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Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review

Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic li...

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Autores principales: Siano, Maria Anna, Mandato, Claudia, Nazzaro, Lucia, Iannicelli, Gennaro, Ciccarelli, Gian Paolo, Barretta, Ferdinando, Mazzaccara, Cristina, Ruoppolo, Margherita, Frisso, Giulia, Baldi, Carlo, Tartaglione, Salvatore, Di Salle, Francesco, Melis, Daniela, Vajro, Pietro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143529/
https://www.ncbi.nlm.nih.gov/pubmed/34041209
http://dx.doi.org/10.3389/fped.2021.672004
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author Siano, Maria Anna
Mandato, Claudia
Nazzaro, Lucia
Iannicelli, Gennaro
Ciccarelli, Gian Paolo
Barretta, Ferdinando
Mazzaccara, Cristina
Ruoppolo, Margherita
Frisso, Giulia
Baldi, Carlo
Tartaglione, Salvatore
Di Salle, Francesco
Melis, Daniela
Vajro, Pietro
author_facet Siano, Maria Anna
Mandato, Claudia
Nazzaro, Lucia
Iannicelli, Gennaro
Ciccarelli, Gian Paolo
Barretta, Ferdinando
Mazzaccara, Cristina
Ruoppolo, Margherita
Frisso, Giulia
Baldi, Carlo
Tartaglione, Salvatore
Di Salle, Francesco
Melis, Daniela
Vajro, Pietro
author_sort Siano, Maria Anna
collection PubMed
description Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic liver involvement. A systematic literature review of liver involvement in MADD was performed as well. Our patient is a 11-year-old otherwise healthy, non-obese, male child admitted for some weakness/asthenia, vomiting and recurrent severe hypertransaminasemia (aspartate and alanine aminotransferases up to ×20 times upper limit of normal). Hepatic ultrasound showed a bright liver. MRI detected mild lipid storage of thighs muscles. A liver biopsy showed a micro-macrovacuolar steatohepatitis with minimal fibrosis. Main causes of hypertransaminasemia were ruled out. Serum aminoacids (increased proline), acylcarnitines (increased C4-C18) and a large excretion of urinary glutaric acid, ethylmalonic, butyric, isobutyric, 2-methyl-butyric and isovaleric acids suggested a diagnosis of MADD. Serum acylcarnitines and urinary organic acids fluctuated overtime paralleling serum transaminases during periods of illness/catabolic stress, confirming their recurrent nature. Genetic testing confirmed the diagnosis [homozygous c.1658A > G (p.Tyr553Cys) in exon 12 of the ETFDH gene]. Lipid-restricted diet and riboflavin treatment rapidly ameliorated symptoms, hepatic ultrasonography/enzymes, and metabolic profiles. Literature review (37 retrieved eligible studies, 283 patients) showed that liver is an extramuscular organ rarely involved in late-onset MADD (70 patients), and that amongst 45 patients who had fatty liver only nine had severe presentation. Conclusion: MADD is a disorder with a clinically heterogeneous phenotype. Our study suggests that MADD warrants consideration in the work-up of obesity-unrelated severe steatohepatitis.
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spelling pubmed-81435292021-05-25 Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review Siano, Maria Anna Mandato, Claudia Nazzaro, Lucia Iannicelli, Gennaro Ciccarelli, Gian Paolo Barretta, Ferdinando Mazzaccara, Cristina Ruoppolo, Margherita Frisso, Giulia Baldi, Carlo Tartaglione, Salvatore Di Salle, Francesco Melis, Daniela Vajro, Pietro Front Pediatr Pediatrics Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic liver involvement. A systematic literature review of liver involvement in MADD was performed as well. Our patient is a 11-year-old otherwise healthy, non-obese, male child admitted for some weakness/asthenia, vomiting and recurrent severe hypertransaminasemia (aspartate and alanine aminotransferases up to ×20 times upper limit of normal). Hepatic ultrasound showed a bright liver. MRI detected mild lipid storage of thighs muscles. A liver biopsy showed a micro-macrovacuolar steatohepatitis with minimal fibrosis. Main causes of hypertransaminasemia were ruled out. Serum aminoacids (increased proline), acylcarnitines (increased C4-C18) and a large excretion of urinary glutaric acid, ethylmalonic, butyric, isobutyric, 2-methyl-butyric and isovaleric acids suggested a diagnosis of MADD. Serum acylcarnitines and urinary organic acids fluctuated overtime paralleling serum transaminases during periods of illness/catabolic stress, confirming their recurrent nature. Genetic testing confirmed the diagnosis [homozygous c.1658A > G (p.Tyr553Cys) in exon 12 of the ETFDH gene]. Lipid-restricted diet and riboflavin treatment rapidly ameliorated symptoms, hepatic ultrasonography/enzymes, and metabolic profiles. Literature review (37 retrieved eligible studies, 283 patients) showed that liver is an extramuscular organ rarely involved in late-onset MADD (70 patients), and that amongst 45 patients who had fatty liver only nine had severe presentation. Conclusion: MADD is a disorder with a clinically heterogeneous phenotype. Our study suggests that MADD warrants consideration in the work-up of obesity-unrelated severe steatohepatitis. Frontiers Media S.A. 2021-05-10 /pmc/articles/PMC8143529/ /pubmed/34041209 http://dx.doi.org/10.3389/fped.2021.672004 Text en Copyright © 2021 Siano, Mandato, Nazzaro, Iannicelli, Ciccarelli, Barretta, Mazzaccara, Ruoppolo, Frisso, Baldi, Tartaglione, Di Salle, Melis and Vajro. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pediatrics
Siano, Maria Anna
Mandato, Claudia
Nazzaro, Lucia
Iannicelli, Gennaro
Ciccarelli, Gian Paolo
Barretta, Ferdinando
Mazzaccara, Cristina
Ruoppolo, Margherita
Frisso, Giulia
Baldi, Carlo
Tartaglione, Salvatore
Di Salle, Francesco
Melis, Daniela
Vajro, Pietro
Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review
title Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review
title_full Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review
title_fullStr Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review
title_full_unstemmed Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review
title_short Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review
title_sort hepatic presentation of late-onset multiple acyl-coa dehydrogenase deficiency (madd): case report and systematic review
topic Pediatrics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143529/
https://www.ncbi.nlm.nih.gov/pubmed/34041209
http://dx.doi.org/10.3389/fped.2021.672004
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