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.
CONCLUSIONS: 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.

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.

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.

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.
METHODS: 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.
CONCLUSIONS: 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.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the variants occurring in the electron transfer flavoprotein-ubiquinone oxidoreductase gene (ETFDH). Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the International Centre for Genomic Medicine in Neuromuscular Diseases study, we recruited a cohort of patients diagnosed with MADD from academic medical centres across SA over a three-year period. The aim was to extensively profile the clinical, biochemical, and genomic characteristics of MADD in this understudied population.
METHODS: Clinical evaluations and whole exome sequencing were conducted on each patient. Metabolic profiling was performed before and after treatment, where possible. The recessive inheritance and phase of the variants were established via segregation analyses using Sanger sequencing. Lastly, the haplotype and allele frequencies were determined for the two main variants in the four largest SA populations.
RESULTS: Twelve unrelated families (ten of White SA and two of mixed ethnicity) with clinically heterogeneous presentations in 14 affected individuals were observed, and five pathogenic ETFDH variants were identified. Based on disease severity and treatment response, three distinct groups emerged. The most severe and fatal presentations were associated with the homozygous c.[1067G > A];c.[1067G > A] and compound heterozygous c.[976G > C];c.[1067G > A] genotypes, causing MADD types I and I/II, respectively. These, along with three less severe compound heterozygous genotypes (c.[1067G > A];c.[1448C > T], c.[740G > T];c.[1448C > T], and c.[287dupA*];c.[1448C > T]), resulting in MADD types II/III, presented before the age of five years, depending on the time and maintenance of intervention. By contrast, the homozygous c.[1448C > T];c.[1448C > T] genotype, which causes MADD type III, presented later in life. Except for the type I, I/II and II cases, urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine. Furthermore, genetic analyses of the most frequent variants (c.[1067G > A] and c.[1448C > T]) revealed a shared haplotype in the region of ETFDH, with SA population-specific allele frequencies of < 0.00067-0.00084%.
CONCLUSIONS: This study reveals the first extensive genotype-phenotype profile of a MADD patient cohort from the diverse and understudied SA population. The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population.

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).

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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: There should be greater awareness to consider MADD in adults presenting with neuromuscular symptoms, if untreated it may cause severe metabolic derangements.

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.
METHODS: 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.
CONCLUSIONS: 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.

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.