metabolic diseases must be kept in mind in the differential diagnosis of recurrent AP attacks in children even in the absence of metabolic disturbances.

• #58 :: PGHN :: Pediatric Gastroenterology, Hepatology & Nutrition

  https://www.pghn.org/DOIx.php?id=10.5223/pghn.2017.20.1.61

  Recurrent acute pancreatic attacks is a rare clinical condition (2-5% of all acute pancreatitis) in children and is mainly idiopathic in most cases. […] Isovaleric acidemia (IVA) is a rare autosomal recessive amino acid metabolism disorder associated with isovaleryl coenzyme A dehydrogenase deficiency presenting the clinical findings such metabolic acidosis with increased anion gap, hyperammonemia, ketonemia, hypoglycemia, the odor of sweaty feet, abdominal pain, vomiting, feeding intolerance, shock and coma. […] The pathogenesis of pancreatitis in organic acidemias is still unclear. Factors such as mitochondrial dysfunction due to ATP deficiency, accumulation of toxic metabolites in the pancreatic cell membrane, carnitine deficiency, decreased levels of antioxidant agents such as vitamins C and E, glutathione and selenium and increased free oxygen radicals have been implicated. […] The patients can be diagnosed IVA after recurrent AP attacks or AP attacks can occur during the follow-up of IVA. […] In conclusion; metabolic diseases must be kept in mind in the differential diagnosis of recurrent AP attacks in children even in the absence of metabolic disturbances.

• #59 :: PGHN :: Pediatric Gastroenterology, Hepatology & Nutrition

  https://www.pghn.org/DOIx.php?id=10.5223/pghn.2017.20.1.61

  Recurrent acute pancreatic attacks is a rare clinical condition (2-5% of all acute pancreatitis) in children and is mainly idiopathic in most cases. […] Isovaleric acidemia (IVA) is a rare autosomal recessive amino acid metabolism disorder associated with isovaleryl coenzyme A dehydrogenase deficiency presenting the clinical findings such metabolic acidosis with increased anion gap, hyperammonemia, ketonemia, hypoglycemia, the odor of sweaty feet, abdominal pain, vomiting, feeding intolerance, shock and coma. […] The pathogenesis of pancreatitis in organic acidemias is still unclear. Factors such as mitochondrial dysfunction due to ATP deficiency, accumulation of toxic metabolites in the pancreatic cell membrane, carnitine deficiency, decreased levels of antioxidant agents such as vitamins C and E, glutathione and selenium and increased free oxygen radicals have been implicated. […] The patients can be diagnosed IVA after recurrent AP attacks or AP attacks can occur during the follow-up of IVA. […] In conclusion; metabolic diseases must be kept in mind in the differential diagnosis of recurrent AP attacks in children even in the absence of metabolic disturbances.

• #60 Isovaleric Acidemia Presenting as Diabetic Ketoacidosis: A Case Report – Journal of Clinical Research in Pediatric Endocrinology

  https://jcrpe.org/articles/isovaleric-acidemia-presenting-as-diabetic-ketoacidosis-a-case-report/doi/Jcrpe.1181

  Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma, ketoacidosis and a ‘sweaty feet’ odor. […] Isovaleric acidemia (IVA) is an autosomal recessive disease of leucine metabolism due to deficiency of isovaleryl-CoA Dehydrogenase (IVD). […] The pathophysiology of hyperglycemia in IVA has not yet been identified. We hypothesize that the patient may have had a transient insulin receptor defect or hypoinsulinemia due to organic acids. […] The diagnosis of IVA is usually based on the detection of typical metabolites of Isovaleryl-CoA in the urine organic acid analyses and of elevated C5-carnitine (isovalerylcarnitine) levels in blood and in molecular analysis. […] Mutation at the cryptic splice site have an effect on splicing of the IVD gene. […] The treatment of acute metabolic decompensation in IVA cases comprises a high-caloric infusion therapy, correction of the metabolic acidosis and supplementation with L-carnitine and L-glycine to enhance the detoxification of isovaleric acid. […] This case illustrates that organic acidemias should be kept in mind in the differential diagnosis of DKA.

• #61 Isovaleric Acidemia Presenting as Diabetic Ketoacidosis: A Case Report – Journal of Clinical Research in Pediatric Endocrinology

  https://jcrpe.org/articles/isovaleric-acidemia-presenting-as-diabetic-ketoacidosis-a-case-report/doi/Jcrpe.1181

  Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma, ketoacidosis and a ‘sweaty feet’ odor. […] Isovaleric acidemia (IVA) is an autosomal recessive disease of leucine metabolism due to deficiency of isovaleryl-CoA Dehydrogenase (IVD). […] The pathophysiology of hyperglycemia in IVA has not yet been identified. We hypothesize that the patient may have had a transient insulin receptor defect or hypoinsulinemia due to organic acids. […] The diagnosis of IVA is usually based on the detection of typical metabolites of Isovaleryl-CoA in the urine organic acid analyses and of elevated C5-carnitine (isovalerylcarnitine) levels in blood and in molecular analysis. […] Mutation at the cryptic splice site have an effect on splicing of the IVD gene. […] The treatment of acute metabolic decompensation in IVA cases comprises a high-caloric infusion therapy, correction of the metabolic acidosis and supplementation with L-carnitine and L-glycine to enhance the detoxification of isovaleric acid. […] This case illustrates that organic acidemias should be kept in mind in the differential diagnosis of DKA.

• #62 Isovaleric Acidemia Presenting as Diabetic Ketoacidosis: A Case Report – Journal of Clinical Research in Pediatric Endocrinology

  https://jcrpe.org/articles/isovaleric-acidemia-presenting-as-diabetic-ketoacidosis-a-case-report/doi/Jcrpe.1181

  Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma, ketoacidosis and a ‘sweaty feet’ odor. […] Isovaleric acidemia (IVA) is an autosomal recessive disease of leucine metabolism due to deficiency of isovaleryl-CoA Dehydrogenase (IVD). […] The pathophysiology of hyperglycemia in IVA has not yet been identified. We hypothesize that the patient may have had a transient insulin receptor defect or hypoinsulinemia due to organic acids. […] The diagnosis of IVA is usually based on the detection of typical metabolites of Isovaleryl-CoA in the urine organic acid analyses and of elevated C5-carnitine (isovalerylcarnitine) levels in blood and in molecular analysis. […] Mutation at the cryptic splice site have an effect on splicing of the IVD gene. […] The treatment of acute metabolic decompensation in IVA cases comprises a high-caloric infusion therapy, correction of the metabolic acidosis and supplementation with L-carnitine and L-glycine to enhance the detoxification of isovaleric acid. […] This case illustrates that organic acidemias should be kept in mind in the differential diagnosis of DKA.

• #63 Isovaleric acidemia: A rare cause of isolated cerebellar atrophy

  https://www.oatext.com/isovaleric-acidemia-a-rare-cause-of-isolated-cerebellar-atrophy.php

  The susceptibility of the cerebellum to selective injury with organic acidurias, such as in particular 3-methylglutaconic aciduria, is another explanation of the cerebellar atrophy seen in our patient. […] Our case demonstrates that isovaleric acidemia is one rare etiology of isolated cerebellar atrophy in children.

• #64 Isovaleric acidemia: A rare cause of isolated cerebellar atrophy

  https://www.oatext.com/isovaleric-acidemia-a-rare-cause-of-isolated-cerebellar-atrophy.php

  The susceptibility of the cerebellum to selective injury with organic acidurias, such as in particular 3-methylglutaconic aciduria, is another explanation of the cerebellar atrophy seen in our patient. […] Our case demonstrates that isovaleric acidemia is one rare etiology of isolated cerebellar atrophy in children.

• #65 Orphanet: Isovaleric acidemia

  https://www.orpha.net/en/disease/detail/33

  Isovaleric acidemia (IVA) is caused by mutations in the IVD gene (15q15.1) encoding the enzyme isovaleryl-CoA dehydrogenase (IVDH) resulting in accumulation of isovaleric acid and its derivatives. […] Patients present along a spectrum. Acute, neonatal presentation is characterized by onset in the first two weeks of life with vomiting, seizures, and lethargy, progressing to coma. […] The characteristic smell of isovaleric acid may be present, and is likened to sweaty feet/body sweat. […] Lifelong management is with a low protein diet. […] Prognosis for patients diagnosed by newborn screening is excellent with the potential for normal neurodevelopmental outcome with appropriate metabolic management.

• #66 Isovaleric acidemia | MedLink Neurology

  https://www.medlink.com/articles/isovaleric-acidemia

  Isovaleric acidemia is an inborn error of leucine metabolism that results from a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase, which is caused by a homozygous mutation in the isovaleryl-CoA dehydrogenase gene on chromosome 15q15.1. […] Isovaleric acidemia is transmitted as an autosomal recessive trait. […] Due to the metabolic block, isovaleryl-CoA accumulates, and the pathognomonic metabolite isovalerylglycine is formed by conjugation of isovaleryl-CoA to the amino group of glycine. […] The mechanism of isovaleric acid toxicity remains unclear, though it is likely to be multifactorial. Some findings point to an inhibition of mitochondrial energy metabolism. […] The catabolic pathway is challenged by increased protein intake or increased endogenous protein degradation. […] The other important therapy principle is to increase the excretion of isovaleric acid as nontoxic glycine and carnitine conjugates.

• #67 Aspects of Newborn Screening in Isovaleric Acidemia

  https://www.mdpi.com/2409-515X/4/1/7

  Isovaleric acidemia (IVA), an inborn error of leucine catabolism, is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene, resulting in the accumulation of derivatives of isovaleryl-CoA including isovaleryl (C5)-carnitine, the marker metabolite used for newborn screening (NBS). […] The pathogenesis of the disease is still not fully understood. Mechanisms thought to be involved include the induction of oxidative stress through accumulating metabolites as seen in the rat brain cortex, the reduction of Na+, K+-ATPase activity by free isovaleric acid as shown in synaptic membranes from the cerebral cortex in young rats, and abnormal cellular growth signaling through activation of the mammalian target of rapamycin complex 1 (mTORC1), as suggested from studies with human IVD deficient cells. […] Deficiency of IVD results in an accumulation of derivatives of isovaleryl-coenzyme A (CoA), the metabolite before the block, such as isovaleric acid, 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine, and isovalerylglycine (IVG).

• #68 Isovaleric acidemia | MedLink Neurology

  https://www.medlink.com/articles/isovaleric-acidemia

  Isovaleric acidemia is an inborn error of leucine metabolism that results from a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase, which is caused by a homozygous mutation in the isovaleryl-CoA dehydrogenase gene on chromosome 15q15.1. […] Isovaleric acidemia is transmitted as an autosomal recessive trait. […] Due to the metabolic block, isovaleryl-CoA accumulates, and the pathognomonic metabolite isovalerylglycine is formed by conjugation of isovaleryl-CoA to the amino group of glycine. […] The mechanism of isovaleric acid toxicity remains unclear, though it is likely to be multifactorial. Some findings point to an inhibition of mitochondrial energy metabolism. […] The catabolic pathway is challenged by increased protein intake or increased endogenous protein degradation. […] The other important therapy principle is to increase the excretion of isovaleric acid as nontoxic glycine and carnitine conjugates.

• #69 Isovaleric Acidaemia – Metabolic Support UKAccessibility ToolsIncrease TextDecrease TextGrayscaleHigh ContrastNegative ContrastLight BackgroundLinks UnderlineReadable FontReset

  https://metabolicsupportuk.org/condition/isovaleric-acidaemia/

  Isovaleric Acidaemia is caused by a problem in the IVD gene. This gene produces an enzyme which breaks down an amino acid called leucine. This process is needed because leucine is a part of many proteins which helps to provide energy to your body. […] If you have a problem in the IVD gene, you will not produce enough of this enzyme. Therefore, you will be unable to break down leucine properly and this causes its compounds to build up to toxic levels. This can damage your brain and your nervous system, leading to a number of serious health issues. […] There is no cure for Isovaleric Acidaemia, however there are a range of ways that the disorder can be managed successfully, and plans can be put in place to reduce the chances of the disorder getting worse. […] One of the most important ways to manage the disorder is through following a specific diet. It is recommended that you follow a low-protein diet, as people with Isovaleric Acidaemia are unable to process protein properly.

• #70 Isovaleric acidaemia – Genomics Education Programme

  http://www.genomicseducation.hee.nhs.uk/documents/isovaleric-acidaemia/

  Isovaleric acidaemia (IVA) is an autosomal recessive disorder caused by the deficiency of the enzyme isovaleryl-CoA dehydrogenase (IVD). […] IVD is responsible for the dehydrogenation of isovaleryl-CoA to produce 3-methylcrotonyl-CoA, and is involved in the metabolism of the amino acid, leucine. […] IVA is an autosomal recessive condition caused by mutations in the IVD gene. […] The IVD gene encodes the enzyme isovaleryl-CoA dehydrogenase. […] The main goal of management is to reduce the production and increase the excretion of isovaleryl-CoA. […] Patients may also be supplemented with carnitine and/or glycine. Carnitine and glycine are used to reduce isovaleric acid levels by the formation of the isovaleryl-CoA conjugates, which can then be excreted in the urine.

• #71 Problem 5 Therapeutic glycine. Isovaleric … [FREE SOLUTION] | Vaia

  https://www.vaia.com/en-us/textbooks/chemistry/biochemistry-6-edition/chapter-24/problem-5-therapeutic-glycine-isovaleric-acidemia-is-an-inhe/

  Glycine conjugates with toxic isovaleric acid to form isovalerylglycine, reducing toxicity and improving clinical outcomes. […] In isovaleric acidemia, excess isovaleric acid can conjugate with glycine to form isovalerylglycine. This conjugation reduces the level of toxic isovaleric acid in the body, as isovalerylglycine is less harmful and can be more easily excreted in urine, leading to clinical improvement. […] By lowering the levels of toxic isovaleric acid through conjugation with glycine, symptoms of toxicity may be alleviated, ensuring a better clinical outcome for infants affected by isovaleric acidemia. […] Glycine plays an essential therapeutic role by binding to excess isovaleric acid. This process creates isovalerylglycine, a much less toxic compound compared to free isovaleric acid. […] This reduction in toxic levels leads to clinical improvements.

• #72 Clinical and neurocognitive outcome in symptomatic isovaleric acidemia | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-9

  Isovaleric acidemia (IVA) is known as one of the „classical” organic acidemias/acidurias. It is caused by a genetic deficiency of isovaleryl-CoA dehydrogenase (IVD) catalyzing the third step in leucine catabolism. The enzyme defect results in the accumulation of derivatives of isovaleryl-CoA including free isovaleric acid, 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine, and isovalerylglycine (IVG) which partly may exert neurotoxicity. […] The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening. […] The underlying pathophysiologic mechanisms leading to cerebral damage are still not fully elucidated. Based on studies in rats it can be presumed that metabolites accumulating in IVA induce oxidative stress in the brain cortex and that oxidative damage may be at least in part involved in the neuropathology of IVA.

• #73 Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2652706/

  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. […] The reaction catalyzed by IVD is initiated upon acyl-CoA substrate binding. […] The molecular mechanism of the oxidative half-reaction and the order of binding of the substrates have not been elucidated. […] Molecular cloning of the IVD gene showed it to be located on chromosome 15q1415, consisting of 12 exons that span ~15 kb of genomic DNA. […] Molecular analysis of the IVD gene in patients with symptomatic IVA has identified numerous point mutations in the protein coding region that lead to the production of an inactive or unstable protein. […] Some of these have been shown to cause only a mild alteration in enzyme function, correlating to some extent with a mild clinical phenotype in patients.

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