2-Methylbutyryl-CoA Dehydrogenase Deficiency

Mendelian MONDO:0012392 Pathograph 18 Show in embeddings browser Organic Acidemia Inborn Error of Metabolism

2-Methylbutyryl-CoA dehydrogenase deficiency (SBCADD) is an autosomal recessive biochemical phenotype of L-isoleucine catabolism caused by biallelic pathogenic variants in ACADSB. Reduced mitochondrial SBCAD activity leads to accumulation of 2-methylbutyrylcarnitine, detected within the unresolved C5 signal in blood, and increased 2-methylbutyrylglycine (2-MBG) in urine. Because C5 includes isobaric isovalerylcarnitine and can also reflect pivaloylcarnitine, confirmatory biochemical and molecular testing is important to distinguish SBCADD from isovaleric acidemia or analytic interference. Newborn-screening cohorts are overwhelmingly clinically well, and current evidence supports a primarily biochemical, largely benign phenotype. Neurologic findings and acute metabolic decompensation have been reported in symptom-ascertained individuals, but their causal relationship to ACADSB deficiency remains unresolved. Clinical benefit from carnitine, protein restriction, or illness protocols has not been established. The c.1165A>G founder variant accounts for the high genotype-based birth prevalence in the Hmong population and is also enriched in some Miao and Dong populations.

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Discussions and Knowledge Gaps

Are neurologic findings and catabolic decompensation causally attributable to ACADSB deficiency, and what is the lifetime penetrance of clinically meaningful disease among screen-detected individuals?

KNOWLEDGE GAP OPEN openq_sbcadd_clinical_significance

Attached to

phenotypes#Largely asymptomatic course phenotypes#Developmental delay phenotypes#Seizures phenotypes#Autism phenotypes#Metabolic acidosis pathophysiology#Possible catabolic-stress susceptibility

Symptom-ascertained reports describe neurologic disease and occasional decompensation, whereas newborn-screening cohorts are overwhelmingly well and include symptomatic people sharing genotypes with asymptomatic people. Authors explicitly question causation, and follow-up is too short and heterogeneous to estimate lifetime penetrance.

Proposed experiments

Genotype-first prospective natural-history registry

exp_sbcadd_natural_history_registry

Enroll newborn-screened and genotype-ascertained individuals irrespective of symptoms; collect uniform developmental, neurologic, illness, biochemical, genomic, and treatment data with population comparators.

Posed 2026-07-14T00:00:00Z

Show evidence (2 references)

PMID:31555323 SUPPORT Human Clinical

"the association between SBCADD and the presence of symptoms has not yet been established."

The cohort states the central causal uncertainty directly.

PMID:41722717 SUPPORT Human Clinical

"Our findings support SBCADD as a primarily biochemical phenotype with a largely benign course"

The newest series reinforces the biochemical-disease distinction.

Do carnitine, fasting or illness protocols, dietary restriction, or valproate avoidance improve patient-important outcomes in SBCADD?

KNOWLEDGE GAP OPEN gap_sbcadd_management_effectiveness

Attached to

treatments#Carnitine supplementation treatments#Precautionary fasting avoidance and illness plan treatments#Dietary management treatments#Valproate avoidance (theoretical precaution)

Studies are uncontrolled, combine interventions, and mainly report metabolite values in asymptomatic children. Recommendations are based on plausibility and precaution rather than demonstrated clinical prevention.

Proposed experiments

Prospective pragmatic management comparison

exp_sbcadd_management_comparison

Within a multicenter natural-history network, compare prespecified strategies using clinical outcomes, treatment burden, adverse effects, free carnitine, and metabolite trajectories, adjusting for indication.

Posed 2026-07-14T00:00:00Z

Show evidence (2 references)

PMID:36147814 SUPPORT Human Clinical

"the effects of proposed treatments remain uncertain as follow-data are lacking."

The longitudinal cohort explicitly identifies effectiveness as unresolved.

PMID:17883863 SUPPORT Human Clinical

"No beneficial effect was detected after 5 months with a low protein diet."

The only cited within-person diet trial was negative and too small to resolve efficacy.

⚙

Pathophysiology

ACADSB molecular function deficiency

Biallelic pathogenic ACADSB variants reduce or abolish mitochondrial short/branched-chain acyl-CoA dehydrogenase activity.

ACADSB hgnc:91

L-isoleucine catabolic process GO:0006550 ↓ DECREASED

short/branched-chain acyl-CoA dehydrogenase activity GO:0003995 ↓ DECREASED

mitochondrion GO:0005739

Downstream

Impaired isoleucine catabolism via SBCAD loss-of-function Loss of SBCAD activity blocks dehydrogenation of (S)-2-methylbutyryl-CoA in the proximal S-pathway of isoleucine oxidation.

Show evidence (2 references)

PMID:11013134 SUPPORT In Vitro

"Enzyme assay of the patient's fibroblasts, using 2-methylbutyryl-CoA as substrate, confirmed the defect."

Patient fibroblasts directly demonstrated deficient SBCAD catalytic activity.

PMID:10832746 SUPPORT In Vitro

"Western blotting revealed absence of 2-MBCDase protein in fibroblast extracts"

A founding case showed loss of SBCAD protein in patient fibroblasts.

Impaired isoleucine catabolism via SBCAD loss-of-function

The block at 2-methylbutyryl-CoA dehydrogenation diverts upstream material to C5 acylcarnitine and 2-methylbutyrylglycine conjugates and is associated with flux through the minor R-pathway of isoleucine oxidation.

L-isoleucine catabolic process GO:0006550 ↓ DECREASED branched-chain amino acid catabolic process GO:0009083 ↓ DECREASED

Downstream

Metabolic rerouting via the R-pathway of isoleucine oxidation S-pathway metabolite overflow is associated with flux through the minor R-pathway, although the responsible alternative enzyme is unresolved.

C5-acylcarnitine signal in blood Accumulated 2-methylbutyryl-CoA is transferred to carnitine and contributes to the unresolved C5 signal.

2-Methylbutyrylglycine (2-MBG) in urine Glycine conjugation of accumulated 2-methylbutyryl-CoA-derived material produces urinary 2-MBG.

2-Methylbutyrylglycinuria Increased urinary 2-MBG is the eponymous biochemical phenotype.

Experimental 2-MBG-mediated neural oxidative stress Exogenous 2-MBG altered oxidative-stress measures in rat cortical preparations and C6 cells; relevance to humans is unknown.

Possible catabolic-stress susceptibility Acute decompensation has been described in isolated reports, but frequency and causal attribution to ACADSB deficiency are uncertain.

Show evidence (1 reference)

PMID:15615815 SUPPORT Human Clinical

"Isolated excretion of 2-methylbutyrylglycine (2-MBG) is the hallmark of short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD), a recently identified defect in the proximal pathway of L-isoleucine oxidation."

Patient biochemistry links the proximal isoleucine block to urinary 2-MBG.

Metabolic rerouting via the R-pathway of isoleucine oxidation

In four patients, substantial R-isomer formation and urinary 2-ethylhydracrylic acid (2-EHA) indicated flux through the minor R-pathway. The authors proposed, but did not prove, that this route acts as a metabolic safety valve contributing to the benign course.

L-isoleucine catabolic process GO:0006550

mitochondrion GO:0005739

Downstream

2-Ethylhydracrylic acid (2-EHA) in urine R-pathway flux produces urinary 2-EHA.

2-Ethylhydracrylic aciduria Increased urinary 2-EHA is a diagnostic biochemical phenotype.

Show evidence (1 reference)

PMID:15615815 SUPPORT Human Clinical

"Approximately 40-46% of total 2-methylbutyric acid conjugates were in the form of the R-isomer, indicating significant metabolism via the R-pathway."

Chiral analysis directly demonstrated R-pathway metabolism in a small series.

Experimental 2-MBG-mediated neural oxidative stress

In-vitro exposure to 2-MBG increased lipid-oxidation measures and reduced nonenzymatic antioxidant defenses in rat cerebral-cortex preparations and C6 glioma cells. The experiments did not show C6-cell death and have not been connected to neurologic outcomes in affected humans.

glial cell CL:0000125

response to oxidative stress GO:0006979 lipid oxidation GO:0034440 ↑ INCREASED

Show evidence (2 references)

PMID:22967964 SUPPORT In Vitro

"2MBG induced sulfhydryl oxidation in cortical supernatants and decreased glutathione (GSH) in these brain preparations, as well as in C6 cells"

Rat cortical preparations and a cell line support oxidative changes caused by exogenous 2-MBG.

PMID:22967964 SUPPORT In Vitro

"we verified that 2MBG did not induce cell death in C6 cells."

The negative result limits interpretation as a demonstrated injury mechanism.

Possible catabolic-stress susceptibility

Acute metabolic decompensation during catabolic stress has been reported, principally in symptom-ascertained cases. Newborn-screening cohorts and a 2026 Central European series observed no attributable episodes, so the absolute risk and mechanism remain unresolved.

Downstream

Metabolic acidosis Acute metabolic acidosis occurred in an early symptom-ascertained patient, but attribution to SBCADD is uncertain.

Show evidence (2 references)

PMID:30730842 SUPPORT Human Clinical

"Acute metabolic decompensation due to catabolic stressors can occur, as observed in one newly reported patient."

One case supports a possible risk but cannot establish frequency or causality.

PMID:41722717 SUPPORT Human Clinical

"Over the available follow-up period, no episodes of metabolic decompensation were observed"

Absence of decompensation in the small current series supports uncertainty.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Genitourinary 1

2-Methylbutyrylglycinuria Organic aciduria HP:0001992

Show evidence (3 references)

PMID:15615815 SUPPORT Human Clinical

"Isolated excretion of 2-methylbutyrylglycine (2-MBG) is the hallmark of short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD)"

The biochemical study identifies urinary 2-MBG as the characteristic finding.

PMID:40598537 SUPPORT Human Clinical

"Both markers showed 100% diagnostic sensitivity, and 2-MBG showed slightly higher specificity than 2-EHA"

In a small retrospective study of 12 genotyped cases and 166 selected controls, 2-MBG detected all cases; external validation is needed.

PMID:36709932 SUPPORT Human Clinical

"Urine organic acid analysis was carried out in 9 cases, and 2-methylbutyrylglycine was increased in 8 cases."

Detection in eight of nine tested cases documents real-world variability.

Head and Neck 1

Microcephaly HP:0000252

Show evidence (2 references)

PMID:20547083 SUPPORT Human Clinical

"dysmorphic features including microcephaly (head circumference 46.5 cm; <3)"

The symptomatic child was directly documented to have microcephaly.

PMID:20547083 SUPPORT Human Clinical

"In addition the symptomatic patient had findings suggestive of a primary neuronal migration defect."

The alternative neurologic explanation argues against causal attribution.

Metabolism 1

Metabolic acidosis HP:0001942

Show evidence (1 reference)

PMID:20547083 SUPPORT Human Clinical

"The first reported patient presented with acute metabolic acidosis at three days of age"

The historical case supports co-occurrence but does not quantify attributable risk.

Musculoskeletal 2

Muscular hypotonia HP:0001252

Show evidence (1 reference)

PMID:12837870 SUPPORT Human Clinical

"Except for 1 patient who developed mild muscle hypotonia, all patients remain asymptomatic at ages ranging from 3 to 14 months of age."

One of eight screen-detected infants had mild hypotonia during short follow-up.

Skeletal muscle atrophy HP:0003202

Show evidence (1 reference)

PMID:12837870 SUPPORT Human Clinical

"One patient developed athetoid cerebral palsy, and another had severe motor developmental delay with muscle atrophy."

A single co-occurrence supports retaining the association with PARTIAL evidence.

Nervous System 3

Developmental delay Global developmental delay HP:0001263

Show evidence (2 references)

PMID:12837870 SUPPORT Human Clinical

"One patient developed athetoid cerebral palsy, and another had severe motor developmental delay with muscle atrophy."

The early series documents co-occurrence, not causation.

PMID:20547083 SUPPORT Human Clinical

"Notably, our one patient identified through an evaluation for significant symptoms had the same SBCAD mutation as an asymptomatic newborn."

Genotype discordance weakens causal attribution of developmental symptoms.

Seizures HP:0001250

Show evidence (1 reference)

PMID:20547083 SUPPORT Human Clinical

"The first reported patient presented with acute metabolic acidosis at three days of age after an uncomplicated pregnancy and delivery, and then exhibited chronic seizures, abnormal movements, and developmental delay"

The full-text cohort documents the historical association while questioning causation.

Autism HP:0000717

Show evidence (1 reference)

PMID:20547083 SUPPORT Human Clinical

"One patient was reported to have autism and mental retardation, but causation could not be established"

The full-text cohort explicitly rejects a causal inference from co-occurrence.

Growth 1

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:30730842 SUPPORT Human Clinical

"Clinical onset occurs in newborns or later in life with seizures, developmental delay, hypotonia, and failure to thrive."

The review documents a reported association, not attributable frequency.

Other 4

Largely asymptomatic course VERY_FREQUENT

Show evidence (3 references)

PMID:30730842 SUPPORT Human Clinical

"Based on our experience and the literature review (162 patients), SBCAD deficiency is symptomatic in about 10% of reported patients."

About 90% of reported patients had no reported symptoms, which maps to VERY_FREQUENT; the explanation preserves the reported-patient denominator.

PMID:20547083 SUPPORT Human Clinical

"Our patients have been well without treatment and call for careful follow-up studies to learn the true clinical impact of this disorder."

Eleven non-Hmong newborn-screened patients were clinically well without treatment.

PMID:41722717 SUPPORT Human Clinical

"Our findings support SBCADD as a primarily biochemical phenotype with a largely benign course"

A 2026 three-person series supports the same interpretation while not resolving lifetime risk.

Elevated C5-acylcarnitine on newborn screening Elevated circulating C5 acylcarnitine concentration HP:0035019

Show evidence (2 references)

PMID:31555323 SUPPORT Human Clinical

"all patients showed slightly or moderately elevated C5-carnitine concentrations"

C5 was the initial signal in all 12 screen-ascertained cases; selection prevents a feature-frequency estimate.

PMID:40598537 SUPPORT Human Clinical

"Ten individuals showed elevated C5 in blood, ranging from 0.32 to 1.64 µmol/L; the remaining two individuals showed C5 levels within the normal reference range."

Two of 12 genotyped cases had C5 within the local reference interval.

2-Ethylhydracrylic aciduria 2-ethylhydracylic aciduria HP:0033220

Show evidence (2 references)

PMID:15615815 SUPPORT Human Clinical

"In multiple urine samples, organic acid analysis revealed a prominent 2-EHA peak usually exceeding the size of the 2-MBG peak."

Repeated samples from four patients established 2-EHA as a prominent finding.

PMID:40598537 SUPPORT Human Clinical

"the lower specificity of 2-EHA and the fact that it can be elevated in several other congenital metabolic disorders means that it should be used as a diagnostic marker only in conjunction with other markers and clinical factors."

The diagnostic study directly limits 2-EHA to an adjunctive role.

Athetoid cerebral palsy

Show evidence (1 reference)

PMID:12837870 SUPPORT Human Clinical

"One patient developed athetoid cerebral palsy, and another had severe motor developmental delay with muscle atrophy."

The early report establishes co-occurrence, not causal attribution.

🧬

Genetic Associations

ACADSB pathogenic variants (Pathogenic Variants)

Gene: ACADSB hgnc:91

Autosomal recessive

Show evidence (1 reference)

CGGV:assertion_8bfa3857-c96c-40ac-b4c1-2cf04fd4eb4f-2019-03-22T160000.000Z SUPPORT Other

ClinGen classifies the autosomal-recessive gene-disease relationship as definitive.

Variants (3)

c.1165A>G (exon 10 skipping), Hmong founder variant

c.1165A>G causes exon 10 skipping and is a founder variant in the Hmong population. In random Wisconsin Hmong newborn cards, 1.3% were homozygous and 21.8% heterozygous. The variant is enriched in Miao and Dong groups in China, but those data do not prove a separate founder event.

Show evidence (3 references)

PMID:12837870 SUPPORT Human Clinical

"Molecular genetic analysis performed for 3 of these patients revealed that all are homozygous for an 1165A>G mutation that causes skipping of exon 10 of the SBCAD gene."

Directly supports the exon-skipping effect.

PMID:23712021 SUPPORT Human Clinical

"This corresponds to a prevalence in this ethnic group of being homozygous for the mutation of 1.3% (95% confidence interval 0.8-2.2%) and of being heterozygous for the mutation of 21.8% (95% confidence interval 19.4-24.3%)"

Random newborn-card genotyping supplies the Hmong homozygote and carrier estimates.

PMID:38784038 SUPPORT Human Clinical

"NM_001609.4:c.1165A>G in the ACADSB gene for Miao and Dong ethnic groups"

The cohort identifies ethnic enrichment but not an independent founder event.

c.303+3A>G, Somali/Eritrean population-enriched splice variant

The intron 3 c.303+3A>G splice-region variant was observed homozygously in a Somali child and in two previously reported people of Somali and Eritrean origin. This small case series suggests population enrichment but does not establish a founder effect or penetrance for neurologic findings.

Show evidence (1 reference)

PMID:17883863 SUPPORT Human Clinical

"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."

The report supports recurrence of c.303+3A>G in people of Somali and Eritrean origin while leaving the population frequency uncertain.

Diverse ACADSB loss-of-function and missense variants

Nonsense, splice, frameshift, and missense variants occur outside the Hmong founder background. Expression studies of selected missense alleles demonstrated inactive or unstable SBCAD protein; genotype-phenotype correlations remain unresolved.

Show evidence (1 reference)

PMID:20547083 SUPPORT In Vitro

"Escherichia coli expression studies revealed that the missense mutations identified lead to inactivation or instability of the mutant SBCAD enzymes."

Functional expression assays support loss of function for selected alleles.

💊

Medical Actions

Carnitine supplementation

Category: Therapeutic Action: carnitine supplementation Ontology label: Nutritional Support NCIT:C15433

Agent: (R)-carnitine CHEBI:16347

L-carnitine has been used or proposed to support acyl-group conjugation. A two-patient report used 100 mg/kg/day, and a small longitudinal cohort observed biochemical changes, but no controlled evidence shows clinical benefit and routine treatment of clinically well individuals is not established.

Show evidence (2 references)

PMID:30730842 SUPPORT Human Clinical

"Longitudinal biochemical monitoring of the two patients while on treatment with carnitine (100 mg/kg/day) was provided."

This documents use in two cases, not an evidence-based dose range or efficacy.

PMID:36147814 SUPPORT Human Clinical

"the effects of proposed treatments remain uncertain as follow-data are lacking."

The longitudinal study explicitly states that treatment effects remain uncertain.

Precautionary fasting avoidance and illness plan

Category: Therapeutic Action: supportive care Ontology label: Supportive Care NCIT:C15747

Avoiding prolonged fasting and providing an illness or emergency plan have been proposed because isolated decompensations occurred during catabolic stress. This is a precaution based on uncertain risk, not a strategy with demonstrated outcome benefit in SBCADD.

Mechanism Target:

MODULATES Possible catabolic-stress susceptibility — The plan is intended to reduce catabolic stress if susceptibility is real; both the mechanism and treatment benefit remain unproven.

Show evidence (1 reference)

PMID:30730842 SUPPORT Human Clinical

"Providing an emergency protocol for the management of acute catabolic episodes seems reasonable in asymptomatic patients with SBCAD deficiency."

“Seems reasonable” is precautionary opinion rather than measured efficacy.

Show evidence (1 reference)

PMID:20547083 SUPPORT Human Clinical

"it would seem more prudent to continue a normal diet in these infants but also have the family maintain some level of vigilance during intercurrent illnesses."

The cohort authors advise illness vigilance while emphasizing uncertainty.

Dietary management

Category: Therapeutic Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Routine protein restriction for an asymptomatic person is not supported by outcome evidence. Early screen-detected infants received presymptomatic dietary treatment, but efficacy was explicitly unestablished; one autism case had no measurable benefit from a five-month low-protein trial.

Mechanism Target:

MODULATES Impaired isoleucine catabolism via SBCAD loss-of-function — Protein or isoleucine restriction could reduce precursor input, but no clinical benefit has been demonstrated.

Show evidence (1 reference)

PMID:12837870 SUPPORT Human Clinical

"The continued efficacy of long-term dietary therapy instituted presymptomatically remains to be established."

The early treated cohort could not establish efficacy.

Show evidence (2 references)

PMID:17883863 SUPPORT Human Clinical

"No beneficial effect was detected after 5 months with a low protein diet."

A single case found no short-term benefit and cannot resolve other outcomes.

PMID:20547083 SUPPORT Human Clinical

"disruptive dietary manipulations for infants identified by newborn screening are of questionable indication."

The untreated cohort questions routine restrictive diets in clinically well infants.

Valproate avoidance (theoretical precaution)

Category: Therapeutic

Valproyl-CoA competitively inhibits purified human SBCAD and is also an SBCAD substrate in vitro. Some reviews therefore advise avoidance, but no SBCADD-specific clinical evidence shows valproate-induced decompensation; medication decisions should be individualized with specialists.

Show evidence (2 references)

PMID:21430231 SUPPORT In Vitro

"valproyl-CoA did inhibit SBCAD activity by a purely competitive mechanism with a K(i) of 249 ± 29 μM."

Purified-enzyme experiments support the theoretical biochemical precaution.

PMID:30730842 SUPPORT Human Clinical

"Carnitine supplementation and valproate avoidance appear to be indicated."

This is a review recommendation without SBCADD-specific clinical outcome data.

Newborn screening via tandem mass spectrometry

Category: Screening Action: disease screening Ontology label: Disease Screening NCIT:C15419

Expanded newborn screening can detect an elevated unresolved C5 signal and thereby incidentally identify SBCADD while screening for serious isovaleric acidemia. Every abnormal C5 result requires prompt confirmation; the cutoff can miss some ACADSB homozygotes.

Show evidence (2 references)

PMID:12837870 SUPPORT Human Clinical

"These cases suggest that SBCAD deficiency is another inborn error of metabolism detectable by newborn screening using tandem mass spectrometry."

Establishes detectability by tandem mass spectrometry.

PMID:23712021 SUPPORT Human Clinical

"Detection of homozygous individuals who were not identified on newborn screening suggests that the C5 screening cut-off would need to be as low as 0.20μmol/L to detect all infants homozygous for the ACADSB c.1165 A>G mutation."

Genotype ascertainment demonstrates imperfect sensitivity of the C5 cutoff.

Genetic counseling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Counseling should explain autosomal-recessive inheritance, a 25% recurrence risk when both parents carry a pathogenic variant, familial testing options, the high c.1165A>G carrier frequency in Hmong people, and uncertain penetrance.

Show evidence (1 reference)

PMID:23712021 SUPPORT Human Clinical

"being heterozygous for the mutation of 21.8% (95% confidence interval 19.4-24.3%)"

The high Hmong carrier frequency makes population-aware counseling relevant.

Longitudinal clinical follow-up

Category: Monitoring Action: clinical monitoring Ontology label: Clinical Evaluation NCIT:C124351

Periodic clinical assessment is reasonable to document development, intercurrent illnesses, and treatment exposure because natural history is incompletely defined. It should not be presented as surveillance for established late neurologic complications, which have not been causally linked.

Show evidence (1 reference)

PMID:31555323 SUPPORT Human Clinical

"longitudinal follow-up may be helpful to further define the natural history of SBCADD."

Follow-up is framed as natural-history data collection under uncertainty.

🔬

Biochemical Markers

C5-acylcarnitine signal in blood (INCREASED)

Context: Elevated C5 is the usual newborn-screening signal. Standard tandem mass spectrometry does not resolve 2-methylbutyrylcarnitine from isovalerylcarnitine or pivaloylcarnitine, so it is a screening trigger rather than proof of SBCADD. C5 can be normal in genetically confirmed cases.

Pathograph Readouts

Readout Of Impaired isoleucine catabolism via SBCAD loss-of-function Positive Diagnostic

In a confirmed case, 2-methylbutyrylcarnitine contributes to the unresolved C5 signal and reports the upstream SBCAD-dependent isoleucine block.

Show evidence (1 reference)

PMID:20547083 SUPPORT Human Clinical

"isovaleryl- and 2-methylbutyrylcarnitine share the same mass/charge ratio"

The full-text discussion establishes why standard C5 requires confirmation.

Show evidence (1 reference)

PMID:40598537 SUPPORT Human Clinical

"Ten individuals showed elevated C5 in blood, ranging from 0.32 to 1.64 µmol/L; the remaining two individuals showed C5 levels within the normal reference range."

C5 was within the local reference interval in two of 12 genotyped cases.

2-Methylbutyrylglycine (2-MBG) in urine (INCREASED)

Context: Urinary 2-MBG is the characteristic acylglycine marker and is more specific than 2-EHA in the available diagnostic study. Excretion can vary, so diagnosis should integrate urine findings with molecular or enzyme confirmation.

Pathograph Readouts

Readout Of Impaired isoleucine catabolism via SBCAD loss-of-function Positive Diagnostic

Urinary 2-MBG reports accumulation and glycine conjugation of 2-methylbutyryl-CoA-derived material upstream of the SBCAD block.

Show evidence (1 reference)

PMID:15615815 SUPPORT Human Clinical

"Isolated excretion of 2-methylbutyrylglycine (2-MBG) is the hallmark of short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD)"

This links the urinary conjugate to the proximal isoleucine-pathway defect.

Show evidence (1 reference)

PMID:40598537 SUPPORT Human Clinical

"Both markers showed 100% diagnostic sensitivity, and 2-MBG showed slightly higher specificity than 2-EHA"

All 12 genotyped cases in this retrospective study had detectable 2-MBG, but the small selected sample limits generalization.

2-Ethylhydracrylic acid (2-EHA) in urine (INCREASED)

Context: Increased urinary 2-EHA is a readout of the minor R-pathway and can be easier to detect than an acylglycine peak. It is not specific to SBCADD and must be combined with 2-MBG, the acylcarnitine pattern, and confirmation.

Pathograph Readouts

Readout Of Metabolic rerouting via the R-pathway of isoleucine oxidation Positive Diagnostic

Urinary 2-EHA reports R-pathway flux associated with interruption or overflow of the predominant S-pathway.

Show evidence (1 reference)

PMID:15615815 SUPPORT Human Clinical

"Approximately 40-46% of total 2-methylbutyric acid conjugates were in the form of the R-isomer, indicating significant metabolism via the R-pathway."

Chiral analysis in four patients directly supports R-pathway metabolism.

Show evidence (1 reference)

PMID:40598537 SUPPORT Human Clinical

"it should be used as a diagnostic marker only in conjunction with other markers and clinical factors."

The diagnostic study limits 2-EHA to a combined-marker role.

🔬

Diagnosis

Follow-up of an elevated C5 newborn screen

An elevated C5 result requires prompt follow-up because standard tandem mass spectrometry cannot distinguish 2-methylbutyrylcarnitine from isovalerylcarnitine, and pivaloylcarnitine can cause an analytic false positive. C5 magnitude and ratios may inform triage but do not establish SBCADD.

clinical assessment NCIT:C124351

Results: An unresolved elevated C5 signal prompts evaluation for SBCADD, isovaleric acidemia, and pivalate-related interference.

Show evidence (1 reference)

PMID:23499962 SUPPORT Human Clinical

"further differentiation of C5-acylcarnitines in order to separate different metabolic disorders and to detect interferents like pivalic acid originating from antibiotics."

The study establishes both C5-isomer resolution and pivalate interference.

Urine organic-acid and acylglycine analysis

Urinary 2-MBG strongly supports SBCADD; 2-EHA is a sensitive but less specific adjunct. Normal or fluctuating values do not alone exclude the condition, and the whole pattern distinguishes other isoleucine disorders.

clinical assessment NCIT:C124351

Results: Increased 2-MBG, often with 2-EHA and without isovalerylglycine, supports SBCADD.

Show evidence (1 reference)

PMID:40598537 SUPPORT Human Clinical

"The urinary markers 2-MBG and 2-EHA show similar sensitivity for diagnosing 2-methylbutyrylglycinuria, but the lower specificity of 2-EHA and the fact that it can be elevated in several other congenital metabolic disorders"

The 12-case study supports both markers while directly limiting 2-EHA.

ACADSB molecular genetic testing

Identification of biallelic pathogenic ACADSB variants confirms the molecular diagnosis in a person with a concordant biochemical profile.

molecular genetic testing NCIT:C19770

Results: Biallelic pathogenic or likely pathogenic ACADSB variants confirm the molecular diagnosis.

Show evidence (1 reference)

PMID:40598537 SUPPORT Human Clinical

"12 individuals diagnosed with 2-methylbutyrylglycinuria based on ACADSB genotyping"

The diagnostic-marker study used ACADSB genotyping to define its case group.

SBCAD enzyme activity testing

When molecular results are incomplete or uncertain, direct SBCAD activity in patient fibroblasts can demonstrate the functional biochemical defect.

clinical assessment NCIT:C124351

Results: Deficient activity toward 2-methylbutyryl-CoA supports functional confirmation.

Show evidence (1 reference)

PMID:11013134 SUPPORT In Vitro

"Enzyme assay of the patient's fibroblasts, using 2-methylbutyryl-CoA as substrate, confirmed the defect."

Directly demonstrates functional confirmation.

📈

Progression

Newborn-screening ascertainment

Age: Neonatal period

SBCADD is usually detected incidentally through elevated C5. Urine organic acid or acylglycine analysis and ACADSB testing distinguish it from isovaleric acidemia and pivalate-related C5 elevations. C5 and urinary metabolites can vary, so a single normal follow-up value does not exclude the biochemical phenotype.

Show evidence (1 reference)

PMID:41722717 SUPPORT Human Clinical

"Accurate differentiation from isovaleric acidemia and careful integration of biochemical, genetic and clinical data remain essential."

The current clinical series emphasizes integrated confirmation after the nonspecific C5 screening signal.

Predominantly asymptomatic follow-up

Age: Infancy through adulthood; long-term data remain limited

Most newborn-screened individuals remain clinically well. A 2019 review counted symptoms in about 10% of published patients, but that literature is enriched for symptom-ascertained cases and later cohorts question whether the neurologic findings were caused by SBCADD. Isolated reports of acute decompensation justify clinical awareness, but the absolute risk and benefit of preventive treatment remain unknown.

Show evidence (2 references)

PMID:20547083 SUPPORT Human Clinical

"Our patients have been well without treatment and call for careful follow-up studies to learn the true clinical impact of this disorder."

Eleven newborn-screened non-Hmong patients remained well without treatment.

PMID:41722717 SUPPORT Human Clinical

"Our findings support SBCADD as a primarily biochemical phenotype with a largely benign course"

The newest clinical series supports a largely benign biochemical phenotype.

📊

Prevalence

Hmong (Wisconsin, USA)

Birth Prevalence 1300.0 per 100,000 >1 in 1,000

Homozygosity for the founder c.1165A>G variant was found in 1.3% of randomly sampled Hmong newborn screening cards. This is a genotype-based birth-prevalence estimate, not clinical penetrance or C5-screen sensitivity.

Show evidence (1 reference)

PMID:23712021 SUPPORT Human Clinical

Random newborn-card genotyping directly supplies the 1.3% homozygous estimate.

Hmong c.1165A>G carriers (Wisconsin, USA)

Carrier Frequency 21800.0 per 100,000 >1 in 1,000

Heterozygosity for the founder ACADSB c.1165A>G variant was found in 21.8% of randomly sampled Hmong newborn screening cards. This carrier-frequency record is distinct from homozygous genotype-based birth prevalence.

Show evidence (1 reference)

PMID:23712021 SUPPORT Human Clinical

Random newborn-card genotyping directly supplies the 21.8% carrier frequency.

Newborns, Huaihua, China

Birth Prevalence 14.0115 per 100,000 1–9 per 10,000

Birth prevalence was 1 in 7,137 in a 206,977-newborn screening cohort (2015-2021); ascertainment may vary by ethnicity and C5 cutoff.

Show evidence (1 reference)

PMID:38784038 SUPPORT Human Clinical

"The two most common disorders were 2-methylbutyryl glycinuria (1:7,137) and phenylalanine hydroxylase deficiency (1:22,997)."

One in 7,137 equals 14.0115 per 100,000 births.

Newborns, Quanzhou, China (2014-2023)

Birth Prevalence 2.5944 per 100,000 1–9 per 100,000

Eighteen confirmed cases among 693,797 screened newborns (1 in 38,544) in the updated 10-year cohort, superseding the earlier 2014-2018 subset estimate.

Show evidence (2 references)

PMID:40835664 SUPPORT Human Clinical

"A total of 693,797 newborns were screened for OADs from 2014 to 2023"

Supplies the denominator for the updated Quanzhou cohort.

PMID:40835664 SUPPORT Human Clinical

"Seven types of OADs were identified, of which 18 were 2-methylbutyryl-CoA dehydrogenase deficiency (MBAD)"

Eighteen of 693,797 equals 2.5944 per 100,000 births.

Newborns, Zhejiang, China (2016-2021)

Birth Prevalence 0.4394 per 100,000 1–9 per 1,000,000

Twelve screen-detected cases among 2,730,852 newborns (1 in 227,571), illustrating geographic and ascertainment variation.

Show evidence (1 reference)

PMID:36709932 SUPPORT Human Clinical

"Twelve cases of SBCAD deficiency were diagnosed, which yielded a prevalence of 1/227 571."

One in 227,571 equals 0.4394 per 100,000 births.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from 2-Methylbutyryl-CoA Dehydrogenase Deficiency:

Isovaleric acidemia MONDO:0009475

Overlapping Features Isovaleric acidemia is the urgent disease differential for elevated C5 because isovalerylcarnitine and 2-methylbutyrylcarnitine are isobaric.

Distinguishing Features

Isovalerylglycine and 3-hydroxyisovaleric acid favor isovaleric acidemia; 2-MBG favors SBCADD.
Pathogenic IVD variants support isovaleric acidemia; ACADSB findings support SBCADD.

Show evidence (1 reference)

PMID:20547083 SUPPORT Human Clinical

"it is crucial to differentiate it from isovaleric acidemia as isovaleryl- and 2-methylbutyrylcarnitine share the same mass/charge ratio"

Identifies the clinically important isobaric differential.

Pivaloylcarnitine interference

Overlapping Features Maternal or infant exposure to pivalate-containing products can produce a C5 signal without SBCADD or isovaleric acidemia.

Distinguishing Features

Chromatographic second-tier testing identifies pivaloylcarnitine as the C5 isomer.
Urinary disease-specific metabolites and confirmatory genotypes are absent.

Show evidence (1 reference)

PMID:23499962 SUPPORT Human Clinical

"Pivaloylcarnitine was identified in 43 samples, isovalerylcarnitine was found in two samples."

Pivaloylcarnitine accounted for most retested C5 elevations in this population.

Other disorders with 2-EHA aciduria

Overlapping Features 2-EHA is not specific to SBCADD and can be elevated in distal isoleucine defects and other organic acid disorders, including beta-ketothiolase deficiency, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, methylmalonic acidemia, ethylmalonic encephalopathy, and Barth syndrome.

Distinguishing Features

A complete urine organic-acid profile reveals disorder-specific companion metabolites.
Molecular or enzyme testing should follow the pattern rather than 2-EHA alone.

Show evidence (2 references)

PMID:40598537 SUPPORT Human Clinical

"it should be used as a diagnostic marker only in conjunction with other markers and clinical factors."

The diagnostic study warns that multiple disorders can produce 2-EHA.

PMID:20547083 SUPPORT Human Clinical

"Three other disorders also accumulate 2-EHA in blood: β-ketothiolase, ethylmalonic encephalopathy, and Barth syndrome, though other metabolites distinguish these disorders from SBCAD deficiency"

This supports the named additional differentials and the need to interpret their full metabolite patterns.

{ }

Source YAML

click to show

name: 2-Methylbutyryl-CoA Dehydrogenase Deficiency
category: Mendelian
creation_date: '2026-02-23T00:00:00Z'
synonyms:
- Short/branched-chain acyl-CoA dehydrogenase deficiency
- SBCADD
- SBCAD deficiency
- 2-methylbutyrylglycinuria
- 2-MBCDD
- 2-methylbutyryl-CoA dehydrogenase deficiency
description: >-
  2-Methylbutyryl-CoA dehydrogenase deficiency (SBCADD) is an autosomal
  recessive biochemical phenotype of L-isoleucine catabolism caused by
  biallelic pathogenic variants in ACADSB. Reduced mitochondrial SBCAD activity
  leads to accumulation of 2-methylbutyrylcarnitine, detected within the
  unresolved C5 signal in blood, and increased 2-methylbutyrylglycine (2-MBG)
  in urine. Because C5 includes isobaric isovalerylcarnitine and can also reflect
  pivaloylcarnitine, confirmatory biochemical and molecular testing is important
  to distinguish SBCADD from isovaleric acidemia or analytic interference.
  Newborn-screening cohorts are overwhelmingly clinically well, and current
  evidence supports a primarily biochemical, largely benign phenotype.
  Neurologic findings and acute metabolic decompensation have been reported in
  symptom-ascertained individuals, but their causal relationship to ACADSB
  deficiency remains unresolved. Clinical benefit from carnitine, protein
  restriction, or illness protocols has not been established. The c.1165A>G
  founder variant accounts for the high genotype-based birth prevalence in the
  Hmong population and is also enriched in some Miao and Dong populations.
disease_term:
  preferred_term: 2-methylbutyryl-CoA dehydrogenase deficiency
  term:
    id: MONDO:0012392
    label: 2-methylbutyryl-CoA dehydrogenase deficiency
parents:
- Organic Acidemia
- Inborn Error of Metabolism
prevalence:
- population: Hmong (Wisconsin, USA)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1300.0
  percentage: 1.3
  notes: >-
    Homozygosity for the founder c.1165A>G variant was found in 1.3% of
    randomly sampled Hmong newborn screening cards. This is a genotype-based
    birth-prevalence estimate, not clinical penetrance or C5-screen sensitivity.
  evidence:
  - reference: PMID:23712021
    reference_title: >-
      Prevalence and mutation analysis of short/branched chain acyl-CoA
      dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This corresponds to a prevalence in this ethnic group of being homozygous
      for the mutation of 1.3% (95% confidence interval 0.8-2.2%) and of being
      heterozygous for the mutation of 21.8% (95% confidence interval
      19.4-24.3%)
    explanation: >-
      Random newborn-card genotyping directly supplies the 1.3% homozygous estimate.
- population: Hmong c.1165A>G carriers (Wisconsin, USA)
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 21800.0
  notes: >-
    Heterozygosity for the founder ACADSB c.1165A>G variant was found in 21.8%
    of randomly sampled Hmong newborn screening cards. This carrier-frequency
    record is distinct from homozygous genotype-based birth prevalence.
  evidence:
  - reference: PMID:23712021
    reference_title: >-
      Prevalence and mutation analysis of short/branched chain acyl-CoA
      dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This corresponds to a prevalence in this ethnic group of being homozygous
      for the mutation of 1.3% (95% confidence interval 0.8-2.2%) and of being
      heterozygous for the mutation of 21.8% (95% confidence interval
      19.4-24.3%)
    explanation: >-
      Random newborn-card genotyping directly supplies the 21.8% carrier frequency.
- population: Newborns, Huaihua, China
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 14.0115
  notes: >-
    Birth prevalence was 1 in 7,137 in a 206,977-newborn screening cohort
    (2015-2021); ascertainment may vary by ethnicity and C5 cutoff.
  evidence:
  - reference: PMID:38784038
    reference_title: >-
      206,977 newborn screening results reveal the ethnic differences in the
      spectrum of inborn errors of metabolism in Huaihua, China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two most common disorders were 2-methylbutyryl glycinuria (1:7,137)
      and phenylalanine hydroxylase deficiency (1:22,997).
    explanation: >-
      One in 7,137 equals 14.0115 per 100,000 births.
- population: Newborns, Quanzhou, China (2014-2023)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.5944
  notes: >-
    Eighteen confirmed cases among 693,797 screened newborns (1 in 38,544) in
    the updated 10-year cohort, superseding the earlier 2014-2018 subset estimate.
  evidence:
  - reference: PMID:40835664
    reference_title: >-
      Large-scale newborn screening for organic acidemias in Quanzhou, China: a
      10-year retrospective observational study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 693,797 newborns were screened for OADs from 2014 to 2023
    explanation: Supplies the denominator for the updated Quanzhou cohort.
  - reference: PMID:40835664
    reference_title: >-
      Large-scale newborn screening for organic acidemias in Quanzhou, China: a
      10-year retrospective observational study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven types of OADs were identified, of which 18 were
      2-methylbutyryl-CoA dehydrogenase deficiency (MBAD)
    explanation: >-
      Eighteen of 693,797 equals 2.5944 per 100,000 births.
- population: Newborns, Zhejiang, China (2016-2021)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.4394
  notes: >-
    Twelve screen-detected cases among 2,730,852 newborns (1 in 227,571),
    illustrating geographic and ascertainment variation.
  evidence:
  - reference: PMID:36709932
    reference_title: >-
      [Analysis of clinical features, biochemical indices and genetic variants
      among children with Short/branched-chain acyl-CoA dehydrogenase
      deficiency detected by neonatal screening].
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twelve cases of SBCAD deficiency were diagnosed, which yielded a
      prevalence of 1/227 571.
    explanation: >-
      One in 227,571 equals 0.4394 per 100,000 births.
progression:
- phase: Newborn-screening ascertainment
  age_range: Neonatal period
  notes: >-
    SBCADD is usually detected incidentally through elevated C5. Urine organic
    acid or acylglycine analysis and ACADSB testing distinguish it from
    isovaleric acidemia and pivalate-related C5 elevations. C5 and urinary
    metabolites can vary, so a single normal follow-up value does not exclude
    the biochemical phenotype.
  evidence:
  - reference: PMID:41722717
    reference_title: >-
      Outlook on ACADSB variants shaping metabolomic patterns and clinical
      outcomes - experience from a Central European country.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Accurate differentiation from isovaleric acidemia and careful integration
      of biochemical, genetic and clinical data remain essential.
    explanation: >-
      The current clinical series emphasizes integrated confirmation after the
      nonspecific C5 screening signal.
- phase: Predominantly asymptomatic follow-up
  age_range: Infancy through adulthood; long-term data remain limited
  notes: >-
    Most newborn-screened individuals remain clinically well. A 2019 review
    counted symptoms in about 10% of published patients, but that literature is
    enriched for symptom-ascertained cases and later cohorts question whether
    the neurologic findings were caused by SBCADD. Isolated reports of acute
    decompensation justify clinical awareness, but the absolute risk and benefit
    of preventive treatment remain unknown.
  evidence:
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patients have been well without treatment and call for careful
      follow-up studies to learn the true clinical impact of this disorder.
    explanation: >-
      Eleven newborn-screened non-Hmong patients remained well without treatment.
  - reference: PMID:41722717
    reference_title: >-
      Outlook on ACADSB variants shaping metabolomic patterns and clinical
      outcomes - experience from a Central European country.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings support SBCADD as a primarily biochemical phenotype with a
      largely benign course
    explanation: >-
      The newest clinical series supports a largely benign biochemical phenotype.
pathophysiology:
- name: ACADSB molecular function deficiency
  description: >-
    Biallelic pathogenic ACADSB variants reduce or abolish mitochondrial
    short/branched-chain acyl-CoA dehydrogenase activity.
  genes:
  - preferred_term: ACADSB
    term:
      id: hgnc:91
      label: ACADSB
  molecular_functions:
  - preferred_term: short/branched-chain acyl-CoA dehydrogenase activity
    term:
      id: GO:0003995
      label: acyl-CoA dehydrogenase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: L-isoleucine catabolic process
    term:
      id: GO:0006550
      label: L-isoleucine catabolic process
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:11013134
    reference_title: >-
      Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA
      dehydrogenase deficiency: identification of a new enzyme defect,
      resolution of its molecular basis, and evidence for distinct acyl-CoA
      dehydrogenases in isoleucine and valine metabolism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Enzyme assay of the patient's fibroblasts, using 2-methylbutyryl-CoA as
      substrate, confirmed the defect.
    explanation: >-
      Patient fibroblasts directly demonstrated deficient SBCAD catalytic activity.
  - reference: PMID:10832746
    reference_title: >-
      2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of
      L-isoleucine metabolism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Western blotting revealed absence of 2-MBCDase protein in fibroblast extracts
    explanation: >-
      A founding case showed loss of SBCAD protein in patient fibroblasts.
  downstream:
  - target: Impaired isoleucine catabolism via SBCAD loss-of-function
    description: >-
      Loss of SBCAD activity blocks dehydrogenation of (S)-2-methylbutyryl-CoA
      in the proximal S-pathway of isoleucine oxidation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11013134
      reference_title: >-
        Isolated 2-methylbutyrylglycinuria caused by short/branched-chain
        acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect,
        resolution of its molecular basis, and evidence for distinct acyl-CoA
        dehydrogenases in isoleucine and valine metabolism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        show that it results in an isolated defect in isoleucine catabolism
      explanation: >-
        Functional and molecular experiments place ACADSB loss directly in
        isoleucine catabolism.
- name: Impaired isoleucine catabolism via SBCAD loss-of-function
  description: >-
    The block at 2-methylbutyryl-CoA dehydrogenation diverts upstream material
    to C5 acylcarnitine and 2-methylbutyrylglycine conjugates and is associated
    with flux through the minor R-pathway of isoleucine oxidation.
  biological_processes:
  - preferred_term: L-isoleucine catabolic process
    term:
      id: GO:0006550
      label: L-isoleucine catabolic process
    modifier: DECREASED
  - preferred_term: branched-chain amino acid catabolic process
    term:
      id: GO:0009083
      label: branched-chain amino acid catabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: 2-methylbutyrylcarnitine
    term:
      id: CHEBI:73026
      label: 2-methylbutyrylcarnitine
    modifier: INCREASED
  evidence:
  - reference: PMID:15615815
    reference_title: >-
      2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
      dehydrogenase deficiency: application to diagnosis and implications for
      the R-pathway of isoleucine oxidation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Isolated excretion of 2-methylbutyrylglycine (2-MBG) is the hallmark of
      short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD), a
      recently identified defect in the proximal pathway of L-isoleucine oxidation.
    explanation: >-
      Patient biochemistry links the proximal isoleucine block to urinary 2-MBG.
  downstream:
  - target: Metabolic rerouting via the R-pathway of isoleucine oxidation
    description: >-
      S-pathway metabolite overflow is associated with flux through the minor
      R-pathway, although the responsible alternative enzyme is unresolved.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - accumulation of 2-methylbutyryl-CoA-derived metabolites
    evidence:
    - reference: PMID:15615815
      reference_title: >-
        2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
        dehydrogenase deficiency: application to diagnosis and implications for
        the R-pathway of isoleucine oxidation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Approximately 40-46% of total 2-methylbutyric acid conjugates were in
        the form of the R-isomer, indicating significant metabolism via the R-pathway.
      explanation: >-
        Chiral metabolite analysis in four patients demonstrated substantial R-pathway metabolism.
  - target: C5-acylcarnitine signal in blood
    description: >-
      Accumulated 2-methylbutyryl-CoA is transferred to carnitine and contributes
      to the unresolved C5 signal.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31555323
      reference_title: >-
        Biochemical, Clinical, and Genetic Characteristics of Short/Branched
        Chain Acyl-CoA Dehydrogenase Deficiency in Chinese Patients by Newborn Screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        all patients showed slightly or moderately elevated C5-carnitine concentrations
      explanation: >-
        All 12 screen-detected cases in this cohort had elevated C5 initially.
  - target: 2-Methylbutyrylglycine (2-MBG) in urine
    description: >-
      Glycine conjugation of accumulated 2-methylbutyryl-CoA-derived material
      produces urinary 2-MBG.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15615815
      reference_title: >-
        2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
        dehydrogenase deficiency: application to diagnosis and implications for
        the R-pathway of isoleucine oxidation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Isolated excretion of 2-methylbutyrylglycine (2-MBG) is the hallmark of
        short/branched-chain acyl-CoA dehydrogenase deficiency
      explanation: Directly supports urinary 2-MBG as the pathway readout.
  - target: 2-Methylbutyrylglycinuria
    description: Increased urinary 2-MBG is the eponymous biochemical phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15615815
      reference_title: >-
        2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
        dehydrogenase deficiency: application to diagnosis and implications for
        the R-pathway of isoleucine oxidation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Isolated excretion of 2-methylbutyrylglycine (2-MBG) is the hallmark of
        short/branched-chain acyl-CoA dehydrogenase deficiency
      explanation: Directly supports the biochemical phenotype.
  - target: Experimental 2-MBG-mediated neural oxidative stress
    description: >-
      Exogenous 2-MBG altered oxidative-stress measures in rat cortical
      preparations and C6 cells; relevance to humans is unknown.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - 2-methylbutyrylglycine exposure
    evidence:
    - reference: PMID:22967964
      reference_title: >-
        2-Methylbutyrylglycine induces lipid oxidative damage and decreases the
        antioxidant defenses in rat brain.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        2MBG increased thiobarbituric acid-reactive species (TBA-RS), indicating
        an increase of lipid oxidation.
      explanation: >-
        This edge is limited to the experimentally observed response and does
        not assert a human neurologic outcome.
  - target: Possible catabolic-stress susceptibility
    description: >-
      Acute decompensation has been described in isolated reports, but frequency
      and causal attribution to ACADSB deficiency are uncertain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30730842
      reference_title: >-
        Clinical, biochemical, and molecular spectrum of short/branched-chain
        acyl-CoA dehydrogenase deficiency: two new cases and review of literature.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Catabolic situations can precipitate acute metabolic decompensation.
      explanation: >-
        The review reports possible stress-associated decompensation but does
        not establish population risk.
- name: Metabolic rerouting via the R-pathway of isoleucine oxidation
  description: >-
    In four patients, substantial R-isomer formation and urinary
    2-ethylhydracrylic acid (2-EHA) indicated flux through the minor R-pathway.
    The authors proposed, but did not prove, that this route acts as a metabolic
    safety valve contributing to the benign course.
  biological_processes:
  - preferred_term: L-isoleucine catabolic process
    term:
      id: GO:0006550
      label: L-isoleucine catabolic process
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:15615815
    reference_title: >-
      2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
      dehydrogenase deficiency: application to diagnosis and implications for
      the R-pathway of isoleucine oxidation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 40-46% of total 2-methylbutyric acid conjugates were in the
      form of the R-isomer, indicating significant metabolism via the R-pathway.
    explanation: >-
      Chiral analysis directly demonstrated R-pathway metabolism in a small series.
  downstream:
  - target: 2-Ethylhydracrylic acid (2-EHA) in urine
    description: R-pathway flux produces urinary 2-EHA.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15615815
      reference_title: >-
        2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
        dehydrogenase deficiency: application to diagnosis and implications for
        the R-pathway of isoleucine oxidation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In multiple urine samples, organic acid analysis revealed a prominent
        2-EHA peak usually exceeding the size of the 2-MBG peak.
      explanation: Urine analysis directly supports 2-EHA as a pathway readout.
  - target: 2-Ethylhydracrylic aciduria
    description: Increased urinary 2-EHA is a diagnostic biochemical phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15615815
      reference_title: >-
        2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
        dehydrogenase deficiency: application to diagnosis and implications for
        the R-pathway of isoleucine oxidation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Awareness of 2-ethylhydracrylic aciduria as a diagnostic marker could
        lead to increased detection of SBCADD
      explanation: The study identifies 2-EHA excretion as a diagnostic marker.
- name: Experimental 2-MBG-mediated neural oxidative stress
  description: >-
    In-vitro exposure to 2-MBG increased lipid-oxidation measures and reduced
    nonenzymatic antioxidant defenses in rat cerebral-cortex preparations and
    C6 glioma cells. The experiments did not show C6-cell death and have not
    been connected to neurologic outcomes in affected humans.
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: lipid oxidation
    term:
      id: GO:0034440
      label: lipid oxidation
    modifier: INCREASED
  cell_types:
  - preferred_term: glial cell
    term:
      id: CL:0000125
      label: glial cell
  evidence:
  - reference: PMID:22967964
    reference_title: >-
      2-Methylbutyrylglycine induces lipid oxidative damage and decreases the
      antioxidant defenses in rat brain.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      2MBG induced sulfhydryl oxidation in cortical supernatants and decreased
      glutathione (GSH) in these brain preparations, as well as in C6 cells
    explanation: >-
      Rat cortical preparations and a cell line support oxidative changes caused
      by exogenous 2-MBG.
  - reference: PMID:22967964
    reference_title: >-
      2-Methylbutyrylglycine induces lipid oxidative damage and decreases the
      antioxidant defenses in rat brain.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we verified that 2MBG did not induce cell death in C6 cells.
    explanation: >-
      The negative result limits interpretation as a demonstrated injury mechanism.
- name: Possible catabolic-stress susceptibility
  description: >-
    Acute metabolic decompensation during catabolic stress has been reported,
    principally in symptom-ascertained cases. Newborn-screening cohorts and a
    2026 Central European series observed no attributable episodes, so the
    absolute risk and mechanism remain unresolved.
  evidence:
  - reference: PMID:30730842
    reference_title: >-
      Clinical, biochemical, and molecular spectrum of short/branched-chain
      acyl-CoA dehydrogenase deficiency: two new cases and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute metabolic decompensation due to catabolic stressors can occur, as
      observed in one newly reported patient.
    explanation: >-
      One case supports a possible risk but cannot establish frequency or causality.
  - reference: PMID:41722717
    reference_title: >-
      Outlook on ACADSB variants shaping metabolomic patterns and clinical
      outcomes - experience from a Central European country.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over the available follow-up period, no episodes of metabolic
      decompensation were observed
    explanation: >-
      Absence of decompensation in the small current series supports uncertainty.
  downstream:
  - target: Metabolic acidosis
    description: >-
      Acute metabolic acidosis occurred in an early symptom-ascertained patient,
      but attribution to SBCADD is uncertain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20547083
      reference_title: >-
        Characterization of new ACADSB gene sequence mutations and clinical
        implications in patients with 2-methylbutyrylglycinuria identified by
        newborn screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The first reported patient presented with acute metabolic acidosis at
        three days of age
      explanation: >-
        The historical presentation supports the association while later cohorts
        leave causal attribution unresolved.
phenotypes:
- name: Largely asymptomatic course
  frequency: VERY_FREQUENT
  description: >-
    Most individuals identified by newborn screening or family studies have
    remained clinically well during available follow-up. A literature review
    described about 10% of reported patients as symptomatic, corresponding to
    about 90% without reported symptoms, but published cases are vulnerable to
    ascertainment bias and do not establish lifetime risk.
  evidence:
  - reference: PMID:30730842
    reference_title: >-
      Clinical, biochemical, and molecular spectrum of short/branched-chain
      acyl-CoA dehydrogenase deficiency: two new cases and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on our experience and the literature review (162 patients), SBCAD
      deficiency is symptomatic in about 10% of reported patients.
    explanation: >-
      About 90% of reported patients had no reported symptoms, which maps to
      VERY_FREQUENT; the explanation preserves the reported-patient denominator.
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patients have been well without treatment and call for careful
      follow-up studies to learn the true clinical impact of this disorder.
    explanation: >-
      Eleven non-Hmong newborn-screened patients were clinically well without treatment.
  - reference: PMID:41722717
    reference_title: >-
      Outlook on ACADSB variants shaping metabolomic patterns and clinical
      outcomes - experience from a Central European country.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings support SBCADD as a primarily biochemical phenotype with a
      largely benign course
    explanation: >-
      A 2026 three-person series supports the same interpretation while not
      resolving lifetime risk.
- name: Elevated C5-acylcarnitine on newborn screening
  description: >-
    Elevated C5 on tandem mass spectrometry is the usual screening trigger, not
    a diagnosis of SBCADD. Standard C5 measurement does not resolve
    2-methylbutyrylcarnitine from isovalerylcarnitine or pivaloylcarnitine, and
    some genetically confirmed individuals have C5 below a program cutoff.
  phenotype_term:
    preferred_term: Elevated circulating C5 acylcarnitine concentration
    term:
      id: HP:0035019
      label: Elevated circulating C5 acylcarnitine concentration
  evidence:
  - reference: PMID:31555323
    reference_title: >-
      Biochemical, Clinical, and Genetic Characteristics of Short/Branched Chain
      Acyl-CoA Dehydrogenase Deficiency in Chinese Patients by Newborn Screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all patients showed slightly or moderately elevated C5-carnitine concentrations
    explanation: >-
      C5 was the initial signal in all 12 screen-ascertained cases; selection
      prevents a feature-frequency estimate.
  - reference: PMID:40598537
    reference_title: >-
      Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid
      in urine for diagnosing 2-methylbutyrylglycinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten individuals showed elevated C5 in blood, ranging from 0.32 to 1.64
      µmol/L; the remaining two individuals showed C5 levels within the normal
      reference range.
    explanation: >-
      Two of 12 genotyped cases had C5 within the local reference interval.
  reports_on:
  - target: C5-acylcarnitine signal in blood
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Tandem mass spectrometry reports the unresolved C5-acylcarnitine signal;
      standard C5 measurement does not identify which isomer is elevated.
    evidence:
    - reference: PMID:31555323
      reference_title: >-
        Biochemical, Clinical, and Genetic Characteristics of Short/Branched
        Chain Acyl-CoA Dehydrogenase Deficiency in Chinese Patients by Newborn Screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        all patients showed slightly or moderately elevated C5-carnitine concentrations
      explanation: >-
        The screening phenotype observationally reports the blood C5 signal in
        this newborn-screened cohort.
- name: 2-Methylbutyrylglycinuria
  diagnostic: true
  description: >-
    Increased urinary 2-methylbutyrylglycine (2-MBG) is the characteristic
    acylglycine finding and a strong confirmatory marker, but excretion varies.
    It should be interpreted with the C5 pattern and ACADSB molecular or enzyme evidence.
  phenotype_term:
    preferred_term: Organic aciduria
    term:
      id: HP:0001992
      label: Organic aciduria
  evidence:
  - reference: PMID:15615815
    reference_title: >-
      2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
      dehydrogenase deficiency: application to diagnosis and implications for
      the R-pathway of isoleucine oxidation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Isolated excretion of 2-methylbutyrylglycine (2-MBG) is the hallmark of
      short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD)
    explanation: >-
      The biochemical study identifies urinary 2-MBG as the characteristic finding.
  - reference: PMID:40598537
    reference_title: >-
      Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid
      in urine for diagnosing 2-methylbutyrylglycinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both markers showed 100% diagnostic sensitivity, and 2-MBG showed
      slightly higher specificity than 2-EHA
    explanation: >-
      In a small retrospective study of 12 genotyped cases and 166 selected
      controls, 2-MBG detected all cases; external validation is needed.
  - reference: PMID:36709932
    reference_title: >-
      [Analysis of clinical features, biochemical indices and genetic variants
      among children with Short/branched-chain acyl-CoA dehydrogenase
      deficiency detected by neonatal screening].
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urine organic acid analysis was carried out in 9 cases, and
      2-methylbutyrylglycine was increased in 8 cases.
    explanation: >-
      Detection in eight of nine tested cases documents real-world variability.
- name: 2-Ethylhydracrylic aciduria
  diagnostic: true
  description: >-
    Urinary 2-ethylhydracrylic acid (2-EHA) reflects increased flux through the
    minor R-pathway and is a useful diagnostic adjunct. It is less specific
    than 2-MBG and can occur in other inborn errors, so it must not be used alone.
  phenotype_term:
    preferred_term: 2-ethylhydracrylic aciduria
    term:
      id: HP:0033220
      label: 2-ethylhydracylic aciduria
  evidence:
  - reference: PMID:15615815
    reference_title: >-
      2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
      dehydrogenase deficiency: application to diagnosis and implications for
      the R-pathway of isoleucine oxidation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In multiple urine samples, organic acid analysis revealed a prominent
      2-EHA peak usually exceeding the size of the 2-MBG peak.
    explanation: >-
      Repeated samples from four patients established 2-EHA as a prominent finding.
  - reference: PMID:40598537
    reference_title: >-
      Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid
      in urine for diagnosing 2-methylbutyrylglycinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the lower specificity of 2-EHA and the fact that it can be elevated in
      several other congenital metabolic disorders means that it should be used
      as a diagnostic marker only in conjunction with other markers and clinical factors.
    explanation: >-
      The diagnostic study directly limits 2-EHA to an adjunctive role.
- name: Developmental delay
  description: >-
    Developmental delay has been reported in symptom-ascertained individuals.
    The same pathogenic genotype has also occurred in an asymptomatic newborn,
    and later cohorts conclude that causal attribution is unestablished.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:12837870
    reference_title: >-
      Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in
      the Hmong population by newborn screening using tandem mass spectrometry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient developed athetoid cerebral palsy, and another had severe
      motor developmental delay with muscle atrophy.
    explanation: >-
      The early series documents co-occurrence, not causation.
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, our one patient identified through an evaluation for significant
      symptoms had the same SBCAD mutation as an asymptomatic newborn.
    explanation: >-
      Genotype discordance weakens causal attribution of developmental symptoms.
- name: Seizures
  description: >-
    Seizures have occurred in symptom-ascertained reports but have not been
    shown to occur more often because of SBCADD. They are retained as a
    historical association of uncertain causality.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first reported patient presented with acute metabolic acidosis at
      three days of age after an uncomplicated pregnancy and delivery, and then
      exhibited chronic seizures, abnormal movements, and developmental delay
    explanation: >-
      The full-text cohort documents the historical association while questioning causation.
- name: Muscular hypotonia
  description: >-
    Mild, sometimes transient hypotonia has been reported in a small number of
    screen-detected individuals, insufficient to establish a characteristic phenotype.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:12837870
    reference_title: >-
      Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in
      the Hmong population by newborn screening using tandem mass spectrometry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Except for 1 patient who developed mild muscle hypotonia, all patients
      remain asymptomatic at ages ranging from 3 to 14 months of age.
    explanation: >-
      One of eight screen-detected infants had mild hypotonia during short follow-up.
- name: Failure to thrive
  description: >-
    Failure to thrive appears in reviews of symptom-ascertained reports, but no
    feature-specific denominator or causal evidence is available.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:30730842
    reference_title: >-
      Clinical, biochemical, and molecular spectrum of short/branched-chain
      acyl-CoA dehydrogenase deficiency: two new cases and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical onset occurs in newborns or later in life with seizures,
      developmental delay, hypotonia, and failure to thrive.
    explanation: >-
      The review documents a reported association, not attributable frequency.
- name: Microcephaly
  description: >-
    Microcephaly has been reported in a symptomatic child who also had evidence
    of a primary neuronal migration defect; causality from SBCADD is uncertain.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysmorphic features including microcephaly (head circumference 46.5 cm; <3)
    explanation: >-
      The symptomatic child was directly documented to have microcephaly.
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition the symptomatic patient had findings suggestive of a primary
      neuronal migration defect.
    explanation: >-
      The alternative neurologic explanation argues against causal attribution.
- name: Autism
  description: >-
    Autism has co-occurred with biochemical or molecular SBCADD in isolated
    individuals. Published cohorts explicitly state that causation is unestablished.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient was reported to have autism and mental retardation, but
      causation could not be established
    explanation: >-
      The full-text cohort explicitly rejects a causal inference from co-occurrence.
- name: Athetoid cerebral palsy
  description: >-
    Athetoid cerebral palsy was reported in one early patient; its causal
    relationship to SBCADD remains uncertain.
  evidence:
  - reference: PMID:12837870
    reference_title: >-
      Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in
      the Hmong population by newborn screening using tandem mass spectrometry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient developed athetoid cerebral palsy, and another had severe
      motor developmental delay with muscle atrophy.
    explanation: >-
      The early report establishes co-occurrence, not causal attribution.
- name: Skeletal muscle atrophy
  description: >-
    Skeletal muscle atrophy accompanied severe motor delay in one early case;
    its relationship to SBCADD remains uncertain.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:12837870
    reference_title: >-
      Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in
      the Hmong population by newborn screening using tandem mass spectrometry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient developed athetoid cerebral palsy, and another had severe
      motor developmental delay with muscle atrophy.
    explanation: >-
      A single co-occurrence supports retaining the association with PARTIAL evidence.
- name: Metabolic acidosis
  description: >-
    Acute metabolic acidosis occurred in the first symptom-ascertained patient.
    Later screen-detected cohorts were overwhelmingly well, leaving attributable risk unresolved.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first reported patient presented with acute metabolic acidosis at
      three days of age
    explanation: >-
      The historical case supports co-occurrence but does not quantify attributable risk.
biochemical:
- name: C5-acylcarnitine signal in blood
  presence: INCREASED
  context: >-
    Elevated C5 is the usual newborn-screening signal. Standard tandem mass
    spectrometry does not resolve 2-methylbutyrylcarnitine from
    isovalerylcarnitine or pivaloylcarnitine, so it is a screening trigger
    rather than proof of SBCADD. C5 can be normal in genetically confirmed cases.
  readouts:
  - target: Impaired isoleucine catabolism via SBCAD loss-of-function
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      In a confirmed case, 2-methylbutyrylcarnitine contributes to the unresolved
      C5 signal and reports the upstream SBCAD-dependent isoleucine block.
    evidence:
    - reference: PMID:20547083
      reference_title: >-
        Characterization of new ACADSB gene sequence mutations and clinical
        implications in patients with 2-methylbutyrylglycinuria identified by
        newborn screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        isovaleryl- and 2-methylbutyrylcarnitine share the same mass/charge ratio
      explanation: >-
        The full-text discussion establishes why standard C5 requires confirmation.
  evidence:
  - reference: PMID:40598537
    reference_title: >-
      Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid
      in urine for diagnosing 2-methylbutyrylglycinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten individuals showed elevated C5 in blood, ranging from 0.32 to 1.64
      µmol/L; the remaining two individuals showed C5 levels within the normal
      reference range.
    explanation: >-
      C5 was within the local reference interval in two of 12 genotyped cases.
- name: 2-Methylbutyrylglycine (2-MBG) in urine
  presence: INCREASED
  context: >-
    Urinary 2-MBG is the characteristic acylglycine marker and is more specific
    than 2-EHA in the available diagnostic study. Excretion can vary, so
    diagnosis should integrate urine findings with molecular or enzyme confirmation.
  readouts:
  - target: Impaired isoleucine catabolism via SBCAD loss-of-function
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Urinary 2-MBG reports accumulation and glycine conjugation of
      2-methylbutyryl-CoA-derived material upstream of the SBCAD block.
    evidence:
    - reference: PMID:15615815
      reference_title: >-
        2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
        dehydrogenase deficiency: application to diagnosis and implications for
        the R-pathway of isoleucine oxidation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Isolated excretion of 2-methylbutyrylglycine (2-MBG) is the hallmark of
        short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD)
      explanation: >-
        This links the urinary conjugate to the proximal isoleucine-pathway defect.
  evidence:
  - reference: PMID:40598537
    reference_title: >-
      Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid
      in urine for diagnosing 2-methylbutyrylglycinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both markers showed 100% diagnostic sensitivity, and 2-MBG showed
      slightly higher specificity than 2-EHA
    explanation: >-
      All 12 genotyped cases in this retrospective study had detectable 2-MBG,
      but the small selected sample limits generalization.
- name: 2-Ethylhydracrylic acid (2-EHA) in urine
  presence: INCREASED
  context: >-
    Increased urinary 2-EHA is a readout of the minor R-pathway and can be
    easier to detect than an acylglycine peak. It is not specific to SBCADD and
    must be combined with 2-MBG, the acylcarnitine pattern, and confirmation.
  readouts:
  - target: Metabolic rerouting via the R-pathway of isoleucine oxidation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Urinary 2-EHA reports R-pathway flux associated with interruption or
      overflow of the predominant S-pathway.
    evidence:
    - reference: PMID:15615815
      reference_title: >-
        2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA
        dehydrogenase deficiency: application to diagnosis and implications for
        the R-pathway of isoleucine oxidation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Approximately 40-46% of total 2-methylbutyric acid conjugates were in
        the form of the R-isomer, indicating significant metabolism via the R-pathway.
      explanation: >-
        Chiral analysis in four patients directly supports R-pathway metabolism.
  evidence:
  - reference: PMID:40598537
    reference_title: >-
      Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid
      in urine for diagnosing 2-methylbutyrylglycinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it should be used as a diagnostic marker only in conjunction with other
      markers and clinical factors.
    explanation: >-
      The diagnostic study limits 2-EHA to a combined-marker role.
genetic:
- name: ACADSB pathogenic variants
  gene_term:
    preferred_term: ACADSB
    term:
      id: hgnc:91
      label: ACADSB
  association: Pathogenic Variants
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:12837870
      reference_title: >-
        Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in
        the Hmong population by newborn screening using tandem mass spectrometry.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        2-methylbutyryl-CoA dehydrogenase deficiency, also known as
        short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency, is a
        recently described autosomal recessive disorder of L-isoleucine metabolism.
      explanation: Directly states autosomal recessive inheritance.
  variants:
  - name: c.1165A>G (exon 10 skipping), Hmong founder variant
    description: >-
      c.1165A>G causes exon 10 skipping and is a founder variant in the Hmong
      population. In random Wisconsin Hmong newborn cards, 1.3% were homozygous
      and 21.8% heterozygous. The variant is enriched in Miao and Dong groups in
      China, but those data do not prove a separate founder event.
    evidence:
    - reference: PMID:12837870
      reference_title: >-
        Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in
        the Hmong population by newborn screening using tandem mass spectrometry.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Molecular genetic analysis performed for 3 of these patients revealed
        that all are homozygous for an 1165A>G mutation that causes skipping of
        exon 10 of the SBCAD gene.
      explanation: Directly supports the exon-skipping effect.
    - reference: PMID:23712021
      reference_title: >-
        Prevalence and mutation analysis of short/branched chain acyl-CoA
        dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This corresponds to a prevalence in this ethnic group of being
        homozygous for the mutation of 1.3% (95% confidence interval 0.8-2.2%)
        and of being heterozygous for the mutation of 21.8% (95% confidence
        interval 19.4-24.3%)
      explanation: >-
        Random newborn-card genotyping supplies the Hmong homozygote and carrier estimates.
    - reference: PMID:38784038
      reference_title: >-
        206,977 newborn screening results reveal the ethnic differences in the
        spectrum of inborn errors of metabolism in Huaihua, China.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        NM_001609.4:c.1165A>G in the ACADSB gene for Miao and Dong ethnic groups
      explanation: >-
        The cohort identifies ethnic enrichment but not an independent founder event.
  - name: c.303+3A>G, Somali/Eritrean population-enriched splice variant
    description: >-
      The intron 3 c.303+3A>G splice-region variant was observed homozygously in
      a Somali child and in two previously reported people of Somali and
      Eritrean origin. This small case series suggests population enrichment but
      does not establish a founder effect or penetrance for neurologic findings.
    evidence:
    - reference: PMID:17883863
      reference_title: >-
        2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and
        mental retardation: a case report.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: >-
        The report supports recurrence of c.303+3A>G in people of Somali and
        Eritrean origin while leaving the population frequency uncertain.
  - name: Diverse ACADSB loss-of-function and missense variants
    description: >-
      Nonsense, splice, frameshift, and missense variants occur outside the
      Hmong founder background. Expression studies of selected missense alleles
      demonstrated inactive or unstable SBCAD protein; genotype-phenotype
      correlations remain unresolved.
    evidence:
    - reference: PMID:20547083
      reference_title: >-
        Characterization of new ACADSB gene sequence mutations and clinical
        implications in patients with 2-methylbutyrylglycinuria identified by
        newborn screening.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Escherichia coli expression studies revealed that the missense mutations
        identified lead to inactivation or instability of the mutant SBCAD enzymes.
      explanation: >-
        Functional expression assays support loss of function for selected alleles.
  features: >-
    Biallelic pathogenic ACADSB variants reduce the activity or stability of the
    mitochondrial short/branched-chain acyl-CoA dehydrogenase. The gene-disease
    relationship is definitive, but variant class does not currently predict
    whether an individual will have attributable clinical symptoms.
  evidence:
  - reference: CGGV:assertion_8bfa3857-c96c-40ac-b4c1-2cf04fd4eb4f-2019-03-22T160000.000Z
    reference_title: >-
      ACADSB / 2-methylbutyryl-CoA dehydrogenase deficiency (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ACADSB | HGNC:91 | 2-methylbutyryl-CoA dehydrogenase deficiency |
      MONDO:0012392 | AR | Definitive
    explanation: >-
      ClinGen classifies the autosomal-recessive gene-disease relationship as definitive.
treatments:
- name: Carnitine supplementation
  description: >-
    L-carnitine has been used or proposed to support acyl-group conjugation. A
    two-patient report used
    100 mg/kg/day, and a small longitudinal cohort observed biochemical changes,
    but no controlled evidence shows clinical benefit and routine treatment of
    clinically well individuals is not established.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: (R)-carnitine
      term:
        id: CHEBI:16347
        label: (R)-carnitine
  evidence:
  - reference: PMID:30730842
    reference_title: >-
      Clinical, biochemical, and molecular spectrum of short/branched-chain
      acyl-CoA dehydrogenase deficiency: two new cases and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Longitudinal biochemical monitoring of the two patients while on treatment
      with carnitine (100 mg/kg/day) was provided.
    explanation: >-
      This documents use in two cases, not an evidence-based dose range or efficacy.
  - reference: PMID:36147814
    reference_title: >-
      Long-term monitoring for short/branched-chain acyl-CoA dehydrogenase
      deficiency: A single-center 4-year experience and open issues.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the effects of proposed treatments remain uncertain as follow-data are lacking.
    explanation: >-
      The longitudinal study explicitly states that treatment effects remain uncertain.
- name: Precautionary fasting avoidance and illness plan
  description: >-
    Avoiding prolonged fasting and providing an illness or emergency plan have
    been proposed because isolated decompensations occurred during catabolic
    stress. This is a precaution based on uncertain risk, not a strategy with
    demonstrated outcome benefit in SBCADD.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Possible catabolic-stress susceptibility
    treatment_effect: MODULATES
    description: >-
      The plan is intended to reduce catabolic stress if susceptibility is real;
      both the mechanism and treatment benefit remain unproven.
    evidence:
    - reference: PMID:30730842
      reference_title: >-
        Clinical, biochemical, and molecular spectrum of short/branched-chain
        acyl-CoA dehydrogenase deficiency: two new cases and review of literature.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Providing an emergency protocol for the management of acute catabolic
        episodes seems reasonable in asymptomatic patients with SBCAD deficiency.
      explanation: >-
        “Seems reasonable” is precautionary opinion rather than measured efficacy.
  evidence:
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it would seem more prudent to continue a normal diet in these infants but
      also have the family maintain some level of vigilance during intercurrent illnesses.
    explanation: >-
      The cohort authors advise illness vigilance while emphasizing uncertainty.
- name: Dietary management
  description: >-
    Routine protein restriction for an asymptomatic person is not supported by
    outcome evidence. Early screen-detected infants received presymptomatic
    dietary treatment, but efficacy was explicitly unestablished; one autism
    case had no measurable benefit from a five-month low-protein trial.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Impaired isoleucine catabolism via SBCAD loss-of-function
    treatment_effect: MODULATES
    description: >-
      Protein or isoleucine restriction could reduce precursor input, but no
      clinical benefit has been demonstrated.
    evidence:
    - reference: PMID:12837870
      reference_title: >-
        Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in
        the Hmong population by newborn screening using tandem mass spectrometry.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The continued efficacy of long-term dietary therapy instituted
        presymptomatically remains to be established.
      explanation: The early treated cohort could not establish efficacy.
  evidence:
  - reference: PMID:17883863
    reference_title: >-
      2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and
      mental retardation: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No beneficial effect was detected after 5 months with a low protein diet.
    explanation: >-
      A single case found no short-term benefit and cannot resolve other outcomes.
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      disruptive dietary manipulations for infants identified by newborn
      screening are of questionable indication.
    explanation: >-
      The untreated cohort questions routine restrictive diets in clinically well infants.
- name: Valproate avoidance (theoretical precaution)
  description: >-
    Valproyl-CoA competitively inhibits purified human SBCAD and is also an
    SBCAD substrate in vitro. Some reviews therefore advise avoidance, but no
    SBCADD-specific clinical evidence shows valproate-induced decompensation;
    medication decisions should be individualized with specialists.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:21430231
    reference_title: >-
      Role of isovaleryl-CoA dehydrogenase and short branched-chain acyl-CoA
      dehydrogenase in the metabolism of valproic acid: implications for the
      branched-chain amino acid oxidation pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      valproyl-CoA did inhibit SBCAD activity by a purely competitive mechanism
      with a K(i) of 249 ± 29 μM.
    explanation: >-
      Purified-enzyme experiments support the theoretical biochemical precaution.
  - reference: PMID:30730842
    reference_title: >-
      Clinical, biochemical, and molecular spectrum of short/branched-chain
      acyl-CoA dehydrogenase deficiency: two new cases and review of literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carnitine supplementation and valproate avoidance appear to be indicated.
    explanation: >-
      This is a review recommendation without SBCADD-specific clinical outcome data.
- name: Newborn screening via tandem mass spectrometry
  description: >-
    Expanded newborn screening can detect an elevated unresolved C5 signal and
    thereby incidentally identify SBCADD while screening for serious isovaleric
    acidemia. Every abnormal C5 result requires prompt confirmation; the cutoff
    can miss some ACADSB homozygotes.
  action_category: SCREENING
  treatment_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  evidence:
  - reference: PMID:12837870
    reference_title: >-
      Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in
      the Hmong population by newborn screening using tandem mass spectrometry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases suggest that SBCAD deficiency is another inborn error of
      metabolism detectable by newborn screening using tandem mass spectrometry.
    explanation: Establishes detectability by tandem mass spectrometry.
  - reference: PMID:23712021
    reference_title: >-
      Prevalence and mutation analysis of short/branched chain acyl-CoA
      dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Detection of homozygous individuals who were not identified on newborn
      screening suggests that the C5 screening cut-off would need to be as low
      as 0.20μmol/L to detect all infants homozygous for the ACADSB c.1165 A>G mutation.
    explanation: >-
      Genotype ascertainment demonstrates imperfect sensitivity of the C5 cutoff.
- name: Genetic counseling
  description: >-
    Counseling should explain autosomal-recessive inheritance, a 25% recurrence
    risk when both parents carry a pathogenic variant, familial testing options,
    the high c.1165A>G carrier frequency in Hmong people, and uncertain penetrance.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:23712021
    reference_title: >-
      Prevalence and mutation analysis of short/branched chain acyl-CoA
      dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      being heterozygous for the mutation of 21.8% (95% confidence interval
      19.4-24.3%)
    explanation: >-
      The high Hmong carrier frequency makes population-aware counseling relevant.
- name: Longitudinal clinical follow-up
  description: >-
    Periodic clinical assessment is reasonable to document development,
    intercurrent illnesses, and treatment exposure because natural history is
    incompletely defined. It should not be presented as surveillance for
    established late neurologic complications, which have not been causally linked.
  action_category: MONITORING
  treatment_term:
    preferred_term: clinical monitoring
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:31555323
    reference_title: >-
      Biochemical, Clinical, and Genetic Characteristics of Short/Branched Chain
      Acyl-CoA Dehydrogenase Deficiency in Chinese Patients by Newborn Screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      longitudinal follow-up may be helpful to further define the natural history of SBCADD.
    explanation: >-
      Follow-up is framed as natural-history data collection under uncertainty.
diagnosis:
- name: Follow-up of an elevated C5 newborn screen
  description: >-
    An elevated C5 result requires prompt follow-up because standard tandem mass
    spectrometry cannot distinguish 2-methylbutyrylcarnitine from
    isovalerylcarnitine, and pivaloylcarnitine can cause an analytic false
    positive. C5 magnitude and ratios may inform triage but do not establish SBCADD.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    An unresolved elevated C5 signal prompts evaluation for SBCADD, isovaleric
    acidemia, and pivalate-related interference.
  evidence:
  - reference: PMID:23499962
    reference_title: UPLC-MS/MS analysis of C5-acylcarnitines in dried blood spots.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      further differentiation of C5-acylcarnitines in order to separate
      different metabolic disorders and to detect interferents like pivalic acid
      originating from antibiotics.
    explanation: >-
      The study establishes both C5-isomer resolution and pivalate interference.
- name: Urine organic-acid and acylglycine analysis
  description: >-
    Urinary 2-MBG strongly supports SBCADD; 2-EHA is a sensitive but less
    specific adjunct. Normal or fluctuating values do not alone exclude the
    condition, and the whole pattern distinguishes other isoleucine disorders.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    Increased 2-MBG, often with 2-EHA and without isovalerylglycine, supports SBCADD.
  evidence:
  - reference: PMID:40598537
    reference_title: >-
      Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid
      in urine for diagnosing 2-methylbutyrylglycinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The urinary markers 2-MBG and 2-EHA show similar sensitivity for
      diagnosing 2-methylbutyrylglycinuria, but the lower specificity of 2-EHA
      and the fact that it can be elevated in several other congenital metabolic disorders
    explanation: >-
      The 12-case study supports both markers while directly limiting 2-EHA.
- name: ACADSB molecular genetic testing
  description: >-
    Identification of biallelic pathogenic ACADSB variants confirms the
    molecular diagnosis in a person with a concordant biochemical profile.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: >-
    Biallelic pathogenic or likely pathogenic ACADSB variants confirm the
    molecular diagnosis.
  evidence:
  - reference: PMID:40598537
    reference_title: >-
      Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid
      in urine for diagnosing 2-methylbutyrylglycinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      12 individuals diagnosed with 2-methylbutyrylglycinuria based on ACADSB genotyping
    explanation: >-
      The diagnostic-marker study used ACADSB genotyping to define its case group.
- name: SBCAD enzyme activity testing
  description: >-
    When molecular results are incomplete or uncertain, direct SBCAD activity
    in patient fibroblasts can demonstrate the functional biochemical defect.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    Deficient activity toward 2-methylbutyryl-CoA supports functional confirmation.
  evidence:
  - reference: PMID:11013134
    reference_title: >-
      Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA
      dehydrogenase deficiency: identification of a new enzyme defect,
      resolution of its molecular basis, and evidence for distinct acyl-CoA
      dehydrogenases in isoleucine and valine metabolism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Enzyme assay of the patient's fibroblasts, using 2-methylbutyryl-CoA as
      substrate, confirmed the defect.
    explanation: Directly demonstrates functional confirmation.
differential_diagnoses:
- name: Isovaleric acidemia
  description: >-
    Isovaleric acidemia is the urgent disease differential for elevated C5
    because isovalerylcarnitine and 2-methylbutyrylcarnitine are isobaric.
  distinguishing_features:
  - Isovalerylglycine and 3-hydroxyisovaleric acid favor isovaleric acidemia; 2-MBG favors SBCADD.
  - Pathogenic IVD variants support isovaleric acidemia; ACADSB findings support SBCADD.
  disease_term:
    preferred_term: isovaleric acidemia
    term:
      id: MONDO:0009475
      label: isovaleric acidemia
  evidence:
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it is crucial to differentiate it from isovaleric acidemia as isovaleryl-
      and 2-methylbutyrylcarnitine share the same mass/charge ratio
    explanation: Identifies the clinically important isobaric differential.
- name: Pivaloylcarnitine interference
  description: >-
    Maternal or infant exposure to pivalate-containing products can produce a C5
    signal without SBCADD or isovaleric acidemia.
  distinguishing_features:
  - Chromatographic second-tier testing identifies pivaloylcarnitine as the C5 isomer.
  - Urinary disease-specific metabolites and confirmatory genotypes are absent.
  evidence:
  - reference: PMID:23499962
    reference_title: UPLC-MS/MS analysis of C5-acylcarnitines in dried blood spots.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pivaloylcarnitine was identified in 43 samples, isovalerylcarnitine was
      found in two samples.
    explanation: >-
      Pivaloylcarnitine accounted for most retested C5 elevations in this population.
- name: Other disorders with 2-EHA aciduria
  description: >-
    2-EHA is not specific to SBCADD and can be elevated in distal isoleucine
    defects and other organic acid disorders, including beta-ketothiolase
    deficiency, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency,
    methylmalonic acidemia, ethylmalonic encephalopathy, and Barth syndrome.
  distinguishing_features:
  - A complete urine organic-acid profile reveals disorder-specific companion metabolites.
  - Molecular or enzyme testing should follow the pattern rather than 2-EHA alone.
  evidence:
  - reference: PMID:40598537
    reference_title: >-
      Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid
      in urine for diagnosing 2-methylbutyrylglycinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it should be used as a diagnostic marker only in conjunction with other
      markers and clinical factors.
    explanation: >-
      The diagnostic study warns that multiple disorders can produce 2-EHA.
  - reference: PMID:20547083
    reference_title: >-
      Characterization of new ACADSB gene sequence mutations and clinical
      implications in patients with 2-methylbutyrylglycinuria identified by
      newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three other disorders also accumulate 2-EHA in blood: β-ketothiolase,
      ethylmalonic encephalopathy, and Barth syndrome, though other metabolites
      distinguish these disorders from SBCAD deficiency
    explanation: >-
      This supports the named additional differentials and the need to interpret
      their full metabolite patterns.
discussions:
- discussion_id: openq_sbcadd_clinical_significance
  prompt: >-
    Are neurologic findings and catabolic decompensation causally attributable
    to ACADSB deficiency, and what is the lifetime penetrance of clinically
    meaningful disease among screen-detected individuals?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Largely asymptomatic course
  - phenotypes#Developmental delay
  - phenotypes#Seizures
  - phenotypes#Autism
  - phenotypes#Metabolic acidosis
  - pathophysiology#Possible catabolic-stress susceptibility
  rationale: >-
    Symptom-ascertained reports describe neurologic disease and occasional
    decompensation, whereas newborn-screening cohorts are overwhelmingly well
    and include symptomatic people sharing genotypes with asymptomatic people.
    Authors explicitly question causation, and follow-up is too short and
    heterogeneous to estimate lifetime penetrance.
  proposed_experiments:
  - experiment_id: exp_sbcadd_natural_history_registry
    name: Genotype-first prospective natural-history registry
    description: >-
      Enroll newborn-screened and genotype-ascertained individuals irrespective
      of symptoms; collect uniform developmental, neurologic, illness,
      biochemical, genomic, and treatment data with population comparators.
  evidence:
  - reference: PMID:31555323
    reference_title: >-
      Biochemical, Clinical, and Genetic Characteristics of Short/Branched Chain
      Acyl-CoA Dehydrogenase Deficiency in Chinese Patients by Newborn Screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the association between SBCADD and the presence of symptoms has not yet been established.
    explanation: The cohort states the central causal uncertainty directly.
  - reference: PMID:41722717
    reference_title: >-
      Outlook on ACADSB variants shaping metabolomic patterns and clinical
      outcomes - experience from a Central European country.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings support SBCADD as a primarily biochemical phenotype with a
      largely benign course
    explanation: The newest series reinforces the biochemical-disease distinction.
  posed_date: "2026-07-14T00:00:00Z"
- discussion_id: gap_sbcadd_management_effectiveness
  prompt: >-
    Do carnitine, fasting or illness protocols, dietary restriction, or
    valproate avoidance improve patient-important outcomes in SBCADD?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Carnitine supplementation
  - treatments#Precautionary fasting avoidance and illness plan
  - treatments#Dietary management
  - treatments#Valproate avoidance (theoretical precaution)
  rationale: >-
    Studies are uncontrolled, combine interventions, and mainly report
    metabolite values in asymptomatic children. Recommendations are based on
    plausibility and precaution rather than demonstrated clinical prevention.
  proposed_experiments:
  - experiment_id: exp_sbcadd_management_comparison
    name: Prospective pragmatic management comparison
    description: >-
      Within a multicenter natural-history network, compare prespecified
      strategies using clinical outcomes, treatment burden, adverse effects,
      free carnitine, and metabolite trajectories, adjusting for indication.
  evidence:
  - reference: PMID:36147814
    reference_title: >-
      Long-term monitoring for short/branched-chain acyl-CoA dehydrogenase
      deficiency: A single-center 4-year experience and open issues.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the effects of proposed treatments remain uncertain as follow-data are lacking.
    explanation: >-
      The longitudinal cohort explicitly identifies effectiveness as unresolved.
  - reference: PMID:17883863
    reference_title: >-
      2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and
      mental retardation: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No beneficial effect was detected after 5 months with a low protein diet.
    explanation: >-
      The only cited within-person diet trial was negative and too small to resolve efficacy.
  posed_date: "2026-07-14T00:00:00Z"
notes: >-
  Manual evidence review completed 2026-07-14. Every reference linked by the
  prior entry was checked against its local cache; duplicate DOI/PMID records
  and unrelated mechanistic papers were removed, and newer primary studies were
  added through the repository reference-fetch workflow. The evidence supports
  a definitive ACADSB biochemical defect but does not establish that the rare
  reported neurologic findings are attributable to it. Follow-up in most
  newborn-screening cohorts is limited to childhood, so “largely benign” should
  not be read as proof of zero lifetime risk. The Hmong c.1165A>G founder effect
  is well supported; enrichment in Miao and Dong groups is not labeled as a
  separate founder effect. Carnitine, restrictive diet, illness protocols, and
  valproate avoidance lack SBCADD-specific clinical outcome evidence. The
  2-MBG oxidative-stress branch is restricted to exogenous-metabolite
  experiments in rat cortical preparations and C6 cells and is not connected to
  human phenotypes.
references:
- reference: CGGV:assertion_8bfa3857-c96c-40ac-b4c1-2cf04fd4eb4f-2019-03-22T160000.000Z
  title: ACADSB / 2-methylbutyryl-CoA dehydrogenase deficiency (Definitive)
- reference: PMID:10832746
  title: >-
    2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of
    L-isoleucine metabolism.
- reference: PMID:11013134
  title: >-
    Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA
    dehydrogenase deficiency: identification of a new enzyme defect, resolution
    of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in
    isoleucine and valine metabolism.
- reference: PMID:12837870
  title: >-
    Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in the
    Hmong population by newborn screening using tandem mass spectrometry.
- reference: PMID:15615815
  title: >-
    2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA dehydrogenase
    deficiency: application to diagnosis and implications for the R-pathway of
    isoleucine oxidation.
- reference: PMID:17883863
  title: >-
    2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and
    mental retardation: a case report.
- reference: PMID:20547083
  title: >-
    Characterization of new ACADSB gene sequence mutations and clinical
    implications in patients with 2-methylbutyrylglycinuria identified by
    newborn screening.
- reference: PMID:21430231
  title: >-
    Role of isovaleryl-CoA dehydrogenase and short branched-chain acyl-CoA
    dehydrogenase in the metabolism of valproic acid: implications for the
    branched-chain amino acid oxidation pathway.
- reference: PMID:22967964
  title: >-
    2-Methylbutyrylglycine induces lipid oxidative damage and decreases the
    antioxidant defenses in rat brain.
- reference: PMID:23499962
  title: UPLC-MS/MS analysis of C5-acylcarnitines in dried blood spots.
- reference: PMID:23712021
  title: >-
    Prevalence and mutation analysis of short/branched chain acyl-CoA
    dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin.
- reference: PMID:30730842
  title: >-
    Clinical, biochemical, and molecular spectrum of short/branched-chain
    acyl-CoA dehydrogenase deficiency: two new cases and review of literature.
- reference: PMID:31555323
  title: >-
    Biochemical, Clinical, and Genetic Characteristics of Short/Branched Chain
    Acyl-CoA Dehydrogenase Deficiency in Chinese Patients by Newborn Screening.
- reference: PMID:36147814
  title: >-
    Long-term monitoring for short/branched-chain acyl-CoA dehydrogenase
    deficiency: A single-center 4-year experience and open issues.
- reference: PMID:36709932
  title: >-
    [Analysis of clinical features, biochemical indices and genetic variants
    among children with Short/branched-chain acyl-CoA dehydrogenase deficiency
    detected by neonatal screening].
- reference: PMID:38784038
  title: >-
    206,977 newborn screening results reveal the ethnic differences in the
    spectrum of inborn errors of metabolism in Huaihua, China.
- reference: PMID:40598537
  title: >-
    Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid
    in urine for diagnosing 2-methylbutyrylglycinuria.
- reference: PMID:40835664
  title: >-
    Large-scale newborn screening for organic acidemias in Quanzhou, China: a
    10-year retrospective observational study.
- reference: PMID:41722717
  title: >-
    Outlook on ACADSB variants shaping metabolomic patterns and clinical
    outcomes - experience from a Central European country.

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