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.

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.

Follow-up and multimodal imaging in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Dear Editor, The deficit of 3-hydroxyacyl-CoA dehydrogenase （LCHAD）is a disease whose incidence is approximately 3 cases/100 000 births, with autosomal recessive inheritance.

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.

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.

Etiology analysis for term newborns with severe hyperbilirubinemia in eastern Guangdong of China

BACKGROUND Neonatal hyperbilirubinemia is one of the common diseases of newborns that typically presents with yellow staining of skin,resulting in sequelaes such as hearing loss,motor and intellectual development disorders,and even death.The pathogenic factors of neonatal hyperbilirubinemia are complex.Different cases of hyperbilirubinemia may have a single or mixed etiology.AIM To explore the etiological characteristics of severe hyperbilirubinemia in term newborns of eastern Guangdong of China.METHODS Term newborns with severe hyperbilirubinemia in one hospital from January 2012 to December 2021 were retrospectively analyzed.The etiology was determined according to the laboratory results and clinical manifestations.RESULTS Among 1602 term newborns with hyperbilirubinemia in eastern Guangdong of China,32.20%(580/1602)was severe hyperbilirubinemia.Among the causes of severe hyperbilirubinemia,neonatal hemolysis accounted for 15.17%,breast milk jaundice accounted for 12.09%,infection accounted for 10.17%,glucose-6-phosphate dehydrogenase(G6PD)deficiency accounted for 9.14%,and the coexistence of multiple etiologies accounted for 6.55%,unknown etiology accounted for 41.72%.ABO hemolysis and G6PD deficiency were the most common causes in the 20 cases with bilirubin encephalopathy.94 severe hyperbilirubinemia newborns were tested for uridine diphosphate glucuronosyl transferase 1A1(UGT1A1)*6 variant(rs4148323,c.211G>A,p.Arg71Gly),9 cases were 211 G to A homozygous variant,37 cases were 211 G to A heterozygous variant,and 48 cases were wild genotypes.CONCLUSION The main cause for severe hyperbilirubinemia and bilirubin encephalopathy in eastern Guangdong of China were the hemolytic disease of the newborns,G6PD deficiency and infection.UGT1A1 gene variant was also a high-risk factor for neonatal hyperbilirubinemia.Targeted prevention and treatment according to the etiology may reduce the occurrence of bilirubin encephalopathy and kernicterus.

A novel mis-sense mutation (G1381A) in the G6PD gene identified in a Chinese man

Objective To detect new mutations among 29 glucose 6 phosphate dehydrogenase (G6PD) deficient individuals from Yunnan province Methods The nitroblue tetrazolium (NBT) method was used to screen G6PD deficient individuals Mutation was identified by single strand conformation polymorphism (SSCP), amplification created restriction site (ACRS), amplification refractory mutation system (ARMS) and DNA sequencing Results Among 29 cases, 18 cases of G1388A, 1 case of C1004A, and 1 case of G1381A were identified Nine cases remained to be defined The G1381A mutation is a novel mis sense mutation, with a substitution of threonine for alanine (A461T) The resultant G6PD had reduced enzymatic activity In addition, G1381A caused a restriction site of Stu I to disappear, providing a rapid method for the detection of this mutation Conclusion A novel mis sense mutation G1381A was found This mutation results in a substitution of threonine for alanine, producing enzyme with reduced activity The loss of the Stu I restriction site offers a rapid method for the detection of this mutation