Materiały źródłowe

• #1 Orphanet: Isovaleric acidemia

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

  A rare, autosomal recessive, organic aciduria that is characterized by variable clinical presentation ranging from acute neonatal onset of metabolic decompensation to later onset of chronic, non-specific manifestations including failure to thrive and/or developmental delay. All patients are prone to intermittent, acute metabolic decompensation. During metabolic episodes, urine analysis demonstrates elevated isovaleric acid derivatives. […] Where implemented, diagnosis is through newborn blood spot screening. Otherwise, in symptomatic individuals diagnosis is suspected based on the clinical presentation. Metabolite or molecular genetic testing confirms diagnosis. Characteristic urine metabolites includes elevated Nisovalerylglycine, Nisovalerylcarnitine and 3hydroxyisovaleric acid. Isovalerylcarnitine (”C5 carnitine”) is elevated in blood. The urine organic acids may normalize when a patient is well.

• #2 Isovaleric Acidemia: A Case Report

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10749218/

  Isovaleric acidemia is an autosomal recessive disease of leucine metabolism. […] Diagnosis is based on the detection of isovalerylglycine CoA in urine and elevated levels of isovaleryl (C5) carnitine in blood. […] Clinical diagnosis is based on the detection of isovalerylglycine CoA metabolites in the urine organic acid analyses and elevated levels of isovaleryl (C5) carnitine in blood by gas chromatography and mass spectrometry (GC-MS). […] Molecular genetic analysis confirms the diagnosis, as it detects the IVD gene mutation located on chromosome 15q14-15. […] Early diagnosis and treatment are necessary to reduce mortality and avoid neurocognitive sequelae. […] Through extended neonatal screening, asymptomatic patients could be diagnosed, thus preventing decompensation and improving cognitive development. […] There is no laboratory marker for monitoring the therapeutic control or status of this disease. […] However, age-appropriate weight gain, growth, and development are the best indicators of treatment efficacy, which should be routinely assessed during office follow-up of these patients.

• #3 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). […] The clinical diagnosis of IVA can be confirmed by mutation of the IVD gene. […] 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. […] Early diagnosis and treatment are necessary to prevent neonatal mortality and improve the neurologic and cognitive outcomes. […] Therefore, early diagnosis is crucial, and asymptomatic detection is possible with expanded neonatal screening. […] When certain clinical manifestations occur in children, the disease can be diagnosed by blood and urinary organic acid or acyl carnitine analysis.

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

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

  Individuals with clinical manifestations of isovaleric acidemia (IVA) have either classic IVA identified on newborn screening or classic IVA with a later diagnosis due to a missed diagnosis or later onset of clinical manifestations. […] The diagnosis of classic IVA is established in a proband by identification of C5-carnitine metabolites by tandem mass spectrometry and isovalerylglycine (IVG) and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry, or identification of biallelic pathogenic variants in IVD by molecular genetic testing. […] NBS for classic isovaleric acidemia (IVA) is based on the quantification of the first-tier analyte isovalerylcarnitine (as C5-carnitine) in dried blood spots. […] C5-carnitine (C5) values above the cutoff reported by the screening laboratory are considered positive and suggest a diagnosis of classic IVA; additional testing of urinary organic acids is required to establish the diagnosis.

• #5 Isovaleric acidaemia

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

  At around 5 days old, babies are now offered newborn blood spot screening to check if they have IVA. […] If IVA is diagnosed, treatment can be given straight away to reduce the risk of serious complications. […] With early diagnosis and the correct treatment, the majority of children with IVA are able to live healthy lives. […] Without treatment, severe and life-threatening symptoms can develop in some children, including seizures (fits) or falling into a coma. […] Children diagnosed with IVA are referred to a specialist metabolic dietitian and given a low-protein diet. […] Your dietitian will provide detailed advice and guidance, as your baby still needs some of these foods for healthy growth and development. […] People with IVA need to follow a modified diet for the rest of their life to reduce their risk of a metabolic crisis.

• #6 Newborn screening information for isovaleric acidemia | Baby’s First Test | Newborn Screening | Baby Health

  https://www.babysfirsttest.org/newborn-screening/conditions/isovaleric-acidemia

  Isovaleric acidemia (IVA) is an inherited condition in which the body is unable to break down certain proteins properly. […] If your babys newborn screening result for isovaleric acidemia (IVA) was out of the normal range, your babys doctor or the state screening program will contact you to arrange for your baby to have additional testing. […] It is important to remember that an out-of-range screening result does not necessarily mean that your child has the condition. […] However, a few babies do have the condition, so it is very important that you go to your follow-up appointment for a confirmatory test. […] Follow-up testing will involve checking your babys urine and blood samples for harmful amounts of acids and toxins. […] For example, high levels of acylcarnitine in the blood and isovalerylglycine in the urine may be signs of the IVA.

• #7 Isovaleric acidaemia – Genomics Education Programme

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

  Biochemical diagnosis is achieved through the detection of elevated isovalerylcarnitine and isovalerylglycine (by acylcarnitine and urine organic acid analysis, respectively). Both compounds are typically elevated in affected patients, regardless of their metabolic condition. […] As part of the NHS newborn blood spot screening (NBS) programme in England, C5 aclycarnitine in dried blood spots is used as the initial diagnostic metabolite. […] Elevated C5 acylcarnitine may also result from increased 2-methylbutyrylcarnitine, caused by short/branched-chain acyl-CoA dehydrogenase deficiency (SBCAD) and pivaloylcarnitine, a derivative of a number of antibiotics. Further diagnostic evaluation is therefore required to confirm the diagnosis of IVA after the initial detection of raised C5 acylcarnitine by NBS.

• #8 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

  Newborn screening for IVA is accomplished by measuring the acylcarnitine C5 by tandem mass spectrometry (MS/MS) […] Testing can be affected by: Newborn screening cannot distinguish between IVA and 2-Methylbutyrylglycinuria (2-MBCD). […] Patients with an abnormal newborn screen for IVA are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of IVA. […] Diagnostic testing may include urine organic acid analysis, plasma amino acid analysis, enzyme analysis and genetic testing of the IVD gene.

• #9 Isovaleric acidemia – Wikipedia

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

  The urine of newborns can be screened for isovaleric acidemia using mass spectrometry, allowing for early diagnosis. Elevations of isovalerylglycine in urine and of isovalerylcarnitine in plasma are found. […] On 9 May 2014, the UK National Screening Committee (UK NSC) announced its recommendation to screen every newborn baby in the UK for four further genetic disorders as part of its NHS Newborn Blood Spot Screening programme, including isovaleric acidemia.

• #10 Aspects of Newborn Screening in Isovaleric Acidemia

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

  Since then, it has been implemented in national NBS programs in about 30 countries worldwide, and most recently (2015), in England and Wales. […] Using a data set of 1.6 million newborns from Germany, the birth prevalence of IVA was calculated to be 1 in 67,000. […] Prevalences from other countries were reported to be lower, such as 1 in 660,000 in Taiwan or 1 in 105,000 in Portugal. […] Because C5-carnitine represents several isomers, such as isovalerylcarnitine, 2-methylbutyrylcarnitine, or pivaloylcarnitine, elevated levels detected in NBS may account for several differential diagnoses of IVA, including short/branched chain specific acyl-CoA dehydrogenase deficiency (SBCADD). […] With NBS becoming an important part of pediatric preventive strategies worldwide, several diagnostic pitfalls have come to attention.

• #11

  https://link.springer.com/article/10.1023/A:1005424331822

  Tandem mass spectrometric analysis of acylcarnitines and amino acids has been applied in newborn screening programmes for the detection of several inborn errors of metabolism. […] We report a false positive result for isovaleric acidaemia in a newborn screening programme using this method. […] We conclude that pivaloylcarnitine can give a false positive result for isovaleric acidaemia in newborns whose mothers are on treatment with pivoxilsulbactam-containing antibiotics.

• #12 Newborn screening information for isovaleric acidemia | Baby’s First Test | Newborn Screening | Baby Health

  https://www.babysfirsttest.org/newborn-screening/conditions/isovaleric-acidemia

  Isovaleric acidemia (IVA) is an inherited condition in which the body is unable to break down certain proteins properly. […] If your babys newborn screening result for isovaleric acidemia (IVA) was out of the normal range, your babys doctor or the state screening program will contact you to arrange for your baby to have additional testing. […] It is important to remember that an out-of-range screening result does not necessarily mean that your child has the condition. […] However, a few babies do have the condition, so it is very important that you go to your follow-up appointment for a confirmatory test. […] Follow-up testing will involve checking your babys urine and blood samples for harmful amounts of acids and toxins. […] For example, high levels of acylcarnitine in the blood and isovalerylglycine in the urine may be signs of the IVA.

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

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

  The diagnosis of classic IVA in a proband with suggestive biochemical and/or clinical findings is established by identification of: C5-carnitine (C5) metabolites, isovalerylglycine (IVG), and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry; OR biallelic pathogenic (or likely pathogenic) variants in IVD by molecular genetic testing.

• #14 Orphanet: Isovaleric acidemia

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

  A rare, autosomal recessive, organic aciduria that is characterized by variable clinical presentation ranging from acute neonatal onset of metabolic decompensation to later onset of chronic, non-specific manifestations including failure to thrive and/or developmental delay. All patients are prone to intermittent, acute metabolic decompensation. During metabolic episodes, urine analysis demonstrates elevated isovaleric acid derivatives. […] Where implemented, diagnosis is through newborn blood spot screening. Otherwise, in symptomatic individuals diagnosis is suspected based on the clinical presentation. Metabolite or molecular genetic testing confirms diagnosis. Characteristic urine metabolites includes elevated Nisovalerylglycine, Nisovalerylcarnitine and 3hydroxyisovaleric acid. Isovalerylcarnitine (”C5 carnitine”) is elevated in blood. The urine organic acids may normalize when a patient is well.

• #15 Isovaleric acidemia | MedLink Neurology

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

  Isovaleric acidemia can be readily diagnosed in newborn screening programs. […] Key metabolites leading to diagnosis are isovalerylglycine in urine and isovaleryl carnitine in plasma or dried blood spots. […] If treatment is initiated before the development of severe metabolic decompensation, the patients prognosis is significantly improved. […] Patients who are diagnosed by newborn screening usually have normal psychomotor development. […] Diagnosis of classic isovaleric acidemia is established in a proband by identification of C5-carnitine metabolites by tandem mass spectrometry and isovalerylglycine (IVG) and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry, or identification of biallelic pathogenic variants in IVD by molecular genetic testing.

• #16 Isovaleric acidemia | MedLink Neurology

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

  During metabolic decompensation, the urinary organic acid profile reveals high excretion of isovalerylglycine (2000 to 9000 mmol/mol creatinine), which remains markedly elevated after recompensation (1000 to 3000 mmol/mol creatinine). […] The acylcarnitine profile in isovaleric aciduria is characterized by high levels of isovalerylcarnitine, depending on the quantity of oral carnitine administration. […] The diagnosis of isovaleric acidemia can be confirmed by enzymatic assay or mutation analysis.

• #17 Orphanet: Diagnosis of Isovaleric Acidemia (IVD gene)

  https://www.orpha.net/en/diagnostic-tests/diagnostic/535413?country=&name=

  Diagnosis of Isovaleric Acidemia (IVD gene) […] Post-natal diagnosis […] Technical procedure(s) Molecular genetics Sequence analysis: entire coding region Sanger sequencing […] List of diseases tested (1) Isovaleric acidemia […] List of genes tested (1) IVD

• #18 Isovaleric acidemia – Knowledge and References – Taylor & Francis

  https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Endocrinology/Isovaleric_acidemia/

  Isovaleric acidemia is a genetic disorder that is inherited in an autosomal recessive manner. It is caused by a deficiency of the mitochondrial enzyme isovaleryl-coenzyme A dehydrogenase, which is involved in the breakdown of the amino acid leucine. This deficiency leads to the accumulation of isovaleric acid in the body, which can cause a range of symptoms including vomiting, seizures, and developmental delays. […] Isovaleric acidemia is caused by a deficiency of the enzyme isovaleryl Co-A dehydrogenase which is in the leucine degradative pathway. The abnormal accumulation of isovalerylglycine is diagnostic. […] Isovaleric acidemia is an autosomal recessive disease caused by deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase. Assay of the enzyme in fibroblasts of a series of patients revealed considerable heterogeneity and residual activity, as much as 13 percent of the control level. The enzyme may also be assayed in leukocytes.

• #19 Isovaleric acidemia | MedLink Neurology

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

  Isovaleric acidemia can be readily diagnosed in newborn screening programs. […] Key metabolites leading to diagnosis are isovalerylglycine in urine and isovaleryl carnitine in plasma or dried blood spots. […] If treatment is initiated before the development of severe metabolic decompensation, the patients prognosis is significantly improved. […] Patients who are diagnosed by newborn screening usually have normal psychomotor development. […] Diagnosis of classic isovaleric acidemia is established in a proband by identification of C5-carnitine metabolites by tandem mass spectrometry and isovalerylglycine (IVG) and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry, or identification of biallelic pathogenic variants in IVD by molecular genetic testing.

• #20 Isovaleric acidemia | MedLink Neurology

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

  During metabolic decompensation, the urinary organic acid profile reveals high excretion of isovalerylglycine (2000 to 9000 mmol/mol creatinine), which remains markedly elevated after recompensation (1000 to 3000 mmol/mol creatinine). […] The acylcarnitine profile in isovaleric aciduria is characterized by high levels of isovalerylcarnitine, depending on the quantity of oral carnitine administration. […] The diagnosis of isovaleric acidemia can be confirmed by enzymatic assay or mutation analysis.

• #21 Orphanet: Isovaleric acidemia

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

  A rare, autosomal recessive, organic aciduria that is characterized by variable clinical presentation ranging from acute neonatal onset of metabolic decompensation to later onset of chronic, non-specific manifestations including failure to thrive and/or developmental delay. All patients are prone to intermittent, acute metabolic decompensation. During metabolic episodes, urine analysis demonstrates elevated isovaleric acid derivatives. […] Where implemented, diagnosis is through newborn blood spot screening. Otherwise, in symptomatic individuals diagnosis is suspected based on the clinical presentation. Metabolite or molecular genetic testing confirms diagnosis. Characteristic urine metabolites includes elevated Nisovalerylglycine, Nisovalerylcarnitine and 3hydroxyisovaleric acid. Isovalerylcarnitine (”C5 carnitine”) is elevated in blood. The urine organic acids may normalize when a patient is well.

• #22 Isovaleric acidaemia – Genomics Education Programme

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

  Biochemical diagnosis is achieved through the detection of elevated isovalerylcarnitine and isovalerylglycine (by acylcarnitine and urine organic acid analysis, respectively). Both compounds are typically elevated in affected patients, regardless of their metabolic condition. […] As part of the NHS newborn blood spot screening (NBS) programme in England, C5 aclycarnitine in dried blood spots is used as the initial diagnostic metabolite. […] Elevated C5 acylcarnitine may also result from increased 2-methylbutyrylcarnitine, caused by short/branched-chain acyl-CoA dehydrogenase deficiency (SBCAD) and pivaloylcarnitine, a derivative of a number of antibiotics. Further diagnostic evaluation is therefore required to confirm the diagnosis of IVA after the initial detection of raised C5 acylcarnitine by NBS.

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

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

  Based on the biochemical and clinical data, eight patients had mild/asymptomatic IVA (p2p9), four had chronic intermittent IVA (p10, p11, p14, p15) and four had acute neonatal IVA (p1, p12, p13, p16). […] 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. […] 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. […] This study has provided information that extends the existing knowledge of IVA.

• #24 IVD Gene Isovaleric acidemia NGS Genetic Test Cost 20000 INR in India

  https://dnalabsindia.com/test/ivd-gene-isovaleric-acidemia-ngs-genetic-dna-test

  NGS Genetic Test detecets for variant and mutation detection in IVD gene for Isovaleric acidemia […] Diagnosis of IVD gene isovaleric acidemia is typically done through a blood test. The test measures the amount of isovaleric acid in the blood. High levels of isovaleric acid can be a sign of the condition. In some cases, a urine test may also be done to confirm the diagnosis. […] IVD gene isovaleric acidemia can be diagnosed using a Genetic Test. Next-generation sequencing (NGS) is a powerful tool that can analyze large amounts of genetic data quickly and accurately. The test can identify the specific mutation in the IVD gene that causes the condition. […] The IVD gene isovaleric acidemia NGS Genetic Test is a powerful tool that can help diagnose the condition quickly and accurately. If you suspect that you or your child may have the condition, it is important to speak with a healthcare provider and consider genetic testing.

• #25 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 diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). […] Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. […] The median follow-up time (median; Q1–Q2) was 2.5 years (1.5–9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0–20) for symptomatic patients. […] We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. […] Although early treatment did not prevent decompensations, they were milder in these patients.

• #26 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 inclusion of IVA in NBS programs in many countries has broadened knowledge of the variability of the condition, whereas prior to NBS, two distinct clinical phenotypes were known, an “acute neonatal” and a “chronic intermittent” form. […] An additional biochemically mild and potentially asymptomatic form of IVA and its association with a common missense mutation, c.932C>T (p.A282V), was discovered in subjects identified through NBS. […] The first countries that introduced IVA to their NBS programs were Australia, where IVA was included in the New South Wales NBS program in 1998, and Germany, where it was first included in the Bavarian NBS program in 1999.

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

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

  Isovaleric acidemia (IVA) is a rare disorder of leucine metabolism. […] Evaluated at diagnosis, data included age, detection method, levels of C5 and IVG, enzymatic studies, clinical presentation parameters and genotype in 16 patients. […] IVA was detected by NBS in 8 patients (prevalence of 1/326629). […] Cognitive function was within normal ranges in all patients but was negatively correlated with IVG at detection (0.592; P0.05). […] The genetic analysis revealed nine novel mutations. […] In conclusion, although blood C5 levels have traditionally been considered the prognostic marker of choice, urine IVG levels would appear to be a better predictor, as they correlated well with severity of mutations and were associated with a lower incorporation rate of IVA in fibroblasts and a less favorable clinical course.

• #28 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). […] Methods: We report the case of a Chinese patient with IVA who was admitted to Tianjin Children’s Hospital and followed up for 8 years. Genetic analysis of the patient and his parents was conducted using the whole-exome sequencing and Sanger sequencing. […] Results: The patient presented with encephalopathic symptoms, such as vomiting, lethargy, and somnolence. […] The child was prescribed a low-protein diet supplemented with L-carnitine. During the 8-year follow-up, no metabolic disorder or encephalopathic symptoms recurred. […] Conclusion: This case report describes an unreported variant c.224A>G (p.Asn75Ser) of the IVD gene, and summarizes previously reported cases. Furthermore, the correlation between the genotype and clinical phenotype of IVA is analyzed to improve the understanding of this disease.

• #29 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

  57% of study patients (12/21) were diagnosed within the first weeks of life and 43% (9/21) in childhood. […] An acute metabolic attack was the main cause of diagnostic work-up. […] The patients’ intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. […] The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening. […] In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days. […] The cognitive performance in terms of IQ was obtained in 13 of the 16 step II participants aged 5 to 24 years, whereas younger children were evaluated using DDST.

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

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

  Based on the biochemical and clinical data, eight patients had mild/asymptomatic IVA (p2p9), four had chronic intermittent IVA (p10, p11, p14, p15) and four had acute neonatal IVA (p1, p12, p13, p16). […] 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. […] 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. […] This study has provided information that extends the existing knowledge of IVA.

• #31 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. […] Health problems related to isovaleric acidemia range from very mild to life-threatening. […] In severe cases, the features of isovaleric acidemia become apparent within a few days after birth.

• #32

  https://omim.org/entry/243500

  A number sign (#) is used with this entry because of evidence that isovaleric acidemia (IVA) is caused by homozygous or compound heterozygous mutation in the isovaleryl CoA dehydrogenase gene (IVD; 607036) on chromosome 15q15. […] Isovaleric acidemia (IVA) is an inborn error of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. […] Two forms of isovaleric acidemia are recognized: the acute neonatal form, leading to massive metabolic acidosis from the first days of life and rapid death (e.g., Newman et al., 1967), and a chronic form in which periodic attacks of severe ketoacidosis occur with asymptomatic intervening periods (e.g., Tanaka et al., 1966). […] Cohn et al. (1978) demonstrated that administration of glycine reduces isovaleric acidemia in neonates by conjugating isovaleric acid, with urinary excretion of the conjugate. […] Vockley et al. (1991) demonstrated with autosomal recessive inheritance of isovaleric acidemia. […] Since the implementation of newborn screening by tandem mass spectrometry in many states and countries, presymptomatic diagnosis of isovaleric acidemia has been possible.

• #33 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 inclusion of IVA in NBS programs in many countries has broadened knowledge of the variability of the condition, whereas prior to NBS, two distinct clinical phenotypes were known, an “acute neonatal” and a “chronic intermittent” form. […] An additional biochemically mild and potentially asymptomatic form of IVA and its association with a common missense mutation, c.932C>T (p.A282V), was discovered in subjects identified through NBS. […] The first countries that introduced IVA to their NBS programs were Australia, where IVA was included in the New South Wales NBS program in 1998, and Germany, where it was first included in the Bavarian NBS program in 1999.

• #34 Isovaleric acidemia: MedlinePlus GeneticsLock

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

  A characteristic sign of isovaleric acidemia is a distinctive odor of sweaty feet during acute illness. […] Some people with gene mutations that cause isovaleric acidemia are asymptomatic, which means they never experience any signs or symptoms of the condition. […] Isovaleric acidemia is estimated to affect at least 1 in 250,000 people in the United States. […] 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. […] This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations.

• #35 Aspects of Newborn Screening in Isovaleric Acidemia

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

  Since then, it has been implemented in national NBS programs in about 30 countries worldwide, and most recently (2015), in England and Wales. […] Using a data set of 1.6 million newborns from Germany, the birth prevalence of IVA was calculated to be 1 in 67,000. […] Prevalences from other countries were reported to be lower, such as 1 in 660,000 in Taiwan or 1 in 105,000 in Portugal. […] Because C5-carnitine represents several isomers, such as isovalerylcarnitine, 2-methylbutyrylcarnitine, or pivaloylcarnitine, elevated levels detected in NBS may account for several differential diagnoses of IVA, including short/branched chain specific acyl-CoA dehydrogenase deficiency (SBCADD). […] With NBS becoming an important part of pediatric preventive strategies worldwide, several diagnostic pitfalls have come to attention.

• #36 (PDF) Diagnosis of isovaleric acidaemia by tandem mass spectrometry: false positive result due to pivaloylcarnitine in a newborn screening programme

  https://www.academia.edu/18023195/Diagnosis_of_isovaleric_acidaemia_by_tandem_mass_spectrometry_false_positive_result_due_to_pivaloylcarnitine_in_a_newborn_screening_programme

  Tandem mass spectrometric analysis of acylcarnitines and amino acids has been applied in newborn screening programmes for the detection of several inborn errors of metabolism. […] We report a false positive result for isovaleric acidaemia in a newborn screening programme using this method. […] The newborn screening sample showed a very prominent signal corresponding to the mass of isovalerylcarnitine. […] However, urine organic acids were normal. […] Gas chromatography-mass spectrometry of the methyl esters demonstrated that the signal in the patient’s urine was due to the presence of pivaloylcarnitine, which is isomeric with isovalerylcarnitine. […] The patient’s mother was receiving an antibiotic containing a derivative of pivalic acid to treat a urinary tract infection. […] During an 18-month period, we noticed an alarming increase of newborn screening false positivity rate in identifying isovaleric acidemia.

• #37 Aspects of Newborn Screening in Isovaleric Acidemia

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

  Pivaloylcarnitine, a derivative of antibiotics containing pivalic acid, can be mistaken for isovalerylcarnitine in NBS blood samples, and treatment of mothers with these antibiotics before delivery has been blamed for a number of false positive NBS results. […] In order to differentiate SBCADD from IVA and to exclude interference from antibiotics, urine acylglycine analysis and/or quantitative organic acid analysis are performed. […] The phenotypical spectrum of IVA is wide and has been further broadened by NBS. […] Available data suggests that early diagnosis by NBS may improve the clinical outcome of IVA, as supported by reports of less frequent relapsing episodes of metabolic decompensation and short-term improvement of neurodevelopmental symptoms, even though studies on the long-term outcome of screened patients are still lacking.

• #38 (PDF) Diagnosis of isovaleric acidaemia by tandem mass spectrometry: false positive result due to pivaloylcarnitine in a newborn screening programme

  https://www.academia.edu/18023195/Diagnosis_of_isovaleric_acidaemia_by_tandem_mass_spectrometry_false_positive_result_due_to_pivaloylcarnitine_in_a_newborn_screening_programme

  Exogenous pivalate administration had been previously identified as the causal agent of this concern. […] The method has the potential to markedly reduce false-positive results and the associated costs and anxiety. […] The simultaneous two tier metabolome testing for screening of IEM is more comprehensive, cost effective, delivering confirmatory results with significantly reduced turnaround time, thus reducing recall rate by eliminating false-positive results and help prevent unnecessary anxiety of parents.

• #39 Aspects of Newborn Screening in Isovaleric Acidemia

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

  Since then, it has been implemented in national NBS programs in about 30 countries worldwide, and most recently (2015), in England and Wales. […] Using a data set of 1.6 million newborns from Germany, the birth prevalence of IVA was calculated to be 1 in 67,000. […] Prevalences from other countries were reported to be lower, such as 1 in 660,000 in Taiwan or 1 in 105,000 in Portugal. […] Because C5-carnitine represents several isomers, such as isovalerylcarnitine, 2-methylbutyrylcarnitine, or pivaloylcarnitine, elevated levels detected in NBS may account for several differential diagnoses of IVA, including short/branched chain specific acyl-CoA dehydrogenase deficiency (SBCADD). […] With NBS becoming an important part of pediatric preventive strategies worldwide, several diagnostic pitfalls have come to attention.

• #40 Aspects of Newborn Screening in Isovaleric Acidemia

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

  Pivaloylcarnitine, a derivative of antibiotics containing pivalic acid, can be mistaken for isovalerylcarnitine in NBS blood samples, and treatment of mothers with these antibiotics before delivery has been blamed for a number of false positive NBS results. […] In order to differentiate SBCADD from IVA and to exclude interference from antibiotics, urine acylglycine analysis and/or quantitative organic acid analysis are performed. […] The phenotypical spectrum of IVA is wide and has been further broadened by NBS. […] Available data suggests that early diagnosis by NBS may improve the clinical outcome of IVA, as supported by reports of less frequent relapsing episodes of metabolic decompensation and short-term improvement of neurodevelopmental symptoms, even though studies on the long-term outcome of screened patients are still lacking.

• #41 Orphanet: Isovaleric acidemia

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

  Prenatal genetic testing is possible when the mutation of a proband has previously been determined. […] The pattern of inheritance is autosomal recessive; genetic counseling is recommended for affected families. The risk of disease transmission at each pregnancy is 25% when the parents are proven or obligate carriers. […] Lifelong management is with a low protein diet. Children diagnosed with IVA should be referred to a metabolic dietician who can tailor the diet to support normal growth and development. Supplementing with artificial protein restricted in leucine may be required. L-carnitine and glycine may be prescribed to clear excess isovaleric acid. Emergency treatment in times of metabolic stress (including illness and fasting) is with an anabolic diet. Reducing, but not eliminating, natural protein in the diet for 12-24 hours may help, but only if additional other calories can be given to promote anabolism.

• #42 Isovaleric acidemia – Knowledge and References – Taylor & Francis

  https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Endocrinology/Isovaleric_acidemia/

  An accurate method for the gas chromatographic-mass spectrometric (GCMS) analysis of 3-hydroxyisovaleric acid or isovalerylglycine permits rapid prenatal diagnosis via direct detection in the amniotic fluid. Isovalerylglycine appears to be the metabolite of choice; it has been diagnostic as early as 12 weeks of gestation. […] Elevated levels of C5 acylcarnitine are characteristic of isovaleric acidemia with clinical features suggestive of significant motor delay. […] The diagnosis of these disorders is based on acylcarnitines profiles identified by primary biomarkers and in some cases by second-tier testing to improve the positive predictive value of NBS.

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

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

  Doctors can identify IVA through a blood test called tandem mass spectrometry. They may order the test as part of routine screening in newborns. […] A DNA test can help confirm the diagnosis. […] If a person has a child with IVA, it may be possible to diagnose the condition prenatally in any future pregnancies. […] Screening can help detect IVA before a person experiences noticeable symptoms. Doctors screen newborns using a tiny amount of blood from the infants heel. This is called blood spot screening. […] A doctor may also recommend prenatal tests to screen for IVA in a fetus if the parents have another child with IVA.

• #44 Isovaleric Acidemia (IVA) | Revvity

  https://www.revvity.com/disorders/isovaleric-acidemia-iva

  Isovaleric acidemia results from a defect in the metabolism of the amino acid, leucine. […] Newborns can be screened for IVA using tandem mass spectrometry analysis of a heel-stick dried blood spot specimen. The finding of elevated five-carbon acylcarnitine (C5) indicates either isovaleryl-CoA dehydrogenase deficiency or 2-methylbutyryl-CoA dehydrogenase deficiency. […] Urine organic acid analysis of a patient with IVA will reveal an elevation of isovalerylglycine with lesser elevation of 3-hydroxyisovaleric acid. […] Prenatal diagnosis is possible by measuring isovalerylglycine in amniotic fluid and by measuring isovaleryl-CoA dehydrogenase enzyme activity in chorionic villus specimens or cultured amniocytes. […] Because the diagnosis and therapy of isovaleric acidemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist and dietician.

• #45 Isovaleric Acidemia (IVA) | Revvity

  https://www.revvity.com/disorders/isovaleric-acidemia-iva

  Isovaleric acidemia results from a defect in the metabolism of the amino acid, leucine. […] Newborns can be screened for IVA using tandem mass spectrometry analysis of a heel-stick dried blood spot specimen. The finding of elevated five-carbon acylcarnitine (C5) indicates either isovaleryl-CoA dehydrogenase deficiency or 2-methylbutyryl-CoA dehydrogenase deficiency. […] Urine organic acid analysis of a patient with IVA will reveal an elevation of isovalerylglycine with lesser elevation of 3-hydroxyisovaleric acid. […] Prenatal diagnosis is possible by measuring isovalerylglycine in amniotic fluid and by measuring isovaleryl-CoA dehydrogenase enzyme activity in chorionic villus specimens or cultured amniocytes. […] Because the diagnosis and therapy of isovaleric acidemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist and dietician.

• #46

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

  If your baby does have mild IVA, the metabolic team will explain the condition in more detail and answer any questions you might have. […] No special diet or medical treatment is required unless your baby becomes unwell. […] 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. […] 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. When you find out that you are pregnant, you should tell your midwife and GP there is a family history of IVA. You should also inform your metabolic team early in the pregnancy.

• #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

  Of patients with an early diagnosis and treatment, 85% (39/46) had a normal cognitive outcome, whereas only 45% (28/62) of patients with a late diagnosis had a normal cognitive 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.

• #48 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 diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). […] Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. […] The median follow-up time (median; Q1–Q2) was 2.5 years (1.5–9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0–20) for symptomatic patients. […] We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. […] Although early treatment did not prevent decompensations, they were milder in these patients.

• #49 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

  57% of study patients (12/21) were diagnosed within the first weeks of life and 43% (9/21) in childhood. […] An acute metabolic attack was the main cause of diagnostic work-up. […] The patients’ intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. […] The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening. […] In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days. […] The cognitive performance in terms of IQ was obtained in 13 of the 16 step II participants aged 5 to 24 years, whereas younger children were evaluated using DDST.

• #50 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

  Analyzing the impact of the time at diagnosis and the number of catabolic episodes on the IQ, it turned out that the IQ of the 13 step II participants was not related to the number of documented moderate/severe catabolic episodes. […] However, there was a significant inverse relationship between the IQ score and age at diagnosis (in days) in patients with not more than one severe catabolic episode. […] When subgrouped according to age at diagnosis, normal cognitive abilities (IQ scores) including academic performance (absence of a learning disability) were evident in 82% (9/11) of the early diagnosed study patients compared to only 44% (4/9) of late diagnosed study patients. […] Mortality in the early diagnosis group was 33% during the initial episode of severe metabolic acidosis. […] In patients diagnosed late, the mortality rate was only 3%.

• #51 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

  Analyzing the impact of the time at diagnosis and the number of catabolic episodes on the IQ, it turned out that the IQ of the 13 step II participants was not related to the number of documented moderate/severe catabolic episodes. […] However, there was a significant inverse relationship between the IQ score and age at diagnosis (in days) in patients with not more than one severe catabolic episode. […] When subgrouped according to age at diagnosis, normal cognitive abilities (IQ scores) including academic performance (absence of a learning disability) were evident in 82% (9/11) of the early diagnosed study patients compared to only 44% (4/9) of late diagnosed study patients. […] Mortality in the early diagnosis group was 33% during the initial episode of severe metabolic acidosis. […] In patients diagnosed late, the mortality rate was only 3%.

• #52 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

  Of patients with an early diagnosis and treatment, 85% (39/46) had a normal cognitive outcome, whereas only 45% (28/62) of patients with a late diagnosis had a normal cognitive 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.

• #53 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

  Analyzing the impact of the time at diagnosis and the number of catabolic episodes on the IQ, it turned out that the IQ of the 13 step II participants was not related to the number of documented moderate/severe catabolic episodes. […] However, there was a significant inverse relationship between the IQ score and age at diagnosis (in days) in patients with not more than one severe catabolic episode. […] When subgrouped according to age at diagnosis, normal cognitive abilities (IQ scores) including academic performance (absence of a learning disability) were evident in 82% (9/11) of the early diagnosed study patients compared to only 44% (4/9) of late diagnosed study patients. […] Mortality in the early diagnosis group was 33% during the initial episode of severe metabolic acidosis. […] In patients diagnosed late, the mortality rate was only 3%.

• #54 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 diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). […] Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. […] The median follow-up time (median; Q1–Q2) was 2.5 years (1.5–9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0–20) for symptomatic patients. […] We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. […] Although early treatment did not prevent decompensations, they were milder in these patients.

• #55 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). […] The clinical diagnosis of IVA can be confirmed by mutation of the IVD gene. […] 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. […] Early diagnosis and treatment are necessary to prevent neonatal mortality and improve the neurologic and cognitive outcomes. […] Therefore, early diagnosis is crucial, and asymptomatic detection is possible with expanded neonatal screening. […] When certain clinical manifestations occur in children, the disease can be diagnosed by blood and urinary organic acid or acyl carnitine analysis.

• #56 Isovaleric acidaemia

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

  At around 5 days old, babies are now offered newborn blood spot screening to check if they have IVA. […] If IVA is diagnosed, treatment can be given straight away to reduce the risk of serious complications. […] With early diagnosis and the correct treatment, the majority of children with IVA are able to live healthy lives. […] Without treatment, severe and life-threatening symptoms can develop in some children, including seizures (fits) or falling into a coma. […] Children diagnosed with IVA are referred to a specialist metabolic dietitian and given a low-protein diet. […] Your dietitian will provide detailed advice and guidance, as your baby still needs some of these foods for healthy growth and development. […] People with IVA need to follow a modified diet for the rest of their life to reduce their risk of a metabolic crisis.

• #57 Newborn screening information for isovaleric acidemia | Baby’s First Test | Newborn Screening | Baby Health

  https://www.babysfirsttest.org/newborn-screening/conditions/isovaleric-acidemia

  If your baby shows any of these signs, be sure to contact your babys doctor immediately. […] Your babys doctor might also prescribe L-carnitine supplements. […] With early and careful treatment, your child will most likely have a healthy life with typical growth and development. […] Without treatment, babies with isovaleric acidemia (IVA) can suffer brain damage or even die within the first year of life. […] A genetic counselor or geneticist can help you understand the causes of the condition, discuss genetic testing for IVA, and understand what this diagnosis means for other family members and future pregnancies. […] Healthcare professionals can learn more about confirmatory testing by reading the American College of Medical Genetics and Genomics’ Algorithm for Diagnosis and ACT Sheet, a guide for follow-up after newborn screening.

• #58 Isovaleric acidaemia

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

  At around 5 days old, babies are now offered newborn blood spot screening to check if they have IVA. […] If IVA is diagnosed, treatment can be given straight away to reduce the risk of serious complications. […] With early diagnosis and the correct treatment, the majority of children with IVA are able to live healthy lives. […] Without treatment, severe and life-threatening symptoms can develop in some children, including seizures (fits) or falling into a coma. […] Children diagnosed with IVA are referred to a specialist metabolic dietitian and given a low-protein diet. […] Your dietitian will provide detailed advice and guidance, as your baby still needs some of these foods for healthy growth and development. […] People with IVA need to follow a modified diet for the rest of their life to reduce their risk of a metabolic crisis.

• #59 Orphanet: Isovaleric acidemia

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

  Prenatal genetic testing is possible when the mutation of a proband has previously been determined. […] The pattern of inheritance is autosomal recessive; genetic counseling is recommended for affected families. The risk of disease transmission at each pregnancy is 25% when the parents are proven or obligate carriers. […] Lifelong management is with a low protein diet. Children diagnosed with IVA should be referred to a metabolic dietician who can tailor the diet to support normal growth and development. Supplementing with artificial protein restricted in leucine may be required. L-carnitine and glycine may be prescribed to clear excess isovaleric acid. Emergency treatment in times of metabolic stress (including illness and fasting) is with an anabolic diet. Reducing, but not eliminating, natural protein in the diet for 12-24 hours may help, but only if additional other calories can be given to promote anabolism.

• #60

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

  If your baby does have mild IVA, the metabolic team will explain the condition in more detail and answer any questions you might have. […] No special diet or medical treatment is required unless your baby becomes unwell. […] 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. […] 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. When you find out that you are pregnant, you should tell your midwife and GP there is a family history of IVA. You should also inform your metabolic team early in the pregnancy.

• #61 Isovaleric acidaemia

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

  Your child may be prescribed medicine to help clear some of the excess isovaleric acid. […] If your baby develops an infection, such as a high temperature or cold, their risk of having a metabolic crisis increases. […] You should also take your baby to hospital if they develop symptoms of a metabolic crisis, such as irritability, loss of energy or breathing difficulties.

• #62 Orphanet: Isovaleric acidemia

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

  Prenatal genetic testing is possible when the mutation of a proband has previously been determined. […] The pattern of inheritance is autosomal recessive; genetic counseling is recommended for affected families. The risk of disease transmission at each pregnancy is 25% when the parents are proven or obligate carriers. […] Lifelong management is with a low protein diet. Children diagnosed with IVA should be referred to a metabolic dietician who can tailor the diet to support normal growth and development. Supplementing with artificial protein restricted in leucine may be required. L-carnitine and glycine may be prescribed to clear excess isovaleric acid. Emergency treatment in times of metabolic stress (including illness and fasting) is with an anabolic diet. Reducing, but not eliminating, natural protein in the diet for 12-24 hours may help, but only if additional other calories can be given to promote anabolism.

• #63 Newborn screening information for isovaleric acidemia | Baby’s First Test | Newborn Screening | Baby Health

  https://www.babysfirsttest.org/newborn-screening/conditions/isovaleric-acidemia

  If your baby shows any of these signs, be sure to contact your babys doctor immediately. […] Your babys doctor might also prescribe L-carnitine supplements. […] With early and careful treatment, your child will most likely have a healthy life with typical growth and development. […] Without treatment, babies with isovaleric acidemia (IVA) can suffer brain damage or even die within the first year of life. […] A genetic counselor or geneticist can help you understand the causes of the condition, discuss genetic testing for IVA, and understand what this diagnosis means for other family members and future pregnancies. […] Healthcare professionals can learn more about confirmatory testing by reading the American College of Medical Genetics and Genomics’ Algorithm for Diagnosis and ACT Sheet, a guide for follow-up after newborn screening.

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

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

  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 leads to early treatment and subsequently results in normal development of the children. […] The clinical and genetic features of this patient help to further expand our knowledge of IVA.

• #65 Isovaleric Acidemia: A Case Report

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10749218/

  Isovaleric acidemia is an autosomal recessive disease of leucine metabolism. […] Diagnosis is based on the detection of isovalerylglycine CoA in urine and elevated levels of isovaleryl (C5) carnitine in blood. […] Clinical diagnosis is based on the detection of isovalerylglycine CoA metabolites in the urine organic acid analyses and elevated levels of isovaleryl (C5) carnitine in blood by gas chromatography and mass spectrometry (GC-MS). […] Molecular genetic analysis confirms the diagnosis, as it detects the IVD gene mutation located on chromosome 15q14-15. […] Early diagnosis and treatment are necessary to reduce mortality and avoid neurocognitive sequelae. […] Through extended neonatal screening, asymptomatic patients could be diagnosed, thus preventing decompensation and improving cognitive development. […] There is no laboratory marker for monitoring the therapeutic control or status of this disease. […] However, age-appropriate weight gain, growth, and development are the best indicators of treatment efficacy, which should be routinely assessed during office follow-up of these patients.

• #66 Orphanet: Isovaleric acidemia

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

  Prenatal genetic testing is possible when the mutation of a proband has previously been determined. […] The pattern of inheritance is autosomal recessive; genetic counseling is recommended for affected families. The risk of disease transmission at each pregnancy is 25% when the parents are proven or obligate carriers. […] Lifelong management is with a low protein diet. Children diagnosed with IVA should be referred to a metabolic dietician who can tailor the diet to support normal growth and development. Supplementing with artificial protein restricted in leucine may be required. L-carnitine and glycine may be prescribed to clear excess isovaleric acid. Emergency treatment in times of metabolic stress (including illness and fasting) is with an anabolic diet. Reducing, but not eliminating, natural protein in the diet for 12-24 hours may help, but only if additional other calories can be given to promote anabolism.

• #67 Isovaleric acidaemia

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

  Your child may be prescribed medicine to help clear some of the excess isovaleric acid. […] If your baby develops an infection, such as a high temperature or cold, their risk of having a metabolic crisis increases. […] You should also take your baby to hospital if they develop symptoms of a metabolic crisis, such as irritability, loss of energy or breathing difficulties.

• #68

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

  If your baby does have mild IVA, the metabolic team will explain the condition in more detail and answer any questions you might have. […] No special diet or medical treatment is required unless your baby becomes unwell. […] 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. […] 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. When you find out that you are pregnant, you should tell your midwife and GP there is a family history of IVA. You should also inform your metabolic team early in the pregnancy.

• #69

  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. […] If your baby has a screen positive result, you will be seen by a metabolic doctor, dietitian and nurse specialist (the metabolic team). The team will provide advice and support. Blood and urine tests will be carried out to confirm if your baby has IVA. […] With treatment, the outcome is usually very good and most children with IVA will avoid any long-term health problems. […] 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.

• #70 Isovaleric acidemia | MedLink Neurology

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

  Isovaleric acidemia can be readily diagnosed in newborn screening programs. […] Key metabolites leading to diagnosis are isovalerylglycine in urine and isovaleryl carnitine in plasma or dried blood spots. […] If treatment is initiated before the development of severe metabolic decompensation, the patients prognosis is significantly improved. […] Patients who are diagnosed by newborn screening usually have normal psychomotor development. […] Diagnosis of classic isovaleric acidemia is established in a proband by identification of C5-carnitine metabolites by tandem mass spectrometry and isovalerylglycine (IVG) and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry, or identification of biallelic pathogenic variants in IVD by molecular genetic testing.

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

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

  The diagnosis of classic IVA in a proband with suggestive biochemical and/or clinical findings is established by identification of: C5-carnitine (C5) metabolites, isovalerylglycine (IVG), and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry; OR biallelic pathogenic (or likely pathogenic) variants in IVD by molecular genetic testing.

• #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

  Of patients with an early diagnosis and treatment, 85% (39/46) had a normal cognitive outcome, whereas only 45% (28/62) of patients with a late diagnosis had a normal cognitive 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.

• #73 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 diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). […] Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. […] The median follow-up time (median; Q1–Q2) was 2.5 years (1.5–9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0–20) for symptomatic patients. […] We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. […] Although early treatment did not prevent decompensations, they were milder in these patients.

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

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

  Based on the biochemical and clinical data, eight patients had mild/asymptomatic IVA (p2p9), four had chronic intermittent IVA (p10, p11, p14, p15) and four had acute neonatal IVA (p1, p12, p13, p16). […] 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. […] 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. […] This study has provided information that extends the existing knowledge of IVA.

• #75 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

  Tandem mass spectrometry (MS/MS) revealed increased blood levels of C5 acylcarnitine, and Gas chromatography–mass spectrometry (GC/MS) revealed increased levels of urinary 3-hydroxyisovaleric acid (3HIV), isovalerylglycine, and urinary ketone bodies, confirming the diagnosis of IVA. […] For genetic analysis, DNA was extracted from the peripheral blood of the patient and his parents using the QIAamp DNA Blood Mini Kit (QIAGEN). […] We identified two compound heterozygous variants of the IVD gene, the unreported variant c.224A>G (p.Asn75Ser) and the reported variant c.1195G>C (p.Asp399His). […] The clinical manifestations and prognosis of IVA vary greatly, and some patients die in the neonatal period. However, many asymptomatic patients are found through family or neonatal screening and remain asymptomatic during the follow-up. […] Early diagnosis and treatment have been reported that cannot prevent the onset of metabolic crisis but can prevent mental impairment.

• #76 Azthena logo with the word Azthena

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

  Diagnosis is based on clinical presentation and laboratory analysis of blood and urine. […] The characteristic symptoms, clinical exam, and blood and urine testing are used to diagnose isovaleric acidemia. Genetic testing results may aid in the confirmation of the diagnosis. […] IVA can be detected through newborn screening (NBS) as well. However, some persons who test positive for IVA as newborns may never have symptoms. IVA is an attractive candidate for NBS programs due to the possibility of pre-symptomatic identification by NBS and the apparent benefit established for patients detected and treated early. […] A better outcome is linked to early diagnosis and treatment.

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

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

  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 leads to early treatment and subsequently results in normal development of the children. […] The clinical and genetic features of this patient help to further expand our knowledge of IVA.

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