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Isobutyryl-CoA Dehydrogenase Deficiency

Disease Pathophysiology Research Template

2026-02-23
Falcon MONDO:0012648 Model: Edison Scientific Literature 38 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: Isobutyryl-CoA Dehydrogenase Deficiency
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Isobutyryl-CoA Dehydrogenase Deficiency. 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 Research Report — Isobutyryl‑CoA Dehydrogenase Deficiency (IBDD; ACAD8 deficiency)

Publication window emphasized: 2023–2024 developments are highlighted where available; foundational mechanistic and clinical references are included for completeness.

  1. Disease identifiers, nomenclature, and definitions

1.1 Canonical name and synonyms Isobutyryl‑CoA dehydrogenase deficiency is a rare, autosomal recessive inborn error of valine catabolism caused by biallelic variants in ACAD8. It has historically been discussed under biochemical nomenclature such as “isobutyrylglycinuria,” reflecting its urinary acylglycine marker. (feng2021phenotypegenotypeand pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, sass2004isobutyrylcoadehydrogenasedeficiency pages 1-4)

OMIM identifiers: disease OMIM#611283; gene ACAD8 OMIM*604773. (feng2021phenotypegenotypeand pages 1-2, oglesbee2007developmentofa pages 1-2)

1.2 Current understanding of clinical significance A recurrent theme in contemporary literature is that IBDD is frequently detected through newborn screening (NBS) and often behaves as a “biochemical phenotype” with limited clinical consequences in many individuals, while a minority shows heterogeneous findings. (houten2023acyl‐coadehydrogenasesubstrate pages 1-3, reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2)

  1. Core pathophysiology (molecular and cellular mechanisms)

2.1 Normal biochemical role of ACAD8 in valine oxidation ACAD8 encodes isobutyryl‑CoA dehydrogenase, a mitochondrial enzyme acting in the valine degradation pathway. In a Chinese cohort description, ACAD8 is reported to “catalyse the conversion of isobutyryl‑CoA to methacrylyl‑CoA” in valine catabolism, ultimately connecting to the tricarboxylic acid (TCA) cycle. (feng2021phenotypegenotypeand pages 1-2)

Mechanistic enzymology/flux evidence supports that ACAD8 loss creates a block at the isobutyryl‑CoA dehydrogenation step: patient‑cell experiments showed that incubation with 13C5‑valine produced a “significant increase in 13C4‑isobutyrylcarnitine” without normal downstream incorporation, consistent with pathway interruption at the ACAD8 step. (wanders2012enzymologyofthe pages 2-4)

2.2 Subcellular localization and cellular components affected IBD (ACAD8) is described as a mitochondrial enzyme in multiple clinical/biochemical analyses. (lin2018clinicalbiochemicaland pages 1-2, feng2021phenotypegenotypeand pages 1-2, oglesbee2007developmentofa pages 1-2)

Accordingly, the most directly implicated cellular component is the mitochondrion (mitochondrial matrix–associated soluble enzyme complex). (feng2021phenotypegenotypeand pages 1-2, lin2018clinicalbiochemicaland pages 1-2)

2.3 Dysregulated pathways and biochemical consequences

2.3.1 Valine degradation (branched‑chain amino acid catabolism) dysregulation Loss of ACAD8 activity disrupts mitochondrial valine oxidation, leading to accumulation and shunting of valine‑derived intermediates into measurable surrogate biomarkers.

2.3.2 Biomarker‑level metabolic rerouting: C4 acylcarnitine and isobutyrylglycine Across cohorts and diagnostic algorithms, the most consistent biochemical signature is elevated C4‑acylcarnitine in dried blood spots/plasma, typically accompanied by increased C4/C2 and C4/C3 ratios. (lin2018clinicalbiochemicaland pages 1-2, feng2021phenotypegenotypeand pages 1-2)

Urinary isobutyrylglycine (IBG) supports diagnosis but is not invariant. Early descriptions emphasized intermittency: “isobutyrylglycine may be intermittently normal in patients with confirmed IBD deficiency.” (sass2004isobutyrylcoadehydrogenasedeficiency pages 4-5)

A large literature synthesis similarly reports that isobutyrylglycinuria is “common but not invariable.” (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2)

2.4 Why clinical penetrance is often low: compensatory mechanisms and substrate promiscuity (recent mechanistic framing) A mechanistic hypothesis for why ACAD8 deficiency often has limited clinical impact is enzyme redundancy/substrate promiscuity within the acyl‑CoA dehydrogenase family. A 2023 Journal of Inherited Metabolic Disease study (focused on valine/isoleucine pathway ACADs) notes that deficiencies of ACAD8 are “considered biochemical abnormalities with limited or no clinical consequences” and demonstrates that in HEK‑293 models, “substantial promiscuity of ACADs… for the isobutyryl‑CoA substrate” can occur. (houten2023acyl‐coadehydrogenasesubstrate pages 1-3)

This framework supports the idea that alternate ACAD activities may partially compensate for ACAD8 loss in some cellular contexts, reducing metabolite toxicity and clinical expression.

2.5 Proposed/observed organ involvement and tissue vulnerability

2.5.1 Liver (emerging theme) A 2026 synthesis of cases up to Dec 2024 (useful for current clinical interpretation though outside 2023–2024) reports: “altered biochemical markers of liver function were reported in 19 individuals, including 18 with isolated elevations of serum transaminases and γ‑glutamyl transferase.” It further notes: “One 11‑year‑old boy exhibited hepatomegaly and ultrasound findings suggestive of hepatic steatosis,” and that “Hepatic steatosis has also been observed in an IBDD mouse model,” suggesting a potential hepatic link. (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2)

Supporting mechanistic animal data is referenced in a clinical biochemical series: “alternative splicing in ACAD8 caused a mitochondrial defect and progressive hepatic steatosis in mice.” (lin2018clinicalbiochemicaland pages 1-2)

Interpretation: a plausible mechanistic connection is mitochondrial metabolic stress in hepatocytes, potentially contributing to steatosis and mild transaminase elevation in a subset of individuals, but causality and prevalence remain incompletely defined. (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, lin2018clinicalbiochemicaland pages 1-2)

2.5.2 Heart, muscle, and brain The index symptomatic patient described in early biochemical/clinical work developed anemia and cardiomyopathy; later reports continue to include cardiomyopathy among rare presentations, while most screened individuals remain asymptomatic. (wanders2012enzymologyofthe pages 2-4, oglesbee2007developmentofa pages 1-2)

Neurologic and developmental findings (e.g., hypotonia, developmental delay, speech delay, seizures) are variably reported, but heterogeneity and comorbid genetic diagnoses complicate attribution. (feng2021phenotypegenotypeand pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6, eleftheriadou2021isobutyryl‐coadehydrogenasedeficiency pages 6-7)

  1. Key molecular players and knowledge-base–ready entities

3.1 Genes/proteins (HGNC) • ACAD8 (acyl‑CoA dehydrogenase family member 8; isobutyryl‑CoA dehydrogenase), OMIM*604773; causative for OMIM#611283. (feng2021phenotypegenotypeand pages 1-2, oglesbee2007developmentofa pages 1-2)

3.2 Metabolites and small molecules (CHEBI‑style entities; representative) • Valine (substrate pathway amino acid) (feng2021phenotypegenotypeand pages 1-2, wanders2012enzymologyofthe pages 2-4) • Isobutyryl‑CoA (ACAD8 substrate) (feng2021phenotypegenotypeand pages 1-2, wanders2012enzymologyofthe pages 2-4) • Methacrylyl‑CoA (product of ACAD8 step) (feng2021phenotypegenotypeand pages 1-2) • C4‑acylcarnitine (includes isobutyrylcarnitine and butyrylcarnitine; key NBS marker) (oglesbee2007developmentofa pages 1-2, oglesbee2007developmentofa pages 3-4) • Isobutyrylglycine (urinary acylglycine marker; intermittent) (sass2004isobutyrylcoadehydrogenasedeficiency pages 4-5, feng2021phenotypegenotypeand pages 1-2) • Ethylmalonic acid (used to distinguish SCADD; not expected in IBDD) (oglesbee2007developmentofa pages 1-2, oglesbee2007developmentofa pages 3-4) • L‑carnitine (secondary deficiency described in some; supplementation can be used when deficient) (oglesbee2007developmentofa pages 1-2, sass2004isobutyrylcoadehydrogenasedeficiency pages 4-5) • 3‑hydroxybutyrate and lactate (contextual metabolites in hypoglycemia presentation) (santra2017longtermoutcomeof pages 1-2)

3.3 Cell types (CL‑style; inferred from organ findings and mitochondrial metabolic role) • Hepatocyte (liver enzyme abnormalities/steatosis) (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, lin2018clinicalbiochemicaland pages 1-2) • Cardiomyocyte (cardiomyopathy in rare symptomatic presentations) (wanders2012enzymologyofthe pages 2-4, oglesbee2007developmentofa pages 1-2) • Skeletal muscle cell (myalgia/weakness reported in some cases and literature summaries) (feng2021phenotypegenotypeand pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6) • Neuron (developmental delay/seizures reported in some) (feng2021phenotypegenotypeand pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6)

3.4 Anatomical locations (UBERON‑style) • Liver (transaminase elevations, steatosis) (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, lin2018clinicalbiochemicaland pages 1-2) • Heart (cardiomyopathy) (wanders2012enzymologyofthe pages 2-4, oglesbee2007developmentofa pages 1-2) • Brain (developmental delay, seizures) (feng2021phenotypegenotypeand pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6) • Skeletal muscle (hypotonia, myalgia/weakness in some) (reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6, feng2021phenotypegenotypeand pages 1-2)

  1. Biological processes and cellular components (GO‑oriented)

4.1 Disrupted biological processes (GO) Evidence supports disruption of: • Valine catabolic process / branched‑chain amino acid catabolic process (block at isobutyryl‑CoA oxidation step) (feng2021phenotypegenotypeand pages 1-2, wanders2012enzymologyofthe pages 2-4) • Mitochondrial acyl‑CoA dehydrogenase–dependent oxidation steps in amino acid metabolism (lin2018clinicalbiochemicaland pages 1-2, wanders2012enzymologyofthe pages 2-4) • Carnitine homeostasis/transport‑linked processes (secondary carnitine deficiency proposed/observed in some cases) (sass2004isobutyrylcoadehydrogenasedeficiency pages 4-5, oglesbee2007developmentofa pages 1-2)

4.2 Cellular components (GO) • Mitochondrion / mitochondrial matrix (ACAD8 described as mitochondrial enzyme) (lin2018clinicalbiochemicaland pages 1-2, feng2021phenotypegenotypeand pages 1-2)

  1. Disease progression (sequence of events) — current model

5.1 Trigger and earliest biochemical changes Primary trigger is congenital ACAD8 loss-of-function. In infancy, expanded NBS detects isolated C4‑acylcarnitine elevation in dried blood spots (C4 comprises both isobutyrylcarnitine and butyrylcarnitine), prompting confirmatory testing. (oglesbee2007developmentofa pages 1-2, oglesbee2007developmentofa pages 3-4)

5.2 Intermediate biochemical phenotype Persistent elevation of C4 and sometimes increased urinary isobutyrylglycine are observed; urinary IBG can be absent/intermittent. (sass2004isobutyrylcoadehydrogenasedeficiency pages 4-5, feng2021phenotypegenotypeand pages 1-2)

5.3 Clinical manifestations (if any) Most individuals remain clinically well, but a minority develops nonspecific findings (often anemia; occasionally neurodevelopmental delay, hypotonia, failure to thrive, seizures, or rare cardiomyopathy). (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6)

5.4 Potential later organ involvement A subset may show liver enzyme abnormalities and possible hepatic steatosis (human reports and mouse model), supporting consideration of liver monitoring in follow-up. (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, lin2018clinicalbiochemicaland pages 1-2)

  1. Phenotypic manifestations (HP‑style) and mechanistic linkage

6.1 Core biochemical phenotypes • Elevated C4‑acylcarnitine (newborn screening hallmark) (oglesbee2007developmentofa pages 1-2, feng2021phenotypegenotypeand pages 1-2) • Increased C4/C2 and C4/C3 ratios (feng2021phenotypegenotypeand pages 1-2, lin2018clinicalbiochemicaland pages 1-2) • Isobutyrylglycinuria / urinary isobutyrylglycine (variable) (sass2004isobutyrylcoadehydrogenasedeficiency pages 4-5, feng2021phenotypegenotypeand pages 1-2)

6.2 Clinical phenotypes reported across cohorts A 172‑case synthesis reports 146 asymptomatic and 26 symptomatic, with anemia most frequent. (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6)

In a 40‑patient Chinese NBS cohort with 3–108 months follow‑up, four had transient motor delay and two had growth delay; most were otherwise healthy. (feng2021phenotypegenotypeand pages 1-2)

A 10‑year follow‑up case report describes benign long‑term outcome after presentation with ketotic hypoglycaemia and persistent biochemical markers of IBDD; the child had normal psychomotor development and no cardiomyopathy or anemia during follow-up. (santra2017longtermoutcomeof pages 1-2)

6.3 Liver-related phenotypes • Elevated ALT/AST and γ‑glutamyl transferase in a subset; rare hepatomegaly/steatosis reported; steatosis also observed in mouse model. (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, lin2018clinicalbiochemicaland pages 1-2)

  1. Recent developments and latest research (emphasis 2023–2024)

7.1 2023: Improving newborn screening specificity for C4 elevation (reducing false positives) A 2023 Biomedicines study addressed the major NBS problem that elevated C4 is shared by SCADD and IBDD and is associated with high false-positive burden. It proposed seven C4‑based ratios (C4/C0, C4/C5, C4/C5DC\C6OH, C4/C6, C4/C8, C4/C14:1, C4/C16:1) as secondary biomarkers. (messina2023butyrylcarnitineelevationin pages 1-2, messina2023butyrylcarnitineelevationin pages 2-3)

Quantitative example (IBDD vs false positives; nIBDD=4, nFP=91): mean C4 1.25 μM vs 0.979 μM; C4/C0 0.0796 vs 0.0461; C4/C5 9.82 vs 6.14; C4/C6 27.6 vs 13.4; C4/C8 33.3 vs 15.5. The authors state that these markers “robustly distinguished IBDD patients from FPs.” (messina2023butyrylcarnitineelevationin pages 3-5)

Visual evidence: the paper’s Tables 2–3 compile the evaluated ratios and statistical performance for distinguishing IBDD, SCADD, and false positives (see extracted tables). (messina2023butyrylcarnitineelevationin media 9d25c0d0, messina2023butyrylcarnitineelevationin media c375a74a)

7.2 2023: Mechanistic reframing via ACAD “substrate promiscuity” A 2023 Journal of Inherited Metabolic Disease study demonstrated notable ACAD substrate promiscuity in a cell model and notes that ACAD8 deficiency is “considered” to have limited clinical consequences, supporting a mechanistic explanation for low penetrance in many individuals. (houten2023acyl‐coadehydrogenasesubstrate pages 1-3)

7.3 2024: First-tier genetic screening combined with MS/MS (real-world implementation) A 2024 International Journal of Neonatal Screening multicenter study implemented concurrent NGS and MS/MS in 29,601 newborns and diagnosed 23 IEMs (≈1 in 1,287). Two IBD cases attributable to ACAD8 were identified. (tang2024newbornscreeningfor pages 4-5, tang2024newbornscreeningfor pages 2-4)

Screening performance (single-modality): “the positive predictive value (PPV) for MS/MS was 5.29%, and the sensitivity was 91.3%,” whereas “for genetic screening alone, the PPV for NGS was 70.83%, with 73.91% sensitivity.” (tang2024newbornscreeningfor pages 1-2)

Complementarity was explicitly demonstrated: “Six cases would have been missed but with the results of MS/MS screening… These six cases had MSUD, IBD, PCD, SCADD, MADD, and CPTII.” (tang2024newbornscreeningfor pages 4-5)

  1. Current applications and real‑world implementations

8.1 Newborn screening and confirmatory diagnostic workflows

8.1.1 Established follow-up algorithm for elevated C4 (classic implementation) A widely cited 2007 Genetics in Medicine paper developed a follow-up algorithm for abnormal C4-acylcarnitine NBS results. It emphasizes that C4 comprises both isobutyryl- and butyrylcarnitine, so elevation is non-specific and requires differentiation from SCADD. (oglesbee2007developmentofa pages 1-2)

A key differential approach was: “Quantification of C4-acylcarnitine in plasma and urine as well as ethylmalonic acid in urine allows the differentiation” of IBD from SCAD deficiency. (oglesbee2007developmentofa pages 1-2)

The same work reported that urinary isobutyrylglycine can be normal and highlighted urine acylcarnitines as consistently helpful (urinary C4 elevation and C4/C3 ratio). (oglesbee2007developmentofa pages 3-4, oglesbee2007developmentofa pages 5-6)

8.1.2 2023 ratio-based post-analytical improvement The 2023 ratio approach provides a pragmatic, implementable enhancement to MS/MS interpretation aimed at improving PPV and reducing family/health-system burden from false positives. (messina2023butyrylcarnitineelevationin pages 1-2, messina2023butyrylcarnitineelevationin media 9d25c0d0)

8.1.3 2024 combined NGS + MS/MS screening implementation The 2024 combined approach provides an operational model for integrating targeted NGS panels with MS/MS to increase diagnostic precision and capture cases that may be missed by one modality alone. (tang2024newbornscreeningfor pages 2-4, tang2024newbornscreeningfor pages 4-5)

8.2 Management approaches and clinical monitoring Clinical significance is often uncertain, so management is frequently conservative and individualized.

• Carnitine supplementation: In a historically symptomatic case (cardiomyopathy, anemia, carnitine deficiency), oral L‑carnitine improved the condition, with long-term dependence on supplementation reported. (oglesbee2007developmentofa pages 1-2)

• Diet/feeding: In a 40‑patient NBS cohort, patients were monitored and “gradually had a normal diet after 6 months of age,” with favorable prognosis in most. (feng2021phenotypegenotypeand pages 1-2)

• Hypoglycemia preparedness: In a 10‑year follow‑up case report, a “15% glucose polymer emergency regimen” was provided (never required), and “carnitine supplementation has not been deemed necessary” when carnitine remained normal; authors suggest emergency regimens may be indicated for recurrent hypoglycemia. (santra2017longtermoutcomeof pages 1-2, santra2017longtermoutcomeof pages 2-3)

• Expert/authoritative opinion: The clinical uncertainty is explicitly stated as a management challenge: “the clinical significance of IBDD is uncertain and it remains a dilemma for clinicians managing children diagnosed through newborn screening programmes.” (santra2017longtermoutcomeof pages 2-3)

  1. Relevant statistics and data (recent and cohort-based)

9.1 Incidence estimates (selected) • 2021 Chinese NBS cohort (Zhejiang): incidence 1:62,599 (n=40). (feng2021phenotypegenotypeand pages 1-2) • 2024 NGS+MS/MS multicenter study: IBD incidence in this dataset includes an entry corresponding to 2 IBD cases in 29,601 newborns; the paper’s table excerpt notes “IBD ACAD8 2” (and includes sub-incidence values). (tang2024newbornscreeningfor pages 4-5) • 2025 regional NBS cohort: incidence 1:45,517 (5 confirmed IBDD among 227,583 screened). (tao2025novelacad8variants pages 3-4)

9.2 Penetrance and symptomatic fraction A comprehensive literature review up to Dec 2024 identified 172 individuals, with 146 asymptomatic and 26 symptomatic at follow-up; anemia was the most frequently reported abnormality among the symptomatic group. (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6)

9.3 2023 biomarker ratio data for reducing false positives Quantitative discrimination between IBDD and false positives is supported by differences in C4 and C4‑based ratios (e.g., C4/C0, C4/C6, C4/C8), in a dataset of 121 newborns with C4 elevation (IBDD n=4). (messina2023butyrylcarnitineelevationin pages 3-5)

  1. Evidence-backed ontology mapping (knowledge-base ready)

10.1 Gene/protein annotations • ACAD8 (OMIM*604773): mitochondrial enzyme in valine degradation; catalyzes isobutyryl‑CoA → methacrylyl‑CoA. (feng2021phenotypegenotypeand pages 1-2)

10.2 GO biological processes (candidate terms; map to evidence) • Branched‑chain amino acid catabolic process / valine catabolic process (block demonstrated by flux accumulation of isobutyrylcarnitine from 13C5‑valine). (wanders2012enzymologyofthe pages 2-4)

10.3 GO cellular components • Mitochondrion / mitochondrial matrix (ACAD8 described as mitochondrial enzyme; mitochondrial defect in mouse splicing model). (lin2018clinicalbiochemicaland pages 1-2)

10.4 HP phenotypes (candidate terms; evidence mapping) • Increased C4 acylcarnitine (feng2021phenotypegenotypeand pages 1-2, oglesbee2007developmentofa pages 1-2) • Isobutyrylglycinuria / increased urinary isobutyrylglycine (sass2004isobutyrylcoadehydrogenasedeficiency pages 4-5, feng2021phenotypegenotypeand pages 1-2) • Anemia (reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6, wanders2012enzymologyofthe pages 2-4) • Developmental delay / motor delay / speech delay (feng2021phenotypegenotypeand pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6) • Hypotonia (reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6) • Failure to thrive / growth delay (feng2021phenotypegenotypeand pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6) • Seizures (feng2021phenotypegenotypeand pages 1-2, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6) • Dilated cardiomyopathy (rare) (wanders2012enzymologyofthe pages 2-4, oglesbee2007developmentofa pages 1-2) • Ketotic hypoglycemia (rare; uncertain causality) (santra2017longtermoutcomeof pages 1-2) • Elevated transaminases / hepatic steatosis (subset) (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, lin2018clinicalbiochemicaland pages 1-2)

10.5 CL cell types and UBERON tissues (candidate terms; evidence mapping) • Hepatocyte / liver (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2, lin2018clinicalbiochemicaland pages 1-2) • Cardiomyocyte / heart (wanders2012enzymologyofthe pages 2-4, oglesbee2007developmentofa pages 1-2) • Neuron / brain (reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6) • Skeletal muscle cell / skeletal muscle (reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6)

  1. Evidence items (PMID-oriented; limitations)

The retrieved texts in this environment did not reliably expose PMID fields for all articles; therefore, the evidence table below uses DOI and journal metadata from the retrieved sources. Where a PMID is explicitly needed, the DOI can be used to retrieve PMID via PubMed.

Evidence table (selected core sources)

• Messina et al., “Butyrylcarnitine Elevation in Newborn Screening…” Biomedicines. Publication date: Dec 2023. URL: https://doi.org/10.3390/biomedicines11123247 (messina2023butyrylcarnitineelevationin pages 1-2, messina2023butyrylcarnitineelevationin pages 3-5) • Tang et al., “Newborn Screening… by NGS Combined with MS/MS.” International Journal of Neonatal Screening. Publication date: Mar 2024. URL: https://doi.org/10.3390/ijns10020028 (tang2024newbornscreeningfor pages 1-2, tang2024newbornscreeningfor pages 4-5) • Houten et al., “Acyl‑CoA dehydrogenase substrate promiscuity…” Journal of Inherited Metabolic Disease. Publication date: Jun 2023. URL: https://doi.org/10.1002/jimd.12642 (houten2023acyl‐coadehydrogenasesubstrate pages 1-3) • Feng et al., “Phenotype, genotype and long‑term prognosis of 40 Chinese patients…” Orphanet Journal of Rare Diseases. Publication date: Sep 2021. URL: https://doi.org/10.1186/s13023-021-02018-6 (feng2021phenotypegenotypeand pages 1-2) • Oglesbee et al., “Development of a newborn screening follow‑up algorithm…” Genetics in Medicine. Publication date: Feb 2007. URL: https://doi.org/10.1097/gim.0b013e31802f78d6 (oglesbee2007developmentofa pages 3-4, oglesbee2007developmentofa pages 1-2) • Wanders et al., “Enzymology of the branched‑chain amino acid oxidation disorders: the valine pathway.” J Inherit Metab Dis. Publication date: Nov 2012. URL: https://doi.org/10.1007/s10545-010-9236-x (wanders2012enzymologyofthe pages 2-4) • Santra et al., “Long‑term outcome… diagnosed following ketotic hypoglycaemia.” Mol Genet Metab Rep. Publication date: Mar 2017. URL: https://doi.org/10.1016/j.ymgmr.2016.11.005 (santra2017longtermoutcomeof pages 1-2) • Reyes & Sass, “IBDD: disease, or non‑disease?” Orphanet Journal of Rare Diseases. Publication date: Jan 2026. URL: https://doi.org/10.1186/s13023-026-04207-7 (useful synthesis; outside requested 2023–2024) (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2)

  1. Summary and expert interpretation

IBDD (ACAD8 deficiency) is best conceptualized as a mitochondrial valine catabolism defect whose most robust phenotype is biochemical (persistent C4‑acylcarnitine elevation; variable isobutyrylglycinuria), with low and heterogeneous clinical penetrance. The best-supported mechanistic explanation for frequent benignity is metabolic compensation via acyl‑CoA dehydrogenase substrate promiscuity in some cellular contexts (2023 mechanistic work), but a minority of individuals show nonspecific clinical findings (especially anemia) and a possibly underrecognized hepatic involvement signal (transaminase elevations/steatosis in some reports and animal models). (houten2023acyl‐coadehydrogenasesubstrate pages 1-3, reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6, reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2)

From a public health and implementation standpoint, 2023–2024 literature highlights that the major practical challenge is not detection but specificity and follow-up burden for C4 elevations. The field is responding with improved post-analytical interpretation (C4‑ratio panels) and with integrated first-tier molecular screening strategies (NGS+MS/MS) that substantially improve PPV relative to MS/MS alone while maintaining complementary sensitivity. (messina2023butyrylcarnitineelevationin pages 1-2, messina2023butyrylcarnitineelevationin media 9d25c0d0, tang2024newbornscreeningfor pages 1-2, tang2024newbornscreeningfor pages 4-5)

References

  1. (feng2021phenotypegenotypeand pages 1-2): Junqi Feng, Chenxi Yang, Ling Zhu, Yuchen Zhang, Xiaoxu Zhao, Chi Chen, Qi-xing Chen, Qiang Shu, Pingping Jiang, and Fan Tong. Phenotype, genotype and long-term prognosis of 40 chinese patients with isobutyryl-coa dehydrogenase deficiency and a review of variant spectra in acad8. Orphanet Journal of Rare Diseases, Sep 2021. URL: https://doi.org/10.1186/s13023-021-02018-6, doi:10.1186/s13023-021-02018-6. This article has 17 citations and is from a peer-reviewed journal.

  2. (reyes2026isobutyrylcoenzymeadehydrogenase pages 1-2): María Daniela Santacruz Reyes and Jörn Oliver Sass. Isobutyryl-coenzyme a dehydrogenase deficiency: disease, or non-disease? Orphanet Journal of Rare Diseases, Jan 2026. URL: https://doi.org/10.1186/s13023-026-04207-7, doi:10.1186/s13023-026-04207-7. This article has 0 citations and is from a peer-reviewed journal.

  3. (sass2004isobutyrylcoadehydrogenasedeficiency pages 1-4): J. O. Sass, S. Sander, and J. Zschocke. Isobutyryl-coa dehydrogenase deficiency: isobutyrylglycinuria and acad8 gene mutations in two infants. Journal of Inherited Metabolic Disease, 27:741-745, Nov 2004. URL: https://doi.org/10.1023/b:boli.0000045798.12425.1b, doi:10.1023/b:boli.0000045798.12425.1b. This article has 41 citations and is from a peer-reviewed journal.

  4. (oglesbee2007developmentofa pages 1-2): Devin Oglesbee, Miao He, Nilanjana Majumder, Jerry Vockley, Ayesha Ahmad, Brad Angle, Barbara Burton, Joel Charrow, Regina Ensenauer, Can H. Ficicioglu, Laura Davis Keppen, Deborah Marsden, Silvia Tortorelli, Si Houn Hahn, and Dietrich Matern. Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-coa dehydrogenase deficiency. Genetics in Medicine, 9:108-116, Feb 2007. URL: https://doi.org/10.1097/gim.0b013e31802f78d6, doi:10.1097/gim.0b013e31802f78d6. This article has 55 citations and is from a highest quality peer-reviewed journal.

  5. (houten2023acyl‐coadehydrogenasesubstrate pages 1-3): Sander M. Houten, Tetyana Dodatko, William Dwyer, Sara Violante, Hongjie Chen, Brandon Stauffer, Robert J. DeVita, Frédéric M. Vaz, Justin R. Cross, Chunli Yu, and João Leandro. acyl‐coa dehydrogenase substrate promiscuity: challenges and opportunities for development of substrate reduction therapy in disorders of valine and isoleucine metabolism. Journal of Inherited Metabolic Disease, 46:931-942, Jun 2023. URL: https://doi.org/10.1002/jimd.12642, doi:10.1002/jimd.12642. This article has 7 citations and is from a peer-reviewed journal.

  6. (wanders2012enzymologyofthe pages 2-4): Ronald J. A. Wanders, Marinus Duran, and Ference J. Loupatty. Enzymology of the branched-chain amino acid oxidation disorders: the valine pathway. Journal of Inherited Metabolic Disease, 35:5-12, Nov 2012. URL: https://doi.org/10.1007/s10545-010-9236-x, doi:10.1007/s10545-010-9236-x. This article has 101 citations and is from a peer-reviewed journal.

  7. (lin2018clinicalbiochemicaland pages 1-2): Yiming Lin, Weilin Peng, Mengyi Jiang, Chunmei Lin, Weihua Lin, Zhenzhu Zheng, Min Li, and Qingliu Fu. Clinical, biochemical and genetic analysis of chinese patients with isobutyryl-coa dehydrogenase deficiency. Clinica chimica acta; international journal of clinical chemistry, 487:133-138, Dec 2018. URL: https://doi.org/10.1016/j.cca.2018.09.033, doi:10.1016/j.cca.2018.09.033. This article has 26 citations.

  8. (sass2004isobutyrylcoadehydrogenasedeficiency pages 4-5): J. O. Sass, S. Sander, and J. Zschocke. Isobutyryl-coa dehydrogenase deficiency: isobutyrylglycinuria and acad8 gene mutations in two infants. Journal of Inherited Metabolic Disease, 27:741-745, Nov 2004. URL: https://doi.org/10.1023/b:boli.0000045798.12425.1b, doi:10.1023/b:boli.0000045798.12425.1b. This article has 41 citations and is from a peer-reviewed journal.

  9. (reyes2026isobutyrylcoenzymeadehydrogenase pages 4-6): María Daniela Santacruz Reyes and Jörn Oliver Sass. Isobutyryl-coenzyme a dehydrogenase deficiency: disease, or non-disease? Orphanet Journal of Rare Diseases, Jan 2026. URL: https://doi.org/10.1186/s13023-026-04207-7, doi:10.1186/s13023-026-04207-7. This article has 0 citations and is from a peer-reviewed journal.

  10. (eleftheriadou2021isobutyryl‐coadehydrogenasedeficiency pages 6-7): Maria Eleftheriadou, Evita Medici‐ van den Herik, Kyra Stuurman, Yolande van Bever, Debby M. E. I. Hellebrekers, Marjon van Slegtenhorst, George Ruijter, and Tahsin Stefan Barakat. Isobutyryl‐coa dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: a case report. Molecular Genetics & Genomic Medicine, Jan 2021. URL: https://doi.org/10.1002/mgg3.1595, doi:10.1002/mgg3.1595. This article has 9 citations and is from a peer-reviewed journal.

  11. (oglesbee2007developmentofa pages 3-4): Devin Oglesbee, Miao He, Nilanjana Majumder, Jerry Vockley, Ayesha Ahmad, Brad Angle, Barbara Burton, Joel Charrow, Regina Ensenauer, Can H. Ficicioglu, Laura Davis Keppen, Deborah Marsden, Silvia Tortorelli, Si Houn Hahn, and Dietrich Matern. Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-coa dehydrogenase deficiency. Genetics in Medicine, 9:108-116, Feb 2007. URL: https://doi.org/10.1097/gim.0b013e31802f78d6, doi:10.1097/gim.0b013e31802f78d6. This article has 55 citations and is from a highest quality peer-reviewed journal.

  12. (santra2017longtermoutcomeof pages 1-2): S. Santra, A. Macdonald, M.A. Preece, R.K. Olsen, and B.S. Andresen. Long-term outcome of isobutyryl-coa dehydrogenase deficiency diagnosed following an episode of ketotic hypoglycaemia. Molecular Genetics and Metabolism Reports, 10:28-30, Mar 2017. URL: https://doi.org/10.1016/j.ymgmr.2016.11.005, doi:10.1016/j.ymgmr.2016.11.005. This article has 17 citations.

  13. (messina2023butyrylcarnitineelevationin pages 1-2): MariaAnna Messina, Alessia Arena, Riccardo Iacobacci, Luisa La Spina, Concetta Meli, Federica Raudino, and Martino Ruggieri. Butyrylcarnitine elevation in newborn screening: reducing false positives and distinguishing between two rare diseases through the evaluation of new ratios. Biomedicines, 11:3247, Dec 2023. URL: https://doi.org/10.3390/biomedicines11123247, doi:10.3390/biomedicines11123247. This article has 2 citations.

  14. (messina2023butyrylcarnitineelevationin pages 2-3): MariaAnna Messina, Alessia Arena, Riccardo Iacobacci, Luisa La Spina, Concetta Meli, Federica Raudino, and Martino Ruggieri. Butyrylcarnitine elevation in newborn screening: reducing false positives and distinguishing between two rare diseases through the evaluation of new ratios. Biomedicines, 11:3247, Dec 2023. URL: https://doi.org/10.3390/biomedicines11123247, doi:10.3390/biomedicines11123247. This article has 2 citations.

  15. (messina2023butyrylcarnitineelevationin pages 3-5): MariaAnna Messina, Alessia Arena, Riccardo Iacobacci, Luisa La Spina, Concetta Meli, Federica Raudino, and Martino Ruggieri. Butyrylcarnitine elevation in newborn screening: reducing false positives and distinguishing between two rare diseases through the evaluation of new ratios. Biomedicines, 11:3247, Dec 2023. URL: https://doi.org/10.3390/biomedicines11123247, doi:10.3390/biomedicines11123247. This article has 2 citations.

  16. (messina2023butyrylcarnitineelevationin media 9d25c0d0): MariaAnna Messina, Alessia Arena, Riccardo Iacobacci, Luisa La Spina, Concetta Meli, Federica Raudino, and Martino Ruggieri. Butyrylcarnitine elevation in newborn screening: reducing false positives and distinguishing between two rare diseases through the evaluation of new ratios. Biomedicines, 11:3247, Dec 2023. URL: https://doi.org/10.3390/biomedicines11123247, doi:10.3390/biomedicines11123247. This article has 2 citations.

  17. (messina2023butyrylcarnitineelevationin media c375a74a): MariaAnna Messina, Alessia Arena, Riccardo Iacobacci, Luisa La Spina, Concetta Meli, Federica Raudino, and Martino Ruggieri. Butyrylcarnitine elevation in newborn screening: reducing false positives and distinguishing between two rare diseases through the evaluation of new ratios. Biomedicines, 11:3247, Dec 2023. URL: https://doi.org/10.3390/biomedicines11123247, doi:10.3390/biomedicines11123247. This article has 2 citations.

  18. (tang2024newbornscreeningfor pages 4-5): Chengfang Tang, Lixin Li, Ting Chen, Yulin Li, Bo Zhu, Yinhong Zhang, Yifan Yin, Xiulian Liu, Cidan Huang, Jingkun Miao, Baosheng Zhu, Xiaohua Wang, Hui Zou, Lianshu Han, Jizhen Feng, and Yonglan Huang. Newborn screening for inborn errors of metabolism by next-generation sequencing combined with tandem mass spectrometry. International Journal of Neonatal Screening, 10:28, Mar 2024. URL: https://doi.org/10.3390/ijns10020028, doi:10.3390/ijns10020028. This article has 19 citations.

  19. (tang2024newbornscreeningfor pages 2-4): Chengfang Tang, Lixin Li, Ting Chen, Yulin Li, Bo Zhu, Yinhong Zhang, Yifan Yin, Xiulian Liu, Cidan Huang, Jingkun Miao, Baosheng Zhu, Xiaohua Wang, Hui Zou, Lianshu Han, Jizhen Feng, and Yonglan Huang. Newborn screening for inborn errors of metabolism by next-generation sequencing combined with tandem mass spectrometry. International Journal of Neonatal Screening, 10:28, Mar 2024. URL: https://doi.org/10.3390/ijns10020028, doi:10.3390/ijns10020028. This article has 19 citations.

  20. (tang2024newbornscreeningfor pages 1-2): Chengfang Tang, Lixin Li, Ting Chen, Yulin Li, Bo Zhu, Yinhong Zhang, Yifan Yin, Xiulian Liu, Cidan Huang, Jingkun Miao, Baosheng Zhu, Xiaohua Wang, Hui Zou, Lianshu Han, Jizhen Feng, and Yonglan Huang. Newborn screening for inborn errors of metabolism by next-generation sequencing combined with tandem mass spectrometry. International Journal of Neonatal Screening, 10:28, Mar 2024. URL: https://doi.org/10.3390/ijns10020028, doi:10.3390/ijns10020028. This article has 19 citations.

  21. (oglesbee2007developmentofa pages 5-6): Devin Oglesbee, Miao He, Nilanjana Majumder, Jerry Vockley, Ayesha Ahmad, Brad Angle, Barbara Burton, Joel Charrow, Regina Ensenauer, Can H. Ficicioglu, Laura Davis Keppen, Deborah Marsden, Silvia Tortorelli, Si Houn Hahn, and Dietrich Matern. Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-coa dehydrogenase deficiency. Genetics in Medicine, 9:108-116, Feb 2007. URL: https://doi.org/10.1097/gim.0b013e31802f78d6, doi:10.1097/gim.0b013e31802f78d6. This article has 55 citations and is from a highest quality peer-reviewed journal.

  22. (santra2017longtermoutcomeof pages 2-3): S. Santra, A. Macdonald, M.A. Preece, R.K. Olsen, and B.S. Andresen. Long-term outcome of isobutyryl-coa dehydrogenase deficiency diagnosed following an episode of ketotic hypoglycaemia. Molecular Genetics and Metabolism Reports, 10:28-30, Mar 2017. URL: https://doi.org/10.1016/j.ymgmr.2016.11.005, doi:10.1016/j.ymgmr.2016.11.005. This article has 17 citations.

  23. (tao2025novelacad8variants pages 3-4): Yilun Tao, Dong Han, Jianfang Li, Xiaoyun Li, Luna Hao, Wenxia Song, Lihong Wang, and Xiaoze Li. Novel acad8 variants identified in isobutyryl-coa dehydrogenase deficiency: challenges in phenotypic variability and management. Frontiers in Genetics, Apr 2025. URL: https://doi.org/10.3389/fgene.2025.1532902, doi:10.3389/fgene.2025.1532902. This article has 0 citations and is from a peer-reviewed journal.