RARE DISEASE
Multiple acyl-CoA dehydrogenase deficiency
Multiple acyl-CoA dehydrogenase deficiency
Multiple acyl-CoA dehydrogenase deficiency
Synonyms: Glutaric acidemia type 2, Glutaric aciduria type 2, MAD deficiency, MADD
Synonyms: Glutaric acidemia type 2, Glutaric aciduria type 2, MAD deficiency, MADD
Synonyms: Glutaric acidemia type 2, Glutaric aciduria type 2, MAD deficiency, MADD
Drug discovery
1
drug
With orphan designation
Overview
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism caused by mutations in ETFA, ETFB, or ETFDH, disrupting mitochondrial electron transfer. It presents with clinical heterogeneity: severe neonatal forms feature metabolic acidosis, cardiomyopathy, and congenital anomalies, while late-onset forms manifest as episodic muscle weakness, exercise intolerance, and metabolic decompensation. Diagnosis involves elevated plasma acylcarnitines (C4–C18), urinary glutaric/ethylmalonic acids, and genetic testing. Riboflavin-responsive cases show dramatic improvement with supplementation, supported by dietary modifications (low-fat, low-protein, high-carbohydrate) and strict fasting avoidance [1][3][6][10].
Burden
Neonatal forms (MADD-S): High mortality (~100%) within weeks without intervention [1][10].
Late-onset forms: Chronic disability from lipid storage myopathy, neuropathy, and episodic crises [4][6][13].
Screening disparities: Newborn screening available in select European countries only; delayed diagnosis worsens outcomes [1][4][10].
Therapies
Riboflavin (100–400 mg/day): First-line for responsive (rr-MADD) patients, reversing muscle and metabolic symptoms [6][10][13].
Dietary management: Low-fat/low-protein intake, carbohydrate-rich meals, and amylase-assisted corn starch to prolong fasting tolerance [1][3][8].
Emergency protocols: Intravenous dextrose, metabolic acidosis correction, and CoQ10/3-hydroxybutyrate supplementation in refractory cases [1][5][11].
Categories: rare cardiac diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
226 drug discovery papers about Multiple acyl-CoA dehydrogenase deficiency, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
226 drug discovery papers about Multiple acyl-CoA dehydrogenase deficiency, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-11 | Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD / Glutaric Acidemia Type IIC) Presenting as Chronic Sensory Ataxic Ganglionopathy, Bilateral Sensorineural Hearing Loss, and Vocal Cord Dysfunction Associated with a Novel ETFDH Variant
Background: Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidaemia type II (GA II), is a rare inherited autosomal recessive disorder involving the metabolic pathways of fatty acid and amino acid oxidation. Catastrophic metabolic crises are observed in the typical neonatal presentation of MADD, whereas variable lipid storage myopathy is a common characteristic of late-onset type IIC. Sensory ataxic ganglionopathy, cranial neuropathies and vocal cord paralysis are relatively atypical presentations of late-onset MADD, and diagnosis is often difficult. Case Presentation: A 39-year-old woman had a 5-year history of insidiously progressive symmetrical paraesthesia, with functionally disabling sensory ataxia requiring ambulatory/mobility aid use, progressively debilitating bilateral hearing loss and dysphonia. On examination, she had diffuse hypotonia, moderate (4/5) proximal lower-limb weakness, atrophy of the distal intrinsic interphalangeal muscles, diffuse hyporeflexia, absent knee and ankle jerks, absent plantar responses bilaterally, a positive Romberg sign, bilateral mixed/sensorineural hearing loss (CN VIII, R>L), and a voice abnormality due to vocal cord paresis with a wide phonatory gap (CN IX/X). Microscopic analysis of the sural nerve biopsy revealed marked loss of myelinated fibres without clusters of regenerating nerve fibres; the histology was definitive for sensory ganglionopathy. Initial serology was positive for anti-beta-2 glycoprotein 1 and anti-cardiolipin IgM, suggesting an immune/antiphospholipid-mediated process. Exome sequencing revealed a novel homozygous missense variant in ETFDH exon 13, c.1826G>A, p.Gly609Glu. Classified as a VUS, this had clinical associations with early-onset GA IIC. Following pulse steroid immunotherapy with the addition of metabolic support (riboflavin, L-carnitine, CoQ10), there was subjective sensory recovery and resolution of voice problems, with regained independence in day-to-day tasks; attribution to individual treatments remains problematic. Conclusion: This study emphasises the phenotypic variability of MADD presenting with features mimicking autoimmune sensory neuronopathy. Exome sequencing is important in resolving diagnostically confusing cases of adult-onset cranial neuropathies and sensory ataxia. Novel ETFDH variants underscore the need for careful clinical and histopathological correlation, while early treatment with riboflavin and metabolic cofactors may contribute to clinical stabilisation.
2026-08-27 | A Family Exhibiting Autosomal Dominant Inheritance of Multiple Acyl-Coenzyme A (CoA) Dehydrogenase Deficiency (MADD) Disease.
Multiple acyl-CoA dehydrogenase deficiency (MADD) is considered an autosomal recessive disorder; yet, recent findings suggest up to 10% of cases may result from heterozygous electron transfer flavoprotein dehydrogenase (ETFDH) variants exhibiting dominant or dominant-like effects. Here, a novel heterozygous ETFDH variant (c.1798A>C, p.Asn600His) was identified within a three-generation family. The grandfather presented with muscular weakness at age 35, and the father developed similar symptoms at 19 following a tonsillectomy. Both were diagnosed with MADD based on muscle biopsies revealing neutral lipid accumulation and acylcarnitine profiles and responded fully to riboflavin therapy (150 mg/day). The two siblings, aged 8 and 10, carry the same mutation and show increased acyl-carnitine levels but remain asymptomatic due to early riboflavin treatment. Skin fibroblasts from affected individuals were immortalized and subjected to normal and reduced riboflavin levels. Gene expression analysis demonstrated unchanged ETFDH RNA but reduced protein levels in mutant cells, particularly under low riboflavin. Structural modelling suggested the Asn600His substitution destabilizes the protein, diminishing its mitochondrial function. Proximity ligation assays indicated a decreased interaction with mitochondrial complex III, while oxygen consumption via fatty acid oxidation was impaired, especially at reduced riboflavin. The novel ETFDH variant found in this family gives a possible dominant pattern of inheritance for MADD, where a single mutant allele impairs the mitochondrial metabolism, particularly under riboflavin-deficient conditions, and highlights the importance of early riboflavin supplementation in preventing clinical symptoms.
2026-08-01 | EP258 - ECE_1779 - When osteoporosis is not the whole story: late-onset multiple acyl-CoA dehydrogenase deficiency in a postmenopausal woman
Abstract Background Osteoporosis is frequently diagnosed in postmenopausal women, yet secondary etiologies account for nearly one-third of cases. Progressive myopathy or accompanying neuromuscular manifestations should prompt a systematic evaluation for underlying metabolic disorders. Case presentation A 57-year-old woman was referred for evaluation of osteoporosis. She was frail and wheelchair-dependent due to progressive proximal muscle weakness over three years, accompanied by diffuse musculoskeletal pain. Although inflammatory myopathy was suspected, myositis autoantibodies were negative, electromyography showed a myopathic pattern, and muscle biopsy was non-specific; nonetheless, she received intravenous immunoglobulin, rituximab, and high-dose corticosteroids. Menopause age was 50 years, had no family history of osteoporosis, did not smoke or consume alcohol. Laboratory evaluation demonstrated normal creatinine, calcium, phosphorus, parathyroid hormone, vitamin D, thyroid function, and 24-hour urinary calcium. Creatine kinase and transaminase levels were mildly elevated. Dual-energy X-ray absorptiometry revealed a lumbar spine T-score of −1.8 and a femoral neck T-score of −3.3, with FRAX-estimated risks of 19% for major osteoporotic fracture and 6.4% for hip fracture. Vertebral imaging revealed mild height loss at L3. Denosumab therapy was initiated, but multiple vertebral fractures occurred eight months later, following a fall, prompting the addition of teriparatide. Given the prominent myopathy, adult-onset metabolic myopathies were considered. Lactate and ammonia levels were normal. There is no ketonuria. Tandem mass spectrometry showed elevated multi-chain acyl carnitine (C4, C5, methyl-glutaryl, C14:2) levels, and urinary organic acid analysis revealed elevated ethyl-malonate, a pattern consistent with multiple acyl-CoA dehydrogenase deficiency(MADD). Pompe disease was excluded by normal alpha-glucosidase activity, while McArdle and Cori diseases were considered unlikely based on clinical features. The only manifestation attributable to MADD was proximal myopathy. Echocardiography revealed no evidence of cardiac involvement. Molecular genetic testing revealed a homozygous pathogenic ETFDH variant (c.1130T > C), thereby establishing the diagnosis of MADD. Treatment with riboflavin, coenzyme Q10, and levocarnitine was initiated along with a low-fat, frequent-meal diet. Within one month, the patient achieved independent ambulation with a 75% reduction in ethylmalonate levels. At six months, there was a marked and sustained improvement in muscle strength and pain, accompanied by an approximately 25% increase in bone mineral density. Conclusions This case underscores the need for a systematic and individualized approach to osteoporosis, particularly when accompanied by progressive myopathy. Late-onset metabolic disorders, including MADD, should be included in the differential diagnosis, as delayed recognition may result in prolonged diagnostic uncertainty and exposure to unnecessary treatments.
2026-07-24 | Progressive Weakness and Hypoglycemia in a Child With Selective Eating: A Nutritional Mimic of a Fatty Acid Oxidation Disorder.
Severe selective eating in children can lead to clinically important nutritional deficiencies. We report a 5-year-old boy with autism spectrum disorder who presented with progressive weakness and hypoglycemia mimicking a fatty acid oxidation disorder (FAOD). His diet had consisted almost exclusively of white rice, and he had developed clinically significant manifestations of folate and vitamin A deficiency before this presentation. After several months of progressive weakness, he developed a generalized seizure with severe hypoglycemia and blunted ketogenesis during an intercurrent infection. Laboratory testing showed low riboflavin, low free carnitine with an elevated acylcarnitine-to-free carnitine ratio, and mild C6-C10 acylcarnitine elevations. Nerve conduction studies suggested sensory-predominant axonal neuropathy. These findings resembled multiple acyl-CoA dehydrogenase deficiency, a FAOD. Riboflavin and levocarnitine supplementation was followed by recovery of independent walking, with no recurrence over 7 years. This case illustrates a nutritional mimic of FAODs and highlights the need for nutritional and metabolic evaluation in selectively eating children with progressive weakness or hypoglycemia.
2026-04-28 | Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review.
Riboflavin (RF, vitamin B2) is an essential vitamin of which the co-factors are critical to numerous cellular processes. RF is used as a treatment for inherited metabolic diseases (IMDs), although its effectiveness in many disorders has not been established. We aim to summarize all available data on the efficacy and safety of RF in the management of IMDs. A systematic literature search was conducted for articles reporting the effectiveness of RF in IMDs. RF therapy was considered "effective" in an IMD if more than 75% of patients showed a positive response, "uncertain" in case of a positive response in fewer than 75% of patients, and "not effective" if patients deteriorated or died following RF therapy. RF therapy was reported in 381 articles addressing 33 separate IMDs. A positive effect was established in MADD type 3 (n=536, 93.1% responsive), RTD 2,3 (n = 94, 90.4% responsive), ACAD 9 (n = 29, 75.9% responsive), and FAD transporter deficiency (n = 5, 100% responsive). The effect was uncertain in complex I and II deficiency, ethylmalonic encephalopathy, FAD synthase deficiency, glutaric aciduria type 1, L2 hydroxyglutaric aciduria, and MADD type 2. RF was not effective in MADD type 1. Adverse effects were infrequent and mild. RF therapy in MADD type 3, RTD 2 and 3, ACAD9, and FAD transporter deficiency is safe and effective. Access to RF for these patients is crucial. For a substantial group of IMDs, the effect of RF remains uncertain. In these conditions, a trial of RF therapy with clearly defined outcome criteria might be considered.
proteins
2026-07-13 | Do Humans Also Have the 'Magnetic Sense' of Migratory Birds?... Secrets of Metabolic Enzymes Unlocked by Quantum Biology
• Researchers at the Johns Hopkins Applied Physics Laboratory (APL) studied 'ETF,' a human metabolic enzyme, and discovered characteristics similar to magnetic field-sensing proteins in birds. • Utilizing molecular dynamics simulations involving millions of hours of CPU computation, they identified specific oxygen binding sites and their characteristic binding times, which are critical for reactive oxygen species (ROS) generation. • It is expected to lead to innovative medical applications in the future, such as treating metabolic diseases (MADD) through magnetic field modulation, and could also be utilized to predict human responses in space environments (like the Moon or Mars). [Quantum Biology Society] Researchers from the Research and Exploratory Development Department at the Johns Hopkins University Applied Physics Laboratory (JHU APL) are garnering significant attention by integrating quantum mechanics with biology. They are unraveling the long-standing mystery of 'magnetosensitivity,' or how the human body responds to the Earth's magnetic field. ■ Similarity Between Human Enzyme 'ETF' and the Compass Protein of Migratory Birds The research team, including Carlos Martino at JHU APL, focused on the 'electron transfer flavoprotein (ETF),' an essential enzyme that transfers electrons to generate energy during human metabolic processes. The research revealed that this ETF is very similar in structure and oxygen-binding mechanism to 'cryptochrome,' a protein known to play a role in sensing magnetic fields in migratory birds. "This is a 'game-changer' study that opens up the possibility, for the first time, that fundamental chemical reactions of proteins found in the human body could be influenced by external magnetic fields," said Martino. ■ Finding the 'ROS' Generation Sites with Millions of Hours of Simulation A key target in the magnetic field response of proteins is the 'reactive oxygen species (ROS)' created when ETF interacts with oxygen. However, since it is difficult to observe exactly where ROS is generated inside the enzyme through experiments alone, the research team conducted 'molecular dynamics simulations' utilizing millions of CPU hours. According to the detailed study published in the international academic journal J. Chem. Inf. Model., the researchers identified five novel, long-lived binding sites where oxygen remains stable near the flavin adenine dinucleotide (FAD) cofactor through all-atom level simulations. At these sites, oxygen maintains a bound state for more than 10 nanoseconds (ns)—sufficient time for electrons to transfer, forming a radical pair and generating superoxide, a type of ROS. ■ Infinite Scalability to Future Medicine and Astrobiology These findings propose a new direction for improving human health. Based on the principles of magnetic field response, the researchers predict that it will be possible to control the production of ROS by artificially engineering proteins. In particular, it can provide crucial clues in identifying how metabolic disorders such as Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), a rare genetic disease caused by ETF deficiency, occur. It also has the potential for broad applications, including injury recovery, bioenergetic improvement, and enhancement of cognitive functions such as memory and learning. Sarah Herman, Program Manager for Biological and Chemical Sciences at APL, expressed her anticipation, stating, "While we are not yet certain exactly what the future applications of this technology will be, it could be used to predict how magnetic field-sensitive brain cells will react in other magnetic field environments, such as the Moon or Mars."
2026-02-28 | IG20/MADD gene functional isoform KIAA0358 can promote insulin secretion in glucose and repaglinide-induced pancreatic β-cells.
Deletion of IG20 (also known as MADD), which can encode multiple isoforms, causes diabetes in mice by impairing glucose-stimulated insulin secretion. To evaluate the role of IG20 in mediating the therapeutic potential of glinide-class insulin secretagogues, we tested their effects in Ig20/Madd-knockout (KMA1ko) mice. Glucose tolerance tests revealed that repaglinide, mitiglinide, and nateglinide failed to lower blood glucose levels or enhance insulin secretion in KMA1ko mice, suggesting that IG20 deficiency significantly diminishes the therapeutic efficacy of glinides. The functional relevance of at least 6 IG20 isoforms remains to be defined. Interestingly, among the six IG20 splicing isoforms re-expressed in IG20-deficient Min6 cells, only KIAA0358 was capable of restoring glucose-stimulated insulin secretion. Notably, KIAA0358 re-expression also rescued repaglinide-induced insulin secretion in vivo. Further transmission electron microscopy and total internal reflection fluorescence microscopy analyses showed that KIAA0358 significantly promoted insulin granule transport and docking impaired by IG20 knockout. Furthermore, guanine nucleotide exchange assay and GST pull-down demonstrated that KIAA0358 functions as a Rab GEF to convert Rab3A and Rab27A from the GDP-bound to the active GTP-bound state, thereby restoring their interactions with the downstream effector proteins Rim2α and Slac-2a that were impaired by IG20 deficiency. Therefore, by regulating the activation states of Rab3A and Rab27A, KIAA0358 mediated the transport and docking of insulin granules to the plasma membrane. This study also highlights that the genes encoding non-drug target proteins can influence drug efficacy and provides a novel conceptual foundation for precision medicine strategies aimed at reducing drug resistance and enhancing the clinical efficacy of glinides.
2026-01-28 | Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD.
Background/Objectives: We have previously demonstrated that fatty acid oxidation (FAO) enzymes physically and functionally interact with electron transfer chain supercomplexes (ETC-SC) at two contact points. The FAO trifunctional protein (TFP) and electron transfer flavoprotein dehydrogenase (ETFDH) interact with the NADH+-binding domain of ETC complex I (com I) and the core 2 subunit of complex III (com III), respectively. In addition, the FAO enzyme very-long-chain acyl-CoA dehydrogenase (VLCAD) interacts with TFP. These interactions define a functional FAO-ETC macromolecular complex (FAO-ETC MEC) in which FAO-generated NADH+ and FADH2 can safely transfer electron equivalents to ETC in order to generate ATP. Methods: In this study, we use multiple mitochondrial functional studies to demonstrate the effect of added VLCAD protein on mutant mitochondria. Results: We demonstrate that heart mitochondria from a VLCAD knockout (KO) mouse exhibit disrupted supercomplexes, with significantly reduced levels of TFPα and TFPβ subunits, electron transfer flavoprotein a-subunit (ETFα), and NDUFV2 subunit of com I in the FAO-ETC MEC. In addition, the activities of individual oxidative phosphorylation (OXPHOS) enzymes are decreased, as is the transfer of reducing equivalents from palmitoyl-CoA to ETC (FAO-ETC flux). However, the total amount of these proteins did not decrease in VLCAD KO animals. These results suggest that loss of VLCAD affects the interactions of FAO and ETC proteins in the FAO-ETC MEC. Reconstitution of VLCAD-deficient heart mitochondria with recombinant VLCAD improved the levels of FAO-ETC MEC proteins and enzyme activities, as well as restoring FAO-ETC flux. It also reduced mitochondrial ROS levels, previously demonstrated to be elevated in VLCAD-deficient mitochondria. In contrast, incubation of VLCAD KO mitochondria with two VLCADs with mutations in the C-terminal domain of the enzyme (A450P and L462P) did not restore FAO-ETC MECs. Conclusions: These results suggest that VLCAD is a necessary component of the FAO-ETC MEC and plays a major role in assembly of the macro-supercomplex. These studies provide evidence that both the level of enzyme and its structural confirmation are necessary to stabilize the FAO-ETC MEC.
2020-08-21 | Molecular and Clinical Investigations on Portuguese Patients with Multiple acyl-CoA Dehydrogenase Deficiency.
Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is a congenital rare metabolic disease with broad clinical phenotypes and variable evolution. This inborn error of metabolism is caused by mutations in the ETFA, ETFB or ETFDH genes, which encode for the mitochondrial ETF and ETF:QO proteins. A considerable group of patients has been described to respond positively to riboflavin oral supplementation, which constitutes the prototypic treatment for the pathology. To report mutations in ETFA, ETFB and ETFDH genes identified in Portuguese patients, correlating, whenever possible, biochemical and clinical outcomes with the effects of mutations on the structure and stability of the affected proteins, to better understand MADD pathogenesis at the molecular level. MADD patients were identified based on the characteristic urinary profile of organic acids and/or acylcarnitine profiles in blood spots during newborn screening. Genotypic, clinical and biochemical data were collected for all patients. In silico structural analysis was employed using bioinformatic tools carried out in an ETF:QO molecular model for the identified missense mutations. A survey describing clinical and biochemical features of eight Portuguese MADD patients was made. Genotype analysis identified five ETFDH mutations, including one extension (p.X618QextX*14), two splice mutations (c.34+5G>C and c.405+3A>T) and two missense mutations (ETF:QO-p.Arg155Gly and ETF:QO-p.Pro534Leu), and one ETFB mutation (ETFβ- p.Arg191Cys). Homozygous patients containing the ETFDH mutations p.X618QextX*14, c.34+5G>C and ETF:QO-p.Arg155Gly, all presented severe (lethal) MADD phenotypes. However, when any of these mutations are in heterozygosity with the known ETF:QO-p.Pro534Leu mild variant, the severe clinical effects are partly and temporarily attenuated. Indeed, the latter destabilizes an ETF-interacting loop, with no major functional consequences. However, the position 155 in ETF:QO is localized at the ubiquinone binding and membrane interacting domain, and is thus expected to perturb protein structure and membrane insertion, with severe functional effects. Structural analysis of molecular models is therefore demonstrated to be a valuable tool to rationalize the effects of mutations in the context of the clinical phenotype severity. Advanced molecular diagnosis, structural analysis and clinical correlations reveal that MADD patients harboring a severe prognosis mutation in one allele can actually revert to a milder phenotype by complementation with a milder mutation in the other allele. However, such patients are nevertheless in a precarious metabolic balance which can revert to severe fatal outcomes during catabolic stress or secondary pathology, thus requiring strict clinical follow-up.
2016-06-06 | Riboflavin transport and metabolism in humans
Abstract Recent studies elucidated how riboflavin transporters and FAD forming enzymes work in humans and create a coordinated flavin network ensuring the maintenance of cellular flavoproteome. Alteration of this network may be causative of severe metabolic disorders such as multiple acyl‐CoA dehydrogenase deficiency (MADD) or Brown‐Vialetto‐van Laere syndrome. A crucial step in the maintenance of FAD homeostasis is riboflavin uptake by plasma and mitochondrial membranes. Therefore, studies on recently identified human plasma membrane riboflavin transporters are presented, together with those in which still unidentified mitochondrial riboflavin transporter(s) have been described. A main goal of future research is to fill the gaps still existing as for some transcriptional, functional and structural details of human FAD synthases (FADS) encoded by FLAD1 gene, a novel “redox sensing” enzyme. In the frame of the hypothesis that FADS, acting as a “FAD chaperone” , could play a crucial role in the biogenesis of mitochondrial flavo‐proteome, several basic functional aspects of flavin cofactor delivery to cognate apo‐flavoenzyme are also briefly dealt with. The establishment of model organisms performing altered FAD homeostasis will improve the molecular description of human pathologies. The molecular and functional studies of transporters and enzymes herereported, provide guidelines for improving therapies which may have beneficial effects on the altered metabolism.
oligonucleotides
2023-07-07 | Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model.
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation (FAO) in humans. Patients exhibit clinical episodes often associated with fasting. Symptoms include hypoketotic hypoglycemia and Reye-like episodes. With limited treatment options, we explored the use of human MCAD (hMCAD) mRNA in fibroblasts from patients with MCAD deficiency to provide functional MCAD protein and reverse the metabolic block. Transfection of hMCAD mRNA into MCAD- deficient patient cells resulted in an increased MCAD protein that localized to mitochondria, concomitant with increased enzyme activity in cell extracts. The therapeutic hMCAD mRNA-lipid nanoparticle (LNP) formulation was also tested in vivo in Acadm-/- mice. Administration of multiple intravenous doses of the hMCAD mRNA-LNP complex (LNP-MCAD) into Acadm-/- mice produced a significant level of MCAD protein with increased enzyme activity in liver, heart and skeletal muscle homogenates. Treated Acadm-/- mice were more resistant to cold stress and had decreased plasma levels of medium-chain acylcarnitines compared to untreated animals. Furthermore, hepatic steatosis in the liver from treated Acadm-/- mice was reduced compared to untreated ones. Results from this study support the potential therapeutic value of hMCAD mRNA-LNP complex treatment for MCAD deficiency.
small molecules
2026-09-11 | Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD / Glutaric Acidemia Type IIC) Presenting as Chronic Sensory Ataxic Ganglionopathy, Bilateral Sensorineural Hearing Loss, and Vocal Cord Dysfunction Associated with a Novel ETFDH Variant
Background: Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidaemia type II (GA II), is a rare inherited autosomal recessive disorder involving the metabolic pathways of fatty acid and amino acid oxidation. Catastrophic metabolic crises are observed in the typical neonatal presentation of MADD, whereas variable lipid storage myopathy is a common characteristic of late-onset type IIC. Sensory ataxic ganglionopathy, cranial neuropathies and vocal cord paralysis are relatively atypical presentations of late-onset MADD, and diagnosis is often difficult. Case Presentation: A 39-year-old woman had a 5-year history of insidiously progressive symmetrical paraesthesia, with functionally disabling sensory ataxia requiring ambulatory/mobility aid use, progressively debilitating bilateral hearing loss and dysphonia. On examination, she had diffuse hypotonia, moderate (4/5) proximal lower-limb weakness, atrophy of the distal intrinsic interphalangeal muscles, diffuse hyporeflexia, absent knee and ankle jerks, absent plantar responses bilaterally, a positive Romberg sign, bilateral mixed/sensorineural hearing loss (CN VIII, R>L), and a voice abnormality due to vocal cord paresis with a wide phonatory gap (CN IX/X). Microscopic analysis of the sural nerve biopsy revealed marked loss of myelinated fibres without clusters of regenerating nerve fibres; the histology was definitive for sensory ganglionopathy. Initial serology was positive for anti-beta-2 glycoprotein 1 and anti-cardiolipin IgM, suggesting an immune/antiphospholipid-mediated process. Exome sequencing revealed a novel homozygous missense variant in ETFDH exon 13, c.1826G>A, p.Gly609Glu. Classified as a VUS, this had clinical associations with early-onset GA IIC. Following pulse steroid immunotherapy with the addition of metabolic support (riboflavin, L-carnitine, CoQ10), there was subjective sensory recovery and resolution of voice problems, with regained independence in day-to-day tasks; attribution to individual treatments remains problematic. Conclusion: This study emphasises the phenotypic variability of MADD presenting with features mimicking autoimmune sensory neuronopathy. Exome sequencing is important in resolving diagnostically confusing cases of adult-onset cranial neuropathies and sensory ataxia. Novel ETFDH variants underscore the need for careful clinical and histopathological correlation, while early treatment with riboflavin and metabolic cofactors may contribute to clinical stabilisation.
2026-08-27 | A Family Exhibiting Autosomal Dominant Inheritance of Multiple Acyl-Coenzyme A (CoA) Dehydrogenase Deficiency (MADD) Disease.
Multiple acyl-CoA dehydrogenase deficiency (MADD) is considered an autosomal recessive disorder; yet, recent findings suggest up to 10% of cases may result from heterozygous electron transfer flavoprotein dehydrogenase (ETFDH) variants exhibiting dominant or dominant-like effects. Here, a novel heterozygous ETFDH variant (c.1798A>C, p.Asn600His) was identified within a three-generation family. The grandfather presented with muscular weakness at age 35, and the father developed similar symptoms at 19 following a tonsillectomy. Both were diagnosed with MADD based on muscle biopsies revealing neutral lipid accumulation and acylcarnitine profiles and responded fully to riboflavin therapy (150 mg/day). The two siblings, aged 8 and 10, carry the same mutation and show increased acyl-carnitine levels but remain asymptomatic due to early riboflavin treatment. Skin fibroblasts from affected individuals were immortalized and subjected to normal and reduced riboflavin levels. Gene expression analysis demonstrated unchanged ETFDH RNA but reduced protein levels in mutant cells, particularly under low riboflavin. Structural modelling suggested the Asn600His substitution destabilizes the protein, diminishing its mitochondrial function. Proximity ligation assays indicated a decreased interaction with mitochondrial complex III, while oxygen consumption via fatty acid oxidation was impaired, especially at reduced riboflavin. The novel ETFDH variant found in this family gives a possible dominant pattern of inheritance for MADD, where a single mutant allele impairs the mitochondrial metabolism, particularly under riboflavin-deficient conditions, and highlights the importance of early riboflavin supplementation in preventing clinical symptoms.
2026-08-01 | EP258 - ECE_1779 - When osteoporosis is not the whole story: late-onset multiple acyl-CoA dehydrogenase deficiency in a postmenopausal woman
Abstract Background Osteoporosis is frequently diagnosed in postmenopausal women, yet secondary etiologies account for nearly one-third of cases. Progressive myopathy or accompanying neuromuscular manifestations should prompt a systematic evaluation for underlying metabolic disorders. Case presentation A 57-year-old woman was referred for evaluation of osteoporosis. She was frail and wheelchair-dependent due to progressive proximal muscle weakness over three years, accompanied by diffuse musculoskeletal pain. Although inflammatory myopathy was suspected, myositis autoantibodies were negative, electromyography showed a myopathic pattern, and muscle biopsy was non-specific; nonetheless, she received intravenous immunoglobulin, rituximab, and high-dose corticosteroids. Menopause age was 50 years, had no family history of osteoporosis, did not smoke or consume alcohol. Laboratory evaluation demonstrated normal creatinine, calcium, phosphorus, parathyroid hormone, vitamin D, thyroid function, and 24-hour urinary calcium. Creatine kinase and transaminase levels were mildly elevated. Dual-energy X-ray absorptiometry revealed a lumbar spine T-score of −1.8 and a femoral neck T-score of −3.3, with FRAX-estimated risks of 19% for major osteoporotic fracture and 6.4% for hip fracture. Vertebral imaging revealed mild height loss at L3. Denosumab therapy was initiated, but multiple vertebral fractures occurred eight months later, following a fall, prompting the addition of teriparatide. Given the prominent myopathy, adult-onset metabolic myopathies were considered. Lactate and ammonia levels were normal. There is no ketonuria. Tandem mass spectrometry showed elevated multi-chain acyl carnitine (C4, C5, methyl-glutaryl, C14:2) levels, and urinary organic acid analysis revealed elevated ethyl-malonate, a pattern consistent with multiple acyl-CoA dehydrogenase deficiency(MADD). Pompe disease was excluded by normal alpha-glucosidase activity, while McArdle and Cori diseases were considered unlikely based on clinical features. The only manifestation attributable to MADD was proximal myopathy. Echocardiography revealed no evidence of cardiac involvement. Molecular genetic testing revealed a homozygous pathogenic ETFDH variant (c.1130T > C), thereby establishing the diagnosis of MADD. Treatment with riboflavin, coenzyme Q10, and levocarnitine was initiated along with a low-fat, frequent-meal diet. Within one month, the patient achieved independent ambulation with a 75% reduction in ethylmalonate levels. At six months, there was a marked and sustained improvement in muscle strength and pain, accompanied by an approximately 25% increase in bone mineral density. Conclusions This case underscores the need for a systematic and individualized approach to osteoporosis, particularly when accompanied by progressive myopathy. Late-onset metabolic disorders, including MADD, should be included in the differential diagnosis, as delayed recognition may result in prolonged diagnostic uncertainty and exposure to unnecessary treatments.
2026-07-24 | Progressive Weakness and Hypoglycemia in a Child With Selective Eating: A Nutritional Mimic of a Fatty Acid Oxidation Disorder.
Severe selective eating in children can lead to clinically important nutritional deficiencies. We report a 5-year-old boy with autism spectrum disorder who presented with progressive weakness and hypoglycemia mimicking a fatty acid oxidation disorder (FAOD). His diet had consisted almost exclusively of white rice, and he had developed clinically significant manifestations of folate and vitamin A deficiency before this presentation. After several months of progressive weakness, he developed a generalized seizure with severe hypoglycemia and blunted ketogenesis during an intercurrent infection. Laboratory testing showed low riboflavin, low free carnitine with an elevated acylcarnitine-to-free carnitine ratio, and mild C6-C10 acylcarnitine elevations. Nerve conduction studies suggested sensory-predominant axonal neuropathy. These findings resembled multiple acyl-CoA dehydrogenase deficiency, a FAOD. Riboflavin and levocarnitine supplementation was followed by recovery of independent walking, with no recurrence over 7 years. This case illustrates a nutritional mimic of FAODs and highlights the need for nutritional and metabolic evaluation in selectively eating children with progressive weakness or hypoglycemia.
2026-04-28 | Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review.
Riboflavin (RF, vitamin B2) is an essential vitamin of which the co-factors are critical to numerous cellular processes. RF is used as a treatment for inherited metabolic diseases (IMDs), although its effectiveness in many disorders has not been established. We aim to summarize all available data on the efficacy and safety of RF in the management of IMDs. A systematic literature search was conducted for articles reporting the effectiveness of RF in IMDs. RF therapy was considered "effective" in an IMD if more than 75% of patients showed a positive response, "uncertain" in case of a positive response in fewer than 75% of patients, and "not effective" if patients deteriorated or died following RF therapy. RF therapy was reported in 381 articles addressing 33 separate IMDs. A positive effect was established in MADD type 3 (n=536, 93.1% responsive), RTD 2,3 (n = 94, 90.4% responsive), ACAD 9 (n = 29, 75.9% responsive), and FAD transporter deficiency (n = 5, 100% responsive). The effect was uncertain in complex I and II deficiency, ethylmalonic encephalopathy, FAD synthase deficiency, glutaric aciduria type 1, L2 hydroxyglutaric aciduria, and MADD type 2. RF was not effective in MADD type 1. Adverse effects were infrequent and mild. RF therapy in MADD type 3, RTD 2 and 3, ACAD9, and FAD transporter deficiency is safe and effective. Access to RF for these patients is crucial. For a substantial group of IMDs, the effect of RF remains uncertain. In these conditions, a trial of RF therapy with clearly defined outcome criteria might be considered.
proteins
2026-07-13 | Do Humans Also Have the 'Magnetic Sense' of Migratory Birds?... Secrets of Metabolic Enzymes Unlocked by Quantum Biology
• Researchers at the Johns Hopkins Applied Physics Laboratory (APL) studied 'ETF,' a human metabolic enzyme, and discovered characteristics similar to magnetic field-sensing proteins in birds. • Utilizing molecular dynamics simulations involving millions of hours of CPU computation, they identified specific oxygen binding sites and their characteristic binding times, which are critical for reactive oxygen species (ROS) generation. • It is expected to lead to innovative medical applications in the future, such as treating metabolic diseases (MADD) through magnetic field modulation, and could also be utilized to predict human responses in space environments (like the Moon or Mars). [Quantum Biology Society] Researchers from the Research and Exploratory Development Department at the Johns Hopkins University Applied Physics Laboratory (JHU APL) are garnering significant attention by integrating quantum mechanics with biology. They are unraveling the long-standing mystery of 'magnetosensitivity,' or how the human body responds to the Earth's magnetic field. ■ Similarity Between Human Enzyme 'ETF' and the Compass Protein of Migratory Birds The research team, including Carlos Martino at JHU APL, focused on the 'electron transfer flavoprotein (ETF),' an essential enzyme that transfers electrons to generate energy during human metabolic processes. The research revealed that this ETF is very similar in structure and oxygen-binding mechanism to 'cryptochrome,' a protein known to play a role in sensing magnetic fields in migratory birds. "This is a 'game-changer' study that opens up the possibility, for the first time, that fundamental chemical reactions of proteins found in the human body could be influenced by external magnetic fields," said Martino. ■ Finding the 'ROS' Generation Sites with Millions of Hours of Simulation A key target in the magnetic field response of proteins is the 'reactive oxygen species (ROS)' created when ETF interacts with oxygen. However, since it is difficult to observe exactly where ROS is generated inside the enzyme through experiments alone, the research team conducted 'molecular dynamics simulations' utilizing millions of CPU hours. According to the detailed study published in the international academic journal J. Chem. Inf. Model., the researchers identified five novel, long-lived binding sites where oxygen remains stable near the flavin adenine dinucleotide (FAD) cofactor through all-atom level simulations. At these sites, oxygen maintains a bound state for more than 10 nanoseconds (ns)—sufficient time for electrons to transfer, forming a radical pair and generating superoxide, a type of ROS. ■ Infinite Scalability to Future Medicine and Astrobiology These findings propose a new direction for improving human health. Based on the principles of magnetic field response, the researchers predict that it will be possible to control the production of ROS by artificially engineering proteins. In particular, it can provide crucial clues in identifying how metabolic disorders such as Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), a rare genetic disease caused by ETF deficiency, occur. It also has the potential for broad applications, including injury recovery, bioenergetic improvement, and enhancement of cognitive functions such as memory and learning. Sarah Herman, Program Manager for Biological and Chemical Sciences at APL, expressed her anticipation, stating, "While we are not yet certain exactly what the future applications of this technology will be, it could be used to predict how magnetic field-sensitive brain cells will react in other magnetic field environments, such as the Moon or Mars."
2026-02-28 | IG20/MADD gene functional isoform KIAA0358 can promote insulin secretion in glucose and repaglinide-induced pancreatic β-cells.
Deletion of IG20 (also known as MADD), which can encode multiple isoforms, causes diabetes in mice by impairing glucose-stimulated insulin secretion. To evaluate the role of IG20 in mediating the therapeutic potential of glinide-class insulin secretagogues, we tested their effects in Ig20/Madd-knockout (KMA1ko) mice. Glucose tolerance tests revealed that repaglinide, mitiglinide, and nateglinide failed to lower blood glucose levels or enhance insulin secretion in KMA1ko mice, suggesting that IG20 deficiency significantly diminishes the therapeutic efficacy of glinides. The functional relevance of at least 6 IG20 isoforms remains to be defined. Interestingly, among the six IG20 splicing isoforms re-expressed in IG20-deficient Min6 cells, only KIAA0358 was capable of restoring glucose-stimulated insulin secretion. Notably, KIAA0358 re-expression also rescued repaglinide-induced insulin secretion in vivo. Further transmission electron microscopy and total internal reflection fluorescence microscopy analyses showed that KIAA0358 significantly promoted insulin granule transport and docking impaired by IG20 knockout. Furthermore, guanine nucleotide exchange assay and GST pull-down demonstrated that KIAA0358 functions as a Rab GEF to convert Rab3A and Rab27A from the GDP-bound to the active GTP-bound state, thereby restoring their interactions with the downstream effector proteins Rim2α and Slac-2a that were impaired by IG20 deficiency. Therefore, by regulating the activation states of Rab3A and Rab27A, KIAA0358 mediated the transport and docking of insulin granules to the plasma membrane. This study also highlights that the genes encoding non-drug target proteins can influence drug efficacy and provides a novel conceptual foundation for precision medicine strategies aimed at reducing drug resistance and enhancing the clinical efficacy of glinides.
2026-01-28 | Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD.
Background/Objectives: We have previously demonstrated that fatty acid oxidation (FAO) enzymes physically and functionally interact with electron transfer chain supercomplexes (ETC-SC) at two contact points. The FAO trifunctional protein (TFP) and electron transfer flavoprotein dehydrogenase (ETFDH) interact with the NADH+-binding domain of ETC complex I (com I) and the core 2 subunit of complex III (com III), respectively. In addition, the FAO enzyme very-long-chain acyl-CoA dehydrogenase (VLCAD) interacts with TFP. These interactions define a functional FAO-ETC macromolecular complex (FAO-ETC MEC) in which FAO-generated NADH+ and FADH2 can safely transfer electron equivalents to ETC in order to generate ATP. Methods: In this study, we use multiple mitochondrial functional studies to demonstrate the effect of added VLCAD protein on mutant mitochondria. Results: We demonstrate that heart mitochondria from a VLCAD knockout (KO) mouse exhibit disrupted supercomplexes, with significantly reduced levels of TFPα and TFPβ subunits, electron transfer flavoprotein a-subunit (ETFα), and NDUFV2 subunit of com I in the FAO-ETC MEC. In addition, the activities of individual oxidative phosphorylation (OXPHOS) enzymes are decreased, as is the transfer of reducing equivalents from palmitoyl-CoA to ETC (FAO-ETC flux). However, the total amount of these proteins did not decrease in VLCAD KO animals. These results suggest that loss of VLCAD affects the interactions of FAO and ETC proteins in the FAO-ETC MEC. Reconstitution of VLCAD-deficient heart mitochondria with recombinant VLCAD improved the levels of FAO-ETC MEC proteins and enzyme activities, as well as restoring FAO-ETC flux. It also reduced mitochondrial ROS levels, previously demonstrated to be elevated in VLCAD-deficient mitochondria. In contrast, incubation of VLCAD KO mitochondria with two VLCADs with mutations in the C-terminal domain of the enzyme (A450P and L462P) did not restore FAO-ETC MECs. Conclusions: These results suggest that VLCAD is a necessary component of the FAO-ETC MEC and plays a major role in assembly of the macro-supercomplex. These studies provide evidence that both the level of enzyme and its structural confirmation are necessary to stabilize the FAO-ETC MEC.
2020-08-21 | Molecular and Clinical Investigations on Portuguese Patients with Multiple acyl-CoA Dehydrogenase Deficiency.
Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is a congenital rare metabolic disease with broad clinical phenotypes and variable evolution. This inborn error of metabolism is caused by mutations in the ETFA, ETFB or ETFDH genes, which encode for the mitochondrial ETF and ETF:QO proteins. A considerable group of patients has been described to respond positively to riboflavin oral supplementation, which constitutes the prototypic treatment for the pathology. To report mutations in ETFA, ETFB and ETFDH genes identified in Portuguese patients, correlating, whenever possible, biochemical and clinical outcomes with the effects of mutations on the structure and stability of the affected proteins, to better understand MADD pathogenesis at the molecular level. MADD patients were identified based on the characteristic urinary profile of organic acids and/or acylcarnitine profiles in blood spots during newborn screening. Genotypic, clinical and biochemical data were collected for all patients. In silico structural analysis was employed using bioinformatic tools carried out in an ETF:QO molecular model for the identified missense mutations. A survey describing clinical and biochemical features of eight Portuguese MADD patients was made. Genotype analysis identified five ETFDH mutations, including one extension (p.X618QextX*14), two splice mutations (c.34+5G>C and c.405+3A>T) and two missense mutations (ETF:QO-p.Arg155Gly and ETF:QO-p.Pro534Leu), and one ETFB mutation (ETFβ- p.Arg191Cys). Homozygous patients containing the ETFDH mutations p.X618QextX*14, c.34+5G>C and ETF:QO-p.Arg155Gly, all presented severe (lethal) MADD phenotypes. However, when any of these mutations are in heterozygosity with the known ETF:QO-p.Pro534Leu mild variant, the severe clinical effects are partly and temporarily attenuated. Indeed, the latter destabilizes an ETF-interacting loop, with no major functional consequences. However, the position 155 in ETF:QO is localized at the ubiquinone binding and membrane interacting domain, and is thus expected to perturb protein structure and membrane insertion, with severe functional effects. Structural analysis of molecular models is therefore demonstrated to be a valuable tool to rationalize the effects of mutations in the context of the clinical phenotype severity. Advanced molecular diagnosis, structural analysis and clinical correlations reveal that MADD patients harboring a severe prognosis mutation in one allele can actually revert to a milder phenotype by complementation with a milder mutation in the other allele. However, such patients are nevertheless in a precarious metabolic balance which can revert to severe fatal outcomes during catabolic stress or secondary pathology, thus requiring strict clinical follow-up.
2016-06-06 | Riboflavin transport and metabolism in humans
Abstract Recent studies elucidated how riboflavin transporters and FAD forming enzymes work in humans and create a coordinated flavin network ensuring the maintenance of cellular flavoproteome. Alteration of this network may be causative of severe metabolic disorders such as multiple acyl‐CoA dehydrogenase deficiency (MADD) or Brown‐Vialetto‐van Laere syndrome. A crucial step in the maintenance of FAD homeostasis is riboflavin uptake by plasma and mitochondrial membranes. Therefore, studies on recently identified human plasma membrane riboflavin transporters are presented, together with those in which still unidentified mitochondrial riboflavin transporter(s) have been described. A main goal of future research is to fill the gaps still existing as for some transcriptional, functional and structural details of human FAD synthases (FADS) encoded by FLAD1 gene, a novel “redox sensing” enzyme. In the frame of the hypothesis that FADS, acting as a “FAD chaperone” , could play a crucial role in the biogenesis of mitochondrial flavo‐proteome, several basic functional aspects of flavin cofactor delivery to cognate apo‐flavoenzyme are also briefly dealt with. The establishment of model organisms performing altered FAD homeostasis will improve the molecular description of human pathologies. The molecular and functional studies of transporters and enzymes herereported, provide guidelines for improving therapies which may have beneficial effects on the altered metabolism.
oligonucleotides
2023-07-07 | Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model.
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation (FAO) in humans. Patients exhibit clinical episodes often associated with fasting. Symptoms include hypoketotic hypoglycemia and Reye-like episodes. With limited treatment options, we explored the use of human MCAD (hMCAD) mRNA in fibroblasts from patients with MCAD deficiency to provide functional MCAD protein and reverse the metabolic block. Transfection of hMCAD mRNA into MCAD- deficient patient cells resulted in an increased MCAD protein that localized to mitochondria, concomitant with increased enzyme activity in cell extracts. The therapeutic hMCAD mRNA-lipid nanoparticle (LNP) formulation was also tested in vivo in Acadm-/- mice. Administration of multiple intravenous doses of the hMCAD mRNA-LNP complex (LNP-MCAD) into Acadm-/- mice produced a significant level of MCAD protein with increased enzyme activity in liver, heart and skeletal muscle homogenates. Treated Acadm-/- mice were more resistant to cold stress and had decreased plasma levels of medium-chain acylcarnitines compared to untreated animals. Furthermore, hepatic steatosis in the liver from treated Acadm-/- mice was reduced compared to untreated ones. Results from this study support the potential therapeutic value of hMCAD mRNA-LNP complex treatment for MCAD deficiency.
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Drug Discovery Landscape
1 orphan drug designation for Multiple acyl-CoA dehydrogenase deficiency.
1 orphan drug designation for Multiple acyl-CoA dehydrogenase deficiency.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
D,L-3-hydroxybutyrate | small molecules | FDA | — | Orpha Labs, AG |
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