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The deficiency of isovaleryl-CoA dehydrogenase leads to an inborn recessive error of leucine metabolism named isovaleric acidemia (IVA). Its presentation may be either in the neonatal period as an acute episode of metabolic acidosis or later as a “chronic intermittent form”. Normal development is promoted by early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine. The present case was a 35-day-old boy admitted with seizure whose initial screening test was in favor of organic acidemia of the isovaric acidemia (Ammonia: 200 µmol/L). As the venous blood gas (VBG) analysis revealed no acidosis, newborn metabolic screening was repeated. Typical laboratory findings and elevated levels of C5 and C5/C2 confirmed isovaleric acidemia again. As the above patient had no acidosis while the other tests including laboratory and genetic analysis were in favor of IVA, he considered to be a rare case.

Newborn screening (NBS) allows early identification of individuals with rare disease, such as isovaleric aciduria (IVA). Reliable early prediction of disease severity of positively screened individuals with IVA is needed to guide therapeutic decision, prevent life‐threatening neonatal disease manifestation in classic IVA and over‐medicalization in attenuated IVA that may remain asymptomatic. We analyzed 84 individuals (median age at last study visit 8.5 years) with confirmed IVA identified by NBS between 1998 and 2018 who participated in the national, observational, multicenter study. Screening results, additional metabolic parameters, genotypes, and clinical phenotypic data were included. Individuals with metabolic decompensation showed a higher median isovalerylcarnitine (C5) concentration in the first NBS sample (10.6 vs. 2.7 μmol/L; p < 0.0001) and initial urinary isovalerylglycine concentration (1750 vs. 180 mmol/mol creatinine; p = 0.0003) than those who remained asymptomatic. C5 was in trend inversely correlated with full IQ (R = −0.255; slope = −0.869; p = 0.0870) and was lower for the "attenuated" variants compared to classic genotypes [median (IQR; range): 2.6 μmol/L (2.1–4.0; 0.7–6.4) versus 10.3 μmol/L (7.4–13.1; 4.3–21.7); N = 73]. In‐silico prediction scores (M‐CAP, MetaSVM, and MetaLR) correlated highly with isovalerylglycine and ratios of C5 to free carnitine and acetylcarnitine, but not sufficiently with clinical endpoints. The results of the first NBS sample and biochemical confirmatory testing are reliable early predictors of the clinical course of IVA, facilitating case definition (attenuated versus classic IVA). Prediction of attenuated IVA is supported by the genotype. On this basis, a reasonable algorithm has been established for neonates with a positive NBS result for IVA, with the aim of providing the necessary treatment immediately, but whenever possible, adjusting the treatment to the individual severity of the disease. [ABSTRACT FROM AUTHOR]

Background: Isovaleric acidemia (IVA) is a rare autosomal-recessive metabolic disorder caused by a genetic deficiency of isovaleryl-CoA dehydrogenase (IVD). Deficiency of IVD leads to the accumulation of organic acids; however, the genotype-phenotype relationship has not been well established. Methods: Two brothers with acute neonatal IVA in a Chinese family were reported, and their clinical manifestations and examination were described. MS/MS and GCMS were used to perform organic acid analysis of blood samples and urine samples, and the patient's blood was sequenced by NGS and Sanger sequencing of the ivd gene. Results: Sequence analysis of the ivd gene identified compound heterozygous mutations in the patient, the c.250T>C (p.W84R) missense mutation (novel) and the c.466-3_466-2 delCAinsGG splicing mutation, which were inherited from their parents. Various bioinformatics prediction algorithms suggest that the p. W84R missense mutation may destabilize the IVD monomer and reduce its ability to bind to substrates. Conclusions: Both the clinical and genetic features of this family will help us to further expand the knowledge of IVA. [ABSTRACT FROM AUTHOR]

Since the UK commenced newborn screening for isovaleric acidemia in 2015, changes in prescribing have increased the incidence of false positive (FP) results due to pivaloylcarnitine. A review of screening results between 2015 and 2022 identified 24 true positive (TP) and 84 FP cases, with pivalate interference confirmed in 76/84. Initial C5 carnitine (C5C) did not discriminate between FP and TP with median (range) C5C of 2.9 (2.0–9.6) and 4.0 (1.8–>70) µmol/L, respectively, and neither did Precision Newborn Screening via Collaborative Laboratory Integrated Reports (CLIR), which identified only 1/47 FP cases. However, among the TP cases, disease severity showed a correlation with initial C5C in ‘asymptomatic’ individuals (n = 17), demonstrating a median (range) C5C of 3.0 (1.8–7.1) whilst ‘clinically affected’ patients (n = 7), showed a median (range) C5C of 13.9 (7.7–70) µmol/L. These findings allowed the introduction of dual cut-off values into the screening algorithm to reduce the incidence of FPs, with initial C5C results ≥ 5 µmol/L triggering urgent referral, and those >2.0 and

Introduction: Isovaleric acidemia is the first recognized organic acidemia disorder in humans caused by a defect in the enzyme isovaleryl-coenzyme A dehydrogenase. There are some cases of this disease in the northern provinces of Iran, where there is a high rate of consanguineous marriages. Therefore, this study aims to identify mutations occurring in patients with isovaleric acidemia diagnosed. Methods: The patient is a 5-year-old male child (weight: 21 kg, height: 105.5 cm, blood group AB+) with a learning and speech disorder. Routine blood and urine tests, as well as metabolic abnormalities tests such as amino acid abnormalities and fatty acid oxidation, were performed. The DNA was extracted from the blood samples of the patient and nine family members and sequenced using the Sanger method. Results: The carnitine/acylcarnitine profile showed an increased amount of isovalerylcarnitine (C5=4.74 micromol/l, cutoff>0.47 micromol/l). Furthermore, in the urine organic acids test, an increase in isovalerylglycine (91.02%, cutoff<0.69) was observed. A new mutation, c.391A>T, was identified in exon 4 of the IVD gene. Some members of the patient's family were also heterozygous. Conclusion: The results indicated that the patient has a new mutation (c.391A>T) in the IVD gene, which leads to a change of amino acid asparagine to tyrosine. [ABSTRACT FROM AUTHOR]

Isovaleric acidemia (IVA), due to isovaleryl-CoA dehydrogenase (IVD) deficiency, results in the accumulation of isovaleryl-CoA, isovaleric acid and secondary metabolites. The increase in these metabolites decreases mitochondrial energy production and increases oxidative stress. This contributes to the neuropathological features of IVA. A general assumption in the literature exists that glycine N-acyltransferase (GLYAT) plays a role in alleviating the symptoms experienced by IVA patients through the formation of N-isovalerylglycine. GLYAT forms part of the phase II glycine conjugation pathway in the liver and detoxifies excess acyl-CoA’s namely benzoyl-CoA. However, very few studies support GLYAT as the enzyme that conjugates isovaleryl-CoA to glycine. Furthermore, GLYATL1, a paralogue of GLYAT, conjugates phenylacetyl-CoA to glutamine. Therefore, GLYATL1 might also be a candidate for the formation of N-isovalerylglycine. Based on the findings from the literature review, we proposed that GLYAT or GLYATL1 can form N-isovalerylglycine in IVA patients. To test this hypothesis, we performed an in-silico analysis to determine which enzyme is more likely to conjugate isovaleryl-CoA with glycine using AutoDock Vina. Thereafter, we performed in vitro validation using purified enzyme preparations. The in-silico and in vitro findings suggested that both enzymes could form N-isovaleryglycine albeit at lower affinities than their preferred substrates. Furthermore, an increase in glycine concentration does not result in an increase in N-isovalerylglycine formation. The results from the critical literature appraisal, in-silico, and in vitro validation, suggest the importance of further investigating the reaction kinetics and binding behaviors between these substrates and enzymes in understanding the pathophysiology of IVA.

Isovaleric aciduria (IVA) is a rare disorder of leucine metabolism and part of newborn screening (NBS) programs worldwide. However, NBS for IVA is hampered by, first, the increased birth prevalence due to the identification of individuals with an attenuated disease variant (so-called "mild" IVA) and, second, an increasing number of false positive screening results due to the use of pivmecillinam contained in the medication. Recently, machine learning (ML) methods have been analyzed, analogous to new biomarkers or second-tier methods, in the context of NBS. In this study, we investigated the application of machine learning classification methods to improve IVA classification using an NBS data set containing 2,106,090 newborns screened in Heidelberg, Germany. Therefore, we propose to combine two methods, linear discriminant analysis, and ridge logistic regression as an additional step, a digital-tier, to traditional NBS. Our results show that this reduces the false positive rate by 69.9 % from 103 to 31 while maintaining 100 % sensitivity in cross-validation. The ML methods were able to classify mild and classic IVA from normal newborns solely based on the NBS data and revealed that besides isovalerylcarnitine (C5), the metabolite concentration of tryptophan (Trp) is important for improved classification. Overall, applying ML methods to improve the specificity of IVA could have a major impact on newborns, as it could reduce the newborns' and families' burden of false positives or over-treatment. [ABSTRACT FROM AUTHOR]

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Background: Newborn screening (NBS) for isovaleric acidemia (IVA) is implemented via tandem mass spectrometry (MS/MS), but false-positive results are still common. In addition, NBS for IVA is limited by a lack of suitable biomarkers, especially after the use of pivaloylester-containing antibiotics., Methods: We conducted a retrospective cohort study to explore the clinical correlation between antibiotic administration and false-positive results for isovalerylcarnitine (C5)., Results: A total of 509,313 newborns were recruited from the initial NBS study, only one of whom underwent genetic confirmation, conducted between 2015 and 2020. Significant associations between false-positive C5-carnitine screening results and treatment with pivalate-generating antibiotics were identified with retrospective analysis., Conclusions: The current results highlight the detrimental effects of false-positive C5-carnitine screening results. Unless the licensing of pivalate-generating antibiotics for use during the neonatal period is reconsidered, a second-tier test for C5 determination will be necessary., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Newborn screening (NBS) for isovaleric acidemia (IVA) reduces mortality and morbidity; however, it has also resulted in the detection of individuals with an asymptomatic or mild presentation for which early detection via newborn screening has not been proven to alter neurological outcome. We reevaluated biochemical and molecular data for newborns flagged positive for IVA in aim of developing a new screening algorithm to exclude the latter from positive screening. Among 2 794 365 newborns underwent routine newborn screening in Israel, 412 flagged positive for IVA, of which, 371 were false positives on recall sample testing and 41 positive newborns were referred to the clinic. 38/41 have biochemical and molecular confirmation in keeping with IVA. Among the 38 patients, 32% (12/38) were classified as symptomatic while, 68% (26/38) were classified as asymptomatic. 69% of the latter group harbor the known variant associated with mild potentially asymptomatic phenotype, c.932C>T; p. Ala311Val. Among asymptomatic patients, only 46% (12/26) are currently treated. Two novel variants have been detected in the IVD gene: c.487G>A; p. Ala163Thr and c.985A>G; p. Met329Val. Cut-off recalculation, of referred newborns' initial biochemical results, after classifying the referred patients to two binary groups of symptomatic and asymptomatic, resulted in an improved NBS algorithm comprising of C5 >5 μM and C5/C2>0.2 and C5/C3>4 flagging only those likely to have the classic symptomatic phenotype., (© 2024 SSIEM.)

OBJECTIVE: Organic acidurias (OAs) are a group of rare metabolic disorders that disrupt the regular amino acid metabolism. OAs are characterized by recurrent episodes of acidemia, ketonuria and hyperammonemia which can result in brain/liver damage and renal failure, and despite the life-long protein-restricted diet, impaired growth and long-term complications can occur. Consequently, a longterm management of OAs patients is required, aimed principally at reducing the frequency and duration of metabolic decompensation/hyperammonemia episodes. Nevertheless, unlike the acute phase, evidence on the chronic management of OAs patients is less consolidated. SUBJECTS AND METHODS: To expand the knowledge on this field, 13 Italian referral centers for the management of OAs were involved in a survey focused on the long-term use of carglumic acid (Carbaglu®, Recordati Rare Diseases). RESULTS: Participating centers reported a reduction between 69% and 81% in the annual number of metabolic decompensations with the chronic use of carglumic acid and an improvement in protein intake. Most centers reported no difficulty using carglumic acid as a long-term therapy, along with a great compliance. CONCLUSIONS: Taken together, obtained data align with the available literature and support a positive clinical experience with the long-term carglumic acid administration. Additional studies aimed at better defining a proper dosage for the chronic administration of carglumic acid and the clinical and biochemical characteristics of patients treated chronically are needed. In addition, the potential impact of this treatment regimen on the neurological development and growth of patients should be elucidated. [ABSTRACT FROM AUTHOR]

Background: Isovaleric acidemia (IVA) is an inborn error of leucine metabolism and different approaches have been applied to its prenatal diagnosis. However, systemic application of a biochemical strategy is rare. To evaluate its reliability and validity, we conducted a retrospective study of our experience with metabolite measurement together with genetic analysis in IVA prenatal diagnosis at a single center. Methods: A total of eight pregnancies whose probands were diagnosed as IVA were referred to our center for prenatal diagnosis. Prenatal data of genetic analysis and metabolite measurement using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) in amniotic fluid (AF) samples were retrospectively reviewed. Results: Genetic and biochemical results were both available in these eight at-risk fetuses. Among them, two fetuses had higher levels of isovalerylcarnitine (C5) and C5/acetylcarnitine (C2) in AF compared with normal reference range and, thus, were determined to be affected, both of whom were found to carry compound heterogeneous mutations according to genetic analysis. The remaining six fetuses were determined to be unaffected based on a normal AF metabolite profile, except one showed slightly elevated C5 and they were found to be carriers according to genetic analysis. However, the level of isovalerylglycine (IVG) could not be detected at all in both groups. Conclusion: The biochemical analysis, as a quick and convenient method, could be an additional reliable option for the prenatal diagnosis of IVA, especially in families with inconclusive genetic results, and can achieve a more precise diagnosis in conjunction with mutation analysis. [ABSTRACT FROM AUTHOR]

Background: Isovaleric acidemia (IVA) is an inborn error of leucine metabolism and different approaches have been applied to its prenatal diagnosis. However, systemic application of a biochemical strategy is rare. To evaluate its reliability and validity, we conducted a retrospective study of our experience with metabolite measurement together with genetic analysis in IVA prenatal diagnosis at a single center.Methods: A total of eight pregnancies whose probands were diagnosed as IVA were referred to our center for prenatal diagnosis. Prenatal data of genetic analysis and metabolite measurement using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) in amniotic fluid (AF) samples were retrospectively reviewed.Results: Genetic and biochemical results were both available in these eight at-risk fetuses. Among them, two fetuses had higher levels of isovalerylcarnitine (C5) and C5/acetylcarnitine (C2) in AF compared with normal reference range and, thus, were determined to be affected, both of whom were found to carry compound heterogeneous mutations according to genetic analysis. The remaining six fetuses were determined to be unaffected based on a normal AF metabolite profile, except one showed slightly elevated C5 and they were found to be carriers according to genetic analysis. However, the level of isovalerylglycine (IVG) could not be detected at all in both groups.Conclusion: The biochemical analysis, as a quick and convenient method, could be an additional reliable option for the prenatal diagnosis of IVA, especially in families with inconclusive genetic results, and can achieve a more precise diagnosis in conjunction with mutation analysis.

With the execution of expanded newborn screen (NBS) program nationwide, it is uncommon to see severe hyperammonemia associated with isovaleric acidemia (IVA). We present a seven-day-old boy with severe IVA complicated by hyperammonemia. This child was flagged by NBS at 4 days old, but confirmatory testing was delayed due to COVID19 pandemic and parental skepticism. His parents did not adhere to the leucine-restricted diet as recommended. On day 7, the patient presented to the ER with ammonia of 588 μg/dL. Ammonia subsequently rose to >1000 μg/dL. This child received carnitine, 1 dose of Ammonul (sodium benzoate and sodium phenylacetate), arginine, carglumic acid (Carbaglu) and CRRT. Plasma amino acid assay revealed a glutamine level of 256 μmol/L, which is below the lower limit of normal upon arrival to ER and PICU. The hyperammonemia was corrected in 15 h and with the continued use of carglumic acid for 3 days, there was no rebound of hyperammonemia. However, the patient suffered from bone marrow suppression associated with the organic acidemia and required frequent platelet transfusions, as well as G-CSF for neutropenia. The management of this patient provides supporting evidence of the many theoretic metabolic “facts” including why Ammonul is not helpful in organic acidemias.

Flow injection analysis–tandem mass spectrometry (FIA-TMS) has been applied in a first-tier test of newborn screening (NBS). Although isovalerylcarnitine (i-C5), which is a diagnostic indicator of isovaleric acidemia (IVA), is isobaric with pivaloylcarnitine (p-C5), 2-methylbutyrylcarnitine, and n-valerylcarnitine, these isomers cannot be distinguished by the FIA-TMS. There are many reports of false positives derived from p-C5 due to the use of pivalate-conjugated antibiotics. In this study, we developed a new FIA-TMS method to distinguish i-C5 and p-C5. We found that the intensity ratio of product ions for i-C5 and p-C5 was different in a certain range even under the same analytical conditions. The product ions with the most distinct differences in ionic intensity between the isomers and the collision energies that produce them were determined to be m/z 246.2 > 187.1 and −15 V, respectively. In addition to the quantification ion, a reference ion was defined, and the similarity of the i-C5 and p-C5 reference ion ratios (i-C5 score and p-C5 score, respectively) were used to estimate which isomer (i-C5 and p-C5) was responsible for elevated C5 acylcarnitine in dried blood spots (DBSs). As a result of analyses of 11 DBS samples derived from pivalate-conjugated antibiotics and four DBS samples from IVA patients using our method, it was found that our method was able to correctly determine the type of C5-acylcarnitine (i-C5 or p-C5) in the DBS samples. Implementation of this new FIA-TMS method into the current NBS protocol will allow for a reduction in false positives in IVA. [ABSTRACT FROM AUTHOR]

Isovaleric Acidemia (IVA) is an autosomal recessive Inborne Error of Metabolism (IEM), i.e., caused by the mutation of isovaleric-CoA dehydrogenase. Two phenotypes of IVA are reported; acute and chronic. The case was a 3-year-old boy with chronic intermittent presentation. Elevated 3-hydroxybutyric acid and isovaleric glycine in urinary acid profile was reported. We also performed a brief review about the presented case; IVA in international databases for English language articles on children. Several manners exist to screen IVA patients and the best one is GC-MS in urine analysis. The prognosis of the disease depends on the early interventions.

Isovaleric aciduria (IVA) is a rare disorder of leucine metabolism and part of newborn screening (NBS) programs worldwide. However, NBS for IVA is hampered by, first, the increased birth prevalence due to the identification of individuals with an attenuated disease variant (so-called “mild” IVA) and, second, an increasing number of false positive screening results due to the use of pivmecillinam contained in the medication. Recently, machine learning (ML) methods have been analyzed, analogous to new biomarkers or second-tier methods, in the context of NBS. In this study, we investigated the application of machine learning classification methods to improve IVA classification using an NBS data set containing 2,106,090 newborns screened in Heidelberg, Germany. Therefore, we propose to combine two methods, linear discriminant analysis, and ridge logistic regression as an additional step, a digital-tier, to traditional NBS. Our results show that this reduces the false positive rate by 69.9% from 103 to 31 while maintaining 100% sensitivity in cross-validation. The ML methods were able to classify mild and classic IVA from normal newborns solely based on the NBS data and revealed that besides isovalerylcarnitine (C5), the metabolite concentration of tryptophan (Trp) is important for improved classification. Overall, applying ML methods to improve the specificity of IVA could have a major impact on newborns, as it could reduce the newborns’ and families’ burden of false positives or over-treatment.

Isovaleric acidemia is a rare autosomal recessive inborn error of metabolism that affects the breakdown of the essential amino acid leucine. Acute metabolic decompensation is often triggered by stressors such as surgery, concurrent illness, excessive protein intake, or dehydration. This can lead to a catabolic state with increased endogenous protein turnover, posing a risk of potentially life-threatening crises due to the accumulation of toxic metabolites from incomplete leucine breakdown. Such episodes are rarely observed beyond childhood and adolescence, and the disease's rarity typically prevents single centers from gaining extensive experience with its full spectrum. This lack of familiarity can be challenging for adult physicians, who may not be well versed in the appropriate management strategies. This case report describes an acute metabolic crisis in a middle-aged man in his late 30s, triggered by an influenza virus infection and presenting as persistent and unresolved metabolic acidosis. We aim to emphasize the importance of early and prompt recognition of metabolic crises in metabolically stable adults with inborn errors of metabolism, particularly for intensivists and acute care physicians., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ravikumar et al.)

Clinical standard of care for newborn screening (NBS) is acylcarnitine metabolites quantitation by tandem mass spectrometry (MS/MS) from dried blood spots. Follow up sequencing often results in identification of one or more variants of uncertain significance (VUS). Isovaleric acidemia (IVA) is an autosomal recessive inborn error of metabolism caused by deficiency of isovaleryl-CoA dehydrogenase (IVDH) in the Leu catabolism pathway. Many IVD mutations are characterized as VUS complicating IVA clinical diagnoses and treatment. We present a testing platform approach to confirm the functional implication of VUS identified in newborns with IVA applicable to multiple inborn errors of metabolism identified by NBS. An IVD null HEK293T cell culture model was generated by using a dual sgRNA CRISPR/Cas9 genome-editing strategy targeting IVD exons 2–3. Clonal cell lines were confirmed by a combination of genomic breakpoint sequencing and droplet digital PCR. The IVD null model had no IVDH antigen signal and 96% reduction in IVDH enzyme activity. The IVD null model was transfected with vectors containing control or variant IVD and functional assays were performed to determine variant pathogenicity. c.149G > C (p.Arg50Pro; precursor numbering), c.986T > C (p.Met329Thr), and c.1010G > A (p.Arg337Gln), c.1179del394 f. mutant proteins had reduced IVDH protein and activity. c.932C > T (p.Ala311Val), c.707C > T (p.Thr236Ile), and c.1232G > A (p.Arg411Gln) had stable IVDH protein, but no enzyme activity. c.521T > G (p.Val174Gly) had normal IVDH protein and activity. IVD variant transfection results confirmed results from IVA fibroblasts containing the same variants. We have developed an IVD null HEK293T cell line to rapidly allow determination of VUS pathogenicity following identification of novel alleles by clinical sequencing following positive NBS results for suspected IVA. We suggest similar models can be generated via genome-editing for high throughput assessment of VUS function for a multitude of inborn errors of metabolism and can ideally supplement NBS programs. [ABSTRACT FROM AUTHOR]

Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long‐term clinical benefit of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi‐center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long‐term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent single (N = 10) or recurrent (N = 7) metabolic decompensations, 13 of them occurring already neonatally. IQ (mean ± SD, 90.7 ± 10.1) was mostly normal but below the reference population (P =.0022) and was even lower in individuals with severe neonatal decompensations (IQ 78.8 ± 7.1) compared to those without crises (IQ 94.7 ± 7.5; P =.01). Similar results were obtained for school placement. In contrast, individuals with mild IVA had excellent neurocognitive outcomes (IQ 105.5 ± 15.8; normal school placement) and a benign disease course (no metabolic decompensation, normal hospitalization rate), which did not appear to be impacted by metabolic maintenance therapy. In conclusion, NBS reduces mortality in classic IVA, but does not reliably protect against severe neonatal metabolic decompensations, crucial for favorable neurocognitive outcome. In contrast, individuals with mild IVA had excellent clinical outcomes regardless of metabolic maintenance therapy, questioning their benefit from NBS. Harmonized stratified therapeutic concepts are urgently needed. [ABSTRACT FROM AUTHOR]

Glycine conjugation is an important phase II reaction and represents a central detoxification pathway which is essential for the recycling of free coenzyme A. Only few sequence variants have been reported in the human GLYAT gene and only two studies have overexpressed the human protein in bacterial systems and partially characterized it. This has prompted us to study the wild-type enzyme and two sequence variants not only in the E. coli strain Origami 2(DE3), but also to overexpress GLYAT in HEK293 cells, a human-derived cell line. Following purification of the recombinant proteins from E. coli the wild-type GLYAT protein and sequence variants, p.(Gln61Leu) yielded decreased specific activity than the wild-type enzyme, while specific activity of p.(Asn156Ser) activity of the latter variant was somewhat increased. K M values were similar for the three forms of GLYAT overexpressed in bacteria and for the wild-type enzyme overexpressed in HEK293 cells. Localization studies demonstrated intramitochondrial localization of human wild-type GLYAT, conjugated with eGFP, in the HEK293 cells. As p.(Gln61Leu) does not only impair GLYAT activity in vitro , but is of high prevalence in a Caucasian Afrikaner cohort in South Africa, potential pharmacogenetic implications, warrant further studies of GLYAT. [ABSTRACT FROM AUTHOR]

Flow injection analysis–tandem mass spectrometry (FIA-TMS) has been applied in a first-tier test of newborn screening (NBS). Although isovalerylcarnitine (i-C5), which is a diagnostic indicator of isovaleric acidemia (IVA), is isobaric with pivaloylcarnitine (p-C5), 2-methylbutyrylcarnitine, and n-valerylcarnitine, these isomers cannot be distinguished by the FIA-TMS. There are many reports of false positives derived from p-C5 due to the use of pivalate-conjugated antibiotics. In this study, we developed a new FIA-TMS method to distinguish i-C5 and p-C5. We found that the intensity ratio of product ions for i-C5 and p-C5 was different in a certain range even under the same analytical conditions. The product ions with the most distinct differences in ionic intensity between the isomers and the collision energies that produce them were determined to be m/z 246.2 > 187.1 and −15 V, respectively. In addition to the quantification ion, a reference ion was defined, and the similarity of the i-C5 and p-C5 reference ion ratios (i-C5 score and p-C5 score, respectively) were used to estimate which isomer (i-C5 and p-C5) was responsible for elevated C5 acylcarnitine in dried blood spots (DBSs). As a result of analyses of 11 DBS samples derived from pivalate-conjugated antibiotics and four DBS samples from IVA patients using our method, it was found that our method was able to correctly determine the type of C5-acylcarnitine (i-C5 or p-C5) in the DBS samples. Implementation of this new FIA-TMS method into the current NBS protocol will allow for a reduction in false positives in IVA.

Since the UK commenced newborn screening for isovaleric acidemia in 2015, changes in prescribing have increased the incidence of false positive (FP) results due to pivaloylcarnitine. A review of screening results between 2015 and 2022 identified 24 true positive (TP) and 84 FP cases, with pivalate interference confirmed in 76/84. Initial C5 carnitine (C5C) did not discriminate between FP and TP with median (range) C5C of 2.9 (2.0-9.6) and 4.0 (1.8->70) µmol/L, respectively, and neither did Precision Newborn Screening via Collaborative Laboratory Integrated Reports (CLIR), which identified only 1/47 FP cases. However, among the TP cases, disease severity showed a correlation with initial C5C in 'asymptomatic' individuals ( n = 17), demonstrating a median (range) C5C of 3.0 (1.8-7.1) whilst 'clinically affected' patients ( n = 7), showed a median (range) C5C of 13.9 (7.7-70) µmol/L. These findings allowed the introduction of dual cut-off values into the screening algorithm to reduce the incidence of FPs, with initial C5C results ≥ 5 µmol/L triggering urgent referral, and those >2.0 and <5.0 µmol/L prompting second-tier C5-isobar testing. This will avoid delayed referral in babies at particular risk whilst reducing the FP rate for the remainder., Competing Interests: The authors declare no conflict of interest.

• Five previously unreported variants in the IVD gene were detected. • The most common variant was c.1208A > G (p.Y403C), with an allele frequency of 30%. • All unreported missense variants may cause structural and functional damage. • Our analysis expanded the IVD mutation spectrum in the Chinese population. • Stringent recall criteria and second-tier tests are needed for IVA screening. Isovaleric acidemia (IVA) is a rare autosomal recessive disorder of leucine metabolism caused by a defective isovaleryl-CoA dehydrogenase (IVD) gene. Reports of IVA diagnoses following newborn screening (NBS) in the Chinese population are few. We investigated the biochemical, clinical, and molecular profiles of 5 patients with IVA in China. The estimated incidence of IVA in Quanzhou, China is 1 in 1:84,469. Initial NBS revealed mild to markedly increased isovalerylcarnitine (C5) concentrations in all 5 patients, and differential diagnosis revealed increased urinary isovaleryglycine concentrations in 2 patients. One patient presented with acute neonatal symptoms, whereas the other 4 remained asymptomatic. Eight distinct IVD gene variants were identified. The most common variant was c.1208A > G (p.Y403C), with an allele frequency of 30%. Five variants were previously unreported, namely, c.499A > G (p.M167V), c.640A > G (p.T214A), c.740G > A (p.G247E), c.832G > C (p.V278L), and c.1195G > C (p.D399H). Different in silico prediction analyses suggested that these previously unreported missense variants are pathogenic. Protein modelling analyses also showed that these missense variants may cause structural damage and dysfunction in IVD. Patients with IVA may have C5 concentrations approaching the cut-off values, highlighting the need for stringent recall criteria and second-tier tests to improve screening performance. [ABSTRACT FROM AUTHOR]

• tNGS improves understanding of the genotypes and phenotypes associated with IVA. • Novel pathogenic variants found in IVD are reported along with patient phenotypes. • IVA NBS with molecular studies identifies forms of IVA; drives treatment decisions. Isovaleric acidemia (IVA) is an inborn error of metabolism caused by deficiency of isovaleryl-CoA dehydrogenase. IVA clinical picture includes gastroenterological and progressive neurological symptoms which can lead to permanent disability and death. Early detection by newborn screening (NBS) and treatment promotes normal development. In this study, clinical summaries, biochemical measurements and targeted next generation sequencing (tNGS) data from the IVD gene were compared in 13 Mexican patients. The main symptoms were vomiting, feeding refusal, abdominal pain, impaired alertness, lethargy, stupor, coma; hypotonia, ataxia, hallucinations, seizures; anemia, neutropenia and pancytopenia. Mean blood concentration of isovalerylcarnintine was above the reference value (0.5 µM) in symptomatic patients (8.78 µM), as well as in the screen positive newborns (2.23 µM). The molecular spectrum of this cohort was heterogeneous, with 14 different variants identified, seven were previously-described, and seven were novel. The most frequent variant was c.158G > C (p.R53P). In this study, we found a long diagnostic delay (average of 44 months). Thus, it is essential to increase physician awareness of this treatable condition. Biochemical IVA NBS accompanied by molecular studies (e.g. tNGS) will permit identification of potentially asymptomatic forms of the disease, and improve genotype-phenotype relationship, management decisions and follow-up. [ABSTRACT FROM AUTHOR]

Background: In Europe, dietary management of isovaleric acidemia (IVA) may vary widely. There is limited collective information about dietetic management. Aim: To describe European practice regarding the dietary management of IVA, prior to the availability of the E-IMD IVA guidelines (E-IMD 2014). Methods: A cross-sectional questionnaire was sent to all European dietitians who were either members of the Society for the Study of Inborn Errors of Metabolism Dietitians Group (SSIEM-DG) or whom had responded to previous questionnaires on dietetic practice (n = 53). The questionnaire comprised 27 questions about the dietary management of IVA. Results: Information on 140 patients with IVA from 39 centres was reported. 133 patients (38 centres) were given a protein restricted diet. Leucine-free amino acid supplements (LFAA) were routinely used to supplement protein intake in 58% of centres. The median total protein intake prescribed achieved the WHO/FAO/UNU [2007] safe levels of protein intake in all age groups. Centres that prescribed LFAA had lower natural protein intakes in most age groups except 1 to 10 y. In contrast, when centres were not using LFAA, the median natural protein intake met WHO/FAO/UNU [2007] safe levels of protein intake in all age groups. Enteral tube feeding was rarely prescribed. Conclusions: This survey demonstrates wide differences in dietary practice in the management of IVA across European centres. It provides unique dietary data collectively representing European practices in IVA which can be used as a foundation to compare dietary management changes as a consequence of the first E-IMD IVA guidelines availability.

Isovaleric acidemia (IVA) is an organic acid disease caused by a deficiency of isovaleryl-CoA dehydrogenase. Deficiency of this enzyme leads to accumulation of organic acids, such as isovalerylcarnitine and isovalerylglycine. The proposed IVA treatments include leucine restriction and l-carnitine and/or glycine supplementation, which convert isovaleric acid into non-toxic isovalerylcarnitine and isovalerylglycine, respectively. We examined the therapeutic response using the leucine load test and performed a 10-year follow-up in the patient. Methods: We evaluated the patient with IVA beginning at 5 years of age, when he presented with a mild to intermediate metabolic phenotype. Ammonia, free carnitine, isovalerylcarnitine, and isovalerylglycine were analyzed in the urine and blood after a meal consisting of 1600 mg leucine with glycine alone (250 mg/kg/day), l-carnitine alone (100 mg/kg/day), or both glycine and l-carnitine for four days each. Results: (Leucine load test) Three hours after the meal, serum ammonia levels increased most dramatically with glycine treatment alone, then with both in combination, and least with l-carnitine alone. Urinary isovalerylglycine levels increased 2-fold more with glycine supplementation than those following supplementation with both agents or with l-carnitine alone. Treatment with both agents resulted in a gradual increase in urinary acylcarnitine levels during the 6-h period following the leucine load, reaching concentrations comparable to those observed with l-carnitine alone. (Clinical course) After initiation of both glycine (200 mg/kg/day) and l-carnitine (100 mg/kg/day) supplementation at 5 years of age, doses were gradually reduced to 111.7 mg/kg/day and 55.8 mg/kg/day, respectively, at 15 years of age. His mind and body had developed without any sequelae. Discussion: We concluded that l-carnitine conjugated isovaleric acid earlier than glycine. Additionally, during the 10-year follow-up period, the patient displayed no clinical deterioration.

While genome-wide association studies (GWAS) and positive selection scans identify genomic loci driving human phenotypic diversity, functional validation is required to discover the variant(s) responsible. We dissected the IVD gene locus-which encodes the isovaleryl-CoA dehydrogenase enzyme-implicated by selection statistics, multiple GWAS, and clinical genetics as important to function and fitness. We combined luciferase assays, CRISPR/Cas9 genome-editing, massively parallel reporter assays (MPRA), and a deletion tiling MPRA strategy across regulatory loci. We identified three regulatory variants, including an indel, that may underpin GWAS signals for pulmonary fibrosis and testosterone, and that are linked on a positively selected haplotype in the Japanese population. These regulatory variants exhibit synergistic and opposing effects on IVD expression experimentally. Alleles at these variants lie on a haplotype tagged by the variant most strongly associated with IVD expression and metabolites, but with no functional evidence itself. This work demonstrates how comprehensive functional investigation and multiple technologies are needed to discover the true genetic drivers of phenotypic diversity., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Isovaleric acidemia (IVA) was the first condition to be recognized as an organic acid disorder. It is marked by metabolic ketoacidosis with an unexplained anion gap. This study examines IVA in Jordan, laying the groundwork for future studies. Furthermore, it seeks to enhance the understanding of clinical characteristics and outcomes in affected individuals., Method: This case series study includes all isovaleric acidemia diagnoses at the metabolic unit of the Queen Rania Al Abdullah Hospital for Children (QRHC) in Amman, Jordan, from 2010 to 2023. The study encompassed sociodemographic features, clinical and laboratory results, familial history, and parental consanguinity., Results: Our cohort was composed of 21 individuals (10 males and 11 females), who presented IVA at an average age of 3.1 years. Positive family history and parental consanguinity were observed in 23.8% and 75% of the cases, respectively. Vomiting was the most prevalent symptom (57.1%), and encephalopathy occurred in 33.3%. Laboratory results showed acidosis (81%), hyperammonemia (71.4%), and hypoglycemia (14.3%)., Conclusions: The early initiation of treatment for organic acid disorders carries a more favorable prognosis. Therefore, we strongly recommend for implementing newborn screening to overcome diagnostic challenges and delays. For effective intervention, healthcare professionals should have a comprehensive understanding of the clinical manifestations of IVA and be proficient in interpreting biochemical test results., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Megdadi et al.)

Isovaleric acidemia (IVA), a rare autosomal recessive disorder in leucine metabolism caused by defected IVD gene, is characterized by episodes of acute metabolic crisis and psychomotor development retardation. This study aimed to determine the clinical, biochemical, and mutation spectrum of patients with IVA from mainland China. Eight patients (three boys and five girls) from eight unrelated families were collected, IVD gene mutations and phenotypes were examined. The patients were admitted because of vomiting, feeding difficulty, psychomotor retardation and "dirty sock" odor. Elevated blood isovaleryl (C5)-carnitine and urine isovalerylglycine were detected from all our patients. Fourteen mutations of the IVD gene were detected, eight of them are novel, c.145C>T (p.Q49Ter), c.359G>A (p.R120Q), c.424C>T (p.R142C), c.458T>C (p.L153P), c.466-1G>T, c.676_677insA (p.T226Nfs*13), c.1039G>A (p.A347T) and c.1076A>G (p.D359G). With this study, a total of 34 alleles were studied in the Chinese population. c.1208A>G (p.Y403C), the common mutation in Taiwan, accounts for 9/34 alleles (7 in previous reports and 2 in this study). We described eight novel mutations detected from eight unrelated Chinese patients and provided evidence to support that the p.Y403C is the hotspot mutation in this population. • Fifteen mutations of the IVD gene were identified from eight Chinese IVA patients. • Eight novel mutations were found. • The mutation p.Y403C is the hotspot mutation in the Han Chinese population. [ABSTRACT FROM AUTHOR]

Introduction: Isovaleric aciduria (IA) is an inborn error of metabolism within the group of organic acidemias (AO). It is secondary to isovaleryl-CoA dehydrogenase deficiency, and has a prevalence that is around one case per 100,000 live births. Neonatal onset IA is more severe than when the presentation is at older ages. Case presentation: We present the case of a male newborn in whom the diagnosis of IA was made, given the clinical picture of neurological condition, metabolic acidosis and hyperammonemia within the first week of life. Specialized dietary management was initiated and the patient evolved satisfactorily. Conclusions: Timely diagnosis of IA can prevent sequelae and fatal outcomes, when early treatment is offered. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We report a patient presenting with developmental delay, Leigh‐like abnormalities on MRI and elevated 3‐hydroxyisovaleric acid levels. Upon whole‐exome sequencing, he was diagnosed with 3‐hydroxyisobutyryl‐CoA hydrolase (HIBCH) deficiency, and hence subjected to specific dietary treatment. HIBCH deficiency should be considered in the differential diagnosis of Leigh‐like disease and/or organic aciduria. We report a patient presenting with developmental delay, Leigh‐like abnormalities on MRI and elevated 3‐hydroxyisovaleric acid levels. Upon whole‐exome sequencing, he was diagnosed with 3‐hydroxyisobutyryl‐CoA hydrolase (HIBCH) deficiency, and hence subjected to specific dietary treatment. HIBCH deficiency should be considered in the differential diagnosis of Leigh‐like disease and/or organic aciduria. [ABSTRACT FROM AUTHOR]

Isovaleric acidemia (IVA) is an autosomal recessive leucine inborn error of metabolism caused by isovaleryl-CoA dehydrogenase deficiency. The disease has various courses, from severe ones manifesting in newborns to the intermittent form with first manifestation in children and adults. The aim of this study was to analyze clinical and neurological outcomes in Polish patients with IVA. Ten patients diagnosed and treated in The Children’s Memorial Health Institute were included in the study. 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. A retrospective analysis of patients’ medical records included: demographics, symptoms at diagnosis, medical management, and biochemical and clinical outcomes following therapy. 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. Five patients were in a good clinical state, four children presented mild neurological symptoms, and one—severely delayed child. In the IVD gene, five known and two novel variants (p.466C>G, c.1132G>A) were identified. Molecular analysis was performed in seven patients leading to identification of biallelic pathogenic variants in the IVD gene in all of them. 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.

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. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individual. We report a case of 1.5 years old child with Isovaleric Acidemia with intact neurological outcome. [ABSTRACT FROM AUTHOR]

We report a toddler affected with Angelman syndrome and isovaleric acidemia (IVA). Such association was due to paternal uniparental isodisomy (UPD) of chromosome 15 in which the proband inherited two paternal copies of an IVA gene point mutation. As both diseases may have severe impact on neurodevelopment, adequate treatment of IVA should be discussed. In our patient however, the variant identified likely causes asymptomatic organic aciduria. Such findings emphasize that paternal UPD 15 can rarely lead to co-occurrence of Angelman syndrome and potentially treatable inborn errors of metabolism.

Tandem MS acylcarnitine “profiles” are extremely valuable. Although used appropriately in newborn screening programs to identify patients with possible diseases, their inadequate quantitative accuracy and lack of selectivity is problematic for confirmatory testing. In this report, we show the application of our validated, selective, accurate, precise, and robust UHPLC–MS/MS method for quantitation of acylcarnitines, specifically to C5 acylcarnitines: pivaloyl-, 2-methylbutyryl-, isovaleryl-, and valerylcarnitine. Standardized calibrants were used to generate 13-point, 200-fold concentration range calibration curves. Samples were isolated by solid-phase extraction and derivatized with pentafluorophenacyl trifluoromethanesulfonate. Acylcarnitine pentafluorophenacyl esters were eluted in 14 min chromatograms. Data demonstrating quantitative stability and method robustness over a five year time period are shown and these results validate the method’s accuracy and robustness. Urine from patients with isovaleric acidemia (with the disease marker isovalerylcarnitine) and with pivaloylcarnitine present are shown. These results demonstrate the method’s ability to distinguish true isovaleric acidemia from pivalate derived interference. Our method for acylcarnitine quantitation is shown to be accurate, precise, and robust for selective quantitation of isovalerylcarnitine, and thus is recommended for confirmatory testing of suspected isovaleric acidemia patients. [ABSTRACT FROM AUTHOR]

Recurrent acute pancreatic attacks is a rare clinical condition (2-5% of all acute pancreatis) in children and is mainly idiopathic in most cases. Sometimes it may be associated with congenital anomalies, metabolic diseases or hereditary conditions. Isovaleric acidemia (IVA) is a rare autosomal recessive amino acid metabolism disorder associated with isovaleryl coenzyme A dehydrogenase deficiency presenting the clinical findings such metabolic acidosis with increased anion gap, hyperammonemia, ketonemia, hypoglycemia, "the odor of sweaty feet," abdominal pain, vomiting, feeding intolerance, shock and coma. Recurrent acute pancreatitis associated with IVA have been rarely reported. Herein; we report a child who admitted with recurrent acute pancreatic attacks and had the final diagnosis of IVA. Mutation analysis revealed a novel homozygous mutation of (p.E117K [c.349G>;A]) in the IVA gene. Organic acidemias must kept in mind in the differential diagnosis of recurrent acute pancreatic attacks in children. [ABSTRACT FROM AUTHOR]

Isovaleric aciduria (IVA) is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD). IVA presents either in the neonatal period as an acute episode of fulminant metabolic acidosis, which may lead to coma or death, or later as a "chronic intermittent form" that is associated with developmental delays, with or without recurrent acidotic episodes during periods of stress, such as infections. Here, we report the case of a 2-year old boy with IVA who presented with the chronic intermittent form. He was admitted to Asan Medical Center Children's Hospital with recurrent vomiting. Metabolic acidosis, hyperammonemia, elevated serum lactate and isovalerylcarnitine levels, and markedly increased urine isovalerylglycine concentration were noted. Sequence analysis of the IVD gene in the patient revealed the novel compound mutations-a missense mutation, c.986T>C (p.Met329Thr) and a frameshift mutation, c.1083del (p.Ile361fs*11). Following stabilization during the acute phase, the patient has remained in a stable condition on a low-leucine diet.

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. Deficiency of short/branched chain specific acyl-CoA dehydrogenase (2-methylbutyryl-CoA dehydrogenase), a defect of isoleucine degradation whose clinical significance remains unclear, also results in elevated C5-carnitine, and may therefore be detected by NBS for IVA. Treatment strategies for the long-term management of symptomatic IVA comprise the prevention of catabolism, dietary restriction of natural protein or leucine intake, and supplementation with l-carnitine and/or l-glycine. Recommendations on how to counsel and manage individuals with the mild phenotype detected by NBS are required.

Background: Isovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia arising partly from secondary deficiency of N-acetylglutamate (NAG) synthase. Rapid reduction in plasma ammonia is required to prevent neurological complications. This retrospective, multicentre, open-label, uncontrolled, phase IIIb study evaluated the efficacy and safety of carglumic acid, a synthetic structural analogue of NAG, for treating hyperammonaemia during OA decompensation.Methods: Eligible patients had confirmed OA and hyperammonaemia (plasma NH3 > 60 μmol/L) in ≥1 decompensation episode treated with carglumic acid (dose discretionary, mean (SD) first dose 96.3 (73.8) mg/kg). The primary outcome was change in plasma ammonia from baseline to endpoint (last available ammonia measurement at ≤18 hours after the last carglumic acid administration, or on Day 15) for each episode. Secondary outcomes included clinical response and safety.Results: The efficacy population (received ≥1 dose of study drug and had post-baseline measurements) comprised 41 patients (MMA: 21, PA: 16, IVA: 4) with 48 decompensation episodes (MMA: 25, PA: 19, IVA: 4). Mean baseline plasma ammonia concentration was 468.3 (±365.3) μmol/L in neonates (29 episodes) and 171.3 (±75.7) μmol/L in non-neonates (19 episodes). At endpoint the mean plasma NH3 concentration was 60.7 (±36.5) μmol/L in neonates and 55.2 (±21.8) μmol/L in non-neonates. Median time to normalise ammonaemia was 38.4 hours in neonates vs 28.3 hours in non-neonates and was similar between OA subgroups (MMA: 37.5 hours, PA: 36.0 hours, IVA: 40.5 hours). Median time to ammonia normalisation was 1.5 and 1.6 days in patients receiving and not receiving concomitant scavenger therapy, respectively. Although patients receiving carglumic acid with scavengers had a greater reduction in plasma ammonia, the endpoint ammonia levels were similar with or without scavenger therapy. Clinical symptoms improved with therapy. Twenty-five of 57 patients in the safety population (67 episodes) experienced AEs, most of which were not drug-related. Overall, carglumic acid seems to have a good safety profile for treating hyperammonaemia during OA decompensation.Conclusion: Carglumic acid when used with or without ammonia scavengers, is an effective treatment for restoration of normal plasma ammonia concentrations in hyperammonaemic episodes in OA patients. [ABSTRACT FROM AUTHOR]

Isovaleric acidemia (IVA), due to isovaleryl-CoA dehydrogenase (IVD) deficiency, results in the accumulation of isovaleryl-CoA, isovaleric acid and secondary metabolites. The increase in these metabolites decreases mitochondrial energy production and increases oxidative stress. This contributes to the neuropathological features of IVA. A general assumption in the literature exists that glycine N -acyltransferase (GLYAT) plays a role in alleviating the symptoms experienced by IVA patients through the formation of N -isovalerylglycine. GLYAT forms part of the phase II glycine conjugation pathway in the liver and detoxifies excess acyl-CoA's namely benzoyl-CoA. However, very few studies support GLYAT as the enzyme that conjugates isovaleryl-CoA to glycine. Furthermore, GLYATL1, a paralogue of GLYAT, conjugates phenylacetyl-CoA to glutamine. Therefore, GLYATL1 might also be a candidate for the formation of N -isovalerylglycine. Based on the findings from the literature review, we proposed that GLYAT or GLYATL1 can form N -isovalerylglycine in IVA patients. To test this hypothesis, we performed an in-silico analysis to determine which enzyme is more likely to conjugate isovaleryl-CoA with glycine using AutoDock Vina. Thereafter, we performed in vitro validation using purified enzyme preparations. The in-silico and in vitro findings suggested that both enzymes could form N -isovaleryglycine albeit at lower affinities than their preferred substrates. Furthermore, an increase in glycine concentration does not result in an increase in N -isovalerylglycine formation. The results from the critical literature appraisal, in-silico , and in vitro validation, suggest the importance of further investigating the reaction kinetics and binding behaviors between these substrates and enzymes in understanding the pathophysiology of IVA., Competing Interests: The authors declare that there are no conflict of interest., (© 2023 The Authors.)