BACKGROUND: Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), also known as Glutaric Aciduria Type II, is an exceptionally rare autosomal recessive genetic disorder that disrupts the metabolism of fatty acids, amino acids, and choline. It presents with a wide range of clinical manifestations, from severe neonatal-onset forms to milder late-onset cases, with symptoms including metabolic disturbances and muscle weakness. Jordan\'s anomaly is a distinctive morphological feature found in peripheral blood white cells and is typically associated with Neutral Lipid Storage Disease (NLSD).
METHODS: In our case report, the patient initially presented with symptoms of vomiting, abdominal pain, and altered consciousness. The presence of white cell Jordan\'s anomaly was detected in the blood smear. Subsequent serum tests revealed elevated levels of transaminases, creatine kinase, uric acid, and multiple acylcarnitines, while blood glucose and free carnitine levels were notably reduced. High-throughput sequencing confirmed heterozygous pathogenic variants in the electron-transferring flavoprotein dehydrogenase (ETFDH) gene, leading to the conclusive diagnosis of MADD. Following a three-month treatment regimen involving high-dose vitamin B2, coenzyme Q10, and other supportive interventions, the patient exhibited significant clinical improvement, ultimately resulting in discharge.
CONCLUSIONS: The identification of Jordan\'s anomaly in a pediatric patient with late-onset MADD sheds light on its broader implications within the realm of lipid storage myopathies. The significance of this finding extends beyond its conventional association with NLSD, challenging the notion of its exclusivity. This novel observation serves as a compelling reminder of the diagnostic significance this morphological abnormality holds, potentially revolutionizing diagnostic practices within the field.

UNASSIGNED: Fatty acid oxidation disorders (FAODs) are a group of autosomal recessive metabolic diseases included in many newborn screening (NBS) programs, but the incidence and disease spectrum vary widely between ethnic groups. We aimed to elucidate the incidence, disease spectrum, and genetic features of FAODs in a southern Chinese population.
UNASSIGNED: The FAODs screening results of 643,606 newborns from 2014 to 2022 were analyzed.
UNASSIGNED: Ninety-two patients were eventually diagnosed with FAODs, of which 61 were PCD, 20 were MADD, 5 were SCADD, 4 were VLCADD, and 2 were CPT-IAD. The overall incidence of FAODs was 1:6996 (95 % CI: 1:5814-1:8772) newborns. All PCD patients had low C0 levels during NBS, while nine patients (14.8 %) had normal C0 levels during the recall review. All but one MADD patients had elevated C8, C10, and C12 levels during NBS, while eight patients (40 %) had normal acylcarnitine levels during the recall review. The most frequent SLC22A5 variant was c.760C > T (p.R254*) with an allele frequency of 29.51 %, followed by c.51C > G (p.F17L) (17.21 %) and c.1400C > G (p.S467C) (16.39 %). The most frequent ETFDH variant was c.250G > A (p.A84T) with an allelic frequency of 47.5 %, followed by c.524G > A (R175H) (12.5 %), c.998A > G (p.Y333C) (12.5 %), and c.1657T > C (p.Y553H) (7.5 %).
UNASSIGNED: The prevalence, disease spectrum, and genetic characteristics of FAODs in a southern Chinese population were clarified. PCD was the most common FAOD, followed by MADD. Hotspot variants were found in SLC22A5 and ETFDH genes, while the remaining FAODs showed great molecular heterogeneity. Incorporating second-tier genetic screening is critical for FAODs.

This article reports the characterization of two siblings diagnosed with late-onset multiple Acyl-CoA dehydrogenase deficiency (MADD) caused by mutations in electron transfer flavoprotein(ETF)-ubiquinone oxidoreductase (ETF-QO) (ETFDH) gene. Whole exome sequencing (WES) was performed in the proband\'s pedigree. Clinical phenotypes of Proband 1 (acidosis, hypoglycemia, hypotonia, muscle weakness, vomiting, hypoglycemia, hepatomegaly, glutaric acidemia, and glutaric aciduria) were consistent with symptoms of MADD caused by the ETFDH mutation. However, Proband 2 presented with only a short stature. The patients (exhibiting Probands 1 and 2) showed identical elevations of C6, C8, C10, C12, and C14:1. c.1842_1845 (exon13)dup, and c.250 (exon3) G > A of the ETFDH gene were compound heterozygous variants in both patients. The novel variant c.1842_1845dup was rated as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines (ACMG). This is the first report on the c.1842_1845dup mutation of the ETFDH gene in patients with late-onset MADD, and the data described herein may help expand the mutation spectrum of ETFDH.

UNASSIGNED: Lipid storage myopathy (LSM) is an autosomal recessive inherited lipid and amino metabolic disorder with great clinical heterogeneity. Variations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene cause multiple acyl-CoA dehydrogenase deficiency (MADD), and have a manifestation of LSM. Muscle biopsy helps clarify the diagnosis of LSM, and next-generation sequencing (NGS) can be useful in identifying genomic mutation sites. The diagnosis of MADD contributes to targeted therapy.
UNASSIGNED: We report on a teenager who appeared to have muscle weakness and exercise intolerance at the onset. Before the referral to our hospital, he was unsuccessfully treated with glucocorticoid for suspected polymyositis. The next-generation sequencing of the proband and his parents revealed heterozygous variations, c.365G>A (p.G122D) inherited from the father, c.176-194_176-193del, and c.832-316C>T inherited from the mother in the ETFDH gene. The tandem mass spectrometry identified the mutations to be pathogenic. However, his parents and his younger sister who were detected with a mutation of c.365G>A presented no clinical symptoms. This indicates that the combination of the three compound heterozygous mutations in ETFDH is significant. After MADD was diagnosed, a dramatic clinical recovery and biochemical improvement presented as riboflavin was given to the patient across a week, which further confirmed the diagnosis of MADD.
UNASSIGNED: Our observations extend the spectrum of ETFDH variants in Chinese the population and reinforce the role of NGS in diagnosis of MADD. Early diagnosis and appropriate treatment of LSM lead to great clinical efficacy and avoid some lethal complications.

BACKGROUND: Newborn screening (NBS) for multiple acyl-CoA dehydrogenase deficiency (MADD) has poor sensitivity. This study aimed to evaluate the feasibility of incorporating second-tier genetic screening for MADD.
METHODS: A total of 453,390 newborns were screened for inherited metabolic disorders using tandem mass spectrometry from January 2017 to May 2022. A matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) assay was developed to identify 23 common ETFDH variants and used for second-tier screening of MADD.
RESULTS: Overall, 185 newborns with suspected MADD received second-tier genetic screening. Thirty-three (17.8 %) newborns with positive results, of which 7 were homozygotes, 5 were compound heterozygotes, 21 were heterozygotes. Further genetic analysis revealed that 6 of the 21 newborns had a second ETFDH variant. Therefore, 18 patients were finally diagnosed with MADD, with a positive predictive value of 9.73 %. The detection rate and diagnostic rate of MALDI-TOF MS assay were 83.33 % and 66.67 %, respectively. Thus the incidence of MADD in our population was estimated at 1:25,188. Nine different ETFDH variants were identified in MADD patients. The most common ETFDH variant being c.250G > A with an allelic frequency of 47.22 %, followed by c.524G > A (13.89 %) and c.998A > G (13.89 %). All patients had elevation of multiple acylcarnitines at NBS. However, seven patients had normal acylcarnitine levels and two patients showed mild elevation of only two acylcarnitines during the recall review.
CONCLUSIONS: We have established a high throughput MALDI-TOF MS assay for MADD screening. Half of the MADD patients would not be detected under conventional screening protocols. Incorporating second-tier genetic screening into the current NBS could improve the performance of MADD NBS.

OBJECTIVE: This study aims to analyse the body composition features and its changes after treatment in patients with late-onset multiple acyl-CoA dehydrogenase deficiency (MADD).
METHODS: Body composition was measured in patients with late-onset MADD, inflammatory myopathies, mitochondrial myopathy, and healthy controls. The correlation analyses between body composition and traditional parameters were performed. Comparisons between groups and receiver operating characteristic curve analyses were performed.
RESULTS: A total of 42 participants included 13 patients with late-onset MADD, 13 healthy controls, 10 with inflammatory myopathy, and 6 with mitochondrial myopathy. Bilateral grip strength and forced vital capacity (FVC) were moderate-strong correlated with skeletal muscle mass (right hand grip strength: r = 0.728, P < 0.001; left hand grip strength: r = 0.676, P < 0.001; FVC: r = 0.754, P < 0.001). Serum CK was moderately and negatively correlated with right hand grip strength (r = - 0.618, P = 0.005), left hand grip strength (r = - 0.630, P = 0.004), FVC (r = - 0.665, P = 0.002), manual muscle testing (MMT) (r = - 0.729, P = 0.000), and lean body mass skeletal muscle percentage (r = - 0.501, P = 0.029). Body composition features in patients with late-onset MADD were as follows: (1) obvious fat accumulation, (2) reduction of muscle mass, and (3) reduction of body water and intracellular water ratio. Some indicators of body composition were found to be valuable in diagnosis and eliminating differential diagnoses, such as visceral fat area (sensitivity 84.62%; specificity 92.31%; AUC 0.905) and fat mass (sensitivity 84.62%; specificity 75.00%; AUC 0.837). Seven patients were followed-up (2-9 months). Prior to treatment, the changes in body composition in these patients were conflicting.
CONCLUSIONS: Hand grip strength and FVC were strongly associated with body composition. Body composition features in late-onset MADD are fat accumulation, muscle loss, decrease in total body water, and intracellular water ratio. Body composition features are valuable for diagnosis and assessment.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive metabolic disease. Patients present with metabolic decompensation, muscle weakness, respiratory failure, and cardiomyopathy. Late-onset MADD is primarily caused by mutations in the ETFDH gene. Here, we report a patient who has been diagnosed with Down syndrome after birth following karyotype analysis and simultaneously carrying compound heterozygous variants of ETFDH (c.3G > C (p. M1?); c.725C > T (p. T242I), which is novel). Further molecular analyses revealed that the novel c.725C > T (p. T242I) mutation enhances the degradation of electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) via the ubiquitin proteasome pathway. Five ubiquitin E3 ligases (STUB1, RNF40, UBE3C, CUL3, and CUL1) and one ubiquitin modification site (Cystein, C101) of the ETF-QO were reported in this study. Our study not only expanded the pathogenic variant spectrum of ETFDH gene but also proved that the c.725C > T (p. T242I) will promote protein degradation through ubiquitin proteasome pathway.

To investigate the incidence rate, clinical and gene mutation characteristics of multiple acyl-CoA dehydrogenase deficiency (MADD) in newborns in Zhejiang province. A total of 3 896 789 newborns were screened for MADD using tandem mass spectrometry in Zhejiang Neonatal Screening Center during January 2009 and December 2020. Patients of MADD were confirmed by urine organic acid and electron transferring flavoprotein (or electron transferring flavoprotein dehydrogenase () gene detection. MADD patients were given diet and life management, supplemented with L-carnitine, riboflavin and coenzyme Q 10 treatment, and their growth and intellectual development were evaluated during the followed up.Thirteen patients with MADD were diagnosed, with an incidence of 1/299 753. One patient was type Ⅱ, and the rest were type Ⅲ. Patients were followed up for 1 case died, 4 cases had acute metabolic disorders with hypoglycemia as the main manifestation due to infection, 1 case had hypotonia, and the rest 7 cases developed well. Patients had raised levels of C4-C18:1 acylcarnitines in the initial screening. Thirteen children were genetically tested, 1 case with compound heterozygous mutation in the gene, 1 case with homozygous mutation in the gene, 1 case with compound heterozygous mutation in the gene, 8 cases with compound heterozygous mutation and 1 case with homozygous mutation in the gene, 1 case that only 1 locus of gene was detected. The c.250G>A was the hotspot mutation in this study.The clinical manifestations of MADD are highly heterogeneous. The neonatal-onset form is serious, and late onset form usually has no obvious clinical symptoms. C4-C18:1 acylcarnitines usually increased in the initial screening, and the hotspot gene mutation is c.250G>A.

OBJECTIVE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS.
METHODS: From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis.
RESULTS: Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12).
CONCLUSIONS: These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.

Multiple Acyl-CoA dehydrogenase deficiency (MADD), one of the most common lipid storage myopathies (LSMs), is a heterogeneous inherited muscular disorder that is pathologically characterized by numerous lipid droplets in muscle fibers due to lipid metabolism disturbance. MADD exhibits a wide range of clinical features, including skeletal muscle weakness and multisystem dysfunctions. However, MADD, as well as other types of LSM, associated with peripheral neuropathy has rarely been reported during the past four decades. Here, we present four Chinese patients affected by MADD with peripheral neuropathy in our neuromuscular center. Clinically, these four patients showed skeletal muscle weakness and prominent paresthesia. Muscle biopsy detected characteristic myopathological patterns of LSM, such as obvious lipid droplets in muscle fibers. Sural nerve biopsy revealed a severe reduction in number of myelinated nerve fibers, which is a typical neuropathological pattern of peripheral neuropathy. Causative ETFDH mutations were found in all four cases. The skeletal muscle weakness was rapidly improved after some treatments while paresthesia showed unsatisfactory improvement. The features of previously reported patients of this specific type are also summarized in this paper. We propose that MADD with peripheral neuropathy may be a new phenotypic subtype because the pathology and reaction to riboflavin treatment are different from those of traditional MADD, although further research on the precise pathogenesis and mechanisms is needed.