scholarly journals Multiple Acyl-CoA Dehydrogenase Deficiency with Variable Presentation Due to a Homozygous Mutation in a Bedouin Tribe

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1140
Author(s):  
Orna Staretz-Chacham ◽  
Shirly Amar ◽  
Shlomo Almashanu ◽  
Ben Pode-Shakked ◽  
Ann Saada ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Newborn Screening ◽  
Dehydrogenase Deficiency ◽  
Late Onset ◽  
Acid Oxidation ◽  
Homozygous Mutation ◽  
Electron Transfer Flavoprotein ◽  
The Difference ◽  
Fad Binding ◽  
Genotype Correlation

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid and amino acid oxidation defect caused by a deficiency of the electron-transfer flavoprotein (ETF) or the electron-transfer flavoprotein dehydrogenase (ETFDH). There are three phenotypes of the disease, two neonatal forms and one late-onset. Previous studies have suggested that there is a phenotype–genotype correlation. We report on six patients from a single Bedouin tribe, five of whom were sequenced and found to be homozygous to the same variant in the ETFDH gene, with variable severity and age of presentation. The variant, NM_004453.3 (ETFDH): c.524G>A, p.(R175H), was previously recognized as pathogenic, although it has not been reported in the literature in a homozygous state before. R175H is located near the FAD binding site, likely affecting the affinity of FAD for EFT:QO. The single homozygous ETFDH pathogenic variant was found to be causing MADD in this cohort with an unexpectedly variable severity of presentation. The difference in severity could partly be explained by early diagnosis via newborn screening and early treatment with the FAD precursor riboflavin, highlighting the importance of early detection by newborn screening.

Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Yiming Lin ◽  
Weifeng Zhang ◽  
Zhixu Chen ◽  
Chunmei Lin ◽  
Weihua Lin ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Genetic Analysis ◽  
Tandem Mass Spectrometry ◽  
Newborn Screening ◽  
Dehydrogenase Deficiency ◽  
Late Onset ◽  
False Negative ◽  
Tandem Mass ◽  
Lipid Storage Myopathy ◽  
Molecular Features

Abstract Objectives 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.

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

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Keechilat Pavithran ◽  
Divya Pachat ◽  
Dehannathparambil Kottarathil Vijaykumar
Keyword(s):  
Dehydrogenase Deficiency ◽  
Late Onset ◽  
Acid Oxidation ◽  
Successful Management ◽  
Carcinoma Of The Breast ◽  
Metabolic Complications ◽  
Case Presentation ◽  
Neonatal Onset ◽  
Gene Mutation Analysis ◽  
Rare Metabolic Disorder

Abstract Background Multiple 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 presentation Here, 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. Conclusion The 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.

Late-onset form of β-electron transfer flavoprotein deficiency

2003 ◽  
Vol 78 (4) ◽  
pp. 247-249 ◽  
Author(s):  
A. Curcoy ◽  
R.K.J. Olsen ◽  
A. Ribes ◽  
V. Trenchs ◽  
M.A. Vilaseca ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Late Onset ◽  
Electron Transfer Flavoprotein

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

BMC Neurology ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Wei Chen ◽  
Youqiao Zhang ◽  
Yifeng Ni ◽  
Shaoyu Cai ◽  
Xin Zheng ◽  
...  
Keyword(s):  
Dehydrogenase Deficiency ◽  
Late Onset ◽  
Southern China ◽  
Case Reports ◽  
Lipid Storage ◽  
Chinese Family ◽  
Homozygous Mutation ◽  
Muscle Enzymes ◽  
Lipid Storage Myopathy ◽  
Southern Min

Abstract Background Multiple 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 presentation Both 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. Conclusions Mutations 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.

Riboflavin-Responsive Multiple Acyl-CoA Dehydrogenase Deficiency Associated with Hepatoencephalomyopathy and White Matter Signal Abnormalities on Brain MRI

2017 ◽  
Vol 48 (03) ◽  
pp. 194-198 ◽  
Author(s):  
Päivi Myllynen ◽  
Marja Perhomaa ◽  
Hannu Tuominen ◽  
Riikka Keski-Filppula ◽  
Seppo Rytky ◽  
...  
Keyword(s):  
White Matter ◽  
Motor Skills ◽  
Dehydrogenase Deficiency ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Acid Oxidation ◽  
Homozygous Mutation ◽  
Liver Size ◽  
Variable Nature ◽  
Rare Inborn Error

AbstractMultiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting both fatty acid and amino acid oxidation. It can manifest at any age, but riboflavin-responsiveness has mainly been described in less severely affected patients. We describe an infant with severe MADD presenting with profound hypotonia and hepatomegaly. Treatment with riboflavin improved his muscle strength, liver size, and biochemical markers. A homozygous mutation of electron transfer flavoprotein dehydrogenase (ETFDH) was found. His motor skills continued to progress until a fatal infection-triggered deterioration at the age of 34 months. We show changes in brain magnetic resonance imaging over the course of the disease, with profound white matter abnormalities during the deterioration phase. Aggregates of mitochondria with abnormal cristae in muscle electron microscopy were noticed already in infancy. An unusual lactate dehydrogenase (LDH) isoenzyme pattern with LDH-1 predominance was additionally observed. This case demonstrates riboflavin-responsiveness in a severely affected infant with both muscular and extramuscular involvement and further underlines the variable nature of this disease.

scholarly journals Beneficial Effect of N-Carbamylglutamate in a Neonatal Form of Multiple Acyl-CoA Dehydrogenase Deficiency

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Sinziana Stanescu ◽  
Amaya Belanger-Quintana ◽  
Carlos Alcalde Martin ◽  
Celia Pérez-Cerdá Silvestre ◽  
Begoña Merinero Cortés ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Dehydrogenase Deficiency ◽  
Autosomal Recessive Disorder ◽  
Acid Oxidation ◽  
Metabolic Decompensation ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Transfer Protein ◽  
Electron Transfer Protein

Background. Multiple acyl-CoA dehydrogenase deficiency is an autosomal recessive disorder of the amino acid metabolism and fatty acid oxidation due to the deficiency of the electron transfer protein or electron transfer protein ubiquinone oxidoreductase. The clinical picture ranges from a severe neonatal lethal presentation to late myopathic forms responsive to riboflavin. Up to now, there is no effective treatment for the neonatal form, which exhibits severe metabolic acidosis, hyperammonemia, hypoketotic hypoglycemia, and rhabdomyolysis. We present the case of a child who has had a good long-term outcome after a typical neonatal onset, with a dramatic drop in ammonia levels during the initial metabolic decompensation crisis and adequate control even during intercurrent diseases thereafter with N-carbamylglutamate treatment.

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