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Background: Glutaric aciduria type II (GA2) is a rare genetic disorder inherited in an autosomal recessive manner. Double dosage mutations in GA2 corresponding genes, ETFDH, ETFA, and ETFB, lead to defects in the catabolism of fatty acids, and amino acids lead to broad‐spectrum phenotypes, including muscle weakness, developmental delay, and seizures. product of these three genes have crucial role in transferring electrons to the electron transport chain (ETC), but are not directly involve in ETC complexes. Methods: Here, by using exome sequencing, the cause of periodic cryptic gastrointestinal complications in a 19‐year‐old girl was resolved after years of diagnostic odyssey. Protein modeling for the novel variant served as another line of validation for it. Results: Exome Sequencing (ES) identified two variants in ETFDH: ETFDH:c.926T>G and ETFDH:c.1141G>C. These variants are likely contributing to the crisis in this case. To the best of our knowledge at the time of writing this manuscript, variant ETFDH:c.926T>G is reported here for the first time. Clinical manifestations of the case and pathological analysis are in consistent with molecular findings. Protein modeling provided another line of evidence proving the pathogenicity of the novel variant. ETFDH:c.926T>G is reported here for the first time in relation to the causation GA2. Conclusion: Given the milder symptoms in this case, a review of GA2 cases caused by compound heterozygous mutations was conducted, highlighting the range of symptoms observed in these patients, from mild fatigue to more severe outcomes. The results underscore the importance of comprehensive genetic analysis in elucidating the spectrum of clinical presentations in GA2 and guiding personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Glutaric aciduria type II (GA II), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is a rare autosomal recessive metabolic disorder with varied manifestations and onset ages. Case Report: This study presents a distinctive case of a 10-year-old girl who experienced episodic, intermittent vomiting and epigastric pain, particularly aggravated by high-fat and sweet foods. Despite inconclusive physical examinations and routine laboratory tests, and an initial suspicion of cyclic vomiting syndrome, the persistence of recurrent symptoms and metabolic abnormalities (metabolic acidosis and hypoglycemia) during her third hospital admission necessitated further investigation. Advanced diagnostic tests, including urinary organic acid analysis and genetic testing, identified heterozygous pathogenic variants in the ETFDH gene, confirming a diagnosis of GA IIc. The patient showed a positive response to a custom low-protein, low-fat diet supplemented with carnitine and riboflavin. Significance: This case emphasizes the diagnostic challenges associated with recurrent, nonspecific gastrointestinal symptoms in pediatric patients, particularly in differentiating between common gastrointestinal disorders and rare metabolic disorders like GA II. It highlights the importance of considering a broad differential diagnosis to enhance understanding and guide future medical approaches in similar cases. [ABSTRACT FROM AUTHOR]

Glutaric aciduria type II, also known as Multiple acyl-CoA Dehydrogenase Deficiency, results from a defect in the mitochondrial electron transport chain resulting in an inability to break down fatty-acids and amino acids. There are three phenotypes- type 1 and 2 are of neonatal onset and severe form, with and without congenital anomalies, respectively, and presents with acidosis, severe hypotonia, cardiomyopathy, hepatomegaly, and non-ketotic hypoglycemia. Type 3 or late-onset Multiple acyl-CoA Dehydrogenase Deficiency usually presents in the adolescent or adult age group with phenotype ranging from mild forms of myopathy and exercise intolerance to severe forms of acute metabolic decompensation on its chronic course. Type 3 Multiple acyl-CoA Dehydrogenase Deficiency rarely presents in infancy and in liver failure. We present a five-month-old developmentally normal female child with acute encephalopathy, hypotonia, non-ketotic hypoglycemia, metabolic acidosis, and liver failure, with a history of sibling death of suspected inborn error of metabolism. The blood acyl-carnitine levels in Tandem Mass Spectrometry and urinary organic acid analysis through Gas Chromatography–Mass Spectrometry were unremarkable. The patient initially responded to riboflavin, CoQ, and supportive management but ultimately succumbed to sepsis with shock and multi-organ dysfunction. The clinical exome sequencing reported a homozygous missense variation in exon 11 of the ETFDH gene (chr4:g.158706270C > T) that resulted in the amino acid substitution of Leucine for Proline at codon 456 (p.Pro456Leu) suggestive of Glutaric aciduria type IIc (OMIM#231,680). [ABSTRACT FROM AUTHOR]

Background: Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare metabolic disorder affecting fatty acid oxidation. Incidence at birth is estimated at 1:250 000, but type III presents in adults. It is characterized by nonspecific symptoms but if undiagnosed may cause ketoacidosis and rhabdomyolysis. A review of 350 patients found less than one third presented with metabolic crises. Our objective is to describe an adult with weakness after carbohydrate restriction that developed a pulmonary embolism and ketoacidosis, and was diagnosed with MADD type III. Case Report: A 27-year-old woman with obesity presented to the hospital with fatigue and weakness worsening over months causing falls and decreased intake. She presented earlier to clinic with milder symptoms starting months after initiating a low carbohydrate diet. Testing revealed mild hypothyroidism and she started Levothyroxine for presumed hypothyroid myopathy but progressed. Muscle biopsy suggested a lipid storage myopathy. Genetic testing revealed a mutation in the ETFDH (electron transfer flavoprotein dehydrogenase) gene likely pathogenic for MADD; however, before this was available she developed severe ketoacidosis and rhabdomyolysis. She empirically started a low-fat diet, carnitine, cyanocobalamin, and coenzyme Q10 supplementation with improvement. Over months her energy and strength normalized. Discussion: MADD may cause ketoacidosis and rhabdomyolysis but this is rare in adults. Diagnosis requires clinical suspicion followed by biochemical and genetic testing. It should be considered when patients present with weakness or fasting intolerance. Treatment includes high carbohydrate, low-fat diets, supplementation, and avoiding fasting. Conclusion: There should be greater awareness to consider MADD in adults presenting with neuromuscular symptoms, if untreated it may cause severe metabolic derangements.

Background: Glutaric aciduria type II (GA II), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is a rare autosomal recessive metabolic disorder with varied manifestations and onset ages. Case Report: This study presents a distinctive case of a 10-year-old girl who experienced episodic, intermittent vomiting and epigastric pain, particularly aggravated by high-fat and sweet foods. Despite inconclusive physical examinations and routine laboratory tests, and an initial suspicion of cyclic vomiting syndrome, the persistence of recurrent symptoms and metabolic abnormalities (metabolic acidosis and hypoglycemia) during her third hospital admission necessitated further investigation. Advanced diagnostic tests, including urinary organic acid analysis and genetic testing, identified heterozygous pathogenic variants in the ETFDH gene, confirming a diagnosis of GA IIc. The patient showed a positive response to a custom low-protein, low-fat diet supplemented with carnitine and riboflavin. Significance: This case emphasizes the diagnostic challenges associated with recurrent, nonspecific gastrointestinal symptoms in pediatric patients, particularly in differentiating between common gastrointestinal disorders and rare metabolic disorders like GA II. It highlights the importance of considering a broad differential diagnosis to enhance understanding and guide future medical approaches in similar cases.

Abstract Background Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II is an extremely rare autosomal recessive inborn error of fatty acid beta oxidation and branched-chain amino acids, secondary to mutations in the genes encoding the electron transfer flavoproteins A and B (ETFs; ETFA or ETFB) or ETF dehydrogenase (ETFDH). The clinical manifestation of MADD are heterogeneous, from severe neonatal forms to mild late-onset forms. Case presentation We report the case of a preterm newborn who died a few days after birth for a severe picture of untreatable metabolic acidosis. The diagnosis of neonatal onset MADD was suggested on the basis of clinical features displaying congenital abnormalities and confirmed by the results of expanded newborn screening, which arrived the day the newborn died. Molecular genetic test revealed a homozygous indel variant c.606 + 1 _606 + 2insT in the ETFDH gene, localized in a canonical splite site. This variant, segregated from the two heterozygous parents, is not present in the general population frequency database and has never been reported in the literature. Discussion and conclusion Recently introduced Expanded Newborn Screening is very important for a timely diagnosis of Inherited Metabolic Disorders like MADD. In some cases which are the most severe, diagnosis may arrive after symptoms are already present or may be the neonate already died. This stress the importance of collecting all possible samples to give parents a proper diagnosis and a genetic counselling for future pregnacies.

Glutaric aciduria type II (GA II) is an autosomal recessive metabolic disorder of fatty acid, amino acid, and choline metabolism. The late-onset form of this disorder is caused by a defect in the mitochondrial electron transfer flavoprotein dehydrogenase or the electron transfer flavoprotein dehydrogenase (ETFDH) gene. Thus far, the high clinical heterogeneity of late-onset GA II has brought a great challenge for its diagnosis. In this study, we reported a 21-year-old Chinese man with muscle weakness, vomiting, and severe pain. Muscle biopsy revealed myopathological patterns of lipid storage myopathy, and urine organic acid analyses showed a slight increase in glycolic acid. All the aforementioned results were consistent with GA II. Whole-exome sequencing (WES), followed by bioinformatics and structural analyses, revealed two compound heterozygous missense mutations: c.1034A > G (p.H345R) on exon 9 and c.1448C>A (p.P483Q) on exon 11, which were classified as “likely pathogenic” according to American College of Medical Genetics and Genomics (ACMG). In conclusion, this study described the phenotype and genotype of a patient with late-onset GA II. The two novel mutations in ETFDH were found in this case, which further expands the list of mutations found in patients with GA II. Because of the treatability of this disease, GA II should be considered in all patients with muscular symptoms and acute metabolism decompensation such as hypoglycemia and acidosis.

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II is an extremely rare autosomal recessive inborn error of fatty acid beta oxidation and branched-chain amino acids, secondary to mutations in the genes encoding the electron transfer flavoproteins A and B (ETFs; ETFA or ETFB) or ETF dehydrogenase (ETFDH). The clinical manifestation of MADD are heterogeneous, from severe neonatal forms to mild late-onset forms. Case presentation: We report the case of a preterm newborn who died a few days after birth for a severe picture of untreatable metabolic acidosis. The diagnosis of neonatal onset MADD was suggested on the basis of clinical features displaying congenital abnormalities and confirmed by the results of expanded newborn screening, which arrived the day the newborn died. Molecular genetic test revealed a homozygous indel variant c.606 + 1 _606 + 2insT in the ETFDH gene, localized in a canonical splite site. This variant, segregated from the two heterozygous parents, is not present in the general population frequency database and has never been reported in the literature. Discussion and conclusion: Recently introduced Expanded Newborn Screening is very important for a timely diagnosis of Inherited Metabolic Disorders like MADD. In some cases which are the most severe, diagnosis may arrive after symptoms are already present or may be the neonate already died. This stress the importance of collecting all possible samples to give parents a proper diagnosis and a genetic counselling for future pregnacies. [ABSTRACT FROM AUTHOR]

Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis. • DNA from 28 patients with biochemical and clinical signs of GAII was analysed. • Two paediatric patients had biallelic pathogenic variants (in ETFDH or ETFA). • Other patients had monoallelic variants or no variants in candidate genes. • Cellular environment/many genetic loci may influence GAII in a single individual. • Antidepressant exposure may cause GAII symptoms and biochemistry in some patients. [ABSTRACT FROM AUTHOR]

Abstract Background Multiple acyl-CoA dehydrogenase deficiency (MAAD) is a rare metabolic disorder resulting from an abnormality in fatty acid oxidation. There are three types of presentations: neonatal onset with or without congenital anomalies and the late-onset type. There is much clinical heterogeneity in the presentation of late-onset variants; hence, the diagnosis is often delayed or missed. Case presentation Here, we report the successful management of a 41-year-old female with late-onset MAAD due to mutation in the ETFDH gene who presented with carcinoma of the breast. Chemotherapy was challenging because there were no previous reports regarding the treatment of such cases. Conclusion The diagnosis was made based on metabolic workup and gene mutation analysis. Unplanned surgery and chemotherapy can be fatal in these patients due to metabolic complications. With proper precautions and monitoring, the patient tolerated surgery and chemotherapy without any complications.

Introduction: Myopathy and rhabdomyolysis are not common in children and, if not detected and do not treated it will be associated with high mortality and morbidity rate. The causes of rhabdomyolysis include hypokalemia, trauma, viral myositis, poisoning, rheumatoid diseases, and metabolic myopathies. Rhabdomyolysis treatment includes rapid supportive care and treatment of the underlying disease leading to rhabdomyolysis. Case Presentation: 10-year-old girl with progressive muscle weakness was admitted in Pediatric Intensive Care Unit (PICU) with acute renal failure and respiratory failure. The laboratory results showed myoglobinuria, high CPK, LDH. The initial diagnosis was severe rhabdomyolysis. In addition to fluid therapy and diuretic, she was treated with carnitine and riboflavin with possible glutaric aciduria type II. The patient showed progressive improvement after a few days. Result of plasma acyl carnitine and urine organic acid analysis stablished the diagnosis of glutaric aciduria type II. Conclusion Late onset glutaric aciduria type II has been described as a rare but treatable cause of myopathy and rhabdomyolysis. Glutaric aciduria type II is an important differential diagnosis to consider in children and adults presenting with myopathy and rhabdomyolysis.

Background Inborn errors of metabolism (IEM) are collectively rare but potentially preventable causes of sudden unexpected death (SUD) in infancy or childhood, and metabolic autopsy serves as the final tool for establishing the diagnosis. We conducted a retrospective review of the metabolic and molecular autopsy on SUD and characterized the biochemical and genetic findings. Methodology A retrospective review of postmortem metabolic investigations (dried blood spot acylcarnitines and amino acid analysis, urine metabolic profiling where available, and next-generation sequencing on a panel of 75 IEM genes) performed for infants and children who presented with SUD between October 2016 and December 2021 with inconclusive autopsy findings or autopsy features suspicious of underlying IEM in our locality was conducted. Clinical and autopsy findings were reviewed for each case. Results A total of 43 infants and children aged between zero days to 10 years at the time of death were referred to the authors' laboratories throughout the study period. One positive case of multiple acyl-CoA dehydrogenase deficiency was diagnosed. Postmortem reference intervals for dried blood spot amino acids and acylcarnitines profile were established based on the results from the remaining patients. Conclusions Our study confirmed the importance of metabolic autopsy and the advantages of incorporating biochemical and genetic testing in this setting., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Hung et al.)

Background: Glutaric aciduria type 2 is a rare, lethal disorder that affects metabolism of fatty acids caused by genetic defects in electron transfer (ETF) or in electron transfer flavoprotein dehydrogenase (ETFDH). We aimed to describe the pathological findings of 15 week old foetus, born from a consanguineous couple with 3 previous perinatal deaths. The last son died at 4 days of life and genetic analyses revealed a novel probably pathogenic variant at ETFDH (c.706dupG + c.706dupG) that codifies for a truncated protein (p.Glu236Glyfs*5 + p.Glu236Glyfs*5). Case: During the gestation, due to the medical familial history, prenatal echography and a chorial biopsy for ETFDH-associated glutaric aciduria analysis were carried out. Sanger sequencing confirmed the presence of the homozygous familial variant in the ETFDH gene. The gestation was terminated and the foetal autopsy performed. Autopsy revealed prominent forehead, flat nasal bridge, malformed ears, intrauterine growth retardation, polycystic kidneys and steatosis in the liver, consistent with the diagnosis of glutaric aciduria type II. The comparison of present cases with the previously reported in the literature confirmed the presence of classical criteria, but also revealed the association with urogenital deformities, not previously stated. Conclusions: Clinical and foetal findings allowed the characterisation of the novel variant (c.706dupG at ETDFH) as pathogenic. Genotype-phenotype relationship is important when studying rare genetic disorders such as glutaric aciduria type II, as variants are usually family-specific, leading to a difficulty in the characterisation of their pathogenicity. [ABSTRACT FROM AUTHOR]

The electron-transfer flavoprotein dehydrogenase gene (ETFDH) encodes the ETF-ubiquinone oxidoreductase (ETF-QO) and has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). In this study, we present the clinical and molecular diagnostic challenges, at the DNA and RNA levels, involved in establishing the genotype of four MADD patients with novel ETFDH variants: a missense variant, two deep intronic variants and a gross deletion. RNA sequencing allowed the identification of the second causative allele in all studied patients. Simultaneous DNA and RNA investigation can increase the number of MADD patients that can be confirmed following the suggestive data results of an expanded newborn screening program. In clinical practice, accurate identification of pathogenic mutations is fundamental, particularly with regard to diagnostic, prognostic, therapeutic and ethical issues. Our study highlights the importance of RNA studies for a definitive molecular diagnosis of MADD patients, expands the background of ETFDH mutations and will be important in providing an accurate genetic counseling and a prenatal diagnosis for the affected families.

Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD type I) is an autosomal recessive disorder of the electron transfer flavoprotein function characterized by a severe clinical and biochemical phenotype, including congenital abnormalities with unresponsiveness to riboflavin treatment as distinguishing features. From a retrospective study, relying mainly on metabolic data, we have identified a novel mutation, c.1067G > A (p.Gly356Glu) in exon 8 of ETFDH , in three South African Caucasian MADD patients with the index patient presenting the hallmark features of type I MADD and two patients with compound heterozygous (c.1067G > A + c.1448C > T) mutations presenting with MADD type III. SDS-PAGE western blot confirmed the significant effect of this mutation on ETFDH structural instability. The identification of this novel mutation in three families originating from the South African Afrikaner population is significant to direct screening and strategies for this disease, which amongst the organic acidemias routinely screened for, is relatively frequently observed in this population group. [ABSTRACT FROM AUTHOR]

Introducción: la aciduria glutárica tipo II, o deficiencia múltiple de acil-CoA deshidrogenasas, es un trastorno causado por deficiencia de la flavoproteína de transferencia de electrones, de su oxidorreductasa o de ambas; se trata de una enfermedad metabólica autosómica recesiva, caracterizada por acidosis, hipoglicemia, aciduria orgánica, olor a pies sudados y malformaciones en cerebro y riñones.Objetivo: analizar las tasas de oxidación de sustratos tritiados por fibroblastos de pacientes con aciduria glutárica tipo II.Materiales y métodos: se incubaron fibroblastos de dos pacientes con aciduria glutárica tipo II y de 20 controles en presencia de ácidos palmítico y mirístico tritiados.Resultados: se encontró muy deprimida (16%-18%) la oxidación de los sustratos tritiados por los fibroblastos procedentes de pacientes con aciduria glutárica tipo II en comparación con los controles.Conclusión: la prueba estudiada permite la confirmación in vitro del diagnóstico de aciduria glutárica tipo II.

Late-onset glutaric aciduria type II has been described recently as a rare but treatable cause of proximal myopathy in teenagers and adults. It is an autosomal recessive disease affecting fatty acid, amino acid, and choline metabolism. This is usually a result of 2 defective flavoproteins: either electron transfer flavoprotein (ETF) or electron transfer flavoprotein–ubiquinone oxidoreductase (ETF:QO). We present a 14-year-old boy with a background of autistic spectrum disorder who presented with severe muscle weakness and significant rhabdomyolysis. Before the onset of muscle weakness, he was very active but was completely bedridden at presentation. Diagnosis was established quickly by urine organic acid and plasma acylcarnitine analysis. He has shown significant improvement after starting oral riboflavin supplementation and is now fully mobile. This case highlights that late-onset glutaric aciduria type II is an important differential diagnosis to consider in teenagers presenting with proximal myopathy and rhabdomyolysis and it may not be associated with hypoglycemia. [ABSTRACT FROM PUBLISHER]

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessively inherited disorder of fatty acid metabolism due to ETFA, ETFB or ETFDH mutations. Riboflavin treatment ameliorates symptoms and metabolic profile in ETFDH-related MADD patients. We report on a 20-year-old boy with an 8-year history of progressive difficulty in walking, running and climbing stairs. Muscle biopsy showed a lipid myopathy and the acylcarnitine profile analysis was suggestive of MADD. Nevertheless, no evidence of molecular defects in the ETFA, ETFB and ETFDH exons or intron-exon boundaries was found. Treatment with riboflavin for 1 year resulted in a clear improvement in motor functions. Our report shows that some cases of MADD are not linked to ETFA, ETFB and ETFDH exon or intron-exon boundary changes. They could be due to quite rare promoter or deep intronic mutations or, most likely, to some unknown genetic defect. We therefore suggest to extend in these cases molecular studies to cDNA analysis and indicate the need of extensive pedigree studies to identify other possible disease-related loci. Most important, treatment of these cases with riboflavin can also be effective. Therefore, early diagnosis is essential to achieve the best treatment response. [ABSTRACT FROM AUTHOR]

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Abstract: We report an adolescent case of late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD) characterized by intermittent nausea and depressive state as early symptoms. At the age of 12years and 11months, the patient experienced intermittent nausea and vomiting, and depressive state. She was on medication for depression for 5months but it was ineffective. Brain magnetic resonance imaging showed disseminated high-intensity areas in the periventricular white matter and in the splenium of the corpus callosum on T2-weighted images and fluid-attenuated inversion-recovery images. Progressive muscle weakness occurred and blood creatine kinase level was found to be elevated. The muscle biopsy revealed lipid storage myopathy. Urine organic acid analysis and mutation analysis of the ETFDH gene confirmed the diagnosis of MADD. With oral supplements of riboflavin and l-carnitine, in addition to a high-calorie and reduced-fat diet, her clinical symptoms improved dramatically. Early diagnosis is important because riboflavin treatment has been effective in a significant number of patients with MADD. [ABSTRACT FROM AUTHOR]

Treatment of the genetic metabolic myopathies remains generally unsatisfactory with the exception of a select few. Multiple Acyl Co-A Dehydrogenase Deficiency (Glutaric Aciduria type II), in particular, has been shown to respond well to riboflavin supplementation. Recently, studies have also confirmed the effectiveness of recombinant enzyme replacement therapy for Acid Maltase Deficiency (Pompe's Disease). Accurate and early diagnosis of these diseases is vital to prevent serious complications and impaired recovery following delayed treatment. [ABSTRACT FROM AUTHOR]

Abstract: A newborn female presented on the first day of life with clinical and biochemical findings consistent with multiple acyl-CoA dehydrogenase deficiency (MADD). Riboflavin supplementation corrected the biochemical abnormalities 24h after commencing the vitamin. In vitro acylcarnitine profiling in intact fibroblasts both in normal and riboflavin depleted media showed normal oxidation of fatty acids excluding defects in electron transfer flavoprotein (ETF), or ETF ubiquinone oxidoreductase (ETF:QO), or a genetic abnormality in flavin metabolism. In addition, sequencing of the genes encoding ETF and ETF:QO in the proband did not reveal any pathogenic mutations. Determination of the maternal riboflavin status after delivery showed that the mother was riboflavin deficient. Repeat testing done two years after the infant’s birth and while on a normal diet showed that the mother was persistently riboflavin deficient and showed a typical MADD profile on plasma acylcarnitine testing. A possible genetic defect in riboflavin transport of metabolism in the mother is postulated to be the cause of the transient MADD seen in the infant. Sequencing of the SLC16A12, RFK and FLAD1 genes encoding key enzymes in riboflavin transport of metabolism in the mother did not identify any pathogenic mutations. The underlying molecular basis of the mother’s defect in riboflavin metabolism remains to be established. [Copyright &y& Elsevier]

Abstract: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a recessively inherited metabolic disorder that can be due to a deficiency of electron transfer flavoprotein (ETF) or its dehydrogenase (ETF-ubiquinone oxidoreductase). ETF is a mitochondrial matrix protein consisting of α- (30kDa) and β- (28kDa) subunits encoded by the ETFA and ETFB genes, respectively. In the present study, we have analysed tissue samples from 16 unrelated patients with ETF deficiency, and we report the results of ETF activity, Western blot analysis and mutation analysis. The ETF assay provides a reliable diagnostic tool to confirm ETF deficiency in patients suspected to suffer from MADD. Activity ranged from less than 1 to 16% of controls with the most severely affected patients disclosing the lowest activity values. The majority of patients had mutations in the ETFA gene while only two of them harboured mutations in the ETFB gene. Nine novel disease-causing ETF mutations are reported. [Copyright &y& Elsevier]

Abstract: Late-onset glutaric aciduria type II (GAII) is a rare but treatable cause of profound proximal myopathy. GAII is caused by defects in intra-mitochondrial acyl-CoA dehydrogenation due to deficiency in one of three molecules: the alpha or beta subunits of the electron transport flavoprotein (ETFA; OMIM 231680, ETFB; OMIM 130410), or ETF-dehydrogenase (ETFDH; OMIM 231675). This case report illustrates that GAII may present in the teenage years and may not be associated with hypoglycaemia. It outlines some important diagnostic conundrums faced in diagnosing and managing juvenile onset myopathies. Mutational analysis from this patient revealed two mutations of the ETF-DH gene: EFTDH-334C>T/His122Tyr and EFTDH-1366C>A/Pro456Thr (OMIM 231675). An outline of this rare but important disease, its clinical characteristics and diagnostic methodology are given. [Copyright &y& Elsevier]

Abstract: Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) is most often caused by mutations in the genes encoding the α- or β-subunit of electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETF-DH). Since not all patients have mutations in these genes, other as yet unidentified genes are predicted to be involved as well. Because all affected mitochondrial flavoproteins in MADD have FAD as a prosthetic group, the underlying defect in these patients may be due to a thus far undisclosed disturbance in the metabolism of FAD. Since a proper mitochondrial flavin balance is maintained by a mitochondrial FAD transporter, a defect of this transporter could also cause an MADD-like phenotype. In yeast, FAD is transported across the mitochondrial inner membrane by the FLX1 protein. An FLX1-mutated Saccharomyces cerevisiae strain exhibits a decreased activity of several mitochondrial flavoproteins. In the present study, we report the identification of the human mitochondrial FAD transporter. Based on sequence similarity to FLX1, we identified two human candidate genes (MFT and N111), which were cloned and characterized by functional expression in an FLX1-mutated yeast strain. Of the two candidate genes, only the previously described mitochondrial folate transporter (MFT) was able to functionally complement the FLX1 mutant. Candidates for mutations in the MFT gene are patients with a clinical suspicion of MADD but without any mutation in the α- or β-subunit of ETF or ETF-DH. [Copyright &y& Elsevier]

The variants of electron transfer flavoprotein (ETFA, ETFB) and ETF dehydrogenase (ETFDH) are the leading cause of glutaric aciduria type II (GA-II). In this study, we identified 13 patients harboring six variants of two genes associated with GA-II. Out of the six variants, four were missense, and two were frameshift mutations. A missense variant (ETFDH:p.Gln269His) was observed in a homozygous state in nine patients. Among nine patients, three had experienced metabolic crises with recurrent vomiting, abdominal pain, and nausea. In one patient with persistent metabolic acidosis, hypoglycemia, and a high anion gap, the ETFDH:p.Gly472Arg, and ETFB:p.Pro94Thrfs*8 variants were identified in a homozygous, and heterozygous state, respectively. A missense variant ETFDH:p.Ser442Leu was detected in a homozygous state in one patient with metabolic acidosis, hypoglycemia, hyperammonemia and liver dysfunction. The ETFDH:p.Arg41Leu, and ETFB:p.Ile346Phefs*19 variants were observed in a homozygous state in one patient each. Both these variants have not been reported so far. In silico approaches were used to evaluate the pathogenicity and structural changes linked with these six variants. Overall, the results indicate the importance of a newborn screening program and genetic investigations for patients with GA-II. Moreover, careful interpretation and correlation of variants of uncertain significance with clinical and biochemical findings are needed to confirm the pathogenicity of such variants. [ABSTRACT FROM AUTHOR]

A method for the measurement of dicarboxylic acids in amniotic fluid was developed that utilizes isolation of the acids by liquid partition chromatography and quantification by ammonia chemical ionization selected ion monitoring, gas chromatography-mass spectrometry. The concentrations of dicarboxylic acids in ten normal samples of amniotic fluid (mumol/l +/- 1 S.D.) were glutaric acid 0.91 +/- 0.15, adipic acid 0.33 +/- 0.08, suberic acid 0.27 +/- 0.08, and sebacic acid 0.21 +/- 0.10. A highly elevated concentration of 14.48 mumol/l glutaric acid was found in the amniotic fluid of a pregnancy in which the fetus was affected with glutaric aciduria type II. Adipic, suberic and sebacic acids were also significantly elevated. The dicarboxylic acids were normal in the amniotic fluid of a pregnancy at risk for glutaric aciduria type II in which the fetus was unaffected. This method is suitable for the rapid prenatal diagnosis of glutaric aciduria types I and II and of potential value for the prenatal diagnosis of other inherited disorders in which dicarboxylic acids accumulate. [ABSTRACT FROM AUTHOR]

Two male siblings suffering from a severe form of glutaric aciduria type II were studied. One patient died within one hour after birth, the other at the age of five days. Both patients presented with respiratory distress soon after birth. They had a variety of congenital morphologic abnormalities. One patient's outstanding 'sweaty-feet' odour on the second day of life led to organic acid analysis of urine revealing massive lactic, glutaric, and ethylmalonic aciduria along with a high excretion of various other carboxylic acids and glycine conjugates of the branched chain carboxylic acids. The pattern of metabolites in serum and urine as well as results of degradation studies with various substrates in cultured fibroblasts were consistent with a defect in multiple acyl-CoA dehydrogenation. The morphological abnormalities are presented in a subsequent paper. [ABSTRACT FROM AUTHOR]

The post mortem and microscopic findings of two newborn male sibling of Turkish origin suffering from multiple acyl-CoA-dehydrogenation deficiency (glutaric aciduria type II) are reported in detail for the first time. The morphological disease pattern was strikingly identical in both siblings: enlarged bilateral polycystic kidneys, symmetric warty dysplasia of the cerebral cortex, and bile duct hypoplasia, cholestasis, siderosis and fatty degeneration of the liver were found in both infants. In addition, features of Potter syndrome (pulmonary hypoplasia and 'Potter face') were observed only in sibling I, and focal hypoplasia and dysplasia of pancreatic ducts only in sibling II. It appears to be a rather remote chance that the rare metabolic disorder accidently coincided with the equally rare developmental abnormality in both siblings. We believe it to be more likely that both conditions are pathogenetically related in that the accumulation of large quantities of carboxylic acids exerted their effect already in intrauterine life, probably leading to cellular damage and secondary developmental defects of the fetal kidneys, liver, pancreas and brain. From the nature of the observed morphological alterations we speculate that the injury did not occur until after cessation of organogenesis during the fetal period of intrauterine development. [ABSTRACT FROM AUTHOR]

A boy, now 22 months old, is described who presented at the age of 6 weeks with hypoglycaemic coma. The excretion pattern of organic acids in the urine was consistent with glutaric aciduria type II (GA II). A high energy diet low in fat and protein was given. Treatment with riboflavine resulted in an improvement of the metabolite profile, and the patient gained weight. However, a tendency to hypoglycaemia and severe hypotonia persisted. Due to muscle weakness, aggravated by infections, artificial ventilation was necessary during three periods. Serum carnitine level was low. Treatment with carnitine, started during the third period of artificial ventilation, led to some improvement of muscle strength, but he still could not breathe without support. Treatment with insulin, combined with further enrichment of the diet with glucose, resulted in an increase in muscular strength and in weight gain. Thirteen families with GA II have been described upto now. This is the first patient with a severe form of the disorder wo has survived the 1st year of life. Treatment and metabolic studies are presented. [ABSTRACT FROM AUTHOR]

The electron-transfer flavoprotein dehydrogenase gene (ETFDH) encodes the ETF-ubiquinone oxidoreductase (ETF-QO) and has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). In this study, we present the clinical and molecular diagnostic challenges, at the DNA and RNA levels, involved in establishing the genotype of four MADD patients with novel ETFDH variants: a missense variant, two deep intronic variants and a gross deletion. RNA sequencing allowed the identification of the second causative allele in all studied patients. Simultaneous DNA and RNA investigation can increase the number of MADD patients that can be confirmed following the suggestive data results of an expanded newborn screening program. In clinical practice, accurate identification of pathogenic mutations is fundamental, particularly with regard to diagnostic, prognostic, therapeutic and ethical issues. Our study highlights the importance of RNA studies for a definitive molecular diagnosis of MADD patients, expands the background of ETFDH mutations and will be important in providing an accurate genetic counseling and a prenatal diagnosis for the affected families. [ABSTRACT FROM AUTHOR]

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD), or glutaric aciduria type II (GAII), is a group of clinically heterogeneous disorders caused by mutations in electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETFQO) – the two enzymes responsible for the re-oxidation of enzyme-bound flavin adenine dinucleotide (FADH 2) via electron transfer to the respiratory chain at the level of coenzyme Q10. Over the past decade, an increasing body of evidence has further coupled mutations in FAD metabolism (including intercellular riboflavin transport, FAD biosynthesis and FAD transport) to MADD-like phenotypes. In this review we provide a detailed description of the overarching and specific metabolic pathways involved in MADD. We examine the eight associated genes (ETFA, ETFB, ETFDH, FLAD1, SLC25A32 and SLC52A1−3) and clinical phenotypes, and report ∼436 causative mutations following a systematic literature review. Finally, we focus attention on the value and shortcomings of current diagnostic approaches, as well as current and future therapeutic options for MADD and its phenotypic disorders. [ABSTRACT FROM AUTHOR]

The article presents a study on multiple acyl-coenzyme A dehydrogenase deficiency (MADD) which is an inherited disease resulting from a deficiency electron transfer flavoprotein (ETF) or its ubiquinone oxidoreductase (ETF-QO). Onset of the illness usually occurs during the neonatal period or in early infancy and very rarely in adolescents and young adults. A unique case was cited wherein a 55-year old woman, complaining of painful subacute myopathy, was found after clinical examination to have MADD.

Multiple-CoA dehydrogenase deficiency (MADD) is an inborn disorder of fatty acid and amino acid metabolism caused by mutations in the genes encoding for human electron transfer flavoprotein (ETF) and its partner electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO). Albeit a rare disease, extensive newborn screening programs contributed to a wider coverage of MADD genotypes. However, the impact of non-lethal mutations on ETF:QO function remains scarcely understood from a structural perspective. To this end, we here revisit the relatively common MADD mutation ETF:QO-p.Pro456Leu, in order to clarify how it affects enzyme structure and folding. Given the limitation in recombinant expression of human ETF:QO, we resort to its bacterial homologue from Rhodobacter sphaeroides (Rs) , in which the corresponding mutation (p.Pro389Leu) was inserted. The in vitro biochemical and biophysical investigations of the Rs ETF:QO-p.Pro389Leu variant showed that, while the mutation does not significantly affect the protein α/β fold, it introduces some plasticity on the tertiary structure and within flavin interactions. Indeed, in the p.Pro389Leu variant, FAD exhibits a higher thermolability during thermal denaturation and a faster rate of release in temperature-induced dissociation experiments, in comparison to the wild type. Therefore, although this clinical mutation occurs in the ubiquinone domain, its effect likely propagates to the nearby FAD binding domain, probably influencing electron transfer and redox potentials. Overall, our results provide a molecular rational for the decreased enzyme activity observed in patients and suggest that compromised FAD interactions in ETF:QO might account for the known riboflavin responsiveness of this mutation. Unlabelled Image • MADD is a rare disease of fatty acid and amino-acid metabolism affecting ETF/ETF:QO. • Over 160 mutations known for ETF:QO but structure-function relations are illusive. • The variant ETF:QO-p.Pro456Leu was studied using a bacterial homologue as model. • Protein folding is unaffected but tertiary interactions and FAD lability are compromised. • Findings contribute to uncover basis for MADD patient's riboflavin-responsiveness. [ABSTRACT FROM AUTHOR]

Multiple acyl-CoA-dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) are a group of metabolic disorders due to deficiency of either electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO). We report the clinical features and biochemical and molecular genetic analyses of a patient with a mild late-onset form of GAII due to β-ETF deficiency. Biochemical data showed an abnormal urine organic acid profile, low levels of free carnitine, increased levels of C10:1n−6, and C14:1n–9 in plasma, and decreased oxidation of [9,10-3H]palmitate and [9,10-3H]myristate in fibroblasts, suggesting MAD deficiency. In agreement with these findings, mutational analysis of the ETF/ETFDH genes demonstrated an ETFB missense mutation 124T>C in exon 2 leading to replacement of cysteine-42 with arginine (C42R), and a 604_606AAG deletion in exon 6 in the ETFB gene resulting in the deletion of lysine-202 (K202del). The present report delineates further the phenotype of mild β-ETF deficiency and illustrates that the differential diagnosis of GAII is readily achieved by mutational analysis. [Copyright &y& Elsevier]

Objectives: Multiple acyl-CoA dehydrogenase deficiency (MADD) is the most severe disorder of mitochondrial fatty acid β-oxidation. Treatment of this disorder is difficult because the functional loss of the electron transfer flavoprotein makes energy supply from fatty acids impossible. Acetyl-CoA, provided by exogenous ketone bodies such as NaßHB, is the only treatment option in severe cases. Short-term therapy attempts have shown positive results. To our knowledge, no reports exist concerning long-term application of ketone body salts in patients with severe MADD., Methods: This case report is a detailed retrospective metabolic analysis of a boy with severe MADD. Treatment with sodium β-hydroxybutyrate (NaβHB) started 8 d after birth using gradually increasing doses. In the initial phase, metabolic and acid-base parameters were checked multiple times a day. After 8 y of standardized therapy with 16 g NaβHB, substitution with calcium β-hydroxybutyrate (CaβHB) was attempted. In addition to the β-hydroxybutyrate (βHB) supplementation, continuous adjustments were made to the child's nutrition to provide necessary nutrients., Results: Treatment with βHB salts leads to adverse effects like gastrointestinal discomfort and alkalosis. Measured concentrations of βHB were predominantly at 0.1 mmol/L or below detectable concentration. Nutritional therapy based on amino acid and acylcarnitine profiles is a necessary part of the therapy in MADD., Conclusions: Therapy with NaβHB is lifesaving in cases of severe MADD but can have significant adverse effects. Supplementation with CaβHB led to gastrointestinal discomfort and had no additional positive clinical effect. The determined tolerable dose of βHB salt for long-term therapy was not high enough for a notable increase of βHB concentrations in blood., (Copyright © 2018 Elsevier Ltd. All rights reserved.)