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Characterization of two ETFDH mutations in a novel case of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.
Lipids Health Dis. 2018 Nov 13; 17(1):254.LH

Abstract

BACKGROUND

Deficiency 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).

METHODS

In 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.

RESULTS

Patient 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.

CONCLUSION

This 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.

Authors+Show Affiliations

Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Catholic University of the Sacred Heart, pz Buonarroti 30, 20145, Milan, Italy. Psychology Department, Catholic University of the Sacred Heart, Largo Gemelli 1, 20123, Milan, Italy.Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Catholic University of the Sacred Heart, pz Buonarroti 30, 20145, Milan, Italy. Psychology Department, Catholic University of the Sacred Heart, Largo Gemelli 1, 20123, Milan, Italy.Department of Pharmaceutical Sciences, University of Piemonte Orientale, Lgo Donegani 2, 28100, Novara, Italy.Fondazione Ospedale San Camillo IRCCS, via Alberoni 70, 30126, Venice, Italy. corrado.angelini@ospedalesancamillo.net.

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

30424791

Citation

Missaglia, Sara, et al. "Characterization of Two ETFDH Mutations in a Novel Case of Riboflavin-responsive Multiple acyl-CoA Dehydrogenase Deficiency." Lipids in Health and Disease, vol. 17, no. 1, 2018, p. 254.
Missaglia S, Tavian D, Moro L, et al. Characterization of two ETFDH mutations in a novel case of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Lipids Health Dis. 2018;17(1):254.
Missaglia, S., Tavian, D., Moro, L., & Angelini, C. (2018). Characterization of two ETFDH mutations in a novel case of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Lipids in Health and Disease, 17(1), 254. https://doi.org/10.1186/s12944-018-0903-5
Missaglia S, et al. Characterization of Two ETFDH Mutations in a Novel Case of Riboflavin-responsive Multiple acyl-CoA Dehydrogenase Deficiency. Lipids Health Dis. 2018 Nov 13;17(1):254. PubMed PMID: 30424791.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of two ETFDH mutations in a novel case of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. AU - Missaglia,Sara, AU - Tavian,Daniela, AU - Moro,Laura, AU - Angelini,Corrado, Y1 - 2018/11/13/ PY - 2018/08/09/received PY - 2018/10/29/accepted PY - 2018/11/15/entrez PY - 2018/11/15/pubmed PY - 2019/1/30/medline KW - Carnitine KW - ETFDH KW - Lipid storage myopathy KW - Multiple acyl-CoA dehydrogenase disorder KW - Riboflavin SP - 254 EP - 254 JF - Lipids in health and disease JO - Lipids Health Dis VL - 17 IS - 1 N2 - BACKGROUND: Deficiency 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). METHODS: In 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. RESULTS: Patient 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. CONCLUSION: This 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. SN - 1476-511X UR - https://www.unboundmedicine.com/medline/citation/30424791/Characterization_of_two_ETFDH_mutations_in_a_novel_case_of_riboflavin_responsive_multiple_acyl_CoA_dehydrogenase_deficiency_ L2 - https://lipidworld.biomedcentral.com/articles/10.1186/s12944-018-0903-5 DB - PRIME DP - Unbound Medicine ER -