Multiple Acyl-CoA Dehydrogenase Deficiency

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Subtypes

3

MADD type I (neonatal with congenital anomalies)

Severe neonatal onset with congenital anomalies such as renal cystic dysplasia and facial dysmorphism, associated with severe metabolic acidosis and high mortality.

MADD type II (neonatal without congenital anomalies)

Severe neonatal onset without structural anomalies, presenting with metabolic acidosis, hypoglycemia, and multiorgan failure.

MADD type III (late-onset, riboflavin-responsive)

Later onset form presenting with proximal muscle weakness, exercise intolerance, and episodic metabolic crises; frequently responsive to riboflavin supplementation. Most commonly due to ETFDH mutations.

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Pathophysiology

8

ETF/ETFDH molecular function deficiency

Biallelic pathogenic variants in ETFA, ETFB, or ETFDH reduce catalytic electron-transfer capacity of the ETF system.

ETFA link ETFB link ETFDH link

mitochondrion link

Downstream

Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone Loss of ETF system activity blocks electron flow into the CoQ pool.

Oxidative stress and apoptosis in neuronal cells ETFDH-mutant neuronal cell models show excessive apoptosis and neurite outgrowth defects through mitochondrial apoptosis signaling.

Show evidence (1 reference)

PMID:17584774 SUPPORT Human Clinical

"Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO)."

Supports ETF/ETFDH molecular dysfunction as the initiating defect in MADD.

Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone

Disrupted electron flow from multiple acyl-CoA dehydrogenases through the ETF/ETFDH system to the mitochondrial coenzyme Q pool blocks fatty acid beta-oxidation, branched-chain amino acid catabolism, and choline oxidation, causing accumulation of metabolic intermediates and energy deficit.

skeletal muscle fiber link hepatocyte link

fatty acid beta-oxidation link ↓ DECREASED electron transport chain link ↓ DECREASED amino acid catabolic process link ↓ DECREASED choline catabolic process link ↓ DECREASED

mitochondrion link

Downstream

ETFDH-driven metabolon disruption and OXPHOS dysfunction ETFDH deficiency disrupts the ETFDH-CIII-COQ2 organization that routes lipid-derived electrons into the respiratory chain.

Systemic metabolic decompensation Impaired mitochondrial fuel oxidation limits fasting energy production and ketogenesis, producing acute metabolic crises.

Acylcarnitines (broad elevation) Blocked ETF/ETFDH-dependent oxidation produces the broad acylcarnitine abnormalities used to diagnose MADD.

Glutaric acid Impaired ETF/ETF:QO electron transfer produces the glutaric aciduria biochemical hallmark of MADD.

Lipid storage myopathy Impaired fatty acid oxidation in skeletal muscle causes lipid storage myopathy.

Show evidence (1 reference)

PMID:17584774 SUPPORT Human Clinical

"Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO)."

Supports downstream multi-pathway catabolic disruption from ETF system failure.

Systemic metabolic decompensation

Catabolic stress and impaired mitochondrial fatty acid oxidation produce a systemic energy crisis, particularly in liver, heart, and brain. Reduced ketone generation, impaired fuel availability, and accumulated organic acids manifest as metabolic acidosis, hypoketotic hypoglycemia, hyperammonemia, encephalopathy, and cardiomyopathy in severe presentations.

hepatocyte link cardiac muscle cell link

generation of precursor metabolites and energy link ↓ DECREASED

liver link heart link

Downstream

Metabolic acidosis Accumulated organic acids during decompensation produce severe metabolic acidosis.

Hypoketotic hypoglycemia Impaired fatty acid oxidation limits hepatic ketogenesis and fasting energy production, causing hypoketotic hypoglycemia.

Hyperammonemia Severe decompensation can include hyperammonemia, which contributes to acute neurologic deterioration.

Encephalopathy Acute energy failure and hyperammonemia can progress to encephalopathy during metabolic crisis.

Cardiomyopathy Mitochondrial fuel oxidation failure can affect myocardium and contribute to cardiomyopathy in severe MADD.

Respiratory insufficiency Severe metabolic and neuromuscular involvement can include respiratory dysfunction requiring ventilatory support.

Vomiting Metabolic decompensation may include recurrent or cyclical vomiting before overt neuromuscular presentation.

Hepatomegaly Severe infantile MADD can involve hepatic enlargement during systemic metabolic decompensation.

Muscular hypotonia Severe infantile energy failure can manifest as marked muscular hypotonia.

Show evidence (1 reference)

PMID:37217231 SUPPORT Human Clinical

"Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations."

Supports the acute metabolic crisis pattern in severe MADD.

FLAD1-related FAD synthesis impairment

FLAD1 variants impair flavin adenine dinucleotide synthesis and can produce a riboflavin-responsive MADD-like lipid storage myopathy with biochemical and fatty-acid metabolism changes overlapping ETFDH-related MADD.

FLAD1 link

FAD biosynthetic process link ↓ DECREASED fatty acid beta-oxidation link ↓ DECREASED

mitochondrion link

Downstream

Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone Reduced FAD synthesis limits FAD-dependent dehydrogenase function and phenocopies the core MADD electron-transfer defect.

Lipid storage myopathy FLAD1-RRMADD and ETFDH-RRMADD both show lipid storage myopathy in muscle.

Show evidence (1 reference)

PMID:38228875 SUPPORT Human Clinical

"We described here a case with riboflavin responsive LSM and MADD resulting from FLAD1 gene variants"

Supports FLAD1 variation as a riboflavin-responsive MADD-like cause.

ETFDH-driven metabolon disruption and OXPHOS dysfunction

Recent work demonstrates that ETFDH participates in a metabolon comprising ETFDH, respiratory chain complex III (CIII), and the CoQ biosynthesis regulator COQ2. This complex maintains coenzyme Q homeostasis, minimizes reduced-Q reductive stress, and supports OXPHOS efficiency. Loss of ETFDH causes CIII dysfunction, pathological QH2 accumulation, reductive stress, and increased ROS.

skeletal muscle fiber link

oxidative phosphorylation link response to oxidative stress link

mitochondrial inner membrane link

Downstream

GDF-15 Mitochondrial stress in riboflavin-responsive MADD is reflected by increased GDF-15 expression in muscle and serum.

Show evidence (1 reference)

PMID:38243131 SUPPORT Model Organism

"We identify a complex (comprising ETFDH, CIII and the Q-biosynthesis regulator COQ2) that directs electrons from lipid substrates to the respiratory chain, thereby reducing electron leaks and reactive oxygen species production."

Identifies the ETFDH-CIII-COQ2 metabolon supporting OXPHOS efficiency.

Oxidative stress and apoptosis in neuronal cells

ETFDH mutations lead to oxidative stress, activation of the BCL-2 family/MOMP apoptotic signaling pathway, and neurite outgrowth defects. In cellular models, ETFDH mutations cause increased pro-apoptotic markers including BAX, cytochrome c, caspase-9 and caspase-3, linking mitochondrial redox disturbance to neurodegeneration.

neuron link

intrinsic apoptotic signaling pathway link

mitochondrial outer membrane link

Downstream

Peripheral neuropathy Neurite outgrowth defects, axonal degeneration, and neuronal apoptosis provide a cellular mechanism for peripheral neuropathy in the MADD spectrum.

Show evidence (1 reference)

PMID:39455656 SUPPORT In Vitro

"Our cellular models of MADD exhibit neurite growth defects and excessive apoptosis."

Demonstrates apoptosis and neurite pathology in ETFDH mutation cellular models.

Sertraline-associated acquired MADD-like metabolic dysfunction

Sertraline exposure has been associated with an acquired late-onset MADD-like phenotype in patients without disease-causing MADD mutations, with muscle weakness, elevated creatine kinase, lipid storage myopathy, and elevated acylcarnitines. The mechanism remains emerging, but the clinical pattern links sertraline exposure to a reversible MADD-like metabolic state.

skeletal muscle fiber link

fatty acid beta-oxidation link ↓ DECREASED

skeletal muscle tissue link

Downstream

Lipid storage myopathy Sertraline-associated cases showed lipid storage myopathy on muscle biopsy.

Acylcarnitines (broad elevation) Sertraline-associated acquired MADD is marked by elevated acylcarnitines.

Elevated creatine kinase Sertraline-associated acquired MADD cases presented with elevated CK.

Show evidence (1 reference)

PMID:39092677 SUPPORT Human Clinical

"Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients."

Clinical cohort evidence supports a sertraline-associated acquired MADD-like metabolic mechanism.

Lipid storage myopathy

Defective fatty acid oxidation leads to pathological lipid droplet accumulation in skeletal muscle fibers, resulting in lipid storage myopathy. Late-onset MADD is the most common lipid storage myopathy.

skeletal muscle fiber link

lipid metabolic process link

skeletal muscle tissue link

Downstream

Proximal muscle weakness Lipid storage myopathy injures skeletal muscle and produces the proximal limb weakness typical of late-onset MADD.

Elevated creatine kinase Myopathic injury causes elevated serum creatine kinase.

Creatine kinase Skeletal muscle injury is reflected biochemically by increased serum creatine kinase.

Exercise intolerance Skeletal muscle energy failure and lipid storage myopathy reduce exercise capacity.

Myalgia Skeletal muscle lipid storage and energy failure can manifest as muscle pain in late-onset MADD.

Rhabdomyolysis Episodic skeletal muscle energy failure and myopathic injury can manifest as rhabdomyolysis.

Show evidence (2 references)

PMID:38365830 SUPPORT Human Clinical

"Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common lipid storage myopathy."

Establishes late-onset MADD as the most common lipid storage myopathy.

PMID:38951975 SUPPORT Human Clinical

"Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of fatty acid oxidation that causes lipid storage myopathy (LSM)."

Confirms MADD causes lipid storage myopathy in a clinical cohort.

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Pathograph

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Phenotypes

15

Cardiovascular 1

Cardiomyopathy OCCASIONAL Cardiomyopathy (HP:0001638)

Show evidence (1 reference)

PMID:37217231 SUPPORT Human Clinical

"The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death."

Cardiomyopathy is listed among variable MADD manifestations.

Digestive 2

Hepatomegaly OCCASIONAL Hepatomegaly (HP:0002240)

Show evidence (1 reference)

PMID:6862997 SUPPORT Human Clinical

"He had hepatomegaly and echocardiographically a non-obstructive cardiomyopathy."

This MADD infant case directly documents hepatomegaly.

Vomiting FREQUENT Vomiting (HP:0002013)

Show evidence (1 reference)

PMID:17584774 SUPPORT Human Clinical

"several had previously suffered cyclical vomiting."

Cyclical vomiting occurred as a prodromal symptom in MADD patients.

Metabolism 4

Metabolic acidosis VERY_FREQUENT Metabolic acidosis (HP:0001942)

Show evidence (1 reference)

PMID:37217231 SUPPORT Human Clinical

"Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations."

Metabolic acidosis is a major presenting feature in MADD.

Hypoketotic hypoglycemia FREQUENT Hypoketotic hypoglycemia (HP:0001985)

Show evidence (1 reference)

PMID:37217231 SUPPORT Human Clinical

"Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations."

Non-ketotic hypoglycemia is listed as a major presenting feature.

Elevated creatine kinase VERY_FREQUENT Elevated circulating creatine kinase concentration (HP:0003236)

Show evidence (1 reference)

PMID:38951975 SUPPORT Human Clinical

"All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography."

All patients in the Malaysian MADD cohort had elevated CK.

Hyperammonemia OCCASIONAL Hyperammonemia (HP:0001987)

Show evidence (1 reference)

PMID:37217231 SUPPORT Human Clinical

"Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations."

Hyperammonemia is a recognized acute presentation in MADD.

Musculoskeletal 3

Proximal muscle weakness VERY_FREQUENT Proximal muscle weakness (HP:0003701)

Show evidence (2 references)

PMID:38951975 SUPPORT Human Clinical

"All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography."

All 14 MADD patients in the Malaysian cohort showed proximal limb weakness.

PMID:37217231 SUPPORT Human Clinical

"The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death."

Myopathy is listed among the common clinical manifestations.

Rhabdomyolysis OCCASIONAL Rhabdomyolysis (HP:0003201)

Show evidence (1 reference)

PMID:39455656 SUPPORT Other

"Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts."

Rhabdomyolysis is recognized among the phenotypic spectrum of MADD.

Muscular hypotonia FREQUENT Hypotonia (HP:0001252)

Show evidence (1 reference)

PMID:6862997 SUPPORT Human Clinical

"Later on, development was retarded with a severe muscular hypotonia."

This MADD infant case directly documents severe muscular hypotonia.

Nervous System 2

Encephalopathy OCCASIONAL Encephalopathy (HP:0001298)

Show evidence (2 references)

PMID:17584774 SUPPORT Human Clinical

"All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms"

Encephalopathy was a presenting feature in the Olsen et al. MADD cohort.

PMID:37217231 SUPPORT Human Clinical

"This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation."

Case report of hyperammonemic encephalopathy as MADD presentation.

Peripheral neuropathy OCCASIONAL Peripheral neuropathy (HP:0009830)

Show evidence (1 reference)

PMID:39455656 SUPPORT Other

"Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts."

Peripheral neuropathy is part of the MADD phenotypic spectrum.

Respiratory 1

Respiratory insufficiency OCCASIONAL Respiratory insufficiency (HP:0002093)

Show evidence (2 references)

PMID:29502916 SUPPORT Other

"Respiratory dysfunction may be present."

Review evidence directly supports respiratory dysfunction in MADD.

PMID:37217231 SUPPORT Human Clinical

"This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation."

Case evidence supports ventilatory support during severe MADD decompensation.

Constitutional 2

Exercise intolerance FREQUENT Exercise intolerance (HP:0003546)

Show evidence (1 reference)

PMID:37217231 SUPPORT Human Clinical

"The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death."

Exercise intolerance is a recognized clinical manifestation of MADD.

Myalgia FREQUENT Myalgia (HP:0003326)

Show evidence (1 reference)

PMID:32550677 SUPPORT Other

"The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain"

GeneReviews identifies muscle pain as one of the most common type III MADD symptoms.

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Genetic Associations

7

ETFDH variants (most common cause)

Autosomal recessive

Show evidence (1 reference)

PMID:17584774 SUPPORT Human Clinical

"All patients had mutations in the gene for ETF:QO."

Landmark paper establishing ETFDH as a major cause of riboflavin-responsive MADD.

ETFA variants

Autosomal recessive

Show evidence (1 reference)

PMID:39273584 SUPPORT Human Clinical

"MADD is an autosomal recessive trait caused by biallelic mutations in the ETFA, ETFB, and ETFDH genes encoding the alpha and beta subunits of the electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase enzymes."

Supports ETFA mutations as one molecular cause of MADD.

ETFB variants

Autosomal recessive

Show evidence (1 reference)

PMID:39273584 SUPPORT Human Clinical

"MADD is an autosomal recessive trait caused by biallelic mutations in the ETFA, ETFB, and ETFDH genes encoding the alpha and beta subunits of the electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase enzymes."

Supports ETFB mutations as one molecular cause of MADD.

FLAD1 variants (MADD-like phenotype)

Autosomal recessive

Show evidence (1 reference)

PMID:38228875 SUPPORT Human Clinical

"Our data revealed that FLAD1-RRMADD (p.Arg530) has similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD except for muscle pathological features."

Comparative study demonstrating FLAD1 as a MADD-like disease gene.

ETFA (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_3d6848e7-6e9e-4545-9f97-69480face058-2018-05-22T160000.000Z SUPPORT Other

ClinGen classifies the ETFA-multiple acyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.

ETFB (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_d9a8d844-c82a-4258-bd48-10e2d977273e-2023-05-23T040000.000Z SUPPORT Other

ClinGen classifies the ETFB-multiple acyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.

ETFDH (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_062e336e-cfda-45f7-b509-cd44a5079034-2018-05-22T040000.000Z SUPPORT Other

ClinGen classifies the ETFDH-multiple acyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.

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Treatments

8

Riboflavin supplementation

Action: nutritional supplementation MAXO:0000106

Riboflavin (vitamin B2) is the cornerstone treatment for late-onset MADD. It increases FAD availability and may stabilize mutant ETFDH/ETF-QO protein folding. Doses of 100-400 mg/day produce dramatic improvement in most late-onset patients, with symptom resolution and CK normalization.

Mechanism Target:

MODULATES Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone — Riboflavin increases FAD availability and can improve riboflavin-responsive ETF:QO-dependent electron transfer.

MODULATES Lipid storage myopathy — Improved flavoprotein function reduces the downstream myopathic phenotype in riboflavin-responsive MADD.

Show evidence (3 references)

PMID:17584774 SUPPORT Human Clinical

"Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment."

Landmark demonstration of riboflavin responsiveness in MADD with ETFDH mutations.

PMID:38951975 SUPPORT Human Clinical

"All of the patients responded well to riboflavin therapy."

All 14 patients in the Malaysian cohort responded to riboflavin.

PMID:39092677 SUPPORT Human Clinical

"All 9 patients responded to riboflavin treatment with normalization of creatine kinase and muscle biopsy findings, and in 8 patients the clinical symptoms clearly improved."

Riboflavin effective in both genetic and sertraline-associated MADD.

Coenzyme Q10 supplementation

Action: nutritional supplementation MAXO:0000106

CoQ10 supplementation is used as adjunctive therapy in MADD. In cellular models, CoQ10 mitigates apoptosis and neurite outgrowth defects caused by ETFDH mutations.

Mechanism Target:

INHIBITS Oxidative stress and apoptosis in neuronal cells — Cellular model evidence shows CoQ10 mitigates ETFDH-mutant apoptosis signaling and neurite outgrowth defects.

Show evidence (2 references)

PMID:39455656 SUPPORT In Vitro

"Subsequent treatment of the mutant cells with coenzyme Q10 downregulated activated protein expression and mitigated neurite growth defects."

Demonstrates CoQ10 rescue of apoptosis and neurite defects in ETFDH mutant cells.

PMID:39950184 SUPPORT Human Clinical

"After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level."

CoQ10 used as part of successful combination therapy in late-onset MADD.

L-carnitine supplementation

Action: carnitine supplementation MAXO:0010006

L-carnitine supplementation addresses secondary carnitine depletion caused by increased acylcarnitine conjugation. It supports acyl group handling and excretion.

Mechanism Target:

MODULATES Systemic metabolic decompensation — L-carnitine supports conjugation and excretion of accumulated toxic acyl groups during MADD metabolic decompensation.

Show evidence (2 references)

PMID:29502916 SUPPORT Other

"Avoidance of fasting and conjugation of toxic metabolites with L-carnitine and glycine are indicated, and a low-fat diet may be helpful."

Review evidence supports L-carnitine for conjugation of toxic metabolites in MAD deficiency.

PMID:39950184 SUPPORT Human Clinical

"After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level."

Levocarnitine used as part of successful treatment regimen in late-onset MADD.

Dietary management and fasting avoidance

Action: dietary intervention MAXO:0000088

Dietary strategies focus on avoiding prolonged fasting and limiting fat/protein intake while ensuring adequate carbohydrate supply. During acute crises, IV dextrose is used to suppress catabolism.

Mechanism Target:

MODULATES Systemic metabolic decompensation — Fasting avoidance and adequate nutrition reduce catabolic stress that precipitates systemic decompensation.

Show evidence (2 references)

PMID:37217231 SUPPORT Human Clinical

"MADD is treatable with riboflavin and appropriate nutrition with a focus on prevention and early management of metabolic decompensation."

Appropriate nutrition and decompensation prevention are core management elements.

PMID:39950184 SUPPORT Human Clinical

"After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level."

Dietary intervention was part of the successful treatment approach.

Acute metabolic crisis management

Action: supportive care MAXO:0000950

Emergency management during metabolic crises includes IV dextrose infusion to suppress catabolism, correction of metabolic acidosis, and initiation of riboflavin therapy. Mechanical ventilation may be required for respiratory failure.

Mechanism Target:

MODULATES Systemic metabolic decompensation — Acute dextrose and supportive care suppress catabolism and stabilize complications during metabolic crisis.

Show evidence (2 references)

PMID:37217231 SUPPORT Human Clinical

"This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation."

Acute metabolic crisis in MADD required intubation and intensive supportive care.

PMID:32550677 SUPPORT Other

"Agents/circumstances to avoid: Inadequate caloric provision during stressors (including following vaccination); prolonged fasting; dehydration; high-fat, high-protein diet; volatile anesthetics and those that contain high doses of long-chain fatty acids; administration of intravenous intralipids..."

GeneReviews supports avoiding volatile anesthetics, long-chain-fat-containing agents, and IV intralipids in MADD crisis contexts.

Newborn screening

Action: disease screening MAXO:0000124

MADD is detectable by newborn screening programs via tandem mass spectrometry acylcarnitine profiling. Early detection enables pre-symptomatic treatment and improved outcomes.

Target Phenotypes: Metabolic acidosis ↗ Hypoketotic hypoglycemia ↗ Hyperammonemia ↗ Cardiomyopathy ↗

Show evidence (1 reference)

PMID:39273584 SUPPORT Human Clinical

"Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs."

TMS-based newborn screening can identify MADD cases.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling is important for affected families given the autosomal recessive inheritance pattern, carrier testing, and prenatal diagnosis options. Genotype-phenotype correlations can inform prognosis.

Show evidence (2 references)

PMID:38221620 SUPPORT Human Clinical

"The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population."

Genetic characterization supports genetic counseling and patient-specific management.

PMID:39273584 SUPPORT Human Clinical

"Despite significant advancements in sequencing techniques, many patients remain undiagnosed, impacting their access to clinical care and genetic counseling."

Highlights the importance of genetic counseling for MADD families.

Sertraline discontinuation

Action: sertraline discontinuation Ontology label: supportive care MAXO:0000950

Recent evidence suggests sertraline may induce an acquired form of MADD in some patients. Discontinuation of sertraline is warranted when MADD develops in the setting of sertraline use, in addition to riboflavin treatment.

Mechanism Target:

INHIBITS Sertraline-associated acquired MADD-like metabolic dysfunction — Discontinuing sertraline removes the suspected pharmacologic trigger for the acquired MADD-like metabolic state.

Show evidence (2 references)

PMID:39092677 SUPPORT Human Clinical

"Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients. Importantly, riboflavin treatment seems to be similarly effective as in genetic MADD, but discontinuation of sertraline is reasonably warranted."

Identifies sertraline as a potential trigger for acquired MADD and recommends discontinuation.

PMID:39092677 SUPPORT Human Clinical

"Remarkably, all 7 patients without disease-causing mutations were treated with sertraline. In some cases, a deterioration of symptoms closely followed dose increase, and discontinuation resulted in an improved acylcarnitine profile."

Dose-response relationship and improvement with sertraline discontinuation.

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Environmental Factors

2

Fasting and catabolic stress

Prolonged fasting, intercurrent illness, surgery, and other catabolic stressors increase reliance on fatty acid oxidation and can trigger acute metabolic decompensation in MADD patients.

Show evidence (1 reference)

PMID:37217231 SUPPORT Human Clinical

"MADD is treatable with riboflavin and appropriate nutrition with a focus on prevention and early management of metabolic decompensation."

Prevention of metabolic decompensation through nutritional management is a core strategy.

Sertraline exposure

Sertraline use has been associated with an acquired form of MADD in patients without identifiable genetic mutations, potentially through interference with mitochondrial flavoprotein function.

Show evidence (1 reference)

PMID:39092677 SUPPORT Human Clinical

"Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients."

Emerging evidence that sertraline can trigger acquired MADD.

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Biochemical Markers

5

Acylcarnitines (broad elevation) (INCREASED)

Context: Broad elevations of short-chain, medium-chain, and long-chain acylcarnitines are the hallmark biochemical finding in MADD, used in newborn screening and diagnostic workup via tandem mass spectrometry.

Pathograph Readouts

Readout Of Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone Positive Diagnostic

Broad acylcarnitine elevations report the combined FAD-dependent dehydrogenase block caused by impaired ETF/ETFDH electron transfer.

Show evidence (1 reference)

PMID:39273584 SUPPORT Human Clinical

"Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs."

Supports acylcarnitine analysis as a diagnostic readout of the MADD biochemical defect.

Show evidence (2 references)

PMID:39273584 SUPPORT Human Clinical

"Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs."

Acylcarnitine profiling by TMS is central to MADD diagnosis and newborn screening.

PMID:17584774 SUPPORT Human Clinical

"Urine organic acid and plasma acyl-carnitine profiles indicated MADD."

Plasma acylcarnitine profiles are key diagnostic indicators of MADD.

Glutaric acid (INCREASED)

Context: Urinary glutaric acid and related dicarboxylic acids (including ethylmalonic acid and 2-hydroxyglutarate) are characteristically elevated in MADD, detectable by GC-MS organic acid analysis.

Pathograph Readouts

Readout Of Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone Positive Diagnostic

Glutaric acid accumulation is a urine organic-acid readout of secondary FAD-dependent dehydrogenase dysfunction in MADD.

Show evidence (1 reference)

PMID:29502916 SUPPORT Other

"The secondary deficiency of all primary mitochondrial FAD-dependent dehydrogenases leads to a complex and variable accumulation of metabolites, including glutaric acid"

Review evidence supports glutaric acid as a diagnostic readout of the FAD-dependent dehydrogenase block.

Show evidence (2 references)

PMID:29502916 SUPPORT Other

"The secondary deficiency of all primary mitochondrial FAD-dependent dehydrogenases leads to a complex and variable accumulation of metabolites, including glutaric acid"

Review evidence directly supports glutaric acid accumulation in MADD.

PMID:39273584 SUPPORT Human Clinical

"Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs."

Urinary organic acid analysis including glutaric acid supports MADD diagnosis.

Creatine kinase (INCREASED)

Context: Serum creatine kinase is elevated in MADD patients, reflecting skeletal muscle damage from lipid storage myopathy and acute rhabdomyolysis. CK normalizes with riboflavin treatment.

Pathograph Readouts

Readout Of Lipid storage myopathy Positive Monitoring

Increased serum CK tracks skeletal muscle injury in MADD lipid storage myopathy and can normalize with treatment response.

Show evidence (1 reference)

PMID:38951975 SUPPORT Human Clinical

"All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography."

Cohort data support CK elevation as a readout of myopathic muscle injury in MADD.

Show evidence (2 references)

PMID:38951975 SUPPORT Human Clinical

"All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography."

Elevated CK was universal in the Malaysian MADD cohort.

PMID:39092677 SUPPORT Human Clinical

"All presented with muscle weakness and elevated levels of creatine kinase."

Elevated CK confirmed in all patients in the sertraline-associated MADD cohort.

GDF-15 (INCREASED)

Context: Growth Differentiation Factor 15, a mitochondrial stress biomarker, is elevated in both genetic and acquired MADD. GDF15 expression is significantly increased in both FLAD1-RRMADD and ETFDH-RRMADD.

Pathograph Readouts

Readout Of ETFDH-driven metabolon disruption and OXPHOS dysfunction Positive Monitoring

Increased GDF-15 reports mitochondrial stress in riboflavin-responsive MADD.

Show evidence (1 reference)

PMID:38228875 SUPPORT Human Clinical

"Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups."

Muscle and serum data support GDF-15 as a mitochondrial-stress readout in FLAD1- and ETFDH-related riboflavin-responsive MADD.

Show evidence (2 references)

PMID:38228875 SUPPORT Human Clinical

"Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups."

Demonstrates elevated GDF-15 as a biomarker in riboflavin-responsive MADD.

PMID:39520827 SUPPORT Human Clinical

"This case adds to the growing literature on the clinical heterogeneity of VLO-MADD, comments on the potential for non-genetic, pharmacologic triggers like sertraline, and highlights that GDF-15 and aldolase can be elevated with normal CK."

GDF-15 elevation noted even when CK is normal in very-late-onset MADD.

Free carnitine (ABNORMAL)

Context: Free carnitine and acylcarnitine/free carnitine balance are abnormal in organic acidemias including MADD. Increased acylcarnitine formation can produce secondary functional carnitine insufficiency even when free carnitine values vary by disease state and treatment.

Pathograph Readouts

Readout Of Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone Threshold Dependent Diagnostic

Abnormal free carnitine together with elevated acylcarnitine/carnitine ratios reports acyl-CoA handling imbalance downstream of the MADD dehydrogenase block.

Show evidence (1 reference)

PMID:6441143 SUPPORT Human Clinical

"The ratios of acylcarnitine/carnitine were elevated above the normal value of 2.0 +/- 1.1."

Patient biochemical data support abnormal acylcarnitine/carnitine balance as a readout of mitochondrial acyl-CoA handling defects including MADD.

Show evidence (2 references)

PMID:6441143 SUPPORT Human Clinical

"In all cases, concentrations of acylcarnitines were greatly increased above normal with free carnitine concentrations ranging from undetectable to supranormal values."

Supports abnormal free carnitine/acylcarnitine balance in organic acid metabolism disorders including MADD.

PMID:38221620 SUPPORT Human Clinical

"urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine."

L-carnitine supplementation is part of standard MADD management, reflecting secondary depletion.

{ }

Source YAML

click to show

name: Multiple Acyl-CoA Dehydrogenase Deficiency
category: Mendelian
creation_date: '2025-06-12T20:16:27Z'
updated_date: '2026-05-18T19:03:24Z'
synonyms:
- MADD
- Glutaric aciduria type II
- Glutaric acidemia type II
- GA2
- GAII
- ETF deficiency
- ETF-QO deficiency
description: 'Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive inborn error of mitochondrial energy metabolism caused by biallelic pathogenic variants in ETFA, ETFB, or ETFDH. These genes encode the electron transfer flavoprotein (ETF) system that shuttles electrons from multiple FAD-dependent acyl-CoA dehydrogenases to the mitochondrial ubiquinone (coenzyme Q) pool. Defective ETF/ETFDH-mediated electron transfer produces a functional block in mitochondrial fatty acid beta-oxidation and amino acid catabolism, resulting in characteristic acylcarnitine and organic acid accumulations. Three clinical forms are recognized: neonatal onset with congenital anomalies (type I), neonatal onset without anomalies (type II), and a milder late-onset form (type III) that is frequently riboflavin responsive. Incidence is approximately 1 in 200,000 live births globally.

  '
disease_term:
  preferred_term: multiple acyl-CoA dehydrogenase deficiency
  term:
    id: MONDO:0009282
    label: multiple acyl-CoA dehydrogenase deficiency
parents:
- Fatty Acid Oxidation Disorder
- Inborn Error of Metabolism
has_subtypes:
- name: MADD type I (neonatal with congenital anomalies)
  description: 'Severe neonatal onset with congenital anomalies such as renal cystic dysplasia and facial dysmorphism, associated with severe metabolic acidosis and high mortality.

    '
- name: MADD type II (neonatal without congenital anomalies)
  description: 'Severe neonatal onset without structural anomalies, presenting with metabolic acidosis, hypoglycemia, and multiorgan failure.

    '
- name: MADD type III (late-onset, riboflavin-responsive)
  description: 'Later onset form presenting with proximal muscle weakness, exercise intolerance, and episodic metabolic crises; frequently responsive to riboflavin supplementation. Most commonly due to ETFDH mutations.

    '
pathophysiology:
- name: ETF/ETFDH molecular function deficiency
  description: 'Biallelic pathogenic variants in ETFA, ETFB, or ETFDH reduce catalytic electron-transfer capacity of the ETF system.

    '
  genes:
  - preferred_term: ETFA
    term:
      id: hgnc:3481
      label: ETFA
  - preferred_term: ETFB
    term:
      id: hgnc:3482
      label: ETFB
  - preferred_term: ETFDH
    term:
      id: hgnc:3483
      label: ETFDH
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:17584774
    reference_title: "ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO).'
    explanation: Supports ETF/ETFDH molecular dysfunction as the initiating defect in MADD.
  downstream:
  - target: Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone
    description: Loss of ETF system activity blocks electron flow into the CoQ pool.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37217231
      reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is inherited in an autosomal recessive manner and impairs electron transfer in the electron transport chain."
      explanation: Supports impaired electron transfer as the direct functional consequence of inherited MADD.
  - target: Oxidative stress and apoptosis in neuronal cells
    description: ETFDH-mutant neuronal cell models show excessive apoptosis and neurite outgrowth defects through mitochondrial apoptosis signaling.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - BCL-2/mitochondrial outer membrane permeabilization/apoptosis signaling
    evidence:
    - reference: PMID:39455656
      reference_title: "ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our cellular models of MADD exhibit neurite growth defects and excessive apoptosis."
      explanation: ETFDH-mutant cellular models support neuronal apoptosis and neurite pathology downstream of the molecular defect.
- name: Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone
  description: 'Disrupted electron flow from multiple acyl-CoA dehydrogenases through the ETF/ETFDH system to the mitochondrial coenzyme Q pool blocks fatty acid beta-oxidation, branched-chain amino acid catabolism, and choline oxidation, causing accumulation of metabolic intermediates and energy deficit.

    '
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  - preferred_term: electron transport chain
    term:
      id: GO:0022900
      label: electron transport chain
    modifier: DECREASED
  - preferred_term: amino acid catabolic process
    term:
      id: GO:0009063
      label: amino acid catabolic process
    modifier: DECREASED
  - preferred_term: choline catabolic process
    term:
      id: GO:0042426
      label: choline catabolic process
    modifier: DECREASED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:17584774
    reference_title: "ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO).'
    explanation: Supports downstream multi-pathway catabolic disruption from ETF system failure.
  downstream:
  - target: ETFDH-driven metabolon disruption and OXPHOS dysfunction
    description: ETFDH deficiency disrupts the ETFDH-CIII-COQ2 organization that routes lipid-derived electrons into the respiratory chain.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - ETFDH-CIII-COQ2 metabolon destabilization
    evidence:
    - reference: PMID:38243131
      reference_title: "An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We identify a complex (comprising ETFDH, CIII and the Q-biosynthesis regulator COQ2) that directs electrons from lipid substrates to the respiratory chain, thereby reducing electron leaks and reactive oxygen species production."
      explanation: Identifies the metabolon that is disrupted when ETFDH-dependent electron flow is impaired.
  - target: Systemic metabolic decompensation
    description: Impaired mitochondrial fuel oxidation limits fasting energy production and ketogenesis, producing acute metabolic crises.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced mitochondrial ATP production
    - Impaired hepatic ketogenesis
    evidence:
    - reference: PMID:37217231
      reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism that results in impairment of mitochondrial β-oxidation of fatty acids."
      explanation: Supports impaired fatty acid oxidation as the upstream metabolic defect leading to decompensation.
  - target: Acylcarnitines (broad elevation)
    description: Blocked ETF/ETFDH-dependent oxidation produces the broad acylcarnitine abnormalities used to diagnose MADD.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17584774
      reference_title: "ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Urine organic acid and plasma acyl-carnitine profiles indicated MADD."
      explanation: Patient biochemical profiles support abnormal acylcarnitines downstream of ETF:QO dysfunction.
  - target: Glutaric acid
    description: Impaired ETF/ETF:QO electron transfer produces the glutaric aciduria biochemical hallmark of MADD.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Organic acid accumulation
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The secondary deficiency of all primary mitochondrial FAD-dependent dehydrogenases leads to a complex and variable accumulation of metabolites, including glutaric acid"
      explanation: Review evidence supports glutaric acid as one of the accumulated metabolites downstream of MADD.
  - target: Lipid storage myopathy
    description: Impaired fatty acid oxidation in skeletal muscle causes lipid storage myopathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38951975
      reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of fatty acid oxidation that causes lipid storage myopathy (LSM)."
      explanation: Clinical cohort evidence directly links MADD fatty acid oxidation impairment to lipid storage myopathy.
- name: Systemic metabolic decompensation
  description: 'Catabolic stress and impaired mitochondrial fatty acid oxidation produce a systemic energy crisis, particularly in liver, heart, and brain. Reduced ketone generation, impaired fuel availability, and accumulated organic acids manifest as metabolic acidosis, hypoketotic hypoglycemia, hyperammonemia, encephalopathy, and cardiomyopathy in severe presentations.

    '
  biological_processes:
  - preferred_term: generation of precursor metabolites and energy
    term:
      id: GO:0006091
      label: generation of precursor metabolites and energy
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  chemical_entities:
  - preferred_term: glucose
    term:
      id: CHEBI:17234
      label: glucose
    modifier: DECREASED
  - preferred_term: ketone body
    term:
      id: CHEBI:73693
      label: ketone body
    modifier: DECREASED
  evidence:
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations."
    explanation: Supports the acute metabolic crisis pattern in severe MADD.
  downstream:
  - target: Metabolic acidosis
    description: Accumulated organic acids during decompensation produce severe metabolic acidosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37217231
      reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations."
      explanation: The clinical presentation explicitly includes severe metabolic acidosis.
  - target: Hypoketotic hypoglycemia
    description: Impaired fatty acid oxidation limits hepatic ketogenesis and fasting energy production, causing hypoketotic hypoglycemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37217231
      reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations."
      explanation: The clinical presentation explicitly includes non-ketotic hypoglycemia.
  - target: Hyperammonemia
    description: Severe decompensation can include hyperammonemia, which contributes to acute neurologic deterioration.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Catabolic crisis
    evidence:
    - reference: PMID:37217231
      reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations."
      explanation: The clinical presentation explicitly includes hyperammonemic presentations.
  - target: Encephalopathy
    description: Acute energy failure and hyperammonemia can progress to encephalopathy during metabolic crisis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hypoglycemia
    - Hyperammonemia
    evidence:
    - reference: PMID:37217231
      reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation."
      explanation: Case evidence links hyperammonemic metabolic crisis to encephalopathy in MADD.
  - target: Cardiomyopathy
    description: Mitochondrial fuel oxidation failure can affect myocardium and contribute to cardiomyopathy in severe MADD.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Myocardial energy deficit
    evidence:
    - reference: PMID:37217231
      reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death."
      explanation: Clinical review evidence supports cardiomyopathy as part of the MADD phenotype spectrum.
  - target: Respiratory insufficiency
    description: Severe metabolic and neuromuscular involvement can include respiratory dysfunction requiring ventilatory support.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Respiratory dysfunction
    - Metabolic crisis
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Respiratory dysfunction may be present."
      explanation: Review evidence supports respiratory dysfunction as part of the MADD clinical spectrum.
  - target: Vomiting
    description: Metabolic decompensation may include recurrent or cyclical vomiting before overt neuromuscular presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17584774
      reference_title: "ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "several had previously suffered cyclical vomiting."
      explanation: Patient series evidence supports vomiting as part of the MADD presentation.
  - target: Hepatomegaly
    description: Severe infantile MADD can involve hepatic enlargement during systemic metabolic decompensation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Acute organic acid accumulation
    - Hepatic energy failure
    evidence:
    - reference: PMID:6862997
      reference_title: "Multiple acyl-Co A dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy. Detection of N-isovalerylglutamic acid and its monoamide."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He had hepatomegaly and echocardiographically a non-obstructive cardiomyopathy."
      explanation: Infant case evidence links MADD metabolic crisis with hepatomegaly.
  - target: Muscular hypotonia
    description: Severe infantile energy failure can manifest as marked muscular hypotonia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Infantile metabolic decompensation
    - Neuromuscular energy deficit
    evidence:
    - reference: PMID:6862997
      reference_title: "Multiple acyl-Co A dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy. Detection of N-isovalerylglutamic acid and its monoamide."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Later on, development was retarded with a severe muscular hypotonia."
      explanation: Infant case evidence directly supports severe muscular hypotonia in MADD.
- name: FLAD1-related FAD synthesis impairment
  description: 'FLAD1 variants impair flavin adenine dinucleotide synthesis and can produce a riboflavin-responsive MADD-like lipid storage myopathy with biochemical and fatty-acid metabolism changes overlapping ETFDH-related MADD.

    '
  genes:
  - preferred_term: FLAD1
    term:
      id: hgnc:24671
      label: FLAD1
  biological_processes:
  - preferred_term: FAD biosynthetic process
    term:
      id: GO:0006747
      label: FAD biosynthetic process
    modifier: DECREASED
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:38228875
    reference_title: "A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We described here a case with riboflavin responsive LSM and MADD resulting from FLAD1 gene variants"
    explanation: Supports FLAD1 variation as a riboflavin-responsive MADD-like cause.
  downstream:
  - target: Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone
    description: Reduced FAD synthesis limits FAD-dependent dehydrogenase function and phenocopies the core MADD electron-transfer defect.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced flavin adenine dinucleotide availability
    - Secondary FAD-dependent dehydrogenase dysfunction
    evidence:
    - reference: PMID:38228875
      reference_title: "A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our data revealed that FLAD1-RRMADD (p.Arg530) has similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD except for muscle pathological features."
      explanation: Comparative patient data support convergence of FLAD1-RRMADD with ETFDH-RRMADD fatty-acid metabolism disruption.
  - target: Lipid storage myopathy
    description: FLAD1-RRMADD and ETFDH-RRMADD both show lipid storage myopathy in muscle.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38228875
      reference_title: "A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "On muscle pathology, both FLAD1-RRMADD and ETFDH-RRMADD were proved with lipid storage myopathy"
      explanation: Muscle pathology supports lipid storage myopathy downstream of FLAD1-related MADD-like disease.
- name: ETFDH-driven metabolon disruption and OXPHOS dysfunction
  description: 'Recent work demonstrates that ETFDH participates in a metabolon comprising ETFDH, respiratory chain complex III (CIII), and the CoQ biosynthesis regulator COQ2. This complex maintains coenzyme Q homeostasis, minimizes reduced-Q reductive stress, and supports OXPHOS efficiency. Loss of ETFDH causes CIII dysfunction, pathological QH2 accumulation, reductive stress, and increased ROS.

    '
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  evidence:
  - reference: PMID:38243131
    reference_title: "An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We identify a complex (comprising ETFDH, CIII and the Q-biosynthesis regulator COQ2) that directs electrons from lipid substrates to the respiratory chain, thereby reducing electron leaks and reactive oxygen species production.
    explanation: Identifies the ETFDH-CIII-COQ2 metabolon supporting OXPHOS efficiency.
  downstream:
  - target: GDF-15
    description: Mitochondrial stress in riboflavin-responsive MADD is reflected by increased GDF-15 expression in muscle and serum.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mitochondrial stress signaling
    evidence:
    - reference: PMID:38228875
      reference_title: "A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups."
      explanation: Clinical muscle and serum data support GDF-15 as a downstream mitochondrial-stress biomarker in riboflavin-responsive MADD.
- name: Oxidative stress and apoptosis in neuronal cells
  description: 'ETFDH mutations lead to oxidative stress, activation of the BCL-2 family/MOMP apoptotic signaling pathway, and neurite outgrowth defects. In cellular models, ETFDH mutations cause increased pro-apoptotic markers including BAX, cytochrome c, caspase-9 and caspase-3, linking mitochondrial redox disturbance to neurodegeneration.

    '
  biological_processes:
  - preferred_term: intrinsic apoptotic signaling pathway
    term:
      id: GO:0097193
      label: intrinsic apoptotic signaling pathway
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: mitochondrial outer membrane
    term:
      id: GO:0005741
      label: mitochondrial outer membrane
  evidence:
  - reference: PMID:39455656
    reference_title: "ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our cellular models of MADD exhibit neurite growth defects and excessive apoptosis.
    explanation: Demonstrates apoptosis and neurite pathology in ETFDH mutation cellular models.
  downstream:
  - target: Peripheral neuropathy
    description: Neurite outgrowth defects, axonal degeneration, and neuronal apoptosis provide a cellular mechanism for peripheral neuropathy in the MADD spectrum.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Neurite outgrowth defects
    - Axonal degeneration
    evidence:
    - reference: PMID:39455656
      reference_title: "ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our cellular models of MADD exhibit neurite growth defects and excessive apoptosis."
      explanation: Cellular model evidence supports a neuronal injury mechanism downstream of ETFDH mutation.
- name: Sertraline-associated acquired MADD-like metabolic dysfunction
  description: 'Sertraline exposure has been associated with an acquired late-onset MADD-like phenotype in patients without disease-causing MADD mutations, with muscle weakness, elevated creatine kinase, lipid storage myopathy, and elevated acylcarnitines. The mechanism remains emerging, but the clinical pattern links sertraline exposure to a reversible MADD-like metabolic state.

    '
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:39092677
    reference_title: "Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients."
    explanation: Clinical cohort evidence supports a sertraline-associated acquired MADD-like metabolic mechanism.
  downstream:
  - target: Lipid storage myopathy
    description: Sertraline-associated cases showed lipid storage myopathy on muscle biopsy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39092677
      reference_title: "Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A lipid storage myopathy was evident in the muscle biopsies, as was elevated acylcarnitines in blood."
      explanation: Sertraline-associated late-onset MADD cases had biopsy-confirmed lipid storage myopathy.
  - target: Acylcarnitines (broad elevation)
    description: Sertraline-associated acquired MADD is marked by elevated acylcarnitines.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39092677
      reference_title: "Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A lipid storage myopathy was evident in the muscle biopsies, as was elevated acylcarnitines in blood."
      explanation: Sertraline-associated cases had elevated acylcarnitines in blood.
  - target: Elevated creatine kinase
    description: Sertraline-associated acquired MADD cases presented with elevated CK.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39092677
      reference_title: "Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All presented with muscle weakness and elevated levels of creatine kinase."
      explanation: Elevated CK was present across the sertraline-associated MADD case series.
- name: Lipid storage myopathy
  description: 'Defective fatty acid oxidation leads to pathological lipid droplet accumulation in skeletal muscle fibers, resulting in lipid storage myopathy. Late-onset MADD is the most common lipid storage myopathy.

    '
  biological_processes:
  - preferred_term: lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:38365830
    reference_title: "The male-to-female ratio in late-onset multiple acyl-CoA dehydrogenase deficiency: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common lipid storage myopathy.
    explanation: Establishes late-onset MADD as the most common lipid storage myopathy.
  - reference: PMID:38951975
    reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of fatty acid oxidation that causes lipid storage myopathy (LSM).
    explanation: Confirms MADD causes lipid storage myopathy in a clinical cohort.
  downstream:
  - target: Proximal muscle weakness
    description: Lipid storage myopathy injures skeletal muscle and produces the proximal limb weakness typical of late-onset MADD.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Skeletal muscle lipid accumulation
    - Myopathic fiber injury
    evidence:
    - reference: PMID:38951975
      reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography."
      explanation: Clinical cohort evidence links MADD myopathy to proximal weakness.
  - target: Elevated creatine kinase
    description: Myopathic injury causes elevated serum creatine kinase.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Myopathic fiber injury
    evidence:
    - reference: PMID:38951975
      reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography."
      explanation: The cohort shows elevated CK alongside myopathic changes in MADD.
  - target: Creatine kinase
    description: Skeletal muscle injury is reflected biochemically by increased serum creatine kinase.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Myopathic fiber injury
    evidence:
    - reference: PMID:38951975
      reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography."
      explanation: Clinical cohort evidence supports CK elevation downstream of myopathic injury.
  - target: Exercise intolerance
    description: Skeletal muscle energy failure and lipid storage myopathy reduce exercise capacity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Skeletal muscle energy deficit
    evidence:
    - reference: PMID:37217231
      reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death."
      explanation: Clinical review evidence lists exercise intolerance and myopathy in the MADD phenotype spectrum.
  - target: Myalgia
    description: Skeletal muscle lipid storage and energy failure can manifest as muscle pain in late-onset MADD.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Skeletal muscle energy deficit
    - Myopathic fiber injury
    evidence:
    - reference: PMID:32550677
      reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain"
      explanation: GeneReviews lists muscle pain among the most common symptoms of type III MADD.
  - target: Rhabdomyolysis
    description: Episodic skeletal muscle energy failure and myopathic injury can manifest as rhabdomyolysis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Skeletal muscle energy deficit
    - Myopathic fiber injury
    evidence:
    - reference: PMID:39455656
      reference_title: "ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts."
      explanation: Published background in this mechanistic study summarizes rhabdomyolysis as part of the reported MADD phenotype spectrum.
phenotypes:
- name: Proximal muscle weakness
  frequency: VERY_FREQUENT
  description: 'Progressive proximal limb weakness is the hallmark presentation of late-onset MADD. All patients in clinical cohorts demonstrated proximal limb weakness.

    '
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:38951975
    reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography.
    explanation: All 14 MADD patients in the Malaysian cohort showed proximal limb weakness.
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death.
    explanation: Myopathy is listed among the common clinical manifestations.
- name: Metabolic acidosis
  frequency: VERY_FREQUENT
  description: 'High-anion-gap metabolic acidosis during acute decompensation is a characteristic feature, particularly in neonatal-onset forms.

    '
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations.
    explanation: Metabolic acidosis is a major presenting feature in MADD.
- name: Hypoketotic hypoglycemia
  frequency: FREQUENT
  description: 'Fasting intolerance with non-ketotic or hypoketotic hypoglycemia due to impaired fatty acid oxidation and inability to generate sufficient ketone bodies.

    '
  phenotype_term:
    preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  evidence:
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations.
    explanation: Non-ketotic hypoglycemia is listed as a major presenting feature.
- name: Elevated creatine kinase
  frequency: VERY_FREQUENT
  description: 'Serum creatine kinase is elevated in virtually all MADD patients, reflecting ongoing skeletal muscle damage.

    '
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:38951975
    reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography.
    explanation: All patients in the Malaysian MADD cohort had elevated CK.
- name: Exercise intolerance
  frequency: FREQUENT
  description: 'Exercise intolerance is a common symptom in late-onset MADD, reflecting impaired energy metabolism in skeletal muscle.

    '
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death.
    explanation: Exercise intolerance is a recognized clinical manifestation of MADD.
- name: Myalgia
  frequency: FREQUENT
  description: 'Muscle pain is a common late-onset MADD symptom accompanying proximal weakness and exercise intolerance.

    '
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:32550677
    reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain"
    explanation: GeneReviews identifies muscle pain as one of the most common type III MADD symptoms.
- name: Cardiomyopathy
  frequency: OCCASIONAL
  description: 'Cardiac involvement including cardiomyopathy may occur in severe or early-onset forms and can also develop during metabolic crises.

    '
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death.
    explanation: Cardiomyopathy is listed among variable MADD manifestations.
- name: Encephalopathy
  frequency: OCCASIONAL
  description: 'Acute encephalopathy with confusion and altered consciousness can occur during metabolic crises, sometimes accompanied by hyperammonemia.

    '
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:17584774
    reference_title: "ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms
    explanation: Encephalopathy was a presenting feature in the Olsen et al. MADD cohort.
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation.
    explanation: Case report of hyperammonemic encephalopathy as MADD presentation.
- name: Hyperammonemia
  frequency: OCCASIONAL
  description: 'Hyperammonemia can occur during metabolic crises, contributing to encephalopathy and requiring urgent management.

    '
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations.
    explanation: Hyperammonemia is a recognized acute presentation in MADD.
- name: Rhabdomyolysis
  frequency: OCCASIONAL
  description: 'Episodic rhabdomyolysis can occur during metabolic crises and may be a presenting feature. In one cohort, a patient died during severe rhabdomyolysis with acute renal failure.

    '
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:39455656
    reference_title: "ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts.
    explanation: Rhabdomyolysis is recognized among the phenotypic spectrum of MADD.
- name: Respiratory insufficiency
  frequency: OCCASIONAL
  description: 'Respiratory dysfunction may occur in MADD, particularly during severe metabolic or neuromuscular presentations. Acute hyperammonemic encephalopathy can require intubation during decompensation.

    '
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Respiratory dysfunction may be present."
    explanation: Review evidence directly supports respiratory dysfunction in MADD.
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation."
    explanation: Case evidence supports ventilatory support during severe MADD decompensation.
- name: Hepatomegaly
  frequency: OCCASIONAL
  description: 'Hepatomegaly and liver dysfunction are features of severe neonatal presentations of MADD.

    '
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:6862997
    reference_title: "Multiple acyl-Co A dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy. Detection of N-isovalerylglutamic acid and its monoamide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had hepatomegaly and echocardiographically a non-obstructive cardiomyopathy."
    explanation: This MADD infant case directly documents hepatomegaly.
- name: Peripheral neuropathy
  frequency: OCCASIONAL
  description: 'Peripheral neuropathy has been reported in both muscular and neuronal contexts of MADD, particularly in late-onset forms.

    '
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:39455656
    reference_title: "ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts.
    explanation: Peripheral neuropathy is part of the MADD phenotypic spectrum.
- name: Vomiting
  frequency: FREQUENT
  description: 'Cyclical vomiting can occur in MADD, sometimes as a presenting symptom preceding the full metabolic phenotype.

    '
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:17584774
    reference_title: "ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: several had previously suffered cyclical vomiting.
    explanation: Cyclical vomiting occurred as a prodromal symptom in MADD patients.
- name: Muscular hypotonia
  frequency: FREQUENT
  description: 'Hypotonia is a common feature in neonatal forms and may also be present in late-onset MADD.

    '
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:6862997
    reference_title: "Multiple acyl-Co A dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy. Detection of N-isovalerylglutamic acid and its monoamide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Later on, development was retarded with a severe muscular hypotonia."
    explanation: This MADD infant case directly documents severe muscular hypotonia.
biochemical:
- name: Acylcarnitines (broad elevation)
  presence: INCREASED
  context: 'Broad elevations of short-chain, medium-chain, and long-chain acylcarnitines are the hallmark biochemical finding in MADD, used in newborn screening and diagnostic workup via tandem mass spectrometry.

    '
  readouts:
  - target: Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Broad acylcarnitine elevations report the combined FAD-dependent dehydrogenase block caused by impaired ETF/ETFDH electron transfer.
    evidence:
    - reference: PMID:39273584
      reference_title: "Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs."
      explanation: Supports acylcarnitine analysis as a diagnostic readout of the MADD biochemical defect.
  evidence:
  - reference: PMID:39273584
    reference_title: "Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs.
    explanation: Acylcarnitine profiling by TMS is central to MADD diagnosis and newborn screening.
  - reference: PMID:17584774
    reference_title: "ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Urine organic acid and plasma acyl-carnitine profiles indicated MADD.
    explanation: Plasma acylcarnitine profiles are key diagnostic indicators of MADD.
- name: Glutaric acid
  presence: INCREASED
  context: 'Urinary glutaric acid and related dicarboxylic acids (including ethylmalonic acid and 2-hydroxyglutarate) are characteristically elevated in MADD, detectable by GC-MS organic acid analysis.

    '
  readouts:
  - target: Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Glutaric acid accumulation is a urine organic-acid readout of secondary FAD-dependent dehydrogenase dysfunction in MADD.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The secondary deficiency of all primary mitochondrial FAD-dependent dehydrogenases leads to a complex and variable accumulation of metabolites, including glutaric acid"
      explanation: Review evidence supports glutaric acid as a diagnostic readout of the FAD-dependent dehydrogenase block.
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The secondary deficiency of all primary mitochondrial FAD-dependent dehydrogenases leads to a complex and variable accumulation of metabolites, including glutaric acid"
    explanation: Review evidence directly supports glutaric acid accumulation in MADD.
  - reference: PMID:39273584
    reference_title: "Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs.
    explanation: Urinary organic acid analysis including glutaric acid supports MADD diagnosis.
- name: Creatine kinase
  presence: INCREASED
  context: 'Serum creatine kinase is elevated in MADD patients, reflecting skeletal muscle damage from lipid storage myopathy and acute rhabdomyolysis. CK normalizes with riboflavin treatment.

    '
  readouts:
  - target: Lipid storage myopathy
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Increased serum CK tracks skeletal muscle injury in MADD lipid storage myopathy and can normalize with treatment response.
    evidence:
    - reference: PMID:38951975
      reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography."
      explanation: Cohort data support CK elevation as a readout of myopathic muscle injury in MADD.
  evidence:
  - reference: PMID:38951975
    reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography.
    explanation: Elevated CK was universal in the Malaysian MADD cohort.
  - reference: PMID:39092677
    reference_title: "Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All presented with muscle weakness and elevated levels of creatine kinase.
    explanation: Elevated CK confirmed in all patients in the sertraline-associated MADD cohort.
- name: GDF-15
  presence: INCREASED
  context: 'Growth Differentiation Factor 15, a mitochondrial stress biomarker, is elevated in both genetic and acquired MADD. GDF15 expression is significantly increased in both FLAD1-RRMADD and ETFDH-RRMADD.

    '
  readouts:
  - target: ETFDH-driven metabolon disruption and OXPHOS dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Increased GDF-15 reports mitochondrial stress in riboflavin-responsive MADD.
    evidence:
    - reference: PMID:38228875
      reference_title: "A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups."
      explanation: Muscle and serum data support GDF-15 as a mitochondrial-stress readout in FLAD1- and ETFDH-related riboflavin-responsive MADD.
  evidence:
  - reference: PMID:38228875
    reference_title: "A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups.
    explanation: Demonstrates elevated GDF-15 as a biomarker in riboflavin-responsive MADD.
  - reference: PMID:39520827
    reference_title: "Very-late-onset multiple Acyl-coenzyme a dehydrogenase deficiency with elevated GDF-15 and Aldolase: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This case adds to the growing literature on the clinical heterogeneity of VLO-MADD, comments on the potential for non-genetic, pharmacologic triggers like sertraline, and highlights that GDF-15 and aldolase can be elevated with normal CK.
    explanation: GDF-15 elevation noted even when CK is normal in very-late-onset MADD.
- name: Free carnitine
  presence: ABNORMAL
  context: 'Free carnitine and acylcarnitine/free carnitine balance are abnormal in organic acidemias including MADD. Increased acylcarnitine formation can produce secondary functional carnitine insufficiency even when free carnitine values vary by disease state and treatment.

    '
  readouts:
  - target: Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone
    relationship: READOUT_OF
    direction: THRESHOLD_DEPENDENT
    endpoint_context: DIAGNOSTIC
    interpretation: Abnormal free carnitine together with elevated acylcarnitine/carnitine ratios reports acyl-CoA handling imbalance downstream of the MADD dehydrogenase block.
    evidence:
    - reference: PMID:6441143
      reference_title: "Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The ratios of acylcarnitine/carnitine were elevated above the normal value of 2.0 +/- 1.1."
      explanation: Patient biochemical data support abnormal acylcarnitine/carnitine balance as a readout of mitochondrial acyl-CoA handling defects including MADD.
  evidence:
  - reference: PMID:6441143
    reference_title: "Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all cases, concentrations of acylcarnitines were greatly increased above normal with free carnitine concentrations ranging from undetectable to supranormal values."
    explanation: Supports abnormal free carnitine/acylcarnitine balance in organic acid metabolism disorders including MADD.
  - reference: PMID:38221620
    reference_title: "Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine.
    explanation: L-carnitine supplementation is part of standard MADD management, reflecting secondary depletion.
genetic:
- name: ETFDH variants (most common cause)
  gene_term:
    preferred_term: ETFDH
    term:
      id: hgnc:3483
      label: ETFDH
  features: 'ETFDH (electron transfer flavoprotein dehydrogenase) mutations are the most common cause of MADD, particularly in late-onset riboflavin- responsive forms. The c.250G>A (p.A84T) variant is a hotspot mutation in East Asian populations. Deep intronic variants causing pseudo-exon inclusion have been identified as a recurrent pathogenic mechanism.

    '
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:39273584
      reference_title: Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        MADD is an autosomal recessive trait caused by biallelic mutations in
        the ETFA, ETFB, and ETFDH genes encoding the alpha and beta subunits of the
        electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase enzymes.
      explanation: Directly supports autosomal recessive inheritance and ETFDH as one biallelic MADD gene.
  variants:
  - name: ETFDH - c.250G>A (p.A84T) hotspot variant
    description: 'Most common ETFDH variant in southern Chinese and East Asian populations. Found in 86% of patients in the Malaysian MADD cohort.

      '
    evidence:
    - reference: PMID:38951975
      reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Notably, 12 (86%) patients, including the 2 Malay sisters, carried a common c.250G>A (p.A84T) variant, consistent with the hotspot mutation reported in southern China.
      explanation: Documents the A84T hotspot variant frequency in the Malaysian cohort.
  - name: Deep intronic ETFDH variants
    description: 'Deep intronic variants in ETFDH intron 1 causing pseudo-exon inclusion have been identified as a recurrent pathogenic mechanism that is missed by standard exome sequencing.

      '
    evidence:
    - reference: PMID:39273584
      reference_title: Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Here, we report a unique
        deep intronic mutation in intron 1 of the ETFDH gene, c.35-959A>G, in a patient
        with early-onset lethal MADD, resulting in pseudo-exon inclusion.
      explanation: Supports deep intronic ETFDH variation as a pathogenic mechanism in MADD.
  evidence:
  - reference: PMID:17584774
    reference_title: "ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients had mutations in the gene for ETF:QO.
    explanation: Landmark paper establishing ETFDH as a major cause of riboflavin-responsive MADD.
- name: ETFA variants
  gene_term:
    preferred_term: ETFA
    term:
      id: hgnc:3481
      label: ETFA
  features: 'Biallelic pathogenic variants in ETFA, encoding the electron transfer flavoprotein alpha subunit, cause MADD and are typically associated with severe neonatal presentations. ETFA variants are less common than ETFDH variants.

    '
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:39273584
      reference_title: Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        MADD is an autosomal recessive trait caused by biallelic mutations in
        the ETFA, ETFB, and ETFDH genes encoding the alpha and beta subunits of the
        electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase enzymes.
      explanation: Directly supports autosomal recessive inheritance and ETFA as one biallelic MADD gene.
  evidence:
  - reference: PMID:39273584
    reference_title: Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      MADD is an autosomal recessive trait caused by biallelic mutations in
      the ETFA, ETFB, and ETFDH genes encoding the alpha and beta subunits of the
      electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase enzymes.
    explanation: Supports ETFA mutations as one molecular cause of MADD.
- name: ETFB variants
  gene_term:
    preferred_term: ETFB
    term:
      id: hgnc:3482
      label: ETFB
  features: 'Biallelic pathogenic variants in ETFB, encoding the electron transfer flavoprotein beta subunit, cause MADD and are typically associated with severe neonatal presentations. ETFB variants are less common than ETFDH variants.

    '
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:39273584
      reference_title: Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        MADD is an autosomal recessive trait caused by biallelic mutations in
        the ETFA, ETFB, and ETFDH genes encoding the alpha and beta subunits of the
        electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase enzymes.
      explanation: Directly supports autosomal recessive inheritance and ETFB as one biallelic MADD gene.
  evidence:
  - reference: PMID:39273584
    reference_title: Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      MADD is an autosomal recessive trait caused by biallelic mutations in
      the ETFA, ETFB, and ETFDH genes encoding the alpha and beta subunits of the
      electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase enzymes.
    explanation: Supports ETFB mutations as one molecular cause of MADD.
- name: FLAD1 variants (MADD-like phenotype)
  gene_term:
    preferred_term: FLAD1
    term:
      id: hgnc:24671
      label: FLAD1
  features: 'Variants in FLAD1 (FAD synthase) can produce a riboflavin-responsive MADD-like lipid storage myopathy phenotype. FLAD1-RRMADD shows similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD, except for subtle differences in muscle pathology.

    '
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:38228875
      reference_title: "A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We described here a case with riboflavin responsive LSM and MADD resulting from FLAD1 gene variants
      explanation: Documents FLAD1 as a cause of riboflavin-responsive MADD phenocopy.
  evidence:
  - reference: PMID:38228875
    reference_title: "A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our data revealed that FLAD1-RRMADD (p.Arg530) has similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD except for muscle pathological features.
    explanation: Comparative study demonstrating FLAD1 as a MADD-like disease gene.
- name: ETFA
  gene_term:
    preferred_term: ETFA
    term:
      id: hgnc:3481
      label: ETFA
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_3d6848e7-6e9e-4545-9f97-69480face058-2018-05-22T160000.000Z
    reference_title: "ETFA / multiple acyl-CoA dehydrogenase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ETFA | HGNC:3481 | multiple acyl-CoA dehydrogenase deficiency | MONDO:0009282 | AR | Definitive"
    explanation: ClinGen classifies the ETFA-multiple acyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
- name: ETFB
  gene_term:
    preferred_term: ETFB
    term:
      id: hgnc:3482
      label: ETFB
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_d9a8d844-c82a-4258-bd48-10e2d977273e-2023-05-23T040000.000Z
    reference_title: "ETFB / multiple acyl-CoA dehydrogenase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ETFB | HGNC:3482 | multiple acyl-CoA dehydrogenase deficiency | MONDO:0009282 | AR | Definitive"
    explanation: ClinGen classifies the ETFB-multiple acyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
- name: ETFDH
  gene_term:
    preferred_term: ETFDH
    term:
      id: hgnc:3483
      label: ETFDH
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_062e336e-cfda-45f7-b509-cd44a5079034-2018-05-22T040000.000Z
    reference_title: "ETFDH / multiple acyl-CoA dehydrogenase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ETFDH | HGNC:3483 | multiple acyl-CoA dehydrogenase deficiency | MONDO:0009282 | AR | Definitive"
    explanation: ClinGen classifies the ETFDH-multiple acyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Riboflavin supplementation
  description: 'Riboflavin (vitamin B2) is the cornerstone treatment for late-onset MADD. It increases FAD availability and may stabilize mutant ETFDH/ETF-QO protein folding. Doses of 100-400 mg/day produce dramatic improvement in most late-onset patients, with symptom resolution and CK normalization.

    '
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
  target_mechanisms:
  - target: Impaired electron transfer from FAD-dependent dehydrogenases to ubiquinone
    treatment_effect: MODULATES
    description: Riboflavin increases FAD availability and can improve riboflavin-responsive ETF:QO-dependent electron transfer.
  - target: Lipid storage myopathy
    treatment_effect: MODULATES
    description: Improved flavoprotein function reduces the downstream myopathic phenotype in riboflavin-responsive MADD.
  evidence:
  - reference: PMID:17584774
    reference_title: "ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment.
    explanation: Landmark demonstration of riboflavin responsiveness in MADD with ETFDH mutations.
  - reference: PMID:38951975
    reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All of the patients responded well to riboflavin therapy.
    explanation: All 14 patients in the Malaysian cohort responded to riboflavin.
  - reference: PMID:39092677
    reference_title: "Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 9 patients responded to riboflavin treatment with normalization of creatine kinase and muscle biopsy findings, and in 8 patients the clinical symptoms clearly improved.
    explanation: Riboflavin effective in both genetic and sertraline-associated MADD.
- name: Coenzyme Q10 supplementation
  description: 'CoQ10 supplementation is used as adjunctive therapy in MADD. In cellular models, CoQ10 mitigates apoptosis and neurite outgrowth defects caused by ETFDH mutations.

    '
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
  target_mechanisms:
  - target: Oxidative stress and apoptosis in neuronal cells
    treatment_effect: INHIBITS
    description: Cellular model evidence shows CoQ10 mitigates ETFDH-mutant apoptosis signaling and neurite outgrowth defects.
  evidence:
  - reference: PMID:39455656
    reference_title: "ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Subsequent treatment of the mutant cells with coenzyme Q10 downregulated activated protein expression and mitigated neurite growth defects.
    explanation: Demonstrates CoQ10 rescue of apoptosis and neurite defects in ETFDH mutant cells.
  - reference: PMID:39950184
    reference_title: "2-[(18)F] FDG PET/CT in Rapid Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level.
    explanation: CoQ10 used as part of successful combination therapy in late-onset MADD.
- name: L-carnitine supplementation
  description: 'L-carnitine supplementation addresses secondary carnitine depletion caused by increased acylcarnitine conjugation. It supports acyl group handling and excretion.

    '
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: MAXO:0010006
      label: carnitine supplementation
  target_mechanisms:
  - target: Systemic metabolic decompensation
    treatment_effect: MODULATES
    description: L-carnitine supports conjugation and excretion of accumulated toxic acyl groups during MADD metabolic decompensation.
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Avoidance of fasting and conjugation of toxic metabolites with L-carnitine and glycine are indicated, and a low-fat diet may be helpful."
    explanation: Review evidence supports L-carnitine for conjugation of toxic metabolites in MAD deficiency.
  - reference: PMID:39950184
    reference_title: "2-[(18)F] FDG PET/CT in Rapid Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level.
    explanation: Levocarnitine used as part of successful treatment regimen in late-onset MADD.
- name: Dietary management and fasting avoidance
  description: 'Dietary strategies focus on avoiding prolonged fasting and limiting fat/protein intake while ensuring adequate carbohydrate supply. During acute crises, IV dextrose is used to suppress catabolism.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Systemic metabolic decompensation
    treatment_effect: MODULATES
    description: Fasting avoidance and adequate nutrition reduce catabolic stress that precipitates systemic decompensation.
  evidence:
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MADD is treatable with riboflavin and appropriate nutrition with a focus on prevention and early management of metabolic decompensation.
    explanation: Appropriate nutrition and decompensation prevention are core management elements.
  - reference: PMID:39950184
    reference_title: "2-[(18)F] FDG PET/CT in Rapid Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level.
    explanation: Dietary intervention was part of the successful treatment approach.
- name: Acute metabolic crisis management
  description: 'Emergency management during metabolic crises includes IV dextrose infusion to suppress catabolism, correction of metabolic acidosis, and initiation of riboflavin therapy. Mechanical ventilation may be required for respiratory failure.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Systemic metabolic decompensation
    treatment_effect: MODULATES
    description: Acute dextrose and supportive care suppress catabolism and stabilize complications during metabolic crisis.
  notes: 'Avoid volatile anesthetics, agents containing high doses of long-chain fatty acids, and intravenous intralipids during acute metabolic crisis because they can worsen metabolic stress in MADD.

    '
  evidence:
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation.
    explanation: Acute metabolic crisis in MADD required intubation and intensive supportive care.
  - reference: PMID:32550677
    reference_title: "Multiple Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Agents/circumstances to avoid: Inadequate caloric provision during stressors (including following vaccination); prolonged fasting; dehydration; high-fat, high-protein diet; volatile anesthetics and those that contain high doses of long-chain fatty acids; administration of intravenous intralipids during an acute metabolic crisis."
    explanation: GeneReviews supports avoiding volatile anesthetics, long-chain-fat-containing agents, and IV intralipids in MADD crisis contexts.
- name: Newborn screening
  description: 'MADD is detectable by newborn screening programs via tandem mass spectrometry acylcarnitine profiling. Early detection enables pre-symptomatic treatment and improved outcomes.

    '
  treatment_term:
    preferred_term: disease screening
    term:
      id: MAXO:0000124
      label: disease screening
  target_phenotypes:
  - preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  - preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  - preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:39273584
    reference_title: "Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs.
    explanation: TMS-based newborn screening can identify MADD cases.
- name: Genetic counseling
  description: 'Genetic counseling is important for affected families given the autosomal recessive inheritance pattern, carrier testing, and prenatal diagnosis options. Genotype-phenotype correlations can inform prognosis.

    '
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:38221620
    reference_title: "Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population.
    explanation: Genetic characterization supports genetic counseling and patient-specific management.
  - reference: PMID:39273584
    reference_title: "Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite significant advancements in sequencing techniques, many patients remain undiagnosed, impacting their access to clinical care and genetic counseling.
    explanation: Highlights the importance of genetic counseling for MADD families.
- name: Sertraline discontinuation
  description: 'Recent evidence suggests sertraline may induce an acquired form of MADD in some patients. Discontinuation of sertraline is warranted when MADD develops in the setting of sertraline use, in addition to riboflavin treatment.

    '
  treatment_term:
    preferred_term: sertraline discontinuation
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Sertraline-associated acquired MADD-like metabolic dysfunction
    treatment_effect: INHIBITS
    description: Discontinuing sertraline removes the suspected pharmacologic trigger for the acquired MADD-like metabolic state.
  notes: 'This is an emerging finding requiring further validation. The mechanism by which sertraline induces MADD-like biochemistry is not fully established.

    '
  evidence:
  - reference: PMID:39092677
    reference_title: "Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients. Importantly, riboflavin treatment seems to be similarly effective as in genetic MADD, but discontinuation of sertraline is reasonably warranted.
    explanation: Identifies sertraline as a potential trigger for acquired MADD and recommends discontinuation.
  - reference: PMID:39092677
    reference_title: "Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Remarkably, all 7 patients without disease-causing mutations were treated with sertraline. In some cases, a deterioration of symptoms closely followed dose increase, and discontinuation resulted in an improved acylcarnitine profile.
    explanation: Dose-response relationship and improvement with sertraline discontinuation.
environmental:
- name: Fasting and catabolic stress
  description: 'Prolonged fasting, intercurrent illness, surgery, and other catabolic stressors increase reliance on fatty acid oxidation and can trigger acute metabolic decompensation in MADD patients.

    '
  evidence:
  - reference: PMID:37217231
    reference_title: "Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MADD is treatable with riboflavin and appropriate nutrition with a focus on prevention and early management of metabolic decompensation.
    explanation: Prevention of metabolic decompensation through nutritional management is a core strategy.
- name: Sertraline exposure
  description: 'Sertraline use has been associated with an acquired form of MADD in patients without identifiable genetic mutations, potentially through interference with mitochondrial flavoprotein function.

    '
  evidence:
  - reference: PMID:39092677
    reference_title: "Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients.
    explanation: Emerging evidence that sertraline can trigger acquired MADD.
prevalence:
- notes: Approximately 1 in 200,000 live births globally. Late-onset MADD is the most common lipid storage myopathy, with a male predominance of approximately 58% in late-onset cases.
progression:
- notes: Disease course varies markedly by subtype. Neonatal forms (types I/II) often have high mortality with severe metabolic acidosis, multiorgan failure, and death in early infancy. Late-onset MADD (type III) is typically progressive with episodic decompensation, proximal weakness, exercise intolerance, and lipid storage myopathy, but responds dramatically to riboflavin in most cases.
notes: 'MADD exhibits remarkable genotype-phenotype correlation. ETFDH mutations predominate in late-onset riboflavin-responsive disease and are enriched in East Asian populations with the c.250G>A hotspot variant. ETFA and ETFB mutations tend to cause more severe neonatal forms. Recent advances include the discovery of an ETFDH-CIII-COQ2 metabolon (Nature Metabolism, 2024) expanding the understanding of MADD beyond a simple substrate oxidation block to a disorder of mitochondrial redox organization. The association of sertraline with acquired MADD (Annals of Neurology, 2024) represents an important pharmacovigilance finding.

  '
references:
- reference: PMID:32550677
  title: Multiple Acyl-CoA Dehydrogenase Deficiency.
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

1

PMID:32550677

Multiple Acyl-CoA Dehydrogenase Deficiency.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Pathophysiology description (narrative)

Edison Scientific Literature 48 citations 2026-02-23T23:43:48.189548

Pathophysiology description (narrative)

MADD/GAII is an autosomal recessive disorder caused by biallelic pathogenic variants in ETFA, ETFB, or ETFDH (and related flavin handling genes in some riboflavin-responsive MADD-like phenotypes). These genes encode components of the electron transfer flavoprotein system that shuttles electrons from multiple FAD-dependent acyl‑CoA dehydrogenases to the mitochondrial ubiquinone (coenzyme Q) pool. Defective ETF/ETFDH-mediated electron transfer produces a functional block in mitochondrial fatty‑acid β‑oxidation and related amino‑acid oxidation pathways, resulting in characteristic acylcarnitine and organic-acid accumulations and a systemic tendency to energy failure during catabolic stress. Recent work further demonstrates that ETFDH can participate in an ETFDH–complex III–COQ2 “metabolon” that supports complex III function and coenzyme Q homeostasis; ETFDH deficiency can thereby induce QH2 reductive stress, increase mitochondrial ROS, and impair OXPHOS efficiency. In neuronal models of ETFDH mutations, oxidative stress links to BCL‑2 family/MOMP signaling with caspase activation, causing apoptosis and neurite outgrowth defects, which can be mitigated by coenzyme Q10.

Gene/protein annotations (HGNC symbols; suggested GO term names)

• ETFDH: inner mitochondrial membrane flavoprotein; electron transfer from ETF to ubiquinone; regulation of respiratory chain complex III efficiency; coenzyme Q redox homeostasis; response to oxidative stress. (martin2024anetfdhdrivenmetabolon pages 1-2, olsen2007etfdhmutationsas pages 2-2) • ETFA/ETFB: ETF subunits enabling electron transfer from multiple acyl‑CoA dehydrogenases into ETFDH/CoQ. (olsen2007etfdhmutationsas pages 2-2, aragao2024revitalisingriboflavinunveiling pages 10-12) • FLAD1: FAD synthesis; riboflavin-responsive MADD-like lipid storage myopathy. (wen2024acomparativestudy pages 4-6) • SLC25A32: mitochondrial flavin transport association evidence (Open Targets). (OpenTargets Search: Multiple acyl-CoA dehydrogenase deficiency,Glutaric acidemia type II,Glutaric aciduria type II)

Phenotype associations (suggested HPO term names)

• Hypoglycemia; metabolic acidosis; hyperammonemia; encephalopathy; muscle weakness; rhabdomyolysis; lipid storage myopathy; cardiomyopathy/arrhythmia risk; hepatomegaly/liver dysfunction; respiratory insufficiency in severe late-onset cohorts. (rao2023lateonsetmultipleacylcoa pages 2-3, rao2023lateonsetmultipleacylcoa pages 3-4, schee2024multipleacylcoadehydrogenase pages 2-3)

Cell types (suggested CL term names)

• Skeletal muscle cell / myofiber; motor neuron–like cells (NSC-34 model). (schee2024multipleacylcoadehydrogenase pages 2-3, lin2024etfdhmutationinvolves pages 1-2)

Anatomy (suggested UBERON term names)

• Skeletal muscle, liver, heart, brain. (rao2023lateonsetmultipleacylcoa pages 3-4, schee2024multipleacylcoadehydrogenase pages 2-3)

Chemical entities (examples; mapable to ChEBI)

• Riboflavin; FAD; coenzyme Q10; L‑carnitine; acylcarnitines; glutaric acid; ethylmalonic acid; 2‑hydroxyglutarate. (martino2024deepintronicetfdh pages 1-2, rao2023lateonsetmultipleacylcoa pages 4-5)

Figure evidence

A pathway schematic of ETF→ETFDH→CoQ electron flow and its connection to OXPHOS is provided in the Nature Metabolism 2024 figures. (martin2024anetfdhdrivenmetabolon media f5fb06a9)

URLs and publication dates (selected)

• Martín et al., Nature Metabolism, Jan 2024: https://doi.org/10.1038/s42255-023-00956-y (martin2024anetfdhdrivenmetabolon pages 1-2) • Lin et al., Scientific Reports, Oct 2024: https://doi.org/10.1038/s41598-024-75286-4 (lin2024etfdhmutationinvolves pages 1-2) • Martino et al., Int J Mol Sci, Sep 2024: https://doi.org/10.3390/ijms25179637 (martino2024deepintronicetfdh pages 1-2) • Ma et al., Orphanet J Rare Dis, Feb 2024: https://doi.org/10.1186/s13023-024-03072-6 (ma2024themaletofemaleratio pages 1-2) • Schee et al., J Clin Neurol, May 2024: https://doi.org/10.3988/jcn.2023.0265 (schee2024multipleacylcoadehydrogenase pages 2-3) • Rao et al., BMJ Case Reports, May 2023: https://doi.org/10.1136/bcr-2022-252668 (rao2023lateonsetmultipleacylcoa pages 2-3) • Olsen et al., Brain, Aug 2007: https://doi.org/10.1093/brain/awm135 (olsen2007etfdhmutationsas pages 1-2)

Limitations note

Some requested items (e.g., comprehensive GO/HP/CL/UBERON ID codes and a fully enumerated list of all causal/associated PMIDs beyond those explicitly present in the provided evidence snippets and OpenTargets listing) require a dedicated ontology cross-referencing step and/or additional full-text retrieval beyond the current evidence set; the mechanistic narrative and statistics above are restricted to statements supported directly by the cited sources. (OpenTargets Search: Multiple acyl-CoA dehydrogenase deficiency,Glutaric acidemia type II,Glutaric aciduria type II)

References

(bisschoff2024clinicalbiochemicaland pages 1-2): Michelle Bisschoff, Izelle Smuts, Marli Dercksen, Maryke Schoonen, Barend C. Vorster, George van der Watt, Careni Spencer, Kireshnee Naidu, Franclo Henning, Surita Meldau, Robert McFarland, Robert W. Taylor, Krutik Patel, Mahmoud R. Fassad, Jana Vandrovcova, Ronald J. A. Wanders, and Francois H. van der Westhuizen. Clinical, biochemical, and genetic spectrum of madd in a south african cohort: an icgnmd study. Orphanet Journal of Rare Diseases, Jan 2024. URL: https://doi.org/10.1186/s13023-023-03014-8, doi:10.1186/s13023-023-03014-8. This article has 3 citations and is from a peer-reviewed journal.
(OpenTargets Search: Multiple acyl-CoA dehydrogenase deficiency,Glutaric acidemia type II,Glutaric aciduria type II): Open Targets Query (Multiple acyl-CoA dehydrogenase deficiency,Glutaric acidemia type II,Glutaric aciduria type II, 20 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(li2024fatalmultipleacylcoa pages 3-4): Xue-Xia Li, Xiao-Nan Yang, Hu-Dan Pan, and Liang Liu. Fatal multiple acyl-coa dehydrogenase deficiency caused by etfdh gene mutation: a case report. World Journal of Clinical Cases, 12:5422-5430, Aug 2024. URL: https://doi.org/10.12998/wjcc.v12.i23.5422, doi:10.12998/wjcc.v12.i23.5422. This article has 0 citations.
(martino2024deepintronicetfdh pages 1-2): Stefania Martino, Pietro D’Addabbo, Antonella Turchiano, Francesca Clementina Radio, Alessandro Bruselles, Viviana Cordeddu, Cecilia Mancini, Alessandro Stella, Nicola Laforgia, Donatella Capodiferro, Simonetta Simonetti, Rosanna Bagnulo, Orazio Palumbo, Flaviana Marzano, Ornella Tabaku, Antonella Garganese, Michele Stasi, Marco Tartaglia, Graziano Pesole, and Nicoletta Resta. Deep intronic etfdh variants represent a recurrent pathogenic event in multiple acyl-coa dehydrogenase deficiency. International Journal of Molecular Sciences, 25:9637, Sep 2024. URL: https://doi.org/10.3390/ijms25179637, doi:10.3390/ijms25179637. This article has 3 citations.
(schee2024multipleacylcoadehydrogenase pages 1-2): Jie Ping Schee, Joo San Tan, Cheng Yin Tan, Nortina Shahrizaila, Kum Thong Wong, and Khean Jin Goh. Multiple acyl-coa dehydrogenase deficiency: phenotypic and genetic features of a malaysian cohort. Journal of Clinical Neurology (Seoul, Korea), 20:422-430, May 2024. URL: https://doi.org/10.3988/jcn.2023.0265, doi:10.3988/jcn.2023.0265. This article has 2 citations.
(баранова2024клиникогенетическаяхарактеристикапациентов pages 1-2): ПВ Баранова and ГВ Байдакова. Клинико-генетическая характеристика пациентов с глутаровой ацидурией типа 2, выявленных по программе расширенного неонатального скрининга в …. Unknown journal, 2024.
(aragao2024revitalisingriboflavinunveiling pages 10-12): M. Ângela Aragão, Lara Pires, Celestino Santos-Buelga, Lillian Barros, and Ricardo C. Calhelha. Revitalising riboflavin: unveiling its timeless significance in human physiology and health. Foods, 13:2255, Jul 2024. URL: https://doi.org/10.3390/foods13142255, doi:10.3390/foods13142255. This article has 31 citations.
(martin2024anetfdhdrivenmetabolon pages 1-2): Juan Cruz Herrero Martín, Beñat Salegi Ansa, Gerardo Álvarez-Rivera, Sonia Domínguez-Zorita, Pilar Rodríguez-Pombo, Belén Pérez, Enrique Calvo, Alberto Paradela, David G. Miguez, Alejandro Cifuentes, José M. Cuezva, and Laura Formentini. An etfdh-driven metabolon supports oxphos efficiency in skeletal muscle by regulating coenzyme q homeostasis. Nature Metabolism, 6:209-225, Jan 2024. URL: https://doi.org/10.1038/s42255-023-00956-y, doi:10.1038/s42255-023-00956-y. This article has 33 citations and is from a domain leading peer-reviewed journal.
(martin2024anetfdhdrivenmetabolon media f5fb06a9): Juan Cruz Herrero Martín, Beñat Salegi Ansa, Gerardo Álvarez-Rivera, Sonia Domínguez-Zorita, Pilar Rodríguez-Pombo, Belén Pérez, Enrique Calvo, Alberto Paradela, David G. Miguez, Alejandro Cifuentes, José M. Cuezva, and Laura Formentini. An etfdh-driven metabolon supports oxphos efficiency in skeletal muscle by regulating coenzyme q homeostasis. Nature Metabolism, 6:209-225, Jan 2024. URL: https://doi.org/10.1038/s42255-023-00956-y, doi:10.1038/s42255-023-00956-y. This article has 33 citations and is from a domain leading peer-reviewed journal.
(olsen2007etfdhmutationsas pages 2-2): R. K. J. Olsen, S. E. Olpin, B. S. Andresen, Z. H. Miedzybrodzka, M. Pourfarzam, B. Merinero, F. E. Frerman, M. W. Beresford, J. C. S. Dean, N. Cornelius, O. Andersen, A. Oldfors, E. Holme, N. Gregersen, D. M. Turnbull, and A. A. M. Morris. Etfdh mutations as a major cause of riboflavin-responsive multiple acyl-coa dehydrogenation deficiency. Brain : a journal of neurology, 130 Pt 8:2045-54, Aug 2007. URL: https://doi.org/10.1093/brain/awm135, doi:10.1093/brain/awm135. This article has 374 citations.
(lin2024etfdhmutationinvolves pages 1-2): Chuang-Yu Lin, Wen-Chen Liang, Yi-Chen Yu, Shin-Cheng Chang, Ming-Chi Lai, and Yuh-Jyh Jong. Etfdh mutation involves excessive apoptosis and neurite outgrowth defect via bcl2 pathway. Scientific Reports, Oct 2024. URL: https://doi.org/10.1038/s41598-024-75286-4, doi:10.1038/s41598-024-75286-4. This article has 1 citations and is from a peer-reviewed journal.
(lin2024etfdhmutationinvolves pages 7-8): Chuang-Yu Lin, Wen-Chen Liang, Yi-Chen Yu, Shin-Cheng Chang, Ming-Chi Lai, and Yuh-Jyh Jong. Etfdh mutation involves excessive apoptosis and neurite outgrowth defect via bcl2 pathway. Scientific Reports, Oct 2024. URL: https://doi.org/10.1038/s41598-024-75286-4, doi:10.1038/s41598-024-75286-4. This article has 1 citations and is from a peer-reviewed journal.
(schee2024multipleacylcoadehydrogenase pages 2-3): Jie Ping Schee, Joo San Tan, Cheng Yin Tan, Nortina Shahrizaila, Kum Thong Wong, and Khean Jin Goh. Multiple acyl-coa dehydrogenase deficiency: phenotypic and genetic features of a malaysian cohort. Journal of Clinical Neurology (Seoul, Korea), 20:422-430, May 2024. URL: https://doi.org/10.3988/jcn.2023.0265, doi:10.3988/jcn.2023.0265. This article has 2 citations.
(wen2024acomparativestudy pages 4-6): Bing Wen, Runqi Tang, Shuyao Tang, Yuan Sun, Jingwen Xu, Dandan Zhao, Tan Wang, and Chuanzhu Yan. A comparative study on riboflavin responsive multiple acyl-coa dehydrogenation deficiency due to variants in flad1 and etfdh gene. Journal of human genetics, 69:125-131, Jan 2024. URL: https://doi.org/10.1038/s10038-023-01216-3, doi:10.1038/s10038-023-01216-3. This article has 10 citations and is from a peer-reviewed journal.
(rao2023lateonsetmultipleacylcoa pages 2-3): Naini Nishita Rao, Kharis Burns, Catherine Manolikos, and Samantha Hodge. Late-onset multiple acyl-coa dehydrogenase deficiency: an insidious presentation. BMJ Case Reports, 16:e252668, May 2023. URL: https://doi.org/10.1136/bcr-2022-252668, doi:10.1136/bcr-2022-252668. This article has 6 citations and is from a peer-reviewed journal.
(murgia2023newinsightsinto pages 7-8): Chiara Murgia, Ankush Dehlia, and Mark A. Guthridge. New insights into the nutritional genomics of adult-onset riboflavin-responsive diseases. Nutrition & Metabolism, Oct 2023. URL: https://doi.org/10.1186/s12986-023-00764-x, doi:10.1186/s12986-023-00764-x. This article has 18 citations and is from a peer-reviewed journal.
(rao2023lateonsetmultipleacylcoa pages 4-5): Naini Nishita Rao, Kharis Burns, Catherine Manolikos, and Samantha Hodge. Late-onset multiple acyl-coa dehydrogenase deficiency: an insidious presentation. BMJ Case Reports, 16:e252668, May 2023. URL: https://doi.org/10.1136/bcr-2022-252668, doi:10.1136/bcr-2022-252668. This article has 6 citations and is from a peer-reviewed journal.
(daher2024diagnosticchallengesand pages 6-8): Rose T. Daher, Katia El Taoum, Jinane Samaha, and Pascale E. Karam. Diagnostic challenges and outcome of fatty acid oxidation defects in a tertiary care center in lebanon. Orphanet Journal of Rare Diseases, Aug 2024. URL: https://doi.org/10.1186/s13023-024-03325-4, doi:10.1186/s13023-024-03325-4. This article has 0 citations and is from a peer-reviewed journal.
(rao2023lateonsetmultipleacylcoa pages 3-4): Naini Nishita Rao, Kharis Burns, Catherine Manolikos, and Samantha Hodge. Late-onset multiple acyl-coa dehydrogenase deficiency: an insidious presentation. BMJ Case Reports, 16:e252668, May 2023. URL: https://doi.org/10.1136/bcr-2022-252668, doi:10.1136/bcr-2022-252668. This article has 6 citations and is from a peer-reviewed journal.
(rao2023lateonsetmultipleacylcoa pages 1-2): Naini Nishita Rao, Kharis Burns, Catherine Manolikos, and Samantha Hodge. Late-onset multiple acyl-coa dehydrogenase deficiency: an insidious presentation. BMJ Case Reports, 16:e252668, May 2023. URL: https://doi.org/10.1136/bcr-2022-252668, doi:10.1136/bcr-2022-252668. This article has 6 citations and is from a peer-reviewed journal.
(ma2024themaletofemaleratio pages 1-2): Jing Ma, Huiqiu Zhang, Feng Liang, Guanxi Li, Xiaomin Pang, Rongjuan Zhao, Juan Wang, Xueli Chang, Junhong Guo, and Wei Zhang. The male-to-female ratio in late-onset multiple acyl-coa dehydrogenase deficiency: a systematic review and meta-analysis. Orphanet Journal of Rare Diseases, Feb 2024. URL: https://doi.org/10.1186/s13023-024-03072-6, doi:10.1186/s13023-024-03072-6. This article has 10 citations and is from a peer-reviewed journal.
(ma2024themaletofemaleratio pages 2-5): Jing Ma, Huiqiu Zhang, Feng Liang, Guanxi Li, Xiaomin Pang, Rongjuan Zhao, Juan Wang, Xueli Chang, Junhong Guo, and Wei Zhang. The male-to-female ratio in late-onset multiple acyl-coa dehydrogenase deficiency: a systematic review and meta-analysis. Orphanet Journal of Rare Diseases, Feb 2024. URL: https://doi.org/10.1186/s13023-024-03072-6, doi:10.1186/s13023-024-03072-6. This article has 10 citations and is from a peer-reviewed journal.
(martino2024deepintronicetfdh pages 2-3): Stefania Martino, Pietro D’Addabbo, Antonella Turchiano, Francesca Clementina Radio, Alessandro Bruselles, Viviana Cordeddu, Cecilia Mancini, Alessandro Stella, Nicola Laforgia, Donatella Capodiferro, Simonetta Simonetti, Rosanna Bagnulo, Orazio Palumbo, Flaviana Marzano, Ornella Tabaku, Antonella Garganese, Michele Stasi, Marco Tartaglia, Graziano Pesole, and Nicoletta Resta. Deep intronic etfdh variants represent a recurrent pathogenic event in multiple acyl-coa dehydrogenase deficiency. International Journal of Molecular Sciences, 25:9637, Sep 2024. URL: https://doi.org/10.3390/ijms25179637, doi:10.3390/ijms25179637. This article has 3 citations.
(wang2023clinicalandgene pages 1-2): Xiaoxia Wang and Haining Fang. Clinical and gene analysis of fatty acid oxidation disorders found in neonatal tandem mass spectrometry screening. Pharmacogenomics and Personalized Medicine, 16:577-587, Jun 2023. URL: https://doi.org/10.2147/pgpm.s402760, doi:10.2147/pgpm.s402760. This article has 4 citations and is from a peer-reviewed journal.
(olsen2007etfdhmutationsas pages 6-7): R. K. J. Olsen, S. E. Olpin, B. S. Andresen, Z. H. Miedzybrodzka, M. Pourfarzam, B. Merinero, F. E. Frerman, M. W. Beresford, J. C. S. Dean, N. Cornelius, O. Andersen, A. Oldfors, E. Holme, N. Gregersen, D. M. Turnbull, and A. A. M. Morris. Etfdh mutations as a major cause of riboflavin-responsive multiple acyl-coa dehydrogenation deficiency. Brain : a journal of neurology, 130 Pt 8:2045-54, Aug 2007. URL: https://doi.org/10.1093/brain/awm135, doi:10.1093/brain/awm135. This article has 374 citations.
(olsen2007etfdhmutationsas pages 1-2): R. K. J. Olsen, S. E. Olpin, B. S. Andresen, Z. H. Miedzybrodzka, M. Pourfarzam, B. Merinero, F. E. Frerman, M. W. Beresford, J. C. S. Dean, N. Cornelius, O. Andersen, A. Oldfors, E. Holme, N. Gregersen, D. M. Turnbull, and A. A. M. Morris. Etfdh mutations as a major cause of riboflavin-responsive multiple acyl-coa dehydrogenation deficiency. Brain : a journal of neurology, 130 Pt 8:2045-54, Aug 2007. URL: https://doi.org/10.1093/brain/awm135, doi:10.1093/brain/awm135. This article has 374 citations.

Multiple Acyl-CoA Dehydrogenase Deficiency

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