Two novel ETFDH mutations in a patient with lipid storage myopathy.
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ABSTRACT:
SUBMITTER: Xu HL
PROVIDER: S-EPMC6759130 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
Publications
Two novel ETFDH mutations in a patient with lipid storage myopathy.
Xu Hong-Liang HL Lian Ya-Jun YJ Chen Xin X Zhang Lu L Cheng Xuan X
Chinese medical journal 20190801 15
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Project description:We present six novel patients affected by lipid storage myopathy (LSM) presenting mutations in the ETFDH gene. Although the diagnosis of multiple acyl-coenzyme-A dehydrogenase deficiency (MADD) in adult life is difficult, it is rewarding because of the possibility of treating patients with carnitine or riboflavin, leading to a full recovery. In our patients, a combination of precipitating risk factors including previous anorexia, alcoholism, poor nutrition, and pregnancy contributed to a metabolic critical condition that precipitated the catabolic state.In the present series of cases, five novel mutations have been identified in the ETFDH gene. We propose clinical guidelines to screen patients with LSM due to different defects, in order to obtain a fast diagnosis and offer appropriate treatment. In such patients, early diagnosis and treatment as well as avoiding risk factors are part of clinical management.Specific biochemical studies are indicated to identify the type of LSM, such as level of free carnitine and acyl-carnitines and studies or organic acidemia. Indeed, when a patient is biochemically diagnosed with secondary carnitine deficiency, a follow-up with appropriate clinical-molecular protocol and genetic analysis is important to establish the final diagnosis, since riboflavin can be supplemented with benefit if riboflavin-responsive MADD is present. In muscle biopsies, increased lipophagy associated with p62-positive aggregates was observed. The clinical improvement can be attributed to the removal of an autophagic block, which appears to be reversible in this LSM.
| S-EPMC5874208 | biostudies-literature
Project description:BackgroundLipid storage myopathy (LSM) is an autosomal recessive inherited lipid and amino metabolic disorder with great clinical heterogeneity. Variations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene cause multiple acyl-CoA dehydrogenase deficiency (MADD), and have a manifestation of LSM. Muscle biopsy helps clarify the diagnosis of LSM, and next-generation sequencing (NGS) can be useful in identifying genomic mutation sites. The diagnosis of MADD contributes to targeted therapy.Case presentationWe report on a teenager who appeared to have muscle weakness and exercise intolerance at the onset. Before the referral to our hospital, he was unsuccessfully treated with glucocorticoid for suspected polymyositis. The next-generation sequencing of the proband and his parents revealed heterozygous variations, c.365G>A (p.G122D) inherited from the father, c.176-194_176-193del, and c.832-316C>T inherited from the mother in the ETFDH gene. The tandem mass spectrometry identified the mutations to be pathogenic. However, his parents and his younger sister who were detected with a mutation of c.365G>A presented no clinical symptoms. This indicates that the combination of the three compound heterozygous mutations in ETFDH is significant. After MADD was diagnosed, a dramatic clinical recovery and biochemical improvement presented as riboflavin was given to the patient across a week, which further confirmed the diagnosis of MADD.ConclusionOur observations extend the spectrum of ETFDH variants in Chinese the population and reinforce the role of NGS in diagnosis of MADD. Early diagnosis and appropriate treatment of LSM lead to great clinical efficacy and avoid some lethal complications.
| S-EPMC9799051 | biostudies-literature
Project description:BackgroundMutations in the TK2 gene are strongly associated with mitochondrial DNA depletion syndrome (MDS), a severe condition with high mortality and poor outcomes. Although many MDS cases are reported, those linked to TK2 mutations with lipid deposition are rare. Large deletions in the TK2 gene are even rarer.MethodsWe conducted whole-exome sequencing to find the gene linked to MDS, followed by genomic and structural analyses, histopathological, and functional analyses to assess the mutations' pathogenicity. Additionally, a HEK293T cell model with TK2 mutations was created to investigate the impact of large deletions on mitochondrial function.ResultsThe patient was found to have a novel compound heterozygous mutation in the TK2 gene, consisting of a large deletion spanning exons 5-10 (E5-E10 del) and a previously reported missense mutation (c.311C > A, p.Arg104His). Analysis of the patient's muscle tissue demonstrated a marked reduction in mtDNA content and a significant impairment in overall mitochondrial function. In the HEK293T cell model, the group with the deletion mutation exhibited a notable reduction in TK2 protein expression and levels of mitochondrial complex subunits when compared to the control group. Furthermore, there was an observed increase in ROS levels, a decrease in ATP production, and compromised mitochondrial respiratory chain function. Moreover, we conducted a comprehensive review of the previously reported genotypic and phenotypic spectrum of TK2 mutations in the literature.ConclusionsThis case report underscores the detrimental impact of large fragment deletion mutations in the TK2 gene and elucidates their role in the pathogenesis of MDS. It broadens the spectrum of known TK2 mutations and enhances our understanding of the structural and functional consequences of these mutations.
| S-EPMC11912596 | biostudies-literature
Project description:In a 28-year-old male with a mild mitochondrial myopathy manifesting as exercise intolerance and early signs of cardiomyopathy without muscle weakness or ophthalmoplegia, we identified two novel mutations in the SLC25A4 gene: c.707G>C in exon 3 (p.(R236P)) and c.116_137del in exon 2 (p.(Q39Lfs*14)). Serum lactate levels at rest were elevated (12.7 mM). Both the patient's father and brother were heterozygous carriers of the c.707G>C mutation and were asymptomatic. The second mutation causes a 22 bp deletion leading to a frame shift likely giving rise to a premature stop codon and nonsense-mediated decay (NMD). The segregation of the mutations could not be tested directly as the mother had died before. However, indirect evidence from NMD experiments showed that the two mutations were situated on two different alleles in the patient. This case is unique compared to other previously reported patients with either progressive external ophthalmoplegia (PEO) or clear hypertrophic cardiomyopathy with exercise intolerance and/or muscle weakness carrying recessive mutations leading to a complete absence of the SLC25A4 protein. Most likely in our patient, although severely reduced, SLC25A4 is still partially present and functional.
| S-EPMC4486268 | biostudies-literature
Project description:Neutral lipid storage disease with myopathy (NLSDM) presents with skeletal muscle myopathy and severe dilated cardiomyopathy in nearly 40% of cases. NLSDM is caused by mutations in the PNPLA2 gene, which encodes the adipose triglyceride lipase (ATGL). Here we report clinical and genetic findings of a patient carrying two novel PNPLA2 mutations (c.696+4A>G and c.553_565delGTCCCCCTTCTCG). She presented at age 39 with right upper limb abduction weakness slowly progressing over the years with asymmetric involvement of proximal upper and lower limb muscles. Cardiological evaluation through ECG and heart echo scan was normal until the age 53, when mild left ventricular diastolic dysfunction was detected. Molecular analysis revealed that only one type of PNPLA2 transcript, with exon 5 skipping, was expressed in patient cells. Such aberrant mRNA causes the production of a shorter ATGL protein, lacking part of the catalytic domain. This is an intriguing case, displaying severe PNPLA2 mutations with clinical presentation characterized by slight cardiac impairment and full expression of severe asymmetric myopathy.
| S-EPMC5424884 | biostudies-literature
Project description:BackgroundDeficiency of electron transfer flavoprotein dehydrogenase (ETFDH) is associated with multiple acyl-CoA dehydrogenase deficiency (MADD). This disorder is an autosomal recessive lipid storage myopathy (LSM) that exhibits a wide range of clinical features, including myopathy, weakness and multisystem dysfunctions. Many patients with late onset of MADD improve when treated with riboflavin and are also referred to as RR-MADD (riboflavin-responsive multiple Acyl-CoA dehydrogenase disorder).MethodsIn this study, we report the clinical and genetic characterization of a novel RR-MADD patient. Biochemical data were obtained from analysis of muscle and plasma samples. DNA and RNA were extracted from peripheral blood, and sequence analysis and expression study of ETFDH gene were performed. Finally, the impact of mutations on ETFDH folding was evaluated using bioinformatic tools.ResultsPatient initially presented with vomiting, muscle weakness, and acidosis. Muscle biopsy revealed typical myopathological patterns of lipid storage myopathy and blood acylcarnitine profiles showed a combined elevation of long and medium chain acylcarnitines, supporting the diagnosis of RR-MADD. Molecular analysis of ETFDH gene revealed two heterozygous mutations, a novel splice variation in intron 10, c.1285 + 1G > A, and the previously reported c.560C > T missense mutation. RT-PCR analysis showed an alteration of ETFDH RNA splicing which in turn should lead to the production of a truncated protein. The in silico prediction analysis of ETFDH tridimensional structure demonstrated that the missense mutation resulted in instability and loss of protein activation, while the splice site variation induced a dramatic conformational change of the truncated protein. After MCT diet supplemented with carnitine and riboflavin, the patient showed significant biochemical and clinical improvement, in spite of severe molecular defect.ConclusionThis case report extends the spectrum of ETFDH mutations in MADD, providing further evidence that patients presenting at least one missense mutation in the FAD-binding domain may respond to either carnitine or riboflavin treatment, due to the recovery of some enzymatic activity.
| S-EPMC6234560 | biostudies-literature
Project description:Glutaric aciduria type II (GA II) is an autosomal recessive metabolic disorder of fatty acid, amino acid, and choline metabolism. The late-onset form of this disorder is caused by a defect in the mitochondrial electron transfer flavoprotein dehydrogenase or the electron transfer flavoprotein dehydrogenase (ETFDH) gene. Thus far, the high clinical heterogeneity of late-onset GA II has brought a great challenge for its diagnosis. In this study, we reported a 21-year-old Chinese man with muscle weakness, vomiting, and severe pain. Muscle biopsy revealed myopathological patterns of lipid storage myopathy, and urine organic acid analyses showed a slight increase in glycolic acid. All the aforementioned results were consistent with GA II. Whole-exome sequencing (WES), followed by bioinformatics and structural analyses, revealed two compound heterozygous missense mutations: c.1034A > G (p.H345R) on exon 9 and c.1448C>A (p.P483Q) on exon 11, which were classified as "likely pathogenic" according to American College of Medical Genetics and Genomics (ACMG). In conclusion, this study described the phenotype and genotype of a patient with late-onset GA II. The two novel mutations in ETFDH were found in this case, which further expands the list of mutations found in patients with GA II. Because of the treatability of this disease, GA II should be considered in all patients with muscular symptoms and acute metabolism decompensation such as hypoglycemia and acidosis.
| S-EPMC9911658 | biostudies-literature
Project description:Lipid storage myopathy due to flavin adenine dinucleotide synthetase 1 (FLAD1) deficiency is an autosomal recessive error of metabolism that causes variable mitochondrial dysfunction.Case presentationAt the age of 3, the patient was found to have movement problems, such as difficulty rising from a chair (Gower's sign) and climbing stairs, which led to hospital admission and diagnosis. At the age of 4, carrier detection for spinal muscular atrophy was normal; however, at the age of 5, whole-exome sequencing revealed a pathogenic variant of Chr1: 154960762: A>T c.A554T:p.D185V in exon-2 of FLAD1 gene was identified as homozygous.Clinical discussionIn general, it is expected that the treatment of type 2 FLAD1 gene mutation with riboflavin has a better prognosis, but these interventions may not be sufficient for the survival of the patient. Treatment with riboflavin has increased various functions, including skeletal-muscular, and cardiovascular function. As a result, like the patient in our study, the mutation in exon-2 is more severe and less responsive to riboflavin treatment.ConclusionChecking the FLAD1 gene is recommended in all people with multiple acyl-CoA dehydrogenase deficiency.
| S-EPMC10205324 | biostudies-literature
Project description: Not available
| S-EPMC9771202 | biostudies-literature
Project description:BackgroundNeutral lipid storage disease with myopathy (NLSDM) is a rare lipid metabolism disorder. In this study, we evaluated some circulating miRNAs levels in serum samples and the MRI of three affected siblings.MethodsThree members of one NLSDM family were identified: two brothers and one sister. Muscles of lower and right upper extremities were studied by MRI. Expression profile of miRNAs, obtained from serum samples, was detected using qRT-PCR.ResultsTwo brothers presented with progressive skeletal myopathy, while the sister had severe hepatosteatosis and diabetes. NLSDM patients showed a significant increase of muscle-specific miRNAs expression compared with healthy subjects. We found a correlation between hepatic damage and elevation of miRNAs expression profile of liver origin.ConclusionsThe dysregulation of miRNAs might represent an indicator of skeletal and hepatic damage and it might be useful to monitor the progression of NLSDM.
| S-EPMC7004093 | biostudies-literature