Late-onset Multiple acyl-CoA Dehydrogenase Deficiency Research Articles

The male-to-female ratio in late-onset multiple acyl-CoA dehydrogenase deficiency: a systematic review and meta-analysis

BackgroundLate-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common lipid storage myopathy. There are sex differences in fat metabolism and it is not known whether late-onset MADD affects men and women equally.MethodsIn this systematic review and meta-analysis, the PubMed, Embase, Web of Science, CNKI, CBM, and Wanfang databases were searched until 01/08/2023. Studies reporting sex distribution in patients with late-onset MADD were included. Two authors independently screened studies for eligibility, extracted data, and assessed risk of bias. Pre-specified outcomes of interest were the male-to-female ratio (MFR) of patients with late-onset MADD, the differences of clinical characteristics between the sexes, and factors influencing the MFR.ResultsOf 3379 identified studies, 34 met inclusion criteria, yielding a total of 609 late-onset MADD patients. The overall pooled percentage of males was 58% (95% CI, 54-63%) with low heterogeneity across studies (I2 = 2.99%; P = 0.42). The mean onset ages, diagnostic delay, serum creatine kinase (CK), and allelic frequencies of 3 hotspot variants in ETFDH gene were similar between male and female patients (P > 0.05). Meta-regressions revealed that ethnic group was associated with the MFR in late-onset MADD, and subgroup meta-analyses demonstrated that East-Asian patients had a higher percentage of male, lower CK, and higher proportion of hotspot variants in ETFDH gene than non-East-Asian patients (P < 0.05).ConclusionsMale patients with late-onset MADD were more common than female patients. Ethnicity was proved to be a factor influencing the MFR in late-onset MADD. These findings suggest that male sex may be a risk factor for the disease.

Features and diagnostic value of body composition in patients with late-onset multiple acyl-CoA dehydrogenase deficiency.

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). 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. 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 (2-9months). Prior to treatment, the changes in body composition in these patients were conflicting. 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.

Novel variant of ETFDH leading to multiple acyl-CoA dehydrogenase deficiency by promoting protein degradation via ubiquitin proteasome pathway

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.

A case report of a first pregnant woman with late-onset multiple acyl-CoA dehydrogenase deficiency in Saudi Arabia

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria II, is a rare autosomal recessively inherited disorder of inborn error of metabolism. It can mainly be presented in three phenotypes: severe neonatal onset with a dysmorphic feature, neonatal-onset without dysmorphic features, and less severe mild late-onset phenotype. Case presentation: A 34-year-old Saudi female previously healthy, Para 4, with severe metabolic acidosis, rhabdomyolysis intrapartum was presented to us. Her previous pregnancy history and deliveries were unremarkable; she has three healthy sons. Since the beginning of this pregnancy, she complained of fatigability and muscle weakness which was progressive with time. At 36 weeks of gestation, she was presented to the emergency room with labor pain. She deteriorated rapidly with significant drowsiness. Her arterial blood gas showed severe metabolic acidosis with a high anion gap and normal lactate. She was intubated and underwent emergency cesarean delivery under general anesthesia. After the operation, she was sent to the intensive care unit. She passed away after a few days. A molecular test confirmed the diagnosis of MADD. Conclusion: First, late-onset MADD is a rare, underdiagnosed disease in adults. Second, the biochemical diagnosis of late-onset MADD is challenging as it mimics medium chain acyl CoA dehydrogenase deficiency which makes the molecular diagnosis essential for diagnosis. Third, for any unexplained myopathy, cardiac dysfunction, encephalopathy, or metabolic acidosis, metabolic disorders must be considered as early consultation with metabolic service.

M145 MULTIPLE ACYL-COA DEHYDROGENASE DEFICIENCY MASQUERADING AS MYOSITIS IN AN ADULT COMMON VARIABLE IMMUNODEFICIENCY PATIENT

Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency characterized by defective B-lymphocyte differentiation, defective antibody production, and inflammation-induced organ damage. Etiologies for myositis associated with CVID are often elusive. The following is a case of late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) mimicking myositis in a patient concurrently diagnosed with CVID.

Late-onset Multiple acyl-CoA dehydrogenase deficiency with proximal myopathy (2730)

Late-onset Multiple acyl-CoA dehydrogenase deficiency with proximal myopathy (2730)

CHIP control degradation of mutant ETF:QO through ubiquitylation in late-onset multiple acyl-CoA dehydrogenase deficiency.

Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common form of lipid storage myopathy. The disease is mainly caused by mutations in electron-transfer flavoprotein dehydrogenase gene (ETFDH), which leads to decreased levels of ETF:QO in skeletal muscle. However, the specific underlying mechanisms triggering such degradation remain unknown. We constructed expression plasmids containing wild type ETF:QO and mutants ETF:QO-A84T, R175H, A215T, Y333C, and cultured patient-derived fibroblasts containing the following mutations in ETFDH: c.250G>A (p.A84T), c.998A>G (p.Y333C), c.770A>G (p.Y257C), c.1254_1257delAACT (p. L418TfsX10), c.524G>A (p.R175H), c.380T>A (p.L127P), and c.892C>T (p.P298S). We used in vitro expression systems and patient-derived fibroblasts to detect stability of ETF:QO mutants then evaluated their interaction with Hsp70 interacting protein CHIP with active/inactive ubiquitin E3 ligase carboxyl terminus using western blot and immunofluorescence staining. This interaction was confirmed in vitro and in vivo by co-immunoprecipitation and immunofluorescence staining. We confirmed the existence two ubiquitination sites in mutant ETF:QO using mass spectrometry (MS) analysis. We found that mutant ETF:QO proteins were unstable and easily degraded in patient fibroblasts and in vitro expression systems by ubiquitin-proteasome pathway, and identified the specific ubiquitin E3 ligase as CHIP, which forms complex to control mutant ETF:QO degradation through poly-ubiquitination. CHIP-dependent degradation of mutant ETF:QO proteins was confirmed by MS and site-directed mutagenesis of ubiquitination sites. Hsp70 is directly involved in this process as molecular chaperone of CHIP. CHIP plays an important role in ubiquitin-proteasome pathway dependent degradation of mutant ETF:QO by working as a chaperone-assisted E3 ligase, which reveals CHIP's potential role in pathological mechanisms of late-onset MADD.

Late-onset multiple acyl-CoA dehydrogenase deficiency mimicking myositis in an elderly patient: a case report

BackgroundLate-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare and treatable inherited lipid storage myopathy. Here, we report an elderly patient with MADD mimicking myositis.Case presentationAn 80-year-old woman had progressive weakness in her limbs, exercise intolerance, and no muscle pain for 3 months. The patient’s serum creatine kinase level was slightly elevated. The initial diagnosis was myositis. However, muscle biopsy showed many cytoplasmic vacuoles stained with oil red O, indicating the presence of lipid storage myopathy. The plasma acylcarnitine profile showed increased medium-chain and long-chain acylcarnitine species, consistent with the diagnosis of MADD. Riboflavin treatment dramatically improved muscle weakness.ConclusionsMADD should be considered when evaluating elderly patients with subacute muscle weakness.

Late-onset multiple acyl-CoA dehydrogenase deficiency with breast cancer

BackgroundMultiple 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 presentationHere, 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.ConclusionThe 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.

Correlation between ETFDH mutations and dysregulation of serum myomiRs in MADD patients.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare fatty acids oxidation disorder which is often associated with deficiency of electron transfer flavoprotein dehydrogenase (ETFDH). In this study we reported clinical features and evaluation of expression profile of circulating muscle-specific miRNAs (myomiRs) in two MADD patients carrying different ETFDH gene mutations. Patient 1 was a compound heterozygote for two missense mutations. She showed a late onset MADD clinical phenotype and a significant increase of serum myomiRs. Patient 2, carrying a missense and a frameshift mutation, displayed early onset symptoms and a slight increase of some serum myomiRs.

Skin damage in a patient with lipid storage myopathy with a novel ETFDH mutation responsive to riboflavin

Background: Recessive mutations in ETFDH gene have been associated with Multiple Acyl-CoA dehydrogenase deficiency (MADD). The late-onset MADD is often muscle involved, presenting with lipid storage myopathy (LSM). The symptoms of LSM were heterogeneous and definite diagnosis of this disease depends on the pathology and gene test.Methods: Neurological examination, muscle biopsy, and MRI examinations were performed in a patient with a novel missense ETFDH mutation.Results: We describe a patient with lipid storage myopathy complicated with skin damage. In addition, the next generation revealed a novel missense mutation (c.970G > T, p.Val324Leu) in exon 8, which was predicted to be a disease-causing mutation by Mutation-taster, and destroy the function of the protein by Sift.Conclusion: These findings expand the known mutational spectrum of ETFDH and phenotype of MADD.

Late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD): case reports and epidemiology of ETFDH gene mutations

BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is a riboflavin-responsive lipid-storage myopathy caused by mutations in the EFTA, EFTB or ETFDH genes. We report a Chinese family of Southern Min origin with two affected siblings with late-onset riboflavin-responsive MADD due to a homozygous c.250G > A EFTDH mutation and review the genetic epidemiology of the c.250G > A mutation.Case presentationBoth siblings presented with exercise-induced myalgia, progressive proximal muscle weakness and high levels of serum muscle enzymes and were initially diagnosed as polymyositis after a muscle biopsy. A repeat biopsy in one sibling subsequently showed features of lipid storage myopathy and genetic analysis identified a homozygous mutation (c.250G > A) in the ETFDH gene in both siblings and carriage of the same mutation by both parents. Glucocorticoid therapy led to improvement in muscle enzyme levels, but little change in muscle symptoms, and only after treatment with riboflavin was there marked improvement in exercise tolerance and muscle strength. The frequency and geographic distribution of the c.250G > A mutation were determined from a literature search for all previously reported cases of MADD with documented mutations. Our study found the c.250G > A mutation is the most common EFTDH mutation in riboflavin-responsive MADD (RR-MADD) and is most prevalent in China and South-East Asia where its epidemiology correlates with the distribution and migration patterns of the southern Min population in Southern China and neighbouring countries.ConclusionsMutations in ETFDH should be screened for in individuals with lipid-storage myopathy to identify patients who are responsive to riboflavin. The c.250G > A mutation should be suspected particularly in individuals of southern Min Chinese background.

EP.04A case of late onset multiple acyl-CoA dehydrogenase deficiency with novel ETFDH mutation

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare disorder of fatty acid and amino acid metabolism characterized by muscle weakness, metabolic acidosis, hepatic dysfunction and encephalopathy. MADD is difficult to diagnose because of its wide range of clinical manifestations. Herein, we report a case of late onset MADD with novel ETFDH gene mutation. A 17-year-old female visited our clinic due to progressive 4-extremity weakness developed 6 months ago. She complained of myalgia and dyspnea. Neurologic examination revealed proximal dominant weakness, which was more severe on the upper extremities. Electromyography showed myopathic patterns. Serum glucose level was low and initial CK level was highly elevated to 5,720 IU/L. Muscle biopsy showed nonspecific myopathic changes with mild mitochondrial abnormality on the electron microscopy. Acid-alpha glucosidase level was normal. After admission, her dyspnea was gradually worsened and she was treated in the ICU after tracheostomy. She showed recurrent generalized tonic-clonic seizure and was treated with antiepileptic drugs. In suspicion of metabolic disease, we screened urine organic acid. Many organic acids levels including glutaric acid, ethylmalonic acid, glycine were increased. The genetic study revealed novel heterogenous mutation in ETFDH gene. She was finally diagnosed as MADD. After flavoprotein supplementation, her symptoms are slowing improving. MADD is an autosomal recessive inherited disease caused by mutations related with electron transfer to respiratory chain by flavoproteins. There is a possibility that it can be treated to some extent by flavoprotein supplementation. Therefore, MADD should be considered in patients with myopathy with progressive respiratory distress.

Late-onset multiple acyl-CoA dehydrogenase deficiency with a complex genetic finding (P4.6-066)

Late-onset multiple acyl-CoA dehydrogenase deficiency with a complex genetic finding (P4.6-066)

Clinical and muscle magnetic resonance image findings in patients with late-onset multiple acyl-CoA dehydrogenase deficiency.

Background:Late-onset multiple acyl-coA dehydrogenase deficiency (MADD) is an autosomal recessive inherited metabolic disorder. It is still unclear about the muscle magnetic resonance image (MRI) pattern of the distal lower limb pre- and post-treatment in patients with late-onset MADD. This study described the clinical and genetic findings in a cohort of patients with late-onset MADD, and aimed to characterize the MRI pattern of the lower limbs.Methods:Clinical data were retrospectively collected from clinic centers of Peking University People's Hospital between February 2014 and February 2018. Muscle biopsy, blood acylcarnitines, and urine organic acids profiles, and genetic analysis were conducted to establish the diagnosis of MADD in 25 patients. Muscle MRI of the thigh and leg were performed in all patients before treatment. Eight patients received MRI re-examinations after treatment.Results:All patients presented with muscle weakness or exercise intolerance associated with variants in the electron transfer flavoprotein dehydrogenase gene. Muscle MRI showed a sign of both edema-like change and fat infiltration selectively involving in the soleus (SO) but sparing of the gastrocnemius (GA) in the leg. Similar sign of selective involvement of the biceps femoris longus (BFL) but sparing of the semitendinosus (ST) was observed in the thigh. The sensitivity and specificity of the combination of either “SO+/GA–” sign or “BFL+/ST–” sign for the diagnosis of late-onset MADD were 80.0% and 83.5%, respectively. Logistic regression model supported the findings. The edema-like change in the SO and BFL muscles were quickly recovered at 1 month after treatment, and the clinical symptom was also relieved.Conclusions:This study expands the clinical and genetic spectrums of late-onset MADD. Muscle MRI shows a distinct pattern in the lower limb of patients with late-onset MADD. The dynamic change of edema-like change in the affected muscles might be a potential biomarker of treatment response.

ETF-QO Mutants Uncoupled Fatty Acid β-Oxidation and Mitochondrial Bioenergetics Leading to Lipid Pathology.

The electron-transfer flavoprotein dehydrogenase gene (ETFDH) that encodes the ETF-ubiquinone oxidoreductase (ETF-QO) has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). ETF-QO is an electron carrier that mainly functions in mitochondrial fatty acid β-oxidation and the delivery of electrons to the ubiquinone pool in the mitochondrial respiratory chain. A high frequency of c.250G>A has been found in Taiwanese patients with late-onset MADD. We postulated that the ETFDH c.250G>A mutation may concomitantly impair fatty acid β-oxidation and mitochondrial function. Using MADD patient-derived lymphoblastoid cells and specifically overexpressed ETFDH c.92C>T, c.250G>A, or coexisted c.92C>T and c.250G>A (c.92C>T + c.250G>A) mutated lymphoblastoid cells, we addressed the genotype-phenotype relationship of ETFDH variation in the pathogenesis of MADD. The decreased adenosine triphosphate synthesis, dissipated mitochondrial membrane potentials, reduced mitochondrial bioenergetics, and increased neutral lipid droplets and lipid peroxides were found in the MADD patient-derived lymphoblastoid cells. Riboflavin and/or coenzyme Q10 supplementation rescued cells from lipid droplet accumulation. All three mutant types, c.92C>T, c.250G>A, or c.92C>T + c.250G>A, had increased lipid droplet accumulation after treatment with palmitic acid. These results help to clarify the molecular pathogenesis of MADD as a result of the high frequency of the ETFDH c.250G>A and c.92C>T mutations.

A Novel Truncating FLAD1 Variant, Causing Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) in an 8-Year-Old Boy.

Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) is a clinically heterogeneous disorder affecting fatty acid and amino acid metabolism. Presentations range from a severe neonatal form with hypoglycemia, metabolic acidosis, and hepatomegaly with or without congenital anomalies to later-onset lipid storage myopathy. Genetic testing for MADD traditionally comprises analysis of ETFA, ETFB, and ETFDH. Patients may respond to pharmacological doses of riboflavin, particularly those with late-onset MADD due to variants in ETFDH. Increasingly other genes involved in riboflavin transport and flavoprotein biosynthesis are recognized as causing a MADD phenotype. Flavin adenine dinucleotide synthase (FADS) deficiency caused by biallelic variants in FLAD1 has been identified in nine previous cases of MADD. FLAD1 missense mutations have been associated with a riboflavin-responsive phenotype; however the effect of riboflavin with biallelic loss of function FLAD1 mutations required further investigation. Herein we describe a novel, truncating variant in FLAD1 causing MADD in an 8-year-old boy. Fibroblast studies showed a dramatic reduction in FADS protein with corresponding reduction in the FAD synthesis rate and FAD cellular content, beyond that previously documented in FLAD1-related MADD. There was apparent biochemical and clinical response to riboflavin treatment, beyond that previously reported in cases of biallelic loss of function variants in FLAD1. Early riboflavin treatment may have attenuated an otherwise severe phenotype.

Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency.

Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) with electron transfer flavoprotein dehydrogenase (ETFDH) gene mutations is the most common lipid storage myopathy (LSM) in China. Its clinical features vary widely and pose a challenge for diagnosis. We presented the significant clinical heterogeneity among three Chinese late-onset MADD patients with similar ETFDH genotype by collecting clinical information, muscle histology, and genetic analysis. Three novel compound heterozygous variants of ETFDH gene were identified: c.892C>T (p.Pro298Ser), c.453delA (p.Glu152ArgfsTer15), and c.449_453delTAACA (p.Leu150Ter). Moreover, all patients carried a hotspot mutation c.250G>A (p.Ala84Thr). Western blot analysis of the patients' muscular tissue showed a significantly reduced ETFDH expression, and normal electron transfer flavoprotein A (ETFA) and electron transfer flavoprotein B (ETFB) expression. Two patients with similar genotypes (c.453delA and c.449_453delTAACA) presented a significant clinical heterogeneity. Among them, one exhibited muscle weakness and exercise intolerance as initial and major symptoms, and the other showed episodic recurrent gastrointestinal symptoms before a serious muscle weakness appeared in later life. The novel variants in ETFDH and the corresponding clinical features enrich the variant spectrum of late-onset MADD and provide a new insight into the genotype-phenotype relationship. Late-onset MADD should be included in differential diagnosis for adult myopathy along with chronic digestive disease.

Multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of late-onset treatable metabolic disease

IntroductionLate-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare, treatable, beta-oxidation disorder responsible for neuromuscular symptoms in adults. This case series describes the clinical and biochemical features of 13 French patients with late-onset MADD. Methods and resultsThirteen ambulant patients (eight women, five men), with a median age at onset of 27 years, initially experienced exercise intolerance (n=9), isolated muscle weakness (n=1) and a multisystemic pattern with either central nervous system or hepatic dysfunction (n=3). During the worsening period, moderate rhabdomyolysis (n=5), a pseudomyasthenic pattern (n=5) and acute respiratory failure (n=1) have been observed. Weakness typically affected the proximal limbs and axial muscles, and there was sometimes facial asymmetry (n=3). Moderate respiratory insufficiency was noted in one case. Median baseline creatine kinase was 190IU/L. Lactacidemia was sometimes moderately increased at rest (3/10) and after exercise (1/3). The acylcarnitine profile was characteristic, with increases in all chain-length acylcarnitine species. Electromyography revealed a myogenic pattern, while muscle biopsy showed lipidosis, sometimes with COX-negative fibers (n=2). The mitochondrial respiratory chain was impaired in five cases, with coenzyme Q10 decreased in two cases. All patients harbored mutations in the ETFDH gene (four homozygous, seven compound heterozygous, two single heterozygous), with nine previously unidentified mutations. All patients were good responders to medical treatment, but exercise intolerance and/or muscular weakness persisted in 11 of them. ConclusionLate-onset forms of MADD may present as atypical beta-oxidation disorders. Acylcarnitine profiling and muscle biopsy remain the most decisive investigations for assessing the diagnosis. These tests should thus probably be performed more widely, particularly in unexplained cases of neuromuscular and multisystemic disorders.

A Historical Cohort Study on the Efficacy of Glucocorticoids and Riboflavin Among Patients with Late-onset Multiple Acyl-CoA Dehydrogenase Deficiency.

Background:Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common type of lipid storage myopathies in China. Most patients with late-onset MADD are well responsive to riboflavin. Up to now, these patients are often treated with glucocorticoids as the first-line drug because they are misdiagnosed as polymyositis without muscle biopsy or gene analysis. Although glucocorticoids seem to improve the fatty acid metabolism of late-onset MADD, the objective evaluation of their rationalization on this disorder and comparison with riboflavin treatment are unknown.Methods:We performed a historical cohort study on the efficacy of the two drugs among 45 patients with late-onset MADD, who were divided into glucocorticoids group and riboflavin group. Detailed clinical information of baseline and 1-month follow-up were collected.Results:After 1-month treatment, a dramatic improvement of muscle strength was found in riboflavin group (P < 0.05). There was no significant difference in muscle enzymes between the two groups. Significantly, the number of patients with full recovery in glucocorticoids group was less than the number in riboflavin group (P < 0.05). On the other hand, almost half of the patients in riboflavin group still presented high-level muscle enzymes and weak muscle strength after 1-month riboflavin treatment, meaning that 1-month treatment duration maybe insufficient and patients should keep on riboflavin supplement for a longer time.Conclusions:Our results provide credible evidences that the overall efficacy of riboflavin is superior to glucocorticoids, and a longer duration of riboflavin treatment is necessary for patients with late-onset MADD.