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Isovaleric Acidemia

Disease Pathophysiology Research Template

2026-02-23
Falcon MONDO:0009475 Model: Edison Scientific Literature 26 citations

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Isovaleric Acidemia
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Isovaleric Acidemia. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Isovaleric Acidemia (Isovaleryl‑CoA Dehydrogenase Deficiency)

Publication scope and identifiers • Disease: Isovaleric acidemia / isovaleric aciduria (IVA) (OMIM 243500) (kuhn2023theglycinenacyltransferases pages 1-2, zaunseder2023machinelearningmethods pages 1-2, thimm2025practicalconsiderationsfor pages 1-2). • MONDO ID: Not available in the retrieved full-text snippets; MONDO mapping would require external lookup. • Note on PMID requirement: The retrieved full-text snippets did not contain PubMed identifiers (“PMID: …”). Therefore, PMIDs cannot be provided from tool-evidence in this run; all claims below are supported by the cited full-text evidence IDs and include DOI URLs and dates where available.

  1. Key concepts and definitions (current understanding)

1.1 Definition and biochemical lesion IVA is an inborn error of leucine catabolism caused by deficiency of isovaleryl‑CoA dehydrogenase (IVD), a mitochondrial enzyme. A core definition used in multiple sources is that IVD “catalyzes the conversion of isovaleryl‑CoA to 3‑methylcrotonyl‑CoA,” and deficiency causes accumulation of isovaleric acid and characteristic derivatives (thimm2025practicalconsiderationsfor pages 1-2).

1.2 Diagnostic biochemical signature (metabolite pattern) The pathognomonic biochemical pattern is accumulation of isovaleryl‑CoA and appearance of downstream “derivates 3‑hydroxyisovaleric acid, isovaleryl (C5)‑carnitine and isovalerylglycine in body fluids” (thimm2025practicalconsiderationsfor pages 1-2). Reviews concur that urine organic acids are typically positive for “isovalerylglycine and 3‑hydroxyisovaleric acid,” and acylcarnitine profiling detects “isovalerylcarnitine (a C5 acylcarnitine)” (ramsay2018organicaciddisorders. pages 3-5).

1.3 Clinical phenotype spectrum IVA spans severe neonatal intoxication-type crises (ketoacidosis, encephalopathy) through attenuated “mild IVA” detected by newborn screening (NBS). The expert review notes clinical presentation “ranging from life‑threatening metabolic crises with metabolic acidosis and hyperammonemia to a clinically asymptomatic only biochemical phenotype” (thimm2025practicalconsiderationsfor pages 1-2).

  1. Core pathophysiology (molecular and cellular mechanisms)

2.1 Primary pathophysiological mechanisms A. Toxic metabolite accumulation and CoA trapping The fundamental lesion is upstream accumulation of isovaleryl‑CoA and isovaleric acid derivatives (thimm2025practicalconsiderationsfor pages 1-2, kuhn2023theglycinenacyltransferases pages 1-2). This is consistent with the “toxic metabolite” model of organic acidemias.

B. Secondary mitochondrial/TCA cycle dysfunction and bioenergetic compromise Mechanistic hypotheses include “impairment of the tricarboxylic acid cycle through the inhibition of citrate synthase and isocitrate dehydrogenase,” with “increased oxidative stress” and energy/acetyl‑CoA perturbation (thimm2025practicalconsiderationsfor pages 1-2). A broader “classical organic acidurias” synthesis frames neurologic injury as involving disruption of mitochondrial homeostasis, inhibition of respiratory chain/TCA enzymes, energy depletion, oxidative stress, and apoptosis-related pathways (villani2017“classicalorganicacidurias” pages 8-10, villani2017“classicalorganicacidurias” pages 14-16).

C. Urea cycle dysregulation → hyperammonemia Hyperammonemia in IVA is mechanistically linked to inhibition of N‑acetylglutamate synthase (NAGS), the enzyme generating the essential allosteric activator of CPS1. One review states explicitly: “Isovaleryl‑CoA functions as an N‑acetyl‑glutamate synthetase (NAGS) inhibitor leading to urea cycle impairment and hyperammonemia” (ramsay2018organicaciddisorders. pages 3-5). The expert review similarly attributes hyperammonemia to “the inhibition of N‑acetylglutamate synthase (NAGS) and acetyl‑CoA depletion” (thimm2025practicalconsiderationsfor pages 1-2). A classic organic aciduria review also connects hyperammonemia to isovaleryl‑CoA inhibition of N‑acetylglutamate synthetase and reduced urea cycle function (villani2017“classicalorganicacidurias” pages 8-10).

2.2 Dysregulated molecular pathways Key dysregulated pathways in IVA pathophysiology evidenced in the retrieved sources: • Leucine catabolic pathway (mitochondrial IVD step) (ramsay2018organicaciddisorders. pages 3-5, thimm2025practicalconsiderationsfor pages 1-2). • TCA cycle perturbation (citrate synthase, isocitrate dehydrogenase inhibition hypotheses) (thimm2025practicalconsiderationsfor pages 1-2). • Urea cycle control via NAGS→N‑acetylglutamate→CPS1 activation, with failure producing hyperammonemia (haberle2018hyperammonaemiainclassic pages 2-4, ramsay2018organicaciddisorders. pages 3-5). • Oxidative stress / ROS increase and impaired antioxidant defense in classic organic acidurias including IVA-relevant metabolite toxicity (villani2017“classicalorganicacidurias” pages 14-16, haberle2018hyperammonaemiainclassic pages 2-4).

2.3 Cellular processes affected Evidence-supported affected cellular processes include: • Mitochondrial energy metabolism / oxidative phosphorylation disruption in organic acidurias broadly, and mitochondrial energy reduction noted for IVA metabolites (haberle2018hyperammonaemiainclassic pages 2-4, kuhn2023theglycinenacyltransferases pages 1-2). • Oxidative damage and lipid peroxidation signaling (villani2017“classicalorganicacidurias” pages 14-16, kuhn2023theglycinenacyltransferases pages 2-3). • Ion homeostasis at neuronal membranes (Na+,K+-ATPase inhibition) (ribeiro2009creatineadministrationprevents pages 1-2, ribeiro2009creatineadministrationprevents pages 2-4).

  1. Key molecular players (genes/proteins, metabolites, cells, anatomy)

3.1 Genes/proteins (HGNC-style symbol naming) • IVD (isovaleryl‑CoA dehydrogenase): deficient enzyme; mitochondrial flavoprotein; catalyzes isovaleryl‑CoA → 3‑methylcrotonyl‑CoA (thimm2025practicalconsiderationsfor pages 1-2). • NAGS (N‑acetylglutamate synthase): inhibited by isovaleryl‑CoA → reduced urea-cycle activation (thimm2025practicalconsiderationsfor pages 1-2, ramsay2018organicaciddisorders. pages 3-5). • CPS1 (carbamoyl phosphate synthetase 1): urea-cycle entry enzyme functionally impaired when N‑acetylglutamate is low (mechanistic description of NAGS→CPS1 regulation) (haberle2018hyperammonaemiainclassic pages 2-4). • GLYAT and GLYATL1 (glycine N‑acyltransferases): implicated in detoxification via glycine conjugation to form N‑isovalerylglycine; 2023 study provides in‑silico/in‑vitro validation that both can form N‑isovalerylglycine, but with “lower affinities” and with the notable observation that “an increase in glycine concentration does not result in an increase in N‑isovalerylglycine formation” (kuhn2023theglycinenacyltransferases pages 1-2).

3.2 Chemical entities (metabolites and therapeutics; CHEBI-style naming) Disease-relevant metabolites/biomarkers: • Isovaleryl‑CoA (toxic intermediate; CoA sequestration) (kuhn2023theglycinenacyltransferases pages 1-2). • Isovaleric acid (free acid; volatile; implicated in neurotoxicity/oxidative injury hypotheses) (thimm2025practicalconsiderationsfor pages 1-2, ribeiro2009creatineadministrationprevents pages 1-2). • Isovalerylglycine (N‑isovalerylglycine; urinary biomarker; detoxification product) (thimm2025practicalconsiderationsfor pages 1-2, villani2017“classicalorganicacidurias” pages 8-10). • Isovalerylcarnitine (C5 acylcarnitine; blood biomarker; NBS analyte) (thimm2025practicalconsiderationsfor pages 1-2, ramsay2018organicaciddisorders. pages 3-5). • 3‑hydroxyisovaleric acid (urine organic acid biomarker) (thimm2025practicalconsiderationsfor pages 1-2, ramsay2018organicaciddisorders. pages 3-5).

Therapeutically relevant small molecules: • Glycine (used to promote glycine conjugation; risk of hyperglycinemia noted; supplementation “should be carefully considered”) (kuhn2023theglycinenacyltransferases pages 2-3). • L‑carnitine (promotes acylcarnitine formation/excretion; noted to decrease free isovaleric acid during acute decompensation) (kuhn2023theglycinenacyltransferases pages 2-3). • N‑carbamylglutamate (a.k.a. carglumic acid): “approved pharmacological agent for the treatment of acute and chronic hyperammonemia in IVA” (kuhn2023theglycinenacyltransferases pages 2-3). • Creatine (experimental neuroprotection in rat model; see §4.2) (ribeiro2009creatineadministrationprevents pages 2-4).

3.3 Cell types primarily implicated (CL-style) Directly referenced cell types in the retrieved evidence: • Periportal hepatocytes and pericentral hepatocytes in the hepatic handling of ammonia/urea cycle and glutamine formation (haberle2018hyperammonaemiainclassic pages 2-4). • “Neuronal and glial cells” referenced in the context of metabolite effects on protein phosphorylation/cytoskeleton signaling in organic acidurias (villani2017“classicalorganicacidurias” pages 14-16, haberle2018hyperammonaemiainclassic pages 2-4).

3.4 Anatomical locations and organs involved (UBERON-style) • Liver (site of urea cycle; “complete urea cycle is mostly active in the liver”; site of phase II glycine conjugation) (haberle2018hyperammonaemiainclassic pages 2-4, kuhn2023theglycinenacyltransferases pages 1-2). • Brain, with explicit brain regions in pathogenesis discussion: “hippocampus,” “striatum,” and “cerebral cortex” (villani2017“classicalorganicacidurias” pages 14-16). • Cerebral cortex (site of Na+,K+-ATPase inhibition experiments) (ribeiro2009creatineadministrationprevents pages 1-2, ribeiro2009creatineadministrationprevents pages 2-4). • Expression sites noted for IVD include “thyroid, liver, and kidney” (kuhn2023theglycinenacyltransferases pages 1-2).

  1. Disease progression model (sequence from trigger to clinical manifestations)

4.1 Trigger → catabolic stress → metabolite surge Clinical decompensations typically follow catabolic triggers (e.g., illness/fasting) and manifest as metabolic acidosis/ketosis and often hyperammonemia (thimm2025practicalconsiderationsfor pages 1-2, haberle2018hyperammonaemiainclassic pages 2-4). Mechanistically, catabolism increases leucine flux, increasing isovaleryl‑CoA production upstream of the IVD block (thimm2025practicalconsiderationsfor pages 1-2).

4.2 Acute crisis phase mechanisms • Organic acid accumulation drives high-anion-gap metabolic acidosis and ketosis (thimm2025practicalconsiderationsfor pages 1-2, haberle2018hyperammonaemiainclassic pages 2-4). • Hyperammonemia can emerge from urea-cycle inhibition due to NAGS inhibition and acetyl‑CoA depletion (thimm2025practicalconsiderationsfor pages 1-2, ramsay2018organicaciddisorders. pages 3-5). • Neurotoxicity can be mediated through impaired neuronal membrane ion homeostasis and TCA flux reduction. In a rat model, intracerebroventricular isovaleric acid inhibited Na+,K+-ATPase “up to ~25%” at both 2 h and 24 h after administration (ribeiro2009creatineadministrationprevents pages 2-4). The same study reports TCA-related effects at 24 h (e.g., ~22% reduced 14CO2 production from acetate; ~20% reduced citrate synthase activity) (ribeiro2009creatineadministrationprevents pages 1-2).

4.3 Chronic/long-term phase A central expert view is that oxidative stress and mitochondrial dysfunction contribute to neurological morbidity over time; one review states that “oxidative stress from chronic, persistent buildup of isovaleric acid is more neurologically detrimental than acute buildup” (ramsay2018organicaciddisorders. pages 3-5). Chronic complications are likely influenced by cumulative metabolic instability and repeated hyperammonemic episodes, where severity increases with longer duration of hyperammonemia (haberle2018hyperammonaemiainclassic pages 2-4).

  1. Phenotypic manifestations and mechanistic linkage

5.1 Core clinical phenotypes (HP-style) Evidence-supported frequent manifestations include vomiting, encephalopathy, metabolic acidosis, hyperammonemia, and hypoglycemia. • A recent (2010–2023) Jordan cohort (n=21) reported vomiting 57.1%, encephalopathy 33.3%, acidosis 81%, hyperammonemia 71.4%, and hypoglycemia 14.3% (published 2024‑01‑10) (megdadi2024isovalericacidemiain pages 1-2, megdadi2024isovalericacidemiain pages 2-3).

5.2 Mechanistic linkage • Encephalopathy aligns with hyperammonemia and direct/indirect neurotoxic effects of metabolites and oxidative stress (haberle2018hyperammonaemiainclassic pages 2-4, villani2017“classicalorganicacidurias” pages 14-16). • Metabolic acidosis and ketosis reflect the intoxication phenotype of organic acid buildup (haberle2018hyperammonaemiainclassic pages 2-4).

  1. Biological process (GO-style) and cellular component mapping (knowledge-base ready)

6.1 Disrupted biological processes (candidate GO terms) Based on explicit phrasing in the evidence: • Leucine catabolic process / branched-chain amino acid catabolism (IVD step) (thimm2025practicalconsiderationsfor pages 1-2, haberle2018hyperammonaemiainclassic pages 2-4). • Urea cycle (via NAGS→CPS1 activation) and ammonia detoxification (haberle2018hyperammonaemiainclassic pages 2-4, thimm2025practicalconsiderationsfor pages 1-2). • Tricarboxylic acid cycle (hypothesized inhibition of citrate synthase/isocitrate dehydrogenase; and in vivo reduction of citrate synthase activity in cortex model) (thimm2025practicalconsiderationsfor pages 1-2, ribeiro2009creatineadministrationprevents pages 1-2). • Response to oxidative stress / ROS metabolic process (villani2017“classicalorganicacidurias” pages 14-16, haberle2018hyperammonaemiainclassic pages 2-4). • Glycine conjugation / acyl-CoA metabolic process (GLYAT/GLYATL1-mediated formation of N-isovalerylglycine) (kuhn2023theglycinenacyltransferases pages 1-2). • Ion transport and maintenance of membrane potential (Na+,K+-ATPase activity) (ribeiro2009creatineadministrationprevents pages 2-4).

6.2 Cellular components (candidate GO CC terms) • Mitochondrion / mitochondrial matrix: IVD is described as a “mitochondrial” enzyme; hepatic urea-cycle steps described in “mitochondrial matrix and cytosol of periportal hepatocytes” (thimm2025practicalconsiderationsfor pages 1-2, haberle2018hyperammonaemiainclassic pages 2-4). • Synaptic plasma membrane / neuronal membrane systems (Na+,K+-ATPase assays in synaptic membrane preparations) (ribeiro2009creatineadministrationprevents pages 2-4).

  1. Current applications and real-world implementations

7.1 Newborn screening (NBS): first-tier and confirmatory strategy NBS is widely implemented using tandem MS/MS measurement of C5 acylcarnitines. However, “standard NBS are the sum of all C5 isomers and isobars,” which creates a known false-positive problem when pivaloylcarnitine co-elutes/isobarically overlaps (murko2023neonatalscreeningfor pages 2-5). The practical diagnostic workflow emphasized across sources includes acylcarnitine profiling plus confirmatory urine organic acids (isovalerylglycine, 3‑hydroxyisovaleric acid) (thimm2025practicalconsiderationsfor pages 4-6, ramsay2018organicaciddisorders. pages 3-5).

7.2 Second-tier LC/UPLC-MS/MS to reduce false positives (implementation evidence) A 2023 German implementation study developed a second-tier UPLC‑MS/MS assay achieving “Excellent separation of pivaloyl-, 2-methylbutyryl-, isovaleryl-, and valerylcarnitine” (murko2023neonatalscreeningfor pages 2-5). In Hamburg (2019–2021), among 156,772 newborns, 100 had elevated C5 but only one was genetically confirmed IVA; 99 were attributed to pivaloylcarnitine (C5 0.5–8.2 μmol/L), with false positives rising “from 20 cases in 2019 to 53 cases in 2021” (murko2023neonatalscreeningfor pages 2-5). Figure evidence shows both chromatographic separation (Figure 1) and the cohort counts/summary (Figure 2) (murko2023neonatalscreeningfor media 6de62afe, murko2023neonatalscreeningfor media 78fa9051).

7.3 Machine learning as a “digital-tier” to improve specificity A 2023 study using 2,106,090 newborns screened in Heidelberg reported that ML reduced the false positive rate by 69.9% “from 103 to 31” while maintaining “100% sensitivity in cross-validation” (published 2023‑02‑18) (zaunseder2023machinelearningmethods pages 1-2). The cleaned dataset contained 22 mild IVA and 6 classic IVA cases, enabling computational separation of mild vs classic IVA from normal profiles using NBS metabolite features (zaunseder2023machinelearningmethods pages 2-3).

  1. Recent developments (prioritizing 2023–2024)

8.1 Mechanistic/biochemical detoxification advances (2023) A 2023 mechanistic study addressed a long-standing uncertainty: which enzymes form N‑isovalerylglycine in humans. It reiterates that “GLYAT forms part of the phase II glycine conjugation pathway in the liver” and provides in‑silico/in‑vitro evidence that “both enzymes could form N-isovaleryglycine albeit at lower affinities,” with the key nuance that “an increase in glycine concentration does not result in an increase in N-isovalerylglycine formation” (available online 2023‑01‑31) (kuhn2023theglycinenacyltransferases pages 1-2).

8.2 Diagnostic innovation and implementation (2023–2024) • Second-tier chromatography to separate C5 isomers was operationalized with explicit platform parameters and strong linearity (R2 > 0.998) in a programmatic NBS setting (murko2023neonatalscreeningfor pages 2-5). • ML “digital-tier” approaches were shown to reduce false positives without sacrificing sensitivity in a >2 million sample dataset (zaunseder2023machinelearningmethods pages 1-2).

8.3 Updated cohort-level phenotype frequencies (2024) A 2024 (Jan) national center case-series provides contemporary frequencies for common presentations (acidosis, hyperammonemia, vomiting, encephalopathy) in a middle-income setting and argues for NBS implementation (megdadi2024isovalericacidemiain pages 1-2).

  1. Expert opinions and analysis (authoritative synthesis)

9.1 Hyperammonemia framing and urgency An authoritative review emphasizes that hyperammonemia and accumulating toxic metabolites are “associated with life-threatening neurological complications” and that brain injury is multifactorial, including TCA/oxidative phosphorylation effects and oxidative stress mechanisms (haberle2018hyperammonaemiainclassic pages 2-4). This mechanistic framing supports aggressive acute management strategies.

9.2 Screening interpretation and “mild IVA” overdiagnosis risk NBS has increased apparent prevalence by detecting attenuated biochemical variants; ML and second-tier LC are proposed/implemented responses to reduce false positives and to mitigate burdens of over-referral/over-treatment (zaunseder2023machinelearningmethods pages 1-2, murko2023neonatalscreeningfor pages 2-5).

  1. Relevant statistics and quantitative data (selected)

10.1 Screening and false positive statistics • Germany (Hamburg NBS cohort): 156,772 newborns; 100 elevated C5; 1 true IVA; 99 false positives due to pivaloylcarnitine; C5 false positive range 0.5–8.2 μmol/L; false positives increased from 20 (2019) to 53 (2021) (murko2023neonatalscreeningfor pages 2-5). (murko2023neonatalscreeningfor media 6de62afe, murko2023neonatalscreeningfor media 78fa9051) • Heidelberg ML dataset: final cleaned dataset 2,106,960 profiles including 103 false positives, 22 mild IVA, 6 classic IVA; ML reduced false positives by 69.9% (103→31) with 100% sensitivity in cross-validation (zaunseder2023machinelearningmethods pages 2-3, zaunseder2023machinelearningmethods pages 1-2).

10.2 Clinical cohort statistics (2024 case series) • Jordan cohort (n=21): acidosis 81%, hyperammonemia 71.4%, vomiting 57.1%, encephalopathy 33.3%, hypoglycemia 14.3% (megdadi2024isovalericacidemiain pages 1-2).

10.3 Experimental neurotoxicity quantitative data • Rat cerebral cortex model: intracerebroventricular IVA (5 μmol; 2 μL of 2.5 M per ventricle) inhibited Na+,K+-ATPase up to ~25% at 2 h and 24 h; creatine pre-treatment (50 mg/kg i.p., twice daily ×7 days) prevented the inhibition (ribeiro2009creatineadministrationprevents pages 2-4).

  1. Structured knowledge-base entry elements (ontology-ready)

11.1 Pathophysiology description (narrative) IVA (OMIM 243500) is caused by deficiency of mitochondrial isovaleryl‑CoA dehydrogenase (IVD), blocking isovaleryl‑CoA conversion to 3‑methylcrotonyl‑CoA in leucine catabolism and causing accumulation of isovaleric acid and characteristic metabolites (3‑hydroxyisovaleric acid, isovaleryl‑carnitine/C5, isovalerylglycine). Accumulated metabolites and CoA sequestration disrupt mitochondrial and cellular homeostasis, with evidence and hypotheses spanning TCA cycle inhibition (citrate synthase/isocitrate dehydrogenase), oxidative stress/ROS, and membrane ion-pump dysfunction (Na+,K+-ATPase inhibition). A key systemic mechanism is secondary urea-cycle impairment: isovaleryl‑CoA inhibits NAGS and contributes to acetyl‑CoA depletion, reducing N‑acetylglutamate availability and impairing CPS1 activation, producing hyperammonemia and encephalopathy risk. Detoxification is supported clinically by shunting isovaleryl‑CoA into less toxic conjugates (isovalerylglycine, isovalerylcarnitine) via glycine/carnitine supplementation; mechanistically, 2023 work supports roles for GLYAT and GLYATL1 in N‑isovalerylglycine formation.

11.2 Gene/protein annotations (examples) • IVD: mitochondrial isovaleryl‑CoA dehydrogenase; leucine catabolism step; deficiency causes IVA (thimm2025practicalconsiderationsfor pages 1-2). • NAGS: inhibited by isovaleryl‑CoA; links IVA to hyperammonemia (ramsay2018organicaciddisorders. pages 3-5). • GLYAT/GLYATL1: glycine N‑acyltransferases implicated in isovaleryl‑CoA detoxification via N‑isovalerylglycine (kuhn2023theglycinenacyltransferases pages 1-2).

11.3 Phenotype associations (HP-style; evidence examples) • Metabolic acidosis: frequent in IVA cohort (81%) (megdadi2024isovalericacidemiain pages 1-2). • Hyperammonemia: frequent in IVA cohort (71.4%); mechanistically NAGS inhibition (megdadi2024isovalericacidemiain pages 1-2, ramsay2018organicaciddisorders. pages 3-5). • Encephalopathy: reported 33.3% in cohort; linked to hyperammonemia and neurotoxicity mechanisms (megdadi2024isovalericacidemiain pages 1-2, haberle2018hyperammonaemiainclassic pages 2-4).

11.4 Cell-type involvement (CL-style; evidence examples) • Periportal hepatocytes / pericentral hepatocytes: urea-cycle localization and glutamine buffering described in organic acidemia hyperammonemia review (haberle2018hyperammonaemiainclassic pages 2-4). • Neuronal and glial cells: affected by toxic metabolites via signaling/cytoskeletal regulation in organic acidurias (villani2017“classicalorganicacidurias” pages 14-16).

11.5 Anatomical locations (UBERON-style; evidence examples) • Liver (urea cycle; glycine conjugation) (haberle2018hyperammonaemiainclassic pages 2-4, kuhn2023theglycinenacyltransferases pages 1-2). • Brain regions: cerebral cortex, hippocampus, striatum (villani2017“classicalorganicacidurias” pages 14-16).

11.6 Chemical entities (CHEBI-style; evidence examples) • Isovaleryl‑CoA, isovaleric acid, isovalerylglycine, isovalerylcarnitine, 3‑hydroxyisovaleric acid (thimm2025practicalconsiderationsfor pages 1-2, ramsay2018organicaciddisorders. pages 3-5). • N‑carbamylglutamate (carglumic acid) as approved therapy for IVA-related hyperammonemia (kuhn2023theglycinenacyltransferases pages 2-3).

  1. Evidence items (selected; includes URLs and publication dates)

• Kühn et al. (Computational and Structural Biotechnology Journal). Available online 31 Jan 2023. DOI: https://doi.org/10.1016/j.csbj.2023.01.041. OMIM: 243500 stated. Evidence for GLYAT/GLYATL1 roles and constraints on glycine-driven conjugation (kuhn2023theglycinenacyltransferases pages 1-2). • Zaunseder et al. (Metabolites). Published 18 Feb 2023. DOI: https://doi.org/10.3390/metabo13020304. ML reduced false positives 69.9% with 100% sensitivity (zaunseder2023machinelearningmethods pages 1-2). • Murko et al. (JIMD Reports). Oct 2023. DOI: https://doi.org/10.1002/jmd2.12345. Second-tier UPLC‑MS/MS implementation; Hamburg cohort false positives largely pivaloylcarnitine; includes chromatographic figures (murko2023neonatalscreeningfor pages 1-2, murko2023neonatalscreeningfor pages 2-5, murko2023neonatalscreeningfor media 6de62afe). • Megdadi et al. (Cureus). Published 10 Jan 2024. DOI: https://doi.org/10.7759/cureus.52039. Cohort frequencies for acidosis/hyperammonemia/vomiting/encephalopathy (megdadi2024isovalericacidemiain pages 1-2).

Limitations • MONDO and PMIDs: not present in retrieved full text; therefore not included. OMIM 243500 is supported by multiple retrieved sources (kuhn2023theglycinenacyltransferases pages 1-2, zaunseder2023machinelearningmethods pages 1-2, thimm2025practicalconsiderationsfor pages 1-2). • Some mechanistic claims in classic organic aciduria reviews (e.g., apoptosis signaling, kinase/phosphatase perturbation) are discussed as broader OA mechanisms and may not be uniquely validated for IVA; this is indicated in those sources (villani2017“classicalorganicacidurias” pages 14-16, haberle2018hyperammonaemiainclassic pages 2-4).

References

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