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2-Methylbutyryl-CoA Dehydrogenase Deficiency

MONDO:0012392 Curated 2026-07-04T00:00:00Z 9 harmonized findings

falcon · 34 citations openscientist · 24 citations

Concordant asserts the finding Partial supports a weaker/qualified form Contradictory conflicts with it Silent does not address it

Harmonized findings

2-Methylbutyryl-CoA dehydrogenase deficiency is a biallelic loss-of-function disorder of the mitochondrial short/branched-chain acyl-CoA dehydrogenase (SBCAD, encoded by ACADSB) that blocks the proximal step of L-isoleucine oxidation.

UNANIMOUS INTEGRATED

pathophysiologygenetic_factorgene_function

Provider	Stance	Score	Evidence
falcon	CONCORDANT	95%	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. Falcon states the primary lesion directly: a mitochondrial ACAD (SBCAD/ACADSB) with impaired activity in proximal isoleucine oxidation. DOI:10.1016/j.ymgme.2010.04.014
openscientist	CONCORDANT	90%	The condition affects the fourth step in the L-isoleucine degradation pathway, where SBCAD catalyzes the dehydrogenation of 2-methylbutyryl-CoA to tiglyl-CoA. OpenScientist agrees on the enzyme and pathway step, adding the specific substrate/product (2-methylbutyryl-CoA to tiglyl-CoA) and the autosomal recessive, biallelic framing elsewhere in the report. PMID:12837870

The metabolic block produces the diagnostic metabolite signature of elevated C5-acylcarnitine (2-methylbutyrylcarnitine) in blood plus urinary 2-methylbutyrylglycine (2-MBG) and 2-ethylhydracrylic acid (2-EHA).

UNANIMOUS INTEGRATED

diagnosispathophysiology

Provider	Stance	Score	Evidence
falcon	CONCORDANT	90%	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). Falcon names 2-MBG as the hallmark and C5 acylcarnitine as the screening finding; 2-EHA is cited separately as a prominent R-pathway urinary marker. DOI:10.1016/j.ymgme.2010.04.014
openscientist	CONCORDANT	95%	The condition results in impaired oxidation of 2-methylbutyryl-CoA, leading to accumulation of 2-methylbutyrylglycine (2-MBG), 2-methylbutyrylcarnitine (C5-acylcarnitine), and 2-ethylhydracrylic acid in body fluids. OpenScientist lists all three accumulating metabolites (2-MBG, C5, 2-EHA) in one sentence, fully concordant with Falcon.

C5-acylcarnitine on newborn screening is isobaric with isovalerylcarnitine, so it cannot alone distinguish SBCAD deficiency from isovaleric acidemia and requires second-tier/confirmatory testing.

UNANIMOUS INTEGRATED

diagnosis

Provider	Stance	Score	Evidence
falcon	CONCORDANT	90%	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.” Falcon states the isobaric C5 limitation of MS/MS newborn screening. DOI:10.1016/j.ymgme.2010.04.014
openscientist	CONCORDANT	90%	C5-acylcarnitine is isobaric — it cannot distinguish between isovalerylcarnitine (elevated in isovaleric acidemia) and 2-methylbutyrylcarnitine (elevated in 2-MBDD) OpenScientist states the same isobaric limitation and names isovaleric acidemia as the differential, adding second-tier LC-MS/MS resolution. PMID:36709932

The condition is clinically benign in the large majority of screen-detected individuals; roughly 10% of reported patients are symptomatic, with neurological features (seizures, developmental delay, hypotonia, failure to thrive).

UNANIMOUS INTEGRATED

phenotypeprognosis

Provider	Stance	Score	Evidence
falcon	CONCORDANT	90%	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. Falcon gives the ~10% symptomatic figure from the 162-patient review with the neurological feature list. DOI:10.1515/jpem-2018-0311
openscientist	CONCORDANT	90%	However, approximately 10% of reported patients develop neurological manifestations including seizures, developmental delay, hypotonia, and failure to thrive. OpenScientist reports the same ~10% symptomatic rate and identical neurological feature set (and states ~90% remain asymptomatic). PMID:30730842

The ACADSB c.1165A>G allele is a major founder mutation in the Hmong population (and recurrent in Chinese cohorts), producing a locally high disease frequency.

UNANIMOUS INTEGRATED

genetic_factorepidemiology

Provider	Stance	Score	Evidence
falcon	CONCORDANT	90%	ACADSB c.1165A>G is repeatedly implicated as a high-frequency/founder allele in specific populations (Hmong in the US; multiple Chinese ethnic groups). Falcon identifies c.1165A>G as the high-frequency founder allele in Hmong and Chinese populations. DOI:10.1016/j.ymgme.2013.03.021
openscientist	CONCORDANT	90%	Of the remaining 92 confirmed SBCADD cases, 90 were of Hmong descent OpenScientist documents the Hmong founder effect quantitatively (90/92 Wisconsin cases Hmong) and adds that c.1165A>G causes exon 10 skipping. PMID:23712021

A second founder allele, the ACADSB c.303+3A>G splice variant, is prevalent in individuals of Somali/Eritrean (East African) descent.

SINGLE LEAD

genetic_factorepidemiology

Provider	Stance	Score	Evidence
openscientist	CONCORDANT	85%	This mutation was also found in two previously reported cases with SBCADD, both originating from Somalia and Eritrea, indicating that it is relatively prevalent in this population OpenScientist reports a distinct Somali/Eritrean founder splice variant (c.303+3A>G) not covered by Falcon. PMID:17883863
falcon	SILENT	—	Falcon discusses only the c.1165A>G Hmong/Chinese founder allele and does not mention the Somali/Eritrean c.303+3A>G variant.

Valproate/valproic acid should be avoided in SBCAD deficiency because valproyl-CoA is a competitive substrate/inhibitor of SBCAD, worsening the metabolic block.

UNANIMOUS INTEGRATED

treatment

Provider	Stance	Score	Evidence
falcon	CONCORDANT	80%	Porta et al. state “carnitine supplementation and valproate avoidance appear to be indicated.” Falcon reports the expert-opinion valproate-avoidance recommendation plus the biochemical rationale that valproyl-CoA can be a substrate of SBCAD. DOI:10.1515/jpem-2018-0311
openscientist	CONCORDANT	95%	valproyl-CoA did inhibit SBCAD activity by a purely competitive mechanism with a K(i) of 249 ± 29 μM OpenScientist strengthens the claim with the quantitative competitive inhibition constant (Ki = 249 ± 29 μM) and frames valproic acid as strictly contraindicated. PMID:21430231

Increased flux through the alternative R-pathway of isoleucine oxidation (with 2-ethylhydracrylic aciduria as its marker) may act as a metabolic safety valve that mitigates accumulation of S-pathway metabolites.

UNANIMOUS INTEGRATED

pathophysiology

Provider	Stance	Score	Evidence
falcon	CONCORDANT	90%	Korman et al. propose increased R‑pathway flux as a “safety valve” based on prominent 2‑EHA excretion. Falcon presents the R-pathway safety-valve hypothesis as a proposed compensatory mechanism from Korman et al. DOI:10.1373/clinchem.2004.043265
openscientist	CONCORDANT	90%	Increased flux through the R-pathway may act as a safety valve for overflow of accumulating S-pathway metabolites OpenScientist states the same R-pathway safety-valve mechanism, quantifying R-isomer flux (~40-46% of conjugates). PMID:15615815

Neurological injury in symptomatic patients is mechanistically attributed to oxidative stress from the accumulating metabolite 2-MBG (lipid peroxidation and glutathione depletion in brain tissue).

MAJORITY LEAD

pathophysiologyphenotype

Provider	Stance	Score	Evidence
openscientist	CONCORDANT	90%	2MBG increased thiobarbituric acid-reactive substances (TBA-RS), indicating an increase of lipid oxidation. 2MBG induced sulfhydryl oxidation in cortical supernatants and decreased glutathione (GSH) in these brain preparations, as well as in C6 cells, indicating a reduction of nonenzymatic brain antioxidant defenses. OpenScientist supplies an explicit in vitro oxidative-stress mechanism (2-MBG lipid peroxidation and GSH depletion in rat cortex and C6 glioma). PMID:22967964
falcon	PARTIAL	40%	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. Falcon proposes brain vulnerability to toxic intermediates but explicitly notes it lacks a direct neurotoxic-mechanism experiment — partial support without the oxidative-stress evidence OpenScientist provides. DOI:10.1016/j.ymgme.2006.07.010

Narrative

Overview

Both providers frame 2-methylbutyryl-CoA dehydrogenase deficiency (SBCADD) as a rare autosomal recessive inborn error of L-isoleucine catabolism caused by biallelic ACADSB loss of function, detected largely through expanded newborn screening and clinically benign in the great majority of identified individuals. Falcon used a pathophysiology-focused prompt and is mechanism-first (isoleucine block, ACAD/ETF electron transfer, R-pathway compensation, founder genetics, biomarkers). OpenScientist used a broad disease-characteristics prompt and adds clinical breadth (etiology, diagnostics, prognosis, treatment, pharmacogenomics, model systems, and knowledge gaps).

Agreement

The reports converge on the core biology and clinical picture: the SBCAD/ACADSB enzymatic block in proximal isoleucine oxidation; the diagnostic triad of elevated C5-acylcarnitine, urinary 2-MBG, and 2-EHA; the isobaric-C5 limitation of MS/MS newborn screening; the ~10% symptomatic rate with neurological features against a mostly asymptomatic background; the c.1165A>G Hmong founder allele; the R-pathway safety-valve hypothesis; and valproate avoidance grounded in valproyl-CoA interaction with SBCAD.

Divergence

Divergence is coverage/depth rather than contradiction. OpenScientist uniquely contributes a second founder allele (c.303+3A>G in the Somali/Eritrean population), a quantitative valproyl-CoA competitive inhibition constant (Ki = 249 ± 29 μM), and an explicit in vitro oxidative-stress neurotoxicity mechanism (2-MBG lipid peroxidation and glutathione depletion) — the latter a point where Falcon explicitly notes the absence of a direct neurotoxic-mechanism experiment. The two reports also cite non-overlapping identifiers (Falcon reports MONDO_0012392; OpenScientist reports MONDO:0012411 and adds Orphanet ORPHA:79157), and report population-specific incidences from different cohorts (Falcon's Huaihua 1:7,137; OpenScientist's Quanzhou ~1:38,544) that reflect different screened populations rather than a genuine conflict.

Integration

Findings on the ACADSB/SBCAD lesion, the C5/2-MBG/2-EHA biomarker signature, the isobaric-C5 screening caveat, the ~10% symptomatic phenotype spectrum, the Hmong c.1165A>G founder allele, valproate avoidance, and the R-pathway safety valve are concordant across both providers and suitable for integration into the disorder YAML. The Somali/Eritrean second founder allele and the 2-MBG oxidative-stress mechanism are retained as leads pending primary-source verification.

Not integrated (leads)

The Somali/Eritrean c.303+3A>G founder allele (single-provider) and the in vitro 2-MBG oxidative-stress neurotoxicity mechanism (single-provider, in vitro only, with Falcon flagging the absence of direct mechanism) are held as research leads. Provider-specific epidemiological rates, the MONDO/Orphanet identifier discrepancies, and speculative therapeutic directions (antioxidants, riboflavin, gene therapy, animal-model gaps) were not promoted as curated disease mechanisms.

Cross-provider synthesis comparing falcon (pathophysiology-focused, Edison Scientific Literature) and openscientist (comprehensive, autonomous). No direct contradictions were found; divergence is coverage/depth (OpenScientist adds the Somali/Eritrean founder allele, the valproyl-CoA Ki, and the in vitro oxidative- stress mechanism) plus benign identifier and cohort-rate differences. The header MONDO (MONDO:0012392) follows the curated kb/disorders entry; note the providers disagree on the MONDO ID (falcon MONDO_0012392 vs openscientist MONDO:0012411). best_matching_text values are verbatim excerpts from the cited report files; literature evidence snippets were intentionally left unpopulated pending fetch-reference verification.