Determinants of Riboflavin Responsiveness in Multiple Acyl-CoA Dehydrogenase Deficiency.
Adolescent
Age of Onset
Child
Child, Preschool
Delayed Diagnosis
Diagnosis, Differential
Drug Resistance
Electron-Transferring Flavoproteins
/ genetics
Genetic Association Studies
Genetic Heterogeneity
Humans
Infant
Iron-Sulfur Proteins
/ genetics
Metabolism, Inborn Errors
/ diagnosis
Multiple Acyl Coenzyme A Dehydrogenase Deficiency
/ diagnosis
Muscle, Skeletal
/ pathology
Mutation, Missense
Oxidoreductases Acting on CH-NH Group Donors
/ genetics
Retrospective Studies
Riboflavin
/ therapeutic use
Symptom Assessment
Treatment Outcome
Young Adult
Electron transport flavoprotein
Glutaric aciduria type 2
Lipid storage myopathy
Multiple acyl-CoA dehydrogenase deficiency
Riboflavin
Journal
Pediatric neurology
ISSN: 1873-5150
Titre abrégé: Pediatr Neurol
Pays: United States
ID NLM: 8508183
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
19
02
2019
revised:
16
06
2019
accepted:
22
06
2019
pubmed:
25
7
2019
medline:
30
7
2020
entrez:
24
7
2019
Statut:
ppublish
Résumé
Multiple acyl-CoA dehydrogenase (MADD) deficiency, which is a rare metabolic disorder involving electron transport flavoproteins, has a wide array of clinical phenotypes. In this article, we describe 25 patients with MADD deficiency and present the clinical and laboratory characteristics and diagnostic challenges associated with riboflavin-responsive MADD deficiency. Hospital records of patients with biallelic mutations in ETFA, ETFB, or ETFDH genes diagnosed in a single center were analyzed retrospectively. Demographic, clinical, and laboratory characteristics of patients with riboflavin-responsive and riboflavin-unresponsive MADD deficiency were compared using Mann-Whitney U and Fisher's exact tests. Respiratory distress and depressed consciousness were significantly more common in patients with riboflavin-unresponsive MADD deficiency (P = 0.015 and P < 0.001), who presented at a younger age (P < 0.001). Patients with riboflavin-responsive MADD deficiency had favorable outcomes but also had life-threatening complications, longer diagnostic delay (median of two years versus 30 days; P < 0.001), and multiple differential diagnoses, resulting in unnecessary investigations and maltreatment. Biopsies showed lipid storage, and complete autopsy was performed in one newborn with riboflavin-unresponsive MADD deficiency, revealing multiple abnormalities. Metabolic profiles were not distinguishable between riboflavin-responsive and riboflavin-unresponsive MADD deficiency (P > 0.05). Four novel variants were detected in ETFDH, one of which (c.1790C>T) may confer riboflavin responsiveness. Siblings with the common myopathic ETFDH c.1130T>C mutation presented with a new phenotype dominated by chronic fatigue without apparent myopathy. Symptoms and outcomes significantly differed between riboflavin-responsive and unresponsive MADD deficiency, but metabolic profiles did not. Functional studies are needed to better characterize the novel ETFDH variants. As treatment is available for riboflavin-responsive MADD deficiency, physicians should maintain a high index of suspicion for MADD deficiency in all age groups.
Sections du résumé
BACKGROUND
Multiple acyl-CoA dehydrogenase (MADD) deficiency, which is a rare metabolic disorder involving electron transport flavoproteins, has a wide array of clinical phenotypes. In this article, we describe 25 patients with MADD deficiency and present the clinical and laboratory characteristics and diagnostic challenges associated with riboflavin-responsive MADD deficiency.
METHODS
Hospital records of patients with biallelic mutations in ETFA, ETFB, or ETFDH genes diagnosed in a single center were analyzed retrospectively. Demographic, clinical, and laboratory characteristics of patients with riboflavin-responsive and riboflavin-unresponsive MADD deficiency were compared using Mann-Whitney U and Fisher's exact tests.
RESULTS
Respiratory distress and depressed consciousness were significantly more common in patients with riboflavin-unresponsive MADD deficiency (P = 0.015 and P < 0.001), who presented at a younger age (P < 0.001). Patients with riboflavin-responsive MADD deficiency had favorable outcomes but also had life-threatening complications, longer diagnostic delay (median of two years versus 30 days; P < 0.001), and multiple differential diagnoses, resulting in unnecessary investigations and maltreatment. Biopsies showed lipid storage, and complete autopsy was performed in one newborn with riboflavin-unresponsive MADD deficiency, revealing multiple abnormalities. Metabolic profiles were not distinguishable between riboflavin-responsive and riboflavin-unresponsive MADD deficiency (P > 0.05). Four novel variants were detected in ETFDH, one of which (c.1790C>T) may confer riboflavin responsiveness. Siblings with the common myopathic ETFDH c.1130T>C mutation presented with a new phenotype dominated by chronic fatigue without apparent myopathy.
CONCLUSIONS
Symptoms and outcomes significantly differed between riboflavin-responsive and unresponsive MADD deficiency, but metabolic profiles did not. Functional studies are needed to better characterize the novel ETFDH variants. As treatment is available for riboflavin-responsive MADD deficiency, physicians should maintain a high index of suspicion for MADD deficiency in all age groups.
Identifiants
pubmed: 31331668
pii: S0887-8994(19)30195-X
doi: 10.1016/j.pediatrneurol.2019.06.015
pii:
doi:
Substances chimiques
ETFA protein, human
0
ETFB protein, human
0
Electron-Transferring Flavoproteins
0
Iron-Sulfur Proteins
0
Oxidoreductases Acting on CH-NH Group Donors
EC 1.5.-
electron-transferring-flavoprotein dehydrogenase
EC 1.5.5.1
Riboflavin
TLM2976OFR
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
69-75Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.