Fatal multiple acyl-CoA dehydrogenase deficiency caused by ETFDH gene mutation:A case report

BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is a disease of rare autosomal recessive disorder.There are three types of MADD.Type I is a neonatalonset form with congenital anomalies.Type II is a neonatal-onset form without congenital anomalies.Type III is considered to a milder form and usually responds to riboflavin.However,late-onset form could also be fatal and not responsive to treatments.CASE SUMMARY We report a severe case of a young man with onset type III MADD induced by drugs and strenuous exercise characterized by rhabdomyolysis and liver dysfunction.Urine analysis indicated 12 out of 70 kinds of organic acids like glutaric acid-2 were detected.Serum analysis in genetic metabolic diseases revealed 24 out of 43 tested items were abnormal,revealing the elevation of several acylcarnitines and the reduction of carnitine in the patient.By next generation sequencing technology for gene sequencing related to fatty acid oxidation and carnitine cycle defects,a rare ETFDH gene variant was identified:NM_004453:4:C.1448C>T(p.Pro483 Leu).The patient was diagnosed with lateonset GAII.He was not responsive to riboflavin and progressively worsened into multiple organ failure that finally led to death.CONCLUSION Type III MADD can also be fatal and not responsive to treatments.

Medium-chain acyl-CoA dehydrogenase deficiency: prevalence of ACADM pathogenic variants c.985A>G and c.199T>C in a healthy population in Rio Grande do Sul, Brazil

Objectives::To investigate the prevalence of ACADM pathogenic variants, c.985A>G and c.199T>C, for medium chain acyl CoA dehydrogenase deficiency (MCADD) in a healthy population in the southern region of Brazil. Methods::This was an observational cross-sectional study with a convenience sampling strategy. The participants were recruited from the blood bank of the Hospital de Clínicas of Porto Alegre, Brazil. A total of 1000 healthy individuals from the state of Rio Grande do Sul were included. Genotyping for the c.199T>C and c.985A>G variants was performed using real-time polymerase chain reaction (PCR) and the PCR-restriction fragment length polymorphism (RFLP) technique, respectively. Individuals considered heterozygous for c.985A>G were subjected to additional acylcarnitine profile analysis using tandem mass spectrometry. Carrier frequency was obtained by calculating the ratio of heterozygous individuals to the total number of individuals analyzed and reported with a 95% confidence interval. Allele and genotype frequencies were calculated based on the Hardy-Weinberg equilibrium.Results::The c.985A>G variant was detected as heterozygotes in three individuals (frequency of the heterozygous genotype = 1:333, allele frequency= 0.0015, minimum frequency of MCADD= 1:444,444) whose acylcarnitine profiles were within normal limits. The c.199T>C variant was not identified.Conclusions::Considering the small sample size and associated allelic heterogeneity with MCADD, these findings are believed to denote the rarity or underdiagnosis of MCADD in southern Brazil. This study provides evidence for the need for further investigation to ascertain the contribution of these diseases to child morbidity and mortality in the country.

Late-onset multiple acyl-CoA dehydrogenase deficiency with cardiac syncope: A case report

BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is an uncommon autosomal recessive disorder of mitochondrial fatty acid beta-oxidation.Syncope is a transient loss of consciousness due to acute global cerebral hypoperfusion.Late-onset MADD with syncope has not been reported previously.CASE SUMMARY We report a 17-year-old girl with exercise intolerance and muscle weakness.She felt palpitation and shortness of breath after short bouts of exercise.She also suffered from a transient loss of consciousness many times.Muscle biopsy showed lipid storage.Genetic mutation analysis indicated a compound heterozygous mutation c.250G>A(p.A84T)and c.872T>G(p.V291G)in the ETFDH gene.The results of Holter electrocardiogram monitoring showed supraventricular tachycardia when the patient experienced a loss of consciousness.After treatment with riboflavin and carnitine,muscle weakness and palpitation symptoms improved rapidly.No loss of consciousness occurred,and the Holter electrocardiogram monitoring was normal.CONCLUSION Late-onset MADD with supraventricular tachycardia can cause cardiac syncope.Carnitine and riboflavin supplement were beneficial for treating the late-onset MADD with cardiac syncope.Attention should be paid to the prevention of cardiac syncope when diagnosing late-onset MADD.

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.

Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency

Background:Very long chain acyl-CoA dehydrogenase deficiency(VLCADD)is an inherited metabolic disease caused by deleterious mutations in the ACADVL gene that encodes very long chain acyl-CoA dehydrogenase(VLCAD),and which can present as cardiomyopathy in neonates,as hypoketotic hypoglycemia in infancy,and as myopathy in late-onset patients.Although many ACADVL mutations have been described,no prevalent mutations in the ACADVL gene have been associated with VLCADD.Herein,we report the clinical course of the disease and explore the genetic mutation spectrum in seven Chinese patients with VLCADD.Methods:Seven Chinese patients,from newborn to 17 years old,were included in this study.Tandem mass spectrometry was performed to screen for VLCAD defi ciency.All exons and fl anking introns of the ACADVL gene were analyzed using polymerase chain reaction and direct sequencing.Online analysis tools were used to predict the impact of novel mutations.Results:All cases had elevated serum levels of tetradecanoylcarnitine(C14:1)which is the characteristic biomarker for VLCADD.The phenotype of VLCADD is heterogeneous.Two patients were hospitalized for hypoactivity and hypoglycemia shortly after birth.Three patients showed hepatomegaly and hypoglycemia in infancy.The other two adolescent patients showed initial manifestations of exercise intolerance or rhabdomyolysis.Three of the patients died at the age of 6-8 months.Eleven different mutations in the ACADVL gene in the 7 patients were identified,including seven reported mutations(p.S22X,p.W427X,p.A213T,p.G222R,p.R450H,c.296-297delCA,c.1605+1G>T)and four novel mutations(p.S72F,p.Q100X,p.M437T,p.D466Y).The p.R450H and p.D466Y(14.28%,2/14 alleles)mutations were identifi ed in two alleles respectively.Conclusions:The clinical manifestations were heterogeneous and ACADVL gene mutations were heterozygous in the seven VLCADD Chinese patients.R450H may be a relatively common mutation in Asian populations.The genotype and phenotype had a certain correlation in our patients.

A Historical Cohort Study on the Efficacy of Glucocorticoids and Riboflavin Among Patients with Late-onset Multiple AcyI-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 l-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.

Muscle Magnetic Resonance Imaging for the Differentiation of Multiple AcyI-CoA Dehydrogenase Deficiency and Immune-mediated Necrotizing Myopathy

Background： Clinically, it is difficult to differentiate multiple acyl-CoA dehydrogenase deficiency （MADD） from immune-mediated necrotizing myopathy （IMNM） because they display similar symptoms. This study aimed to determine whether muscle magnetic resonance imaging （MRI） could be used for differential diagnosis between MADD and IMNM. Methods： The study evaluated 25 MADD patients, confirmed by muscle biopsy and ETFDH gene testing, and 30 IMNM patients, confirmed by muscle biopsy. Muscles were assessed for edema and fatty replacement using thigh MRI （tMRI）. Degrees and distribution patterns of fatty infiltration and edema in gluteus maximus and thigh muscles were compared. Results： Total fatty infiltration and edema scores （median, [Q 1, Q3]） were 4.00 （1.00, 15.00） and 0 （0, 4.00） in MADD and 14.50 （8.00, 20.75） and 22.00 （16.75, 32.00） in IMNM, respectively, which were significantly more severe in IMNM than that in MADD （P = 0.000 and P = 0.004~ respectively）. Edema scores tbr gluteus maximus, long head of biceps femoris, and semimembranosus were significantly higher in IMNM than in MADD （all P = 0.000）. Fatty infiltration scores for anterior and medial compartments were significantly more severe in IMNM than that in MADD （all P = 0.000）. Conclusion： Different patterns of muscle involvement on tMRI can contribute to differential diagnosis between MADD and IMNM when clinical suspicions alone are insufficient, thereby reducing the need for muscle biopsy.