Home / Deep Research / 2-Methylbutyryl-CoA Dehydrogenase Deficiency

2-Methylbutyryl-CoA Dehydrogenase Deficiency

Disease Pathophysiology Research Template

2026-02-23
Falcon MONDO:0012392 Model: Edison Scientific Literature 34 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: 2-Methylbutyryl-CoA Dehydrogenase Deficiency
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of 2-Methylbutyryl-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

Comprehensive Research Report: 2‑Methylbutyryl‑CoA Dehydrogenase Deficiency (SBCAD deficiency; “2‑methylbutyrylglycinuria”)

Publication scope and evidence base This report synthesizes mechanistic and clinical pathophysiology evidence from primary literature and authoritative reviews, emphasizing the most recent available disease-specific sources retrieved (notably a 2024 population newborn-screening study and a 2023 mechanistic cell-model paper), plus key foundational work defining biomarkers and pathways. (houten2023acyl‐coadehydrogenasesubstrate pages 6-8, xiao2024206977newbornscreening pages 1-2)

  1. Key concepts and definitions (current understanding)

Disease definition and identifiers • Disease entity: 2‑methylbutyryl‑CoA dehydrogenase deficiency (also called short/branched-chain acyl‑CoA dehydrogenase deficiency; SBCADD/SBCAD deficiency). (porta2019clinicalbiochemicaland pages 1-2) • MONDO: MONDO_0012392 (2‑methylbutyryl‑CoA dehydrogenase deficiency) (derived from Open Targets disease record for this entity; evidence snippets were not returned, but the MONDO identifier itself was returned by the tool call). (calcar2013prevalenceandmutation pages 1-3) • OMIM: sources variably cite OMIM 600301 and/or 610006 for SBCAD deficiency; some texts also use OMIM 600301 for the gene entry and OMIM 610006 for the disease phenotype entry. (lin2019biochemicalclinicaland pages 1-2, porta2019clinicalbiochemicaland pages 1-2)

Core biochemical concept SBCAD deficiency is an inborn error of branched-chain amino acid metabolism in which the mitochondrial acyl‑CoA dehydrogenase SBCAD (encoded by ACADSB) has impaired activity in the proximal pathway of L‑isoleucine oxidation. A defining biochemical hallmark is increased urinary 2‑methylbutyrylglycine (2‑MBG), and patients are often detected by elevated C5 acylcarnitine on MS/MS newborn screening (recognizing that “C5” is isobaric with isovalerylcarnitine). (jaffar2010characterizationofnew pages 5-7)

  1. Core pathophysiology (molecular/cellular mechanisms)

2.1 Primary pathophysiological mechanisms Primary lesion: mitochondrial SBCAD (ACADSB) loss-of-function SBCAD is a mitochondrial acyl‑CoA dehydrogenase (ACAD) family enzyme. ACAD enzymes catalyze α,β‑dehydrogenation of acyl‑CoAs and transfer electrons to electron transferring flavoprotein (ETF). (jaffar2010characterizationofnew pages 1-2)

Block in isoleucine oxidation with metabolite accumulation and “overflow” routes • The metabolic block leads to accumulation of upstream metabolites that are diverted to measurable diagnostic conjugates, including C5 (2‑methylbutyrylcarnitine), urinary 2‑MBG (2‑methylbutyrylglycine), and urinary 2‑ethylhydracrylic acid (2‑EHA). (korman20052ethylhydracrylicaciduriain pages 2-3, jaffar2010characterizationofnew pages 5-7) • A central mechanistic hypothesis explaining variable severity is partial compensation via alternative enzymes/pathways and stereochemical “R‑pathway” flux. Korman et al. report that 2‑EHA (a normally minor R‑pathway intermediate) is prominent in SBCADD urine and that this “raises questions regarding the presumed role of SBCAD in the R‑pathway of isoleucine oxidation,” implying compensatory enzymology and rerouting. (korman20052ethylhydracrylicaciduriain pages 2-3) • Pathway schematic evidence: Figure 1 in Korman et al. depicts the S‑ and R‑pathways of L‑isoleucine catabolism and highlights 2‑MBG and 2‑EHA as accumulating/diagnostic metabolites. (korman20052ethylhydracrylicaciduriain media 5fdd71b3)

Stress-sensitive phenotype model A mechanistic interpretation in the review literature is that overlapping substrate specificity (“compensation by other ACAD enzymes”) may mask biochemical consequences at baseline but may fail during metabolic stress (infection/fasting), contributing to sporadic decompensation in a minority of patients. (korman2006inbornerrorsof pages 8-9)

2.2 Dysregulated pathways • Branched-chain amino acid (BCAA) catabolism: L‑isoleucine oxidation (proximal steps; S‑pathway and minor R‑pathway). (korman20052ethylhydracrylicaciduriain pages 1-2, korman20052ethylhydracrylicaciduriain media 5fdd71b3) • Mitochondrial acyl‑CoA dehydrogenation / fatty‑acid-oxidation–adjacent electron-transfer processes via ETF (shared biochemical machinery across ACAD enzymes). (jaffar2010characterizationofnew pages 1-2)

2.3 Cellular processes affected • Mitochondrial substrate processing and redox electron transfer during acyl‑CoA dehydrogenation (via ETF). (jaffar2010characterizationofnew pages 1-2) • Metabolic rerouting and detoxification via conjugation (acylcarnitine formation; glycine conjugation) producing C5‑carnitine and 2‑MBG. (jaffar2010characterizationofnew pages 5-7)

  1. Key molecular players

3.1 Genes / proteins (HGNC) • ACADSB (protein: short/branched-chain acyl‑CoA dehydrogenase; SBCAD). ACADSB is reported on chromosome 10q26.13 and comprises 11 exons. (wanders2015branchedchainamino pages 10-12) • Enzyme features: SBCAD is a homotetrameric mitochondrial ACAD; the crystal structure context supports flavin (FAD) binding and structural sensitivity of pathogenic variants. (jaffar2010characterizationofnew pages 11-14)

Functional evidence for loss-of-function variants • In vitro mutagenesis and heterologous expression studies support that multiple ACADSB missense variants destabilize protein and/or abolish activity. For example, Jaffar et al. describe variants that were “minimally or not detectable” by Western blot and show markedly reduced enzyme activity relative to wild type in recombinant assays. (jaffar2010characterizationofnew pages 11-14, jaffar2010characterizationofnew pages 2-4)

Population founder variant • ACADSB c.1165A>G is repeatedly implicated as a high-frequency/founder allele in specific populations (Hmong in the US; multiple Chinese ethnic groups). (calcar2013prevalenceandmutation pages 4-6, xiao2024206977newbornscreening pages 1-2)

3.2 Chemical entities / metabolites (CHEBI-style) Key diagnostic/biomarker metabolites in this disorder include: • C5 acylcarnitine (2‑methylbutyrylcarnitine; isobaric with isovalerylcarnitine on many MS/MS workflows). (jaffar2010characterizationofnew pages 5-7) • 2‑methylbutyrylglycine (2‑MBG) in urine (hallmark). (jaffar2010characterizationofnew pages 5-7, porta2019clinicalbiochemicaland pages 1-2) • 2‑ethylhydracrylic acid (2‑EHA) in urine (prominent R‑pathway marker; sensitive but not fully specific). (jaffar2010characterizationofnew pages 5-7, korman20052ethylhydracrylicaciduriain pages 2-3)

Drug-relevant small molecules • Valproate: Porta et al. state “valproate avoidance appear to be indicated,” and also note biochemical rationale that valproyl‑CoA can be a substrate of SBCAD, supporting an expert-opinion contraindication/avoidance approach. (porta2019clinicalbiochemicaland pages 1-2, porta2019clinicalbiochemicaland pages 3-5)

3.3 Cell types (CL) and anatomical locations (UBERON) Evidence in the retrieved sources primarily supports a systemic mitochondrial metabolic defect with clinically relevant readouts in: • Blood (dried blood spots for acylcarnitines; plasma acylcarnitines). (matern2003prospectivediagnosisof pages 2-4, jaffar2010characterizationofnew pages 5-7) • Urine (organic acids/acylglycines, including 2‑MBG and 2‑EHA). (porta2019clinicalbiochemicaland pages 1-2, korman20052ethylhydracrylicaciduriain pages 2-3) • Cultured skin fibroblasts are used for confirmatory enzyme and acylcarnitine studies. (matern2003prospectivediagnosisof pages 2-4, wanders2015branchedchainamino pages 10-12) Given the pathway, the most relevant tissues are high-oxidative organs (liver, skeletal muscle, brain) by biological plausibility; however, explicit tissue-level mechanistic localization was not directly stated in the retrieved excerpts and is therefore not asserted here without additional sourced evidence.

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

4.1 Disrupted biological processes (candidate GO terms) Based on direct pathway and mechanism descriptions: • Branched-chain amino acid catabolic process / isoleucine catabolic process (block in proximal L‑isoleucine oxidation with S‑ and R‑pathway involvement). (korman20052ethylhydracrylicaciduriain pages 1-2, korman20052ethylhydracrylicaciduriain media 5fdd71b3) • Acyl‑CoA dehydrogenase activity–linked fatty acid β‑oxidation/electron transfer module (ACAD enzymes transfer electrons to ETF). (jaffar2010characterizationofnew pages 1-2) • Acylcarnitine metabolic process and glycine conjugation/detoxification processes (reflected by elevated C5‑carnitine and 2‑MBG). (jaffar2010characterizationofnew pages 5-7)

4.2 Cellular components (candidate GO cellular component terms) • Mitochondrion / mitochondrial matrix: ACAD enzymes including SBCAD are described as mitochondrial enzymes. (jaffar2010characterizationofnew pages 1-2)

  1. Disease progression model (sequence of events)

Trigger → metabolic block → biomarker accumulation → clinical outcomes (variable) 1) Genetic biallelic ACADSB variants reduce SBCAD protein abundance and/or catalytic activity (shown by recombinant assays and Western blot evidence for instability/inactivity). (jaffar2010characterizationofnew pages 11-14, jaffar2010characterizationofnew pages 2-4) 2) The isoleucine oxidation pathway step(s) handled by SBCAD become limiting, leading to increased upstream 2‑methylbutyryl‑CoA–related metabolites. These are shunted to measurable C5‑carnitine (blood) and 2‑MBG/2‑EHA (urine). (jaffar2010characterizationofnew pages 5-7, korman20052ethylhydracrylicaciduriain pages 2-3) 3) Compensation via alternative enzymes and/or increased R‑pathway flux may mitigate metabolite burden; Korman et al. propose increased R‑pathway flux as a “safety valve” based on prominent 2‑EHA excretion. (korman20052ethylhydracrylicaciduriain pages 1-2) 4) Clinical expression is often absent or mild, but catabolic stress (infection/fasting) is proposed as a precipitating factor for overt symptoms in susceptible individuals because compensatory capacity may be exceeded. (korman2006inbornerrorsof pages 8-9)

  1. Phenotypic manifestations (HP-aligned) and mechanistic linkage

Clinical spectrum The phenotype is heterogeneous; many individuals identified through newborn screening remain asymptomatic, while a minority develop neurological/developmental features. • Porta et al. review 162 patients and conclude SBCAD deficiency is symptomatic in ~10% of reported patients; reported symptomatic features include seizures, developmental delay, hypotonia, failure to thrive, and later outcomes including epilepsy, microcephaly, and autism. (porta2019clinicalbiochemicaland pages 1-2) • Newborn screening cohorts in multiple regions show largely benign follow-up in many cases (e.g., the Chinese cohort in Quanzhou followed 12 patients reported “asymptomatic at diagnosis” with normal development during follow-up). (lin2019biochemicalclinicaland pages 1-2)

Mechanistic mapping Neurological features (seizures/developmental delay) are consistent with brain vulnerability to mitochondrial metabolic stress and accumulation of potentially toxic intermediates during catabolic states; however, the retrieved excerpts largely describe this association clinically and infer stress-triggering rather than providing direct neurotoxic mechanism experiments specific to SBCADD. (korman2006inbornerrorsof pages 8-9, porta2019clinicalbiochemicaland pages 1-2)

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

7.1 2024: large newborn-screening cohort with ethnic stratification and ACADSB variant spectrum Xiao et al. (Frontiers in Genetics; published 09 May 2024; screening January 2015–December 2021; n=206,977) report: • Overall IEM incidence 1:3,000, and 2‑methylbutyryl glycinuria (SBCADD) as the most common disorder with incidence 1:7,137 in the screened cohort. (xiao2024206977newbornscreening pages 1-2) • Ethnic differences: minority groups (Miao, Dong, Tujia, Yao) IEM incidence 1:1,852 vs Han 1:4,741. (xiao2024206977newbornscreening pages 1-2) • Variant spectrum: 29 confirmed SBCADD cases; c.1165A>G is the most prevalent variant (reported as 85.96% in the excerpted table/text), and 21/29 cases were homozygous, all for c.1165A>G. (xiao2024206977newbornscreening pages 12-12) These data reinforce that SBCADD can be relatively common in specific ethnic/geographic contexts and that founder alleles can dominate local case series. (xiao2024206977newbornscreening pages 12-12, xiao2024206977newbornscreening pages 1-2)

7.2 2023: mechanistic cell-model work on ACAD substrate promiscuity and implications for therapy development Houten et al. (Journal of Inherited Metabolic Disease; June 2023) provide a contemporary mechanistic perspective relevant to SBCAD biology: • They note that ACAD8 and SBCAD deficiencies are “considered biochemical abnormalities with limited or no clinical consequences,” reflecting current expert consensus in many metabolic clinics and the broader literature. (houten2023acyl‐coadehydrogenasesubstrate pages 1-3) • In HEK‑293 cell models, ACADSB knockout caused a marked increase in C5‑carnitine (~10‑fold, range 4–11‑fold across clones) and a substantial decrease in C3‑carnitine (~4‑fold on average), indicating that SBCAD activity influences short‑chain acyl‑CoA/acylcarnitine pools beyond a single metabolite. (houten2023acyl‐coadehydrogenasesubstrate pages 6-8) • Pharmacologic inhibition using MCPA (which inhibits SBCAD among multiple ACADs) shifted acylcarnitine profiles (large reductions in C3‑carnitine with corresponding increases in C5‑carnitine and other acylcarnitines), highlighting ACAD substrate promiscuity as both a challenge and an opportunity for “substrate reduction therapy” strategies in propionic acidemia/methylmalonic acidemia. (houten2023acyl‐coadehydrogenasesubstrate pages 6-8) Although not a therapy for SBCADD itself, this work is a recent, high-mechanistic-content source clarifying SBCAD’s network role in mitochondrial acyl‑CoA handling and the consequences of reduced SBCAD function/inhibition. (houten2023acyl‐coadehydrogenasesubstrate pages 6-8)

  1. Current applications and real-world implementations

8.1 Newborn screening (NBS) implementation Primary screening marker • Elevated C5 on dried blood spot MS/MS is the main NBS finding, but it is not specific because “isovaleryl- and 2-methylbutyrylcarnitine share the same mass/charge ratio.” (jaffar2010characterizationofnew pages 5-7) Cut-offs and algorithm considerations (example: Wisconsin) • In Wisconsin (2001–2011), infants were flagged with C5 ≥0.44 μmol/L and ratio criteria (C5/C2 ≥0.05 and C5/C3 ≥0.50) in the described program; 97 infants met C5 ≥0.44 μmol/L and 92 were confirmed SBCADD. (calcar2013prevalenceandmutation pages 3-4)

8.2 Confirmatory diagnostics Recommended confirmatory tests after elevated C5 • ACMG ACT-sheet–aligned approach: urine organic acids and urine acylglycine determination are recommended as initial follow-up tests. (jaffar2010characterizationofnew pages 5-7) Biochemical confirmation markers • Increased urinary 2‑MBG is repeatedly emphasized as a diagnostic hallmark. (porta2019clinicalbiochemicaland pages 1-2) • 2‑EHA can be a prominent urinary marker and may facilitate recognition, though it is not fully specific. (korman20052ethylhydracrylicaciduriain pages 2-3, jaffar2010characterizationofnew pages 5-7) Molecular confirmation • ACADSB sequencing (Sanger/NGS/WES depending on context) is used for confirmation and for variant interpretation; this is standard in modern NBS follow-up workflows and is explicitly reported in multiple cohorts/case studies. (nasri2026identificationofa pages 1-2, matern2003prospectivediagnosisof pages 2-4)

8.3 Management practices (expert-opinion guidance reflected in the literature) Because many individuals remain asymptomatic, management recommendations are cautious and emphasize prevention/monitoring rather than aggressive chronic restriction. Commonly described measures • Carnitine supplementation: reported doses include 50–100 mg/kg/day in early NBS-identified cohorts and 100 mg/kg/day in later case series, often with biochemical monitoring of C5. (matern2003prospectivediagnosisof pages 2-4, porta2019clinicalbiochemicaland pages 2-3) • Catabolic stress management: Porta et al. recommend avoiding fasting/protein overload and providing “an emergency protocol for the management of inter-current febrile illnesses” / acute catabolic episodes. (porta2019clinicalbiochemicaland pages 2-3, porta2019clinicalbiochemicaland pages 6-7) Dietary interventions: uncertain indication in asymptomatic NBS cases • Jaffar et al. state that early cases used “a low protein diet, avoidance of fasting, and carnitine supplementation,” but caution that “disruptive dietary manipulations for infants identified by newborn screening are of questionable indication” and suggest maintaining a normal diet with vigilance during intercurrent illnesses. (jaffar2010characterizationofnew pages 5-7) Medication avoidance • Porta et al. state “carnitine supplementation and valproate avoidance appear to be indicated.” (porta2019clinicalbiochemicaland pages 1-2)

  1. Expert opinion and analysis (authoritative interpretations)

Clinical significance remains uncertain for many genotypes Multiple authoritative sources emphasize that the condition is frequently a biochemical phenotype with limited clinical consequences, but not invariably benign. • The 2023 JIMD perspective states ACAD8 and SBCAD deficiencies are “considered biochemical abnormalities with limited or no clinical consequences,” reflecting a current expert synthesis. (houten2023acyl‐coadehydrogenasesubstrate pages 1-3) • The 2019 literature review emphasizes that labeling SBCADD a non-disease may be unsafe in non-Hmong subjects, notes catabolic stressors can precipitate decompensation, and supports longitudinal follow-up. (porta2019clinicalbiochemicaland pages 1-2) • The 2006 review highlights small case numbers, possible compensation by overlapping ACAD activities, and the role of stressors (fever/infection/fasting) in precipitating symptoms, framing the disorder as conditionally expressed. (korman2006inbornerrorsof pages 8-9)

  1. Relevant statistics and data (recent studies prioritized; older landmark datasets included)

10.1 2024 Huaihua, China (Frontiers in Genetics; published 09 May 2024) • Screened: 206,977 newborns (2015–2021). (xiao2024206977newbornscreening pages 1-2) • 2‑methylbutyryl glycinuria incidence: 1:7,137 (one of the most common IEMs in this cohort). (xiao2024206977newbornscreening pages 1-2) • Confirmed SBCADD cases: 29; c.1165A>G most prevalent, with 21/29 homozygous (all c.1165A>G homozygotes). (xiao2024206977newbornscreening pages 12-12)

10.2 2019 Quanzhou, China (Frontiers in Genetics; Aug 2019) • Estimated incidence of SBCADD in Quanzhou: 1 in 30,379 based on NBS ascertainment. (lin2019biochemicalclinicaland pages 1-2)

10.3 2013 Wisconsin, USA (Molecular Genetics and Metabolism; Sep 2013) • Ten years of NBS (2001–2011): 97 infants with C5 ≥0.44 μmol/L; 92 confirmed SBCADD. (calcar2013prevalenceandmutation pages 1-3) • Hmong birth prevalence among screen-positives: 1 in 131 (7.6 per 1000; 95% CI 6.2–9.3 per 1000). (calcar2013prevalenceandmutation pages 4-6) • Genotype frequencies in an anonymous Hmong sample (n=1,139): c.1165A>G homozygotes 1.3% (≈1 in 77; 95% CI 0.8–2.2%); heterozygotes 21.8% (95% CI 19.4–24.3%). (calcar2013prevalenceandmutation pages 4-6)

10.4 2003 Hmong cohort inference (Pediatrics; Jul 2003) • Authors report that “the incidence of SBCAD deficiency among the Hmong could be higher than 1 in 500 live births,” based on clustered ascertainment in the screened Hmong population. (matern2003prospectivediagnosisof pages 5-7)

  1. Knowledge-base–ready ontology-style annotations (evidence-linked)

Gene/protein • HGNC: ACADSB (short/branched-chain acyl‑CoA dehydrogenase; SBCAD). (wanders2015branchedchainamino pages 10-12)

Molecular function / process (GO-like) • Mitochondrial acyl‑CoA dehydrogenase activity coupled to ETF electron transfer (ACAD family property). (jaffar2010characterizationofnew pages 1-2) • Isoleucine catabolic process (S‑ and R‑pathway; accumulation of S-pathway conjugates and R‑pathway metabolite 2‑EHA). (korman20052ethylhydracrylicaciduriain pages 2-3, korman20052ethylhydracrylicaciduriain media 5fdd71b3)

Cellular component • Mitochondrion / mitochondrial matrix (enzyme class described as mitochondrial). (jaffar2010characterizationofnew pages 1-2)

Phenotypes (HP-like; evidence of spectrum) • Seizures, developmental delay, hypotonia, failure to thrive, epilepsy/autism reported in a minority; many asymptomatic. (porta2019clinicalbiochemicaland pages 1-2)

Anatomical locations (UBERON-like; evidence-supported) • Blood (dried blood spots/plasma) and urine are the main sampled compartments for clinical biomarkers. (jaffar2010characterizationofnew pages 5-7, porta2019clinicalbiochemicaland pages 1-2)

Chemical entities (CHEBI-like) • C5 acylcarnitine (2‑methylbutyrylcarnitine / isovalerylcarnitine isobar). (jaffar2010characterizationofnew pages 5-7) • 2‑methylbutyrylglycine (2‑MBG). (porta2019clinicalbiochemicaland pages 1-2) • 2‑ethylhydracrylic acid (2‑EHA). (korman20052ethylhydracrylicaciduriain pages 2-3)

  1. Evidence items with PMIDs (availability note) The tool-retrieved excerpts did not include PMID fields; therefore, this report cites DOI/URL and bibliographic metadata as retrieved. Key sources include: • Xiao et al., Frontiers in Genetics (09 May 2024): https://doi.org/10.3389/fgene.2024.1387423 (xiao2024206977newbornscreening pages 1-2) • Houten et al., J Inherit Metab Dis (Jun 2023): https://doi.org/10.1002/jimd.12642 (houten2023acyl‐coadehydrogenasesubstrate pages 6-8) • Van Calcar et al., Mol Genet Metab (Sep 2013): https://doi.org/10.1016/j.ymgme.2013.03.021 (calcar2013prevalenceandmutation pages 4-6) • Porta et al., J Pediatr Endocrinol Metab (Feb 2019): https://doi.org/10.1515/jpem-2018-0311 (porta2019clinicalbiochemicaland pages 1-2) • Korman et al., Clin Chem (Mar 2005): https://doi.org/10.1373/clinchem.2004.043265 (korman20052ethylhydracrylicaciduriain media 5fdd71b3) • Matern et al., Pediatrics (Jul 2003): https://doi.org/10.1542/peds.112.1.74 (matern2003prospectivediagnosisof pages 5-7)

Limitations of this retrieval • No Orphanet identifier was located in the retrieved evidence. • Some mechanistic details commonly described for ACAD enzymes (e.g., exact sub-mitochondrial localization, full electron-transfer chain context) are partially supported (mitochondrial enzyme; ETF transfer) but not fully elaborated in the available excerpts; this report confines mechanistic claims to what is directly supported by the cited sources. (jaffar2010characterizationofnew pages 1-2)

References

  1. (houten2023acyl‐coadehydrogenasesubstrate pages 6-8): 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.

  2. (xiao2024206977newbornscreening pages 1-2): Gang Xiao, Zonghui Feng, Chaochao Xu, Xuzhen Huang, Maosheng Chen, Min Zhao, Yanbin Li, Yang Gao, Shulin Wu, Yuyan Shen, and Ying Peng. 206,977 newborn screening results reveal the ethnic differences in the spectrum of inborn errors of metabolism in huaihua, china. Frontiers in Genetics, May 2024. URL: https://doi.org/10.3389/fgene.2024.1387423, doi:10.3389/fgene.2024.1387423. This article has 1 citations and is from a peer-reviewed journal.

  3. (porta2019clinicalbiochemicaland pages 1-2): Francesco Porta, Nicoletta Chiesa, Diego Martinelli, and Marco Spada. Clinical, biochemical, and molecular spectrum of short/branched-chain acyl-coa dehydrogenase deficiency: two new cases and review of literature. Journal of Pediatric Endocrinology and Metabolism, 32:101-108, Feb 2019. URL: https://doi.org/10.1515/jpem-2018-0311, doi:10.1515/jpem-2018-0311. This article has 27 citations and is from a peer-reviewed journal.

  4. (calcar2013prevalenceandmutation pages 1-3): Sandra C. Van Calcar, Mei W. Baker, Phillip Williams, Susan A. Jones, Blia Xiong, Mai Choua Thao, Sheng Lee, Mai Khou Yang, Greg M. Rice, William Rhead, Jerry Vockley, Gary Hoffman, and Maureen S. Durkin. Prevalence and mutation analysis of short/branched chain acyl-coa dehydrogenase deficiency (sbcadd) detected on newborn screening in wisconsin. Molecular genetics and metabolism, 110 1-2:111-5, Sep 2013. URL: https://doi.org/10.1016/j.ymgme.2013.03.021, doi:10.1016/j.ymgme.2013.03.021. This article has 32 citations and is from a peer-reviewed journal.

  5. (lin2019biochemicalclinicaland pages 1-2): Yiming Lin, Hongzhi Gao, Chunmei Lin, Yanru Chen, Shuang Zhou, Weihua Lin, Zhenzhu Zheng, Xiaoqing Li, Min Li, and Qingliu Fu. Biochemical, clinical, and genetic characteristics of short/branched chain acyl-coa dehydrogenase deficiency in chinese patients by newborn screening. Frontiers in Genetics, Aug 2019. URL: https://doi.org/10.3389/fgene.2019.00802, doi:10.3389/fgene.2019.00802. This article has 17 citations and is from a peer-reviewed journal.

  6. (jaffar2010characterizationofnew pages 5-7): Jaffar Alfardan, Al-Walid Mohsen, Sara Copeland, Jay Ellison, Laura Keppen-Davis, Marianne Rohrbach, Berkley R Powell, Jane Gillis, Dietrich Matern, Jeffrey Kant, and Jerry Vockley. Characterization of new acadsb gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening. Molecular genetics and metabolism, 100 4:333-8, Aug 2010. URL: https://doi.org/10.1016/j.ymgme.2010.04.014, doi:10.1016/j.ymgme.2010.04.014. This article has 52 citations and is from a peer-reviewed journal.

  7. (jaffar2010characterizationofnew pages 1-2): Jaffar Alfardan, Al-Walid Mohsen, Sara Copeland, Jay Ellison, Laura Keppen-Davis, Marianne Rohrbach, Berkley R Powell, Jane Gillis, Dietrich Matern, Jeffrey Kant, and Jerry Vockley. Characterization of new acadsb gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening. Molecular genetics and metabolism, 100 4:333-8, Aug 2010. URL: https://doi.org/10.1016/j.ymgme.2010.04.014, doi:10.1016/j.ymgme.2010.04.014. This article has 52 citations and is from a peer-reviewed journal.

  8. (korman20052ethylhydracrylicaciduriain pages 2-3): Stanley H Korman, Brage S Andresen, Avraham Zeharia, Alisa Gutman, Avihu Boneh, and James J Pitt. 2-ethylhydracrylic aciduria in short/branched-chain acyl-coa dehydrogenase deficiency: application to diagnosis and implications for the r-pathway of isoleucine oxidation. Clinical Chemistry, 51:610-617, Mar 2005. URL: https://doi.org/10.1373/clinchem.2004.043265, doi:10.1373/clinchem.2004.043265. This article has 41 citations and is from a highest quality peer-reviewed journal.

  9. (korman20052ethylhydracrylicaciduriain media 5fdd71b3): Stanley H Korman, Brage S Andresen, Avraham Zeharia, Alisa Gutman, Avihu Boneh, and James J Pitt. 2-ethylhydracrylic aciduria in short/branched-chain acyl-coa dehydrogenase deficiency: application to diagnosis and implications for the r-pathway of isoleucine oxidation. Clinical Chemistry, 51:610-617, Mar 2005. URL: https://doi.org/10.1373/clinchem.2004.043265, doi:10.1373/clinchem.2004.043265. This article has 41 citations and is from a highest quality peer-reviewed journal.

  10. (korman2006inbornerrorsof pages 8-9): Stanley H. Korman. Inborn errors of isoleucine degradation: a review. Molecular genetics and metabolism, 89 4:289-99, Dec 2006. URL: https://doi.org/10.1016/j.ymgme.2006.07.010, doi:10.1016/j.ymgme.2006.07.010. This article has 94 citations and is from a peer-reviewed journal.

  11. (korman20052ethylhydracrylicaciduriain pages 1-2): Stanley H Korman, Brage S Andresen, Avraham Zeharia, Alisa Gutman, Avihu Boneh, and James J Pitt. 2-ethylhydracrylic aciduria in short/branched-chain acyl-coa dehydrogenase deficiency: application to diagnosis and implications for the r-pathway of isoleucine oxidation. Clinical Chemistry, 51:610-617, Mar 2005. URL: https://doi.org/10.1373/clinchem.2004.043265, doi:10.1373/clinchem.2004.043265. This article has 41 citations and is from a highest quality peer-reviewed journal.

  12. (wanders2015branchedchainamino pages 10-12): Ronald J. A. Wanders, Marinus Duran, and Ference Loupatty. Branched chain amino acid oxidation disorders. Nutrition and Health, pages 129-143, Jan 2015. URL: https://doi.org/10.1007/978-1-4939-1923-9_11, doi:10.1007/978-1-4939-1923-9_11. This article has 1 citations and is from a peer-reviewed journal.

  13. (jaffar2010characterizationofnew pages 11-14): Jaffar Alfardan, Al-Walid Mohsen, Sara Copeland, Jay Ellison, Laura Keppen-Davis, Marianne Rohrbach, Berkley R Powell, Jane Gillis, Dietrich Matern, Jeffrey Kant, and Jerry Vockley. Characterization of new acadsb gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening. Molecular genetics and metabolism, 100 4:333-8, Aug 2010. URL: https://doi.org/10.1016/j.ymgme.2010.04.014, doi:10.1016/j.ymgme.2010.04.014. This article has 52 citations and is from a peer-reviewed journal.

  14. (jaffar2010characterizationofnew pages 2-4): Jaffar Alfardan, Al-Walid Mohsen, Sara Copeland, Jay Ellison, Laura Keppen-Davis, Marianne Rohrbach, Berkley R Powell, Jane Gillis, Dietrich Matern, Jeffrey Kant, and Jerry Vockley. Characterization of new acadsb gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening. Molecular genetics and metabolism, 100 4:333-8, Aug 2010. URL: https://doi.org/10.1016/j.ymgme.2010.04.014, doi:10.1016/j.ymgme.2010.04.014. This article has 52 citations and is from a peer-reviewed journal.

  15. (calcar2013prevalenceandmutation pages 4-6): Sandra C. Van Calcar, Mei W. Baker, Phillip Williams, Susan A. Jones, Blia Xiong, Mai Choua Thao, Sheng Lee, Mai Khou Yang, Greg M. Rice, William Rhead, Jerry Vockley, Gary Hoffman, and Maureen S. Durkin. Prevalence and mutation analysis of short/branched chain acyl-coa dehydrogenase deficiency (sbcadd) detected on newborn screening in wisconsin. Molecular genetics and metabolism, 110 1-2:111-5, Sep 2013. URL: https://doi.org/10.1016/j.ymgme.2013.03.021, doi:10.1016/j.ymgme.2013.03.021. This article has 32 citations and is from a peer-reviewed journal.

  16. (porta2019clinicalbiochemicaland pages 3-5): Francesco Porta, Nicoletta Chiesa, Diego Martinelli, and Marco Spada. Clinical, biochemical, and molecular spectrum of short/branched-chain acyl-coa dehydrogenase deficiency: two new cases and review of literature. Journal of Pediatric Endocrinology and Metabolism, 32:101-108, Feb 2019. URL: https://doi.org/10.1515/jpem-2018-0311, doi:10.1515/jpem-2018-0311. This article has 27 citations and is from a peer-reviewed journal.

  17. (matern2003prospectivediagnosisof pages 2-4): Dietrich Matern, Miao He, Susan A. Berry, Piero Rinaldo, Chester B. Whitley, Pia P. Madsen, Sandra C. van Calcar, Richard C. Lussky, Brage S. Andresen, Jon A. Wolff, and Jerry Vockley. Prospective diagnosis of 2-methylbutyryl-coa dehydrogenase deficiency in the hmong population by newborn screening using tandem mass spectrometry. Pediatrics, 112 1 Pt 1:74-8, Jul 2003. URL: https://doi.org/10.1542/peds.112.1.74, doi:10.1542/peds.112.1.74. This article has 70 citations and is from a highest quality peer-reviewed journal.

  18. (xiao2024206977newbornscreening pages 12-12): Gang Xiao, Zonghui Feng, Chaochao Xu, Xuzhen Huang, Maosheng Chen, Min Zhao, Yanbin Li, Yang Gao, Shulin Wu, Yuyan Shen, and Ying Peng. 206,977 newborn screening results reveal the ethnic differences in the spectrum of inborn errors of metabolism in huaihua, china. Frontiers in Genetics, May 2024. URL: https://doi.org/10.3389/fgene.2024.1387423, doi:10.3389/fgene.2024.1387423. This article has 1 citations and is from a peer-reviewed journal.

  19. (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.

  20. (calcar2013prevalenceandmutation pages 3-4): Sandra C. Van Calcar, Mei W. Baker, Phillip Williams, Susan A. Jones, Blia Xiong, Mai Choua Thao, Sheng Lee, Mai Khou Yang, Greg M. Rice, William Rhead, Jerry Vockley, Gary Hoffman, and Maureen S. Durkin. Prevalence and mutation analysis of short/branched chain acyl-coa dehydrogenase deficiency (sbcadd) detected on newborn screening in wisconsin. Molecular genetics and metabolism, 110 1-2:111-5, Sep 2013. URL: https://doi.org/10.1016/j.ymgme.2013.03.021, doi:10.1016/j.ymgme.2013.03.021. This article has 32 citations and is from a peer-reviewed journal.

  21. (nasri2026identificationofa pages 1-2): Maryam Nasri, Nejat Mahdieh, Farzaneh Abbasi, Reihaneh Mohsenipour, and Saeideh Abdolahpour. Identification of a novel acadsb variant for the presymptomatic diagnosis of 2-methylbutyryl-coa dehydrogenase deficiency through newborn screening in iran. Orphanet Journal of Rare Diseases, Jan 2026. URL: https://doi.org/10.1186/s13023-025-04163-8, doi:10.1186/s13023-025-04163-8. This article has 0 citations and is from a peer-reviewed journal.

  22. (porta2019clinicalbiochemicaland pages 2-3): Francesco Porta, Nicoletta Chiesa, Diego Martinelli, and Marco Spada. Clinical, biochemical, and molecular spectrum of short/branched-chain acyl-coa dehydrogenase deficiency: two new cases and review of literature. Journal of Pediatric Endocrinology and Metabolism, 32:101-108, Feb 2019. URL: https://doi.org/10.1515/jpem-2018-0311, doi:10.1515/jpem-2018-0311. This article has 27 citations and is from a peer-reviewed journal.

  23. (porta2019clinicalbiochemicaland pages 6-7): Francesco Porta, Nicoletta Chiesa, Diego Martinelli, and Marco Spada. Clinical, biochemical, and molecular spectrum of short/branched-chain acyl-coa dehydrogenase deficiency: two new cases and review of literature. Journal of Pediatric Endocrinology and Metabolism, 32:101-108, Feb 2019. URL: https://doi.org/10.1515/jpem-2018-0311, doi:10.1515/jpem-2018-0311. This article has 27 citations and is from a peer-reviewed journal.

  24. (matern2003prospectivediagnosisof pages 5-7): Dietrich Matern, Miao He, Susan A. Berry, Piero Rinaldo, Chester B. Whitley, Pia P. Madsen, Sandra C. van Calcar, Richard C. Lussky, Brage S. Andresen, Jon A. Wolff, and Jerry Vockley. Prospective diagnosis of 2-methylbutyryl-coa dehydrogenase deficiency in the hmong population by newborn screening using tandem mass spectrometry. Pediatrics, 112 1 Pt 1:74-8, Jul 2003. URL: https://doi.org/10.1542/peds.112.1.74, doi:10.1542/peds.112.1.74. This article has 70 citations and is from a highest quality peer-reviewed journal.