Clinical and muscle magnetic resonance image findings in patients with late-onset multiple acyl-CoA dehydrogenase deficiency / 中华医学杂志(英文版)

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.

Analysis of ETFDH gene variation in a Chinese family affected with lipid storage myopathy / 中华医学遗传学杂志

OBJECTIVE@#To detect potential variation in an ethnic Han Chinese family affected with late-onset lipid storage myopathy.@*METHODS@#Next generation sequencing (NGS) was used to screen disease-related genes in the proband. Suspected mutation was validated with PCR and Sanger sequencing in two patients, their father, and 100 healthy controls.@*RESULTS@#Heterozygous c.770A>G (p.Tyr257Cys) and c.1395dupT (p.Gly466Tryfs) mutation were detected in the two patients. Their father was found to be heterozygous for the c.770A>G (p.Tyr257Cys) mutation, while the c.1395dupT (p.Gly466Tryfs) variation was not reported previously and not found among the healthy controls.@*CONCLUSION@#Mutations of the ETFDH gene probably underlie the pathogenesis in this family. The novel c.1395dupT (p.Gly466Tryfs) has enriched the mutation spectrum of EDFDH gene.

Tandem mass spectrometry analysis and genetic diagnosis of neonates with fatty acid oxidation disorders in central and northern regions of Guangxi / 中华医学遗传学杂志

OBJECTIVE@#To determine the incidence and mutational types of fatty acid oxidation disorders (FAOD) in central-northern region of Guangxi.@*METHODS@#A total of 62 953 neonates were screened for FAOD during December 2012 and December 2017. Acyl-carnitine profiling of neonatal blood sample was performed by tandem mass spectrometry using dry blood spots on a filter paper. The diagnosis of FAOD was confirmed by organic acid profiling of urea and genetic testing.@*RESULTS@#Eighteen cases of FAOD were diagnosed among the 62 953 neonates. Among these, primary carnitine deficiency (PCD) was the most common type (n=13), which was followed by short-chain acyl-CoA dehydrogenase deficiency (SCADD) (n=2), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) (n=1), multiple acyl-CoA dehydrogenase deficiency (MADD) (n=1), and carnitine palmitoyltransferase II deficiency (CPT II D) (n=1). Genetic testing has revealed two previously unreported variants, i.e., c.337G to A (p.Gly113Arg) of ACADS gene and c.737G TO T (p.Gly246Val) of ETFA gene.@*CONCLUSION@#PCD is the most common FAOD in central-northern Guangxi. Tandem mass spectrometry combined with genetic testing may facilitate early diagnosis of FAOD.

A novel mutation in the ETFDH gene of an infant with multiple acyl-CoA dehydrogenase deficiency / 中国当代儿科杂志

This article reports the results of tandem mass spectrometry and the mutation features of the ETFDH gene for an infant with multiple acyl-CoA dehydrogenase deficiency. The results of tandem mass spectrometry showed that C14 : 1, C8, C6, C10, and C12 increased. Exon sequencing was performed on this infant and his parents and revealed double heterozygous mutations in the ETFDH gene of the infant: c.992A>T and c.1450T>C. The former was inherited from his mother, and the latter was inherited from his father. c.1450T>C was shown to be the pathogenic mutation in the HGMD database. PolyPhen2, SIFT, and PROVEAN all predicted that the novel mutation c.992A>T might be pathogenic, and the mutant amino acids were highly conserved across various species. The findings expand the mutation spectrum of the ETFDH gene, and provide molecular evidence for the etiological diagnosis of the patient with multiple acyl-CoA dehydrogenase deficiency as well as for the genetic counseling and prenatal diagnosis in the family.

Clinical features and ETFDH mutations of children with late-onset glutaric aciduria type II: a report of two cases / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the clinical and genetic features of two families with late-onset glutaric aciduria type II caused by ETFDH mutations.</p><p><b>METHODS</b>Target gene sequence capture and next generation sequencing were used for sequencing of suspected patients and their family members. The patients' clinical features were retrospectively analyzed and literature review was performed.</p><p><b>RESULTS</b>The probands of the two families had a clinical onset at the ages of 10 years and 5.5 years respectively, with the clinical manifestations of muscle weakness and muscle pain. Laboratory examinations revealed significant increases in the serum levels of creatine kinase, creatine kinase-MB, and lactate dehydrogenase. Tandem mass spectrometry showed increases in various types of acylcarnitines. The analysis of urine organic acids showed an increase in glutaric acid. Electromyography showed myogenic damage in both patients. Gene detection showed two novel mutations in the ETFDH gene (c.1331T>C from the mother and c.824C>T from the father) in patient 1, and the patient's younger brother carried the c.1331T>C mutation but had a normal phenotype. In patient 2, there was a novel mutation (c.177insT from the father) and a known mutation (c.1474T>C from the mother) in the ETFDH gene. Several family members carried such mutations. Both patients were diagnosed with glutaric aciduria type II. Their symptoms were improved after high-dose vitamin B2 treatment.</p><p><b>CONCLUSIONS</b>For patients with unexplained muscle weakness and pain, serum creatine kinase, acylcarnitines, and urinary organic acids should be measured, and the possibility of glutaric aciduria type II should be considered. Genetic detection is helpful to make a confirmed diagnosis.</p>

Clinical features and gene mutations in a patient with multiple aeyl-CoA dehydrogenase deficiency with severe fatty liver / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To analyze the clinical features and gene mutations in an adolescent patient affected with late-onset multiple aeyl-CoA dehydrogenase deficiency (MADD) with severe fatty liver.</p><p><b>METHODS</b>Potential mutations of the ETFDH gene were detected with polymerase chain reaction (PCR) and DNA sequencing.</p><p><b>RESULTS</b>The 13-year-and-10-month girl has presented with weakness without any other special manifestation. Laboratory tests demonstrated an elevation of myocardial enzyme levels, total cholesterol, lactic acid and abnormal serum free fatty acids. H magnetic resonance spectroscopy revealed severe fatty liver. An increase in multiple plasma acyl-carnitines was detected by gas chromatography/mass spectrometry and isobutyrylglycine in urine by screening with tandem mass spectrometry. Genetic analysis demonstrated 2 heterozygous missense mutations c.250G>A (p.Ala84Thr) and c.353G>T (p.Cys118Phe) in the ETFDH gene. The diagnosis of MADD was confirmed. The patient was given large dose of vitamin B2, which resulted in rapid clinical and biochemical improvement.</p><p><b>CONCLUSION</b>A common mutation c.250G>A and a novel mutation c.353G>T in the ETFDH gene were identified in the patient. The pathogenic role of c.353G>T (p.Cys118Phe) deserves further study. Early diagnosis of MADD and appropriate therapy is crucial for the prognosis.</p>

Skeletal Muscle Magnetic Resonance Imaging of the Lower Limbs in Late-onset Lipid Storage Myopathy with Electron Transfer Flavoprotein Dehydrogenase Gene Mutations / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Lipid storage myopathy (LSM) is a genetically heterogeneous group with variable clinical phenotypes. Late-onset multiple acyl-coenzyme A dehydrogenation deficiency (MADD) is a rather common form of LSM in China. Diagnosis and clinical management of it remain challenging, especially without robust muscle biopsy result and genetic detection. As the noninvasion and convenience, muscle magnetic resonance imaging (MRI) is a helpful assistant, diagnostic tool for neuromuscular disorders. However, the disease-specific MRI patterns of muscle involved and its diagnostic value in late-onset MADD have not been systematic analyzed.</p><p><b>METHODS</b>We assessed the MRI pattern and fat infiltration degree of the lower limb muscles in 28 late-onset MADD patients, combined with detailed clinical features and gene spectrum. Fat infiltration degree of the thigh muscle was scored while that of gluteus was described as obvious or not. Associated muscular atrophy was defined as obvious muscle bulk reduction.</p><p><b>RESULTS</b>The mean scores were significantly different among the anterior, medial, and posterior thigh muscle groups. The mean of fat infiltration scores on posterior thigh muscle group was significantly higher than either anterior or medial thigh muscle group (P < 0.001). Moreover, the mean score on medial thigh muscle group was significantly higher than that of anterior thigh muscle group (P < 0.01). About half of the patients displayed fat infiltration and atrophy in gluteus muscles. Of 28 patients, 12 exhibited atrophy in medial and/or posterior thigh muscle groups, especially in posterior thigh muscle group. Muscle edema pattern was not found in all the patients.</p><p><b>CONCLUSIONS</b>Late-onset MADD patients show a typical muscular imaging pattern of fat infiltration and atrophy on anterior, posterior, and medial thigh muscle groups, with major involvement of posterior thigh muscle group and gluteus muscles and a sparing involvement of anterior thigh compartment. Our findings also suggest that muscle MRI of lower limbs is a helpful tool in guiding clinical evaluation on late-onset MADD.</p>

Mutation analysis for a family affected with riboflavin responsive-multiple acyl-CoA dehydrogenase deficiency / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To identify pathogenic mutation in a boy affected with riboflavin responsive-multiple acyl-CoA dehydrogenase deficiency (RR-MADD).</p><p><b>METHODS</b>The patient was initially diagnosed as primary carnitine deficiency (PCD) and has been treated with carnitine supplementation for 7 years. Clinical manifestations and characteristics of fibula muscle specimen were analyzed. Potential mutation in electron transfer flavoprotein dehydrogenase (ETFDH) gene (for the patient and his parents) and carnitine transfer protein gene (SLC22A5) (for the patient) was screened.</p><p><b>RESULTS</b>Electronic microscopy of the muscle specimen has suggested lipid storage myopathy. Mutation analysis has found that the patient carried compound heterozygous mutations, c.250G>A and c.380T>C, in exon 3 of the ETFDH gene, whilst his father and mother were heterozygous for the c.380T>C and c.250G>A mutations, respectively. Screening of the SLC22A5 gene has yielded no clinically meaningful result. After the establishment of diagnosis of RR-MADD, the condition of the patient has improved greatly with supplementation of high doses of riboflavin along with continuous carnitine supplement.</p><p><b>CONCLUSION</b>The c.250G>A (p.Ala84Thr) mutation of exon 3 of the ETFDH gene has been a hot spot in Southern Chinese population, whilst the c.380T>C (p.Leu127Pro) is rarely reported. Our case has suggested that therapeutic diagnosis cannot substitute genetic testing. The mechanism for having stabilized the patient with only carnitine supplementation for 7 years needs further investigation.</p>

Identification of aging related proteins in human normal colonic epithelium / 中南大学学报(医学版)

OBJECTIVE@#To explore the molecular mechanisms of colonic epithelial aging related proteins and aged colonic epithelial susceptibility to tumor.@*METHODS@#The proteins of normal human colonic epithelial tissue from young and old people were separated by 2-dimensional gel electrophoresis (2DGE), respectively. Then gels were stained by silver, scanned by imagescanner and analyzed with PDQuest software. The differentially expressed protein spots of colonic epithelium between the old and the young groups were identified by peptide mass fingerprint based on matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and database searching.@*RESULTS@#Well-resolved and reproducible 2DGE maps of normal human colonic epithelium from the young and the old were acquired. Nineteen more than 2 fold differentially expressed protein spots were identified representing 17 different proteins by MALDI-TOF-MS. The functions of these proteins involve in metabolism, energy generation, transportation, antioxidation, translation and protein folding.@*CONCLUSION@#Seventeen aging related proteins of human colonic epithelium identified indicate that injury of mitochondrial function and decline of antioxidant capability are important reasons for the aging of human colonic epithelium. These data provided useful clues for elucidating the mechanisms of colonic epithelial aging and aged colonic epithelial susceptibility to cancer.