Materiały źródłowe

• #1 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. […] Mutations in both copies of the IVD gene result in isovaleric 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.

• #2 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. […] People inherit IVA in an autosomal recessive pattern. This means that both biological parents must pass on altered IVD genes for the condition to develop. […] Isovaleric acidemia (IVA) is a rare inherited condition that affects leucine breakdown. […] After an IVA diagnosis, people will need to avoid high protein food and take lifelong medications to clear waste acids from the body.

• #3 NEWBORN SCREENING

  http://w.newbornscreening.info/Parents/organicaciddisorders/IVA.html

  When both parents are carriers, there is a 25% chance in each pregnancy for the child to have IVA. […] Genetic testing for IVA can be done on a blood sample. […] Special tests on blood, urine, or skin samples can be done to confirm IVA. […] About one in every 230,000 babies in the United States is born with IVA. […] IVA does not happen more often in any specific race, ethnic group, geographical area, or country. […] IVA is sometimes also called: isovaleric Acid CoA Dehydrogenase Deficiency, IVD deficiency, isovaleryl CoA carboxylase deficiency.

• #4 An unusual case of oral surgical management in a patient with isovaleric acidemia and schizophrenia: A case report

  https://www.spandidos-publications.com/10.3892/br.2022.1547

  Oral/dental surgical care in patients with chronic medical comorbidities, such as isovaleric acidemia (IVA), can be challenging. […] IVA, a congenital error of metabolism, is a rare organic acidemia with a predisposition towards acute acidosis and lifethreatening metabolic decompensation during stressful conditions, such as prolonged fasting and surgery. […] IVA (MIM #243500) is a rare autosomal recessive congenital metabolic disorder categorized as organic acidemia. […] Furthermore, IVA is relatively uncommon, with a frequency of 1:250,000, 1:365,000 and 1:62,500 births in the United States, Taiwan and Germany, respectively. […] IVA disorder results from an accumulation of isovaleric acid in the body, which is toxic to the central nervous system. […] During IVA crises, detoxification is achieved through alternative pathways that produce isovaleric glycine, 3-hydroxyisovaleric acid and other metabolites excreted via the urinary system.

• #5 Isovaleric acidemia | MedLink Neurology

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

  Isovaleric acidemia is caused by a deficiency of isovaleryl-CoA dehydrogenase, an enzyme located proximally in the catabolic pathway of the essential branched-chain amino acid leucine. […] 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. […] Both clinical presentations, acute neonatal and infantile chronic-episodic, may be found within the same family and, thus, are determined by other genes or nongenetic factors. […] 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.

• #6 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. […] Asymptomatic patients with specific mutations have been reported, especially when identified through newborn screening.

• #7 Isovaleric Acidemia | Encyclopedia MDPI

  https://encyclopedia.pub/entry/4194

  Isovaleric acidemia is a rare disorder in which the body is unable to properly break down a particular protein building block (amino acid). […] 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. […] This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

• #8 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). […] 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. […] The characteristic odor of sweaty feet caused by isovaleric acid is often noted during metabolic crisis. […] To date, more than 70 heterogeneous mutations in the IVD gene have been reported in patients with IVA. […] The patient had compound heterozygous mutations: c.1193GA (p.Arg398Gln) and c.1208AG (p.Try403Cys). […] The clinical manifestations vary, and disease onset can range from the neonatal period to the adult period.

• #9 Isovaleric Acidemia | Encyclopedia MDPI

  https://encyclopedia.pub/entry/4194

  Isovaleric acidemia is a rare disorder in which the body is unable to properly break down a particular protein building block (amino acid). […] 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. […] This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

• #10 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. […] Mutations in both copies of the IVD gene result in isovaleric 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.

• #11 Isovaleric Acidemia | Encyclopedia MDPI

  https://encyclopedia.pub/entry/4194

  Isovaleric acidemia is a rare disorder in which the body is unable to properly break down a particular protein building block (amino acid). […] 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. […] This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

• #12 Isovaleric acidaemia

  https://www.nhs.uk/conditions/isovaleric-acidaemia/

  Isovaleric acidaemia (IVA) is a rare, but potentially serious, inherited condition. It means the body can’t process the amino acid leucine (amino acids are „building blocks” of protein). This causes a harmful build-up of the substance in the blood and urine. […] Babies with IVA are unable to fully break down the amino acid leucine. […] Normally, leucine is broken down into a substance called isovaleric acid, which is then converted into energy. Babies with IVA don’t have the enzyme that breaks down isovaleric acid, leading to a harmfully high level of this substance in the body. […] The genetic change (mutation) responsible for IVA is passed on by the parents, who usually don’t have any symptoms of the condition. […] A baby needs to receive 2 copies of the mutated gene to develop the condition 1 from their mother and 1 from their father (known as autosomal recessive inheritance). If the baby only receives 1 affected gene, they’ll just be a carrier of IVA and won’t have the condition themselves.

• #13 Isovaleric acidaemia

  https://www.nhs.uk/conditions/isovaleric-acidaemia/

  Isovaleric acidaemia (IVA) is a rare, but potentially serious, inherited condition. It means the body can’t process the amino acid leucine (amino acids are „building blocks” of protein). This causes a harmful build-up of the substance in the blood and urine. […] Babies with IVA are unable to fully break down the amino acid leucine. […] Normally, leucine is broken down into a substance called isovaleric acid, which is then converted into energy. Babies with IVA don’t have the enzyme that breaks down isovaleric acid, leading to a harmfully high level of this substance in the body. […] The genetic change (mutation) responsible for IVA is passed on by the parents, who usually don’t have any symptoms of the condition. […] A baby needs to receive 2 copies of the mutated gene to develop the condition 1 from their mother and 1 from their father (known as autosomal recessive inheritance). If the baby only receives 1 affected gene, they’ll just be a carrier of IVA and won’t have the condition themselves.

• #14 Condition Acidemia, Isovaleric

  https://digestivetracthealth.com/symptoms/Low+level+of+certain+types+of+white+blood+cells+and+other+body+cells

  Isovaleric acidemia is a genetic disorder inherited in an autosomal recessive pattern. […] In patients with isovaleric acidemia, there is a mutation in the IVD gene that inactivates the enzyme isovaleryl-Co-enzyme A (CoA) dehydrogenase. This enzyme is needed for the breakdown of the amino acid leucine into energy. […] The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. […] Since it is a hereditary disease, it passes to the child through parents. This results when an individual inherits a non-working gene from each parent.

• #15

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

  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 2 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. […] Children from the same parents have a 1 in 4 chance of having IVA. Your other children might be at risk of IVA even if they have never shown any symptoms. It is therefore very important to get them tested if they have not been previously screened for IVA. Your metabolic team will be able to arrange this testing. […] A new baby from the same parents will also have a 1 in 4 chance of having IVA.

• #16

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

  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 2 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. […] Children from the same parents have a 1 in 4 chance of having IVA. Your other children might be at risk of IVA even if they have never shown any symptoms. It is therefore very important to get them tested if they have not been previously screened for IVA. Your metabolic team will be able to arrange this testing. […] A new baby from the same parents will also have a 1 in 4 chance of having IVA.

• #17 Isovaleric Acidemia (IVA) | New York State Department of Health, Wadsworth Center

  https://www.wadsworth.org/public-health-programs/newborn-screening/newborn-screening-program/isovaleric-acidemia-iva

  Isovaleric acidemia (IVA) is caused by mutations in the IVD gene. […] Mutations in the IVD gene cause a deficiency of an important enzyme, isovaleryl-CoA dehydrogenase. […] Without this enzyme, leucine is not broken down; the toxic metabolite isovaleric acid accumulates and causes neurologic symptoms.

• #18 Isovaleric acidaemia

  https://www.nhs.uk/conditions/isovaleric-acidaemia/

  Isovaleric acidaemia (IVA) is a rare, but potentially serious, inherited condition. It means the body can’t process the amino acid leucine (amino acids are „building blocks” of protein). This causes a harmful build-up of the substance in the blood and urine. […] Babies with IVA are unable to fully break down the amino acid leucine. […] Normally, leucine is broken down into a substance called isovaleric acid, which is then converted into energy. Babies with IVA don’t have the enzyme that breaks down isovaleric acid, leading to a harmfully high level of this substance in the body. […] The genetic change (mutation) responsible for IVA is passed on by the parents, who usually don’t have any symptoms of the condition. […] A baby needs to receive 2 copies of the mutated gene to develop the condition 1 from their mother and 1 from their father (known as autosomal recessive inheritance). If the baby only receives 1 affected gene, they’ll just be a carrier of IVA and won’t have the condition themselves.

• #19 Isovaleric acidemia | MedLink Neurology

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

  Isovaleric acidemia is caused by a deficiency of isovaleryl-CoA dehydrogenase, an enzyme located proximally in the catabolic pathway of the essential branched-chain amino acid leucine. […] 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. […] Both clinical presentations, acute neonatal and infantile chronic-episodic, may be found within the same family and, thus, are determined by other genes or nongenetic factors. […] 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.

• #20 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 clinical presentation of IVA appears to be highly variable ranging from severely affected to asymptomatic subjects. It may present either in the neonatal period as an acute episode of fulminant metabolic acidosis which may lead to coma and death („acute neonatal form”) or later as a „chronic intermittent form” associated with developmental delay, with or without recurrent acidotic episodes during catabolic stress.

• #21 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). […] IVA is due to a defect of isovalery-CoA dehydrogenase (IVD; Mendelian Inheritance in Man [MIM] #607036; enzyme commission [EC] 1.3.8.4), an acyl-CoA dehydrogenase (ACAD) catalyzing the third step in the intramitochondrial breakdown of leucine. It is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene and is inherited as an autosomal recessive trait. More than 60 disease-causing mutations in the IVD gene have been described. […] 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).

• #22 Isovaleric acidemia (IVA) | European registry and network for Intoxication type Metabolic Diseases – E-IMD

  https://www.e-imd.org/diseases/organic-acidurias-oads/isovaleric-acidemia-iva

  Isovaleric acidemia (IVA) is inherited as an autosomal recessive trait. The gene encoding isovaleryl-CoA dehydrogenase has been cloned and localized to chromosome 15 (15q14-15), and multiple disease-causing mutations have been identified. A significant proportion of the mutant IVD alleles sequenced from infants diagnosed by newborn screening have been found to contain a common recurring missense mutation (932CT; A282V). […] The mechanism of the toxicity of isovaleric acid is not known, but it is an inhibitor of succinyl-CoA ligase in the tricarboxylic acid cycle and inhibits liver but not muscle mitochondrial oxygen consumption with glutamic, 2-oxoglutaric, and succinic acids. Isovaleric acid is an inhibitor of granulopoietic progenitor cell proliferation in bone marrow cultures with half-maximal inhibition at 1.6 mM, and this may account for the neutropenia frequently seen in isovaleric acidemia.

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

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

  The first was an acute, neonatal presentation with patients becoming symptomatic within the first two weeks of life. […] The second group presented with relatively non-specific failure to thrive and/or developmental delay (chronic intermittent presentation). […] In reality it is now apparent that patients can fall anywhere on the spectrum of acute to chronic presentation and that there is probably little predictive value to the initial presentation. […] Moreover, with the application of MS/MS in newborn screening, potentially asymptomatic patients with one recurring IVD gene mutation and a mild biochemical phenotype are being identified in increasing numbers, representing an additional phenotype of IVA. […] The majority of patients with IVA today are diagnosed pre-symptomatically through newborn screening by use of MS/MS which reveals elevations of the marker metabolite C5 acylcarnitine in dried blood spots.

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

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

  The first was an acute, neonatal presentation with patients becoming symptomatic within the first two weeks of life. […] The second group presented with relatively non-specific failure to thrive and/or developmental delay (chronic intermittent presentation). […] In reality it is now apparent that patients can fall anywhere on the spectrum of acute to chronic presentation and that there is probably little predictive value to the initial presentation. […] Moreover, with the application of MS/MS in newborn screening, potentially asymptomatic patients with one recurring IVD gene mutation and a mild biochemical phenotype are being identified in increasing numbers, representing an additional phenotype of IVA. […] The majority of patients with IVA today are diagnosed pre-symptomatically through newborn screening by use of MS/MS which reveals elevations of the marker metabolite C5 acylcarnitine in dried blood spots.

• #25 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). […] The clinical manifestations of IVA include paroxysmal vomiting, lethargy or altered mental status, epilepsy, poor feeding, developmental delay, severe metabolic acidosis, hyperammonaemia, ketosis, hyper- or hypoglycaemia, and cytopenia. […] IVA can be categorized into three subtypes: (1) Acute neonatal type: disease presents in the first 2 weeks after birth, including severe metabolic acidosis and encephalopathy, often accompanied by leukopenia, neutropenia, thrombocytopenia, electrolyte disturbances, and hypo- or hyperglycaemia.

• #26 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). […] 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. […] The characteristic odor of sweaty feet caused by isovaleric acid is often noted during metabolic crisis. […] To date, more than 70 heterogeneous mutations in the IVD gene have been reported in patients with IVA. […] The patient had compound heterozygous mutations: c.1193GA (p.Arg398Gln) and c.1208AG (p.Try403Cys). […] The clinical manifestations vary, and disease onset can range from the neonatal period to the adult period.

• #27 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 etiology of hyperglycemia in IVA needs further investigation. […] 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.

• #28 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

  Mortality in the early diagnosis group was 33% during the initial episode of severe metabolic acidosis. In the early diagnosis group, the mean age at onset of symptoms as reported for 55 of 81 cases, was 6.8 days. […] The neurocognitive outcome in surviving patients with neonatal manifestation and early start of treatment is more favourable than in patients with a late diagnosis. […] Age at diagnosis but not the number of catabolic episodes has an impact on the neurocognitive outcome. […] The potential to avoid early mortality and to improve neurocognitive outcome by early diagnosis and treatment encourages pre-symptomatic diagnosis and reinforces IVA to be qualified for NBS.

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

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

  The first was an acute, neonatal presentation with patients becoming symptomatic within the first two weeks of life. […] The second group presented with relatively non-specific failure to thrive and/or developmental delay (chronic intermittent presentation). […] In reality it is now apparent that patients can fall anywhere on the spectrum of acute to chronic presentation and that there is probably little predictive value to the initial presentation. […] Moreover, with the application of MS/MS in newborn screening, potentially asymptomatic patients with one recurring IVD gene mutation and a mild biochemical phenotype are being identified in increasing numbers, representing an additional phenotype of IVA. […] The majority of patients with IVA today are diagnosed pre-symptomatically through newborn screening by use of MS/MS which reveals elevations of the marker metabolite C5 acylcarnitine in dried blood spots.

• #30 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

  (2) Chronic intermittent type: findings include psychomotor delay and paroxysmal metabolic disorder. […] (3) Asymptomatic type: findings include mild biochemical abnormalities (5). […] 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). […] 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. […] The c.932C>T (p.Ala282Val) and c.941C>T (p.Ala314Val) variants were common in asymptomatic and neonatal screening patients who remained asymptomatic during the follow-up period.

• #31 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. […] Isovaleric acidemia is a very rare autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-coenzyme A dehydrogenase, leading to accumulation of isovaleric acid, a catabolite of leucine. […] The disease has two well-known clinical phenotypes: an acute neonatal presentation in the first two weeks of life with vomiting, lethargy and metabolic acidosis that can progress to coma and death and a chronic intermittent phenotype presenting with failure to thrive and/or developmental delay with or without intermittent acute episodes of acidotic decompensation due to intercurrent catabolic stress. […] Our case demonstrates that isovaleric acidemia is one rare etiology of isolated cerebellar atrophy in children.

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

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

  The first was an acute, neonatal presentation with patients becoming symptomatic within the first two weeks of life. […] The second group presented with relatively non-specific failure to thrive and/or developmental delay (chronic intermittent presentation). […] In reality it is now apparent that patients can fall anywhere on the spectrum of acute to chronic presentation and that there is probably little predictive value to the initial presentation. […] Moreover, with the application of MS/MS in newborn screening, potentially asymptomatic patients with one recurring IVD gene mutation and a mild biochemical phenotype are being identified in increasing numbers, representing an additional phenotype of IVA. […] The majority of patients with IVA today are diagnosed pre-symptomatically through newborn screening by use of MS/MS which reveals elevations of the marker metabolite C5 acylcarnitine in dried blood spots.

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

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

  The first was an acute, neonatal presentation with patients becoming symptomatic within the first two weeks of life. […] The second group presented with relatively non-specific failure to thrive and/or developmental delay (chronic intermittent presentation). […] In reality it is now apparent that patients can fall anywhere on the spectrum of acute to chronic presentation and that there is probably little predictive value to the initial presentation. […] Moreover, with the application of MS/MS in newborn screening, potentially asymptomatic patients with one recurring IVD gene mutation and a mild biochemical phenotype are being identified in increasing numbers, representing an additional phenotype of IVA. […] The majority of patients with IVA today are diagnosed pre-symptomatically through newborn screening by use of MS/MS which reveals elevations of the marker metabolite C5 acylcarnitine in dried blood spots.

• #34 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

  (2) Chronic intermittent type: findings include psychomotor delay and paroxysmal metabolic disorder. […] (3) Asymptomatic type: findings include mild biochemical abnormalities (5). […] 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). […] 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. […] The c.932C>T (p.Ala282Val) and c.941C>T (p.Ala314Val) variants were common in asymptomatic and neonatal screening patients who remained asymptomatic during the follow-up period.

• #35 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. […] 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. […] 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.

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

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

  Prior to newborn screening, this mutation was identified only in a single patient with mild IVD deficiency originally evaluated for a tic disorder and slight developmental delay. […] It is clear that the newborn screening patients who carry the common mutation either in a homozygous or compound heterozygous state and their sibs skew the spectrum of IVA with more than half of individuals representing a new mild phenotype and potentially remaining asymptomatic. […] The necessity of any treatment for individuals diagnosed by newborn screening and carrying the common 932CT (A282V) mutation is unclear.

• #37 Aspects of Newborn Screening in Isovaleric Acidemia

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

  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. […] A certain missense mutation, c.932C>T (p.A282V), in either a homozygous or compound heterozygous state, is associated with this “mild” form of IVA. […] The first patient with SBCADD was reported in 1999. […] The ACADSB gene structure was described in 2000, and several mutations in this gene have been reported.

• #38

  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. […] The 932CT variant is a mild form of IVA. The risk of problems for babies with this variant is much lower than for those with the more serious variant of the disorder.

• #39 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

  (2) Chronic intermittent type: findings include psychomotor delay and paroxysmal metabolic disorder. […] (3) Asymptomatic type: findings include mild biochemical abnormalities (5). […] 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). […] 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. […] The c.932C>T (p.Ala282Val) and c.941C>T (p.Ala314Val) variants were common in asymptomatic and neonatal screening patients who remained asymptomatic during the follow-up period.

• #40 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

  (2) Chronic intermittent type: findings include psychomotor delay and paroxysmal metabolic disorder. […] (3) Asymptomatic type: findings include mild biochemical abnormalities (5). […] 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). […] 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. […] The c.932C>T (p.Ala282Val) and c.941C>T (p.Ala314Val) variants were common in asymptomatic and neonatal screening patients who remained asymptomatic during the follow-up period.

• #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

  (2) Chronic intermittent type: findings include psychomotor delay and paroxysmal metabolic disorder. […] (3) Asymptomatic type: findings include mild biochemical abnormalities (5). […] 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). […] 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. […] The c.932C>T (p.Ala282Val) and c.941C>T (p.Ala314Val) variants were common in asymptomatic and neonatal screening patients who remained asymptomatic during the follow-up period.

• #42 Isovaleric acidemia (IVA) | European registry and network for Intoxication type Metabolic Diseases – E-IMD

  https://www.e-imd.org/diseases/organic-acidurias-oads/isovaleric-acidemia-iva

  The intensity or even necessity of treatment for individuals diagnosed by newborn screening and carrying the common 932CT (A282V) mutation is unclear. Specifically, the potential for metabolic decompensation under stress conditions remains to be elucidated. It appears reasonable to observe these individuals clinically, particularly when exposed to metabolic stressors such as febrile illnesses or fasting (e.g. when undergoing surgery). Low-dose carnitine supplementation is recommended. […] As opposed to the severe forms of IVA, it is still uncertain whether individuals with the mild type have a disease, a risk of clinical manifestation, or simply express a clinically insignificant biochemical phenotype. While these individuals may have normal leucine homeostasis under physiological conditions, their risk of metabolic decompensation under stress conditions remains to be elucidated.

• #43 Isovaleric acidemia (IVA) | European registry and network for Intoxication type Metabolic Diseases – E-IMD

  https://www.e-imd.org/diseases/organic-acidurias-oads/isovaleric-acidemia-iva

  Isovaleric acidemia (IVA) is inherited as an autosomal recessive trait. The gene encoding isovaleryl-CoA dehydrogenase has been cloned and localized to chromosome 15 (15q14-15), and multiple disease-causing mutations have been identified. A significant proportion of the mutant IVD alleles sequenced from infants diagnosed by newborn screening have been found to contain a common recurring missense mutation (932CT; A282V). […] The mechanism of the toxicity of isovaleric acid is not known, but it is an inhibitor of succinyl-CoA ligase in the tricarboxylic acid cycle and inhibits liver but not muscle mitochondrial oxygen consumption with glutamic, 2-oxoglutaric, and succinic acids. Isovaleric acid is an inhibitor of granulopoietic progenitor cell proliferation in bone marrow cultures with half-maximal inhibition at 1.6 mM, and this may account for the neutropenia frequently seen in isovaleric acidemia.

• #44 Isovaleric acidemia (IVA) | European registry and network for Intoxication type Metabolic Diseases – E-IMD

  https://www.e-imd.org/diseases/organic-acidurias-oads/isovaleric-acidemia-iva

  The intensity or even necessity of treatment for individuals diagnosed by newborn screening and carrying the common 932CT (A282V) mutation is unclear. Specifically, the potential for metabolic decompensation under stress conditions remains to be elucidated. It appears reasonable to observe these individuals clinically, particularly when exposed to metabolic stressors such as febrile illnesses or fasting (e.g. when undergoing surgery). Low-dose carnitine supplementation is recommended. […] As opposed to the severe forms of IVA, it is still uncertain whether individuals with the mild type have a disease, a risk of clinical manifestation, or simply express a clinically insignificant biochemical phenotype. While these individuals may have normal leucine homeostasis under physiological conditions, their risk of metabolic decompensation under stress conditions remains to be elucidated.

• #45 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. […] People inherit IVA in an autosomal recessive pattern. This means that both biological parents must pass on altered IVD genes for the condition to develop. […] Isovaleric acidemia (IVA) is a rare inherited condition that affects leucine breakdown. […] After an IVA diagnosis, people will need to avoid high protein food and take lifelong medications to clear waste acids from the body.

• #46 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. […] Isovaleric acidemia has an autosomal recessive inheritance pattern. […] Prolonged periods without food, fasting, infections, or eating more protein-rich foods can cause serious health problems in these youngsters. […] IVA can be detected through newborn screening (NBS) as well. […] A particular protein-restricted diet and drugs are used to minimize the amount of isovaleric acid in the body.

• #47 An unusual case of oral surgical management in a patient with isovaleric acidemia and schizophrenia: A case report

  https://www.spandidos-publications.com/10.3892/br.2022.1547

  In both IVA forms, acute episodes of metabolic decompensation can appear during catabolic states due to impaired protein and fatty acid metabolism, infection, fasting and other physiological stresses. […] Patients with IVA requiring surgery also present various challenges to the choice of anesthesia, as certain anesthetics can trigger metabolic crises, including poor nutrition, electrolyte imbalance, prolonged periods of fasting and other forms of stress. […] Despite various studies on IVA, there are few reports on its perioperative management. […] Here, the unusual case of successful oral surgical treatment in a patient with two coexisting chronic medical conditions is described. […] The surgical management of comorbid dental diseases in mental and metabolic disorders is associated with an increased risk of postoperative complications.

• #48 An unusual case of oral surgical management in a patient with isovaleric acidemia and schizophrenia: A case report

  https://www.spandidos-publications.com/10.3892/br.2022.1547

  In both IVA forms, acute episodes of metabolic decompensation can appear during catabolic states due to impaired protein and fatty acid metabolism, infection, fasting and other physiological stresses. […] Patients with IVA requiring surgery also present various challenges to the choice of anesthesia, as certain anesthetics can trigger metabolic crises, including poor nutrition, electrolyte imbalance, prolonged periods of fasting and other forms of stress. […] Despite various studies on IVA, there are few reports on its perioperative management. […] Here, the unusual case of successful oral surgical treatment in a patient with two coexisting chronic medical conditions is described. […] The surgical management of comorbid dental diseases in mental and metabolic disorders is associated with an increased risk of postoperative complications.

• #49 Isovaleric Acidaemia (IVA) – Inherited Metabolic Disorders in Scotland

  https://www.imd.scot.nhs.uk/isovaleric-acidaemia-iva/

  Isovaleric acidaemia (IVA) is a rare but treatable inherited disorder that prevents the normal breakdown of protein. […] Babies with IVA have inherited two faulty copies of the gene for IVA, one from each parent. […] Babies with IVA have problems breaking down an amino acid called leucine because an enzyme is missing. This causes harmful substances to build up in their blood and urine. […] Causes of a metabolic crisis can include an infection such as a stomach upset or vomiting illness.

• #50 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. […] An acute metabolic decompensation in a patient with IVA is almost always precipitated by a stressor, such as infection, injury, surgery, hormonal changes, or significant dietary changes (involving increased protein intake). It is of utmost importance to identify and address the precipitating factor for the patients metabolic decompensation. Treatment of the stressor will facilitate treatment of the metabolic derangements.

• #51 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. […] An acute metabolic decompensation in a patient with IVA is almost always precipitated by a stressor, such as infection, injury, surgery, hormonal changes, or significant dietary changes (involving increased protein intake). It is of utmost importance to identify and address the precipitating factor for the patients metabolic decompensation. Treatment of the stressor will facilitate treatment of the metabolic derangements.

• #52 Aspects of Newborn Screening in Isovaleric Acidemia

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

  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. […] A certain missense mutation, c.932C>T (p.A282V), in either a homozygous or compound heterozygous state, is associated with this “mild” form of IVA. […] The first patient with SBCADD was reported in 1999. […] The ACADSB gene structure was described in 2000, and several mutations in this gene have been reported.

• #53 Isovaleric acidemia (IVA) | European registry and network for Intoxication type Metabolic Diseases – E-IMD

  https://www.e-imd.org/diseases/organic-acidurias-oads/isovaleric-acidemia-iva

  Isovaleric acidemia (IVA) is inherited as an autosomal recessive trait. The gene encoding isovaleryl-CoA dehydrogenase has been cloned and localized to chromosome 15 (15q14-15), and multiple disease-causing mutations have been identified. A significant proportion of the mutant IVD alleles sequenced from infants diagnosed by newborn screening have been found to contain a common recurring missense mutation (932CT; A282V). […] The mechanism of the toxicity of isovaleric acid is not known, but it is an inhibitor of succinyl-CoA ligase in the tricarboxylic acid cycle and inhibits liver but not muscle mitochondrial oxygen consumption with glutamic, 2-oxoglutaric, and succinic acids. Isovaleric acid is an inhibitor of granulopoietic progenitor cell proliferation in bone marrow cultures with half-maximal inhibition at 1.6 mM, and this may account for the neutropenia frequently seen in isovaleric acidemia.

• #54 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). […] 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. […] The characteristic odor of sweaty feet caused by isovaleric acid is often noted during metabolic crisis. […] To date, more than 70 heterogeneous mutations in the IVD gene have been reported in patients with IVA. […] The patient had compound heterozygous mutations: c.1193GA (p.Arg398Gln) and c.1208AG (p.Try403Cys). […] The clinical manifestations vary, and disease onset can range from the neonatal period to the adult period.

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

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

  The typical clinical manifestations are severe metabolic acidosis and encephalopathy, often accompanied by leukopenia, neutropenia and thrombocytopenia due to bone marrow suppression and other abnormal blood systems in the neonatal period, and hypocalcemia, hyperglycemia, coma and death may occur if appropriate treatment is not initiated. […] Therefore, the fatality rate is very high. […] The use of glycine has been effective in the treatment of IVA, and it has been shown that glycine administration reduced the rise in serum isovaleric acid produced by a leucine load. […] Early diagnosis and treatment are necessary to prevent neonatal mortality and improve the neurologic and cognitive outcomes. […] Early diagnosis as well as the detection of genetic metabolic diseases may improve patient outcomes.

• #56 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. […] Isovaleric acidemia has an autosomal recessive inheritance pattern. […] Prolonged periods without food, fasting, infections, or eating more protein-rich foods can cause serious health problems in these youngsters. […] IVA can be detected through newborn screening (NBS) as well. […] A particular protein-restricted diet and drugs are used to minimize the amount of isovaleric acid in the body.

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

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

  The first was an acute, neonatal presentation with patients becoming symptomatic within the first two weeks of life. […] The second group presented with relatively non-specific failure to thrive and/or developmental delay (chronic intermittent presentation). […] In reality it is now apparent that patients can fall anywhere on the spectrum of acute to chronic presentation and that there is probably little predictive value to the initial presentation. […] Moreover, with the application of MS/MS in newborn screening, potentially asymptomatic patients with one recurring IVD gene mutation and a mild biochemical phenotype are being identified in increasing numbers, representing an additional phenotype of IVA. […] The majority of patients with IVA today are diagnosed pre-symptomatically through newborn screening by use of MS/MS which reveals elevations of the marker metabolite C5 acylcarnitine in dried blood spots.

• #58 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

  Mortality in the early diagnosis group was 33% during the initial episode of severe metabolic acidosis. In the early diagnosis group, the mean age at onset of symptoms as reported for 55 of 81 cases, was 6.8 days. […] The neurocognitive outcome in surviving patients with neonatal manifestation and early start of treatment is more favourable than in patients with a late diagnosis. […] Age at diagnosis but not the number of catabolic episodes has an impact on the neurocognitive outcome. […] The potential to avoid early mortality and to improve neurocognitive outcome by early diagnosis and treatment encourages pre-symptomatic diagnosis and reinforces IVA to be qualified for NBS.

• #59 Recurrent vomiting in a child: a rare case of isovaleric acidemia | Pediatric Oncall Journal

  https://www.pediatriconcall.com/pediatric-journal/view-article/419

  A 3 1/2 years old girl, born to 2nd degree consanguineous marriage was admitted with chief complaints of recurrent episodes of projectile non-bilious vomiting since 6 months of age each lasting for 3-4 days and recurs every 4 to 5 months and each time requires hospital admission. […] Isovaleric acidemia is a rare autosomal recessive disorder with an incidence of 1 in 2 lakhs. […] It is due to deficiency of Isovaleryl-CoA Dehydrogenase required for the metabolism of the amino acid, leucine. […] Diagnosis involves screening for isovaleric acidemia using tandem mass spectrometry analysis of dried blood spot specimen. […] Treatment involves reducing protein intake, particularly the branched-chain amino acid leucine. […] The response to L-carnitine and glycine therapy in isovaleric acidaemia.

• #60 Aspects of Newborn Screening in Isovaleric Acidemia

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

  However, most patients seem to be asymptomatic despite metabolic abnormalities. […] There is little information on the long-term clinical outcome of individuals with SBCADD, but overall, this condition is assumed to be benign. […] The possibility of pre-symptomatic diagnosis through NBS and the apparent benefit that has been demonstrated for patients diagnosed and treated early make IVA an ideal candidate for NBS programs.

• #61 NEWBORN SCREENING

  http://w.newbornscreening.info/Parents/organicaciddisorders/IVA.html

  When both parents are carriers, there is a 25% chance in each pregnancy for the child to have IVA. […] Genetic testing for IVA can be done on a blood sample. […] Special tests on blood, urine, or skin samples can be done to confirm IVA. […] About one in every 230,000 babies in the United States is born with IVA. […] IVA does not happen more often in any specific race, ethnic group, geographical area, or country. […] IVA is sometimes also called: isovaleric Acid CoA Dehydrogenase Deficiency, IVD deficiency, isovaleryl CoA carboxylase deficiency.

• #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 etiology of hyperglycemia in IVA needs further investigation. […] 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.

• #63 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). […] IVA is due to a defect of isovalery-CoA dehydrogenase (IVD; Mendelian Inheritance in Man [MIM] #607036; enzyme commission [EC] 1.3.8.4), an acyl-CoA dehydrogenase (ACAD) catalyzing the third step in the intramitochondrial breakdown of leucine. It is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene and is inherited as an autosomal recessive trait. More than 60 disease-causing mutations in the IVD gene have been described. […] 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).

• #64 NEWBORN SCREENING

  http://w.newbornscreening.info/Parents/organicaciddisorders/IVA.html

  When both parents are carriers, there is a 25% chance in each pregnancy for the child to have IVA. […] Genetic testing for IVA can be done on a blood sample. […] Special tests on blood, urine, or skin samples can be done to confirm IVA. […] About one in every 230,000 babies in the United States is born with IVA. […] IVA does not happen more often in any specific race, ethnic group, geographical area, or country. […] IVA is sometimes also called: isovaleric Acid CoA Dehydrogenase Deficiency, IVD deficiency, isovaleryl CoA carboxylase deficiency.

• #65 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. […] 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. […] 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.

• #66 Isovaleric Acidemia – CAGS

  https://cags.org.ae/en/ctga-details/1129/isovaleric-acidemia

  Isovaleric acidemia (IVA) is a branched-chain amino acidemia characterized by a defect in the catabolism of leucine and the build-up of isovaleryl CoA in the body. […] IVA results from mutations in the IVD gene, which codes for the IVD enzyme. The IVD enzyme plays an important role in the metabolism of lysine in the body. Mutations in this gene result in defective or no production of the enzyme, causing a build up of isovaleric acid in the body. […] Mutations in the IVD gene can be point mutations or large deletions and insertions. About 60% of affected patients show loss of function of the enzyme, whereas the remaining 40% have absolutely no production of the enzyme at all.

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

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

  The typical clinical manifestations are severe metabolic acidosis and encephalopathy, often accompanied by leukopenia, neutropenia and thrombocytopenia due to bone marrow suppression and other abnormal blood systems in the neonatal period, and hypocalcemia, hyperglycemia, coma and death may occur if appropriate treatment is not initiated. […] Therefore, the fatality rate is very high. […] The use of glycine has been effective in the treatment of IVA, and it has been shown that glycine administration reduced the rise in serum isovaleric acid produced by a leucine load. […] Early diagnosis and treatment are necessary to prevent neonatal mortality and improve the neurologic and cognitive outcomes. […] Early diagnosis as well as the detection of genetic metabolic diseases may improve patient outcomes.

• #68 Newborn Bloodspot Screening – Your baby’s screening result – Isovaleric acidaemia (IVA) is suspected – Public Health Wales

  https://phw.nhs.wales/services-and-teams/screening/newborn-bloodspot-screening-wales/information-resources/leaflets/information-for-parents/newborn-bloodspot-screening-your-babys-screening-result-isovaleric-acidaemia-iva-is-suspected/

  Isovaleric acidaemia (IVA), pronounced iso-val-air-ik-acid-e-mia, is a rare but treatable inherited disorder that prevents the normal breakdown of protein. […] Babies with IVA inherit two faulty copies of the gene for IVA, one from each parent. […] Babies with IVA do not have one of the enzymes that help break down one of the amino acids. This causes harmful substances to build up in their blood and urine. […] Without early diagnosis and treatment they can develop serious illness and damage to the brain. […] There is also a milder version of IVA, which only requires treatment when a baby is unwell, for example if they have an infection. […] IVA can be treated with a special low-protein diet and dietary supplements. This prevents the build-up of harmful substances. […] If IVA is confirmed, your specialist metabolic team will explain how to give your baby the special low-protein diet.

• #69 Isovaleric Acidemia | DHHS Newborn Screening Program

  https://newbornscreening.utah.gov/disorder/iva/

  Isovaleric Acidemia causes harmful amounts of organic acids and toxins to build up in the body. Children affected by Isovaleric Acidemia are not able to properly break down certain proteins. […] If untreated, Isovaleric Acidemia can cause seizures, brain damage, and death. However, if the condition is detected early and proper treatment is begun, the severity of symptoms of symptoms can be reduced. […] Isovaleric Acidemia is an Organic Acid Disorder.

• #70 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

  Mortality in the early diagnosis group was 33% during the initial episode of severe metabolic acidosis. In the early diagnosis group, the mean age at onset of symptoms as reported for 55 of 81 cases, was 6.8 days. […] The neurocognitive outcome in surviving patients with neonatal manifestation and early start of treatment is more favourable than in patients with a late diagnosis. […] Age at diagnosis but not the number of catabolic episodes has an impact on the neurocognitive outcome. […] The potential to avoid early mortality and to improve neurocognitive outcome by early diagnosis and treatment encourages pre-symptomatic diagnosis and reinforces IVA to be qualified for NBS.

• #71 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

  Mortality in the early diagnosis group was 33% during the initial episode of severe metabolic acidosis. In the early diagnosis group, the mean age at onset of symptoms as reported for 55 of 81 cases, was 6.8 days. […] The neurocognitive outcome in surviving patients with neonatal manifestation and early start of treatment is more favourable than in patients with a late diagnosis. […] Age at diagnosis but not the number of catabolic episodes has an impact on the neurocognitive outcome. […] The potential to avoid early mortality and to improve neurocognitive outcome by early diagnosis and treatment encourages pre-symptomatic diagnosis and reinforces IVA to be qualified for NBS.

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

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

  The typical clinical manifestations are severe metabolic acidosis and encephalopathy, often accompanied by leukopenia, neutropenia and thrombocytopenia due to bone marrow suppression and other abnormal blood systems in the neonatal period, and hypocalcemia, hyperglycemia, coma and death may occur if appropriate treatment is not initiated. […] Therefore, the fatality rate is very high. […] The use of glycine has been effective in the treatment of IVA, and it has been shown that glycine administration reduced the rise in serum isovaleric acid produced by a leucine load. […] Early diagnosis and treatment are necessary to prevent neonatal mortality and improve the neurologic and cognitive outcomes. […] Early diagnosis as well as the detection of genetic metabolic diseases may improve patient outcomes.

• #73 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). […] 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. […] The characteristic odor of sweaty feet caused by isovaleric acid is often noted during metabolic crisis. […] To date, more than 70 heterogeneous mutations in the IVD gene have been reported in patients with IVA. […] The patient had compound heterozygous mutations: c.1193GA (p.Arg398Gln) and c.1208AG (p.Try403Cys). […] The clinical manifestations vary, and disease onset can range from the neonatal period to the adult period.

• #74 Isovaleric Acidemia

  http://trose.20m.com/IVA/IVA.html

  Isovaleric Acidemia (IVA) is a hereditary metabolic disorder that prevents protein from properly breaking down in the system. IVA is caused by an enzyme that isn’t working right, so the isovaleric acid doesn’t get broken down properly. […] The result was IVA. For parents who both possess this mutated gene there is a 25% chance, with each pregnancy, that the baby will have IVA. […] Untreated IVA can cause severe health problems such as: lethargy, coma, seizures, vomiting, acidosis, ataxia, mental retardation, elevated isovaleric acid, moderate to severe hyperammonemia, hypocalcemia, pancytopenia – neutropenia, thrombocytopenia, and/or anemia, and death soon after birth. […] With early detection of IVA the prognosis and quality of life greatly improves. […] There’s ongoing research in gene therapy that holds great promise for the future treatment of IVA and other metabolic disorders.

• #75

  https://journals.lww.com/ijaweb/fulltext/2016/60060/case_of_isovaleric_acidaemia_for_cataract_surgery_.11.aspx

  Millington et al. differentiated the dietary and endogenous sources of abnormal metabolism and the accurate contribution to toxicity in the disease. Turnover of endogenous proteins rather than diet was confirmed to produce toxic metabolites in IVA. Therefore, suppression of endogenous catabolism rather than dietary restriction was conclusively stated to be the more effective therapy. […] Patients with IVA have feeding difficulties and vomiting leading to dehydration and acidosis with risk for aspiration. Prolonged fasting and surgical stress cause further decompensation.

• #76 NEWBORN SCREENING

  http://w.newbornscreening.info/Parents/organicaciddisorders/IVA.html

  When both parents are carriers, there is a 25% chance in each pregnancy for the child to have IVA. […] Genetic testing for IVA can be done on a blood sample. […] Special tests on blood, urine, or skin samples can be done to confirm IVA. […] About one in every 230,000 babies in the United States is born with IVA. […] IVA does not happen more often in any specific race, ethnic group, geographical area, or country. […] IVA is sometimes also called: isovaleric Acid CoA Dehydrogenase Deficiency, IVD deficiency, isovaleryl CoA carboxylase deficiency.

• #77 An unusual case of oral surgical management in a patient with isovaleric acidemia and schizophrenia: A case report

  https://www.spandidos-publications.com/10.3892/br.2022.1547

  Oral/dental surgical care in patients with chronic medical comorbidities, such as isovaleric acidemia (IVA), can be challenging. […] IVA, a congenital error of metabolism, is a rare organic acidemia with a predisposition towards acute acidosis and lifethreatening metabolic decompensation during stressful conditions, such as prolonged fasting and surgery. […] IVA (MIM #243500) is a rare autosomal recessive congenital metabolic disorder categorized as organic acidemia. […] Furthermore, IVA is relatively uncommon, with a frequency of 1:250,000, 1:365,000 and 1:62,500 births in the United States, Taiwan and Germany, respectively. […] IVA disorder results from an accumulation of isovaleric acid in the body, which is toxic to the central nervous system. […] During IVA crises, detoxification is achieved through alternative pathways that produce isovaleric glycine, 3-hydroxyisovaleric acid and other metabolites excreted via the urinary system.

• #78 Recurrent vomiting in a child: a rare case of isovaleric acidemia | Pediatric Oncall Journal

  https://www.pediatriconcall.com/pediatric-journal/view-article/419

  A 3 1/2 years old girl, born to 2nd degree consanguineous marriage was admitted with chief complaints of recurrent episodes of projectile non-bilious vomiting since 6 months of age each lasting for 3-4 days and recurs every 4 to 5 months and each time requires hospital admission. […] Isovaleric acidemia is a rare autosomal recessive disorder with an incidence of 1 in 2 lakhs. […] It is due to deficiency of Isovaleryl-CoA Dehydrogenase required for the metabolism of the amino acid, leucine. […] Diagnosis involves screening for isovaleric acidemia using tandem mass spectrometry analysis of dried blood spot specimen. […] Treatment involves reducing protein intake, particularly the branched-chain amino acid leucine. […] The response to L-carnitine and glycine therapy in isovaleric acidaemia.

• #79 NEWBORN SCREENING

  http://w.newbornscreening.info/Parents/organicaciddisorders/IVA.html

  When both parents are carriers, there is a 25% chance in each pregnancy for the child to have IVA. […] Genetic testing for IVA can be done on a blood sample. […] Special tests on blood, urine, or skin samples can be done to confirm IVA. […] About one in every 230,000 babies in the United States is born with IVA. […] IVA does not happen more often in any specific race, ethnic group, geographical area, or country. […] IVA is sometimes also called: isovaleric Acid CoA Dehydrogenase Deficiency, IVD deficiency, isovaleryl CoA carboxylase deficiency.

• #80 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

  This indicates that the variants in the first two regions are highly pathogenic, whereas the concentrated distribution of variants with an asymptomatic phenotype indicates that the amino acid variations are pathogenically milder. […] The hotspots for pathogenic variants depend on ethnicity and region. […] The variant c.1199A>G (p.Tyr371Cys) and c.1208A>G (p.Tyr403Cys) are common among the Han Chinese population (17). […] For IVA treatment, daily protein intake should be limited, and the dietary supplementation with L-carnitine and glycine should be prescribed to convert isovaleric acid to non-toxic isovalerylcarnitine and isovalerylglycine, respectively (11).

• #81 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. […] 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. […] 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.

• #82 Isovaleric Acidemia

  http://trose.20m.com/IVA/IVA.html

  Isovaleric Acidemia (IVA) is a hereditary metabolic disorder that prevents protein from properly breaking down in the system. IVA is caused by an enzyme that isn’t working right, so the isovaleric acid doesn’t get broken down properly. […] The result was IVA. For parents who both possess this mutated gene there is a 25% chance, with each pregnancy, that the baby will have IVA. […] Untreated IVA can cause severe health problems such as: lethargy, coma, seizures, vomiting, acidosis, ataxia, mental retardation, elevated isovaleric acid, moderate to severe hyperammonemia, hypocalcemia, pancytopenia – neutropenia, thrombocytopenia, and/or anemia, and death soon after birth. […] With early detection of IVA the prognosis and quality of life greatly improves. […] There’s ongoing research in gene therapy that holds great promise for the future treatment of IVA and other metabolic disorders.

• #83 Aspects of Newborn Screening in Isovaleric Acidemia

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

  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. […] A certain missense mutation, c.932C>T (p.A282V), in either a homozygous or compound heterozygous state, is associated with this “mild” form of IVA. […] The first patient with SBCADD was reported in 1999. […] The ACADSB gene structure was described in 2000, and several mutations in this gene have been reported.

• #84

  https://journals.lww.com/ijaweb/fulltext/2016/60060/case_of_isovaleric_acidaemia_for_cataract_surgery_.11.aspx

  Millington et al. differentiated the dietary and endogenous sources of abnormal metabolism and the accurate contribution to toxicity in the disease. Turnover of endogenous proteins rather than diet was confirmed to produce toxic metabolites in IVA. Therefore, suppression of endogenous catabolism rather than dietary restriction was conclusively stated to be the more effective therapy. […] Patients with IVA have feeding difficulties and vomiting leading to dehydration and acidosis with risk for aspiration. Prolonged fasting and surgical stress cause further decompensation.

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

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

  Prior to newborn screening, this mutation was identified only in a single patient with mild IVD deficiency originally evaluated for a tic disorder and slight developmental delay. […] It is clear that the newborn screening patients who carry the common mutation either in a homozygous or compound heterozygous state and their sibs skew the spectrum of IVA with more than half of individuals representing a new mild phenotype and potentially remaining asymptomatic. […] The necessity of any treatment for individuals diagnosed by newborn screening and carrying the common 932CT (A282V) mutation is unclear.

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