Yılmaz Yıldız1, Beril Talim2, Goknur Haliloglu3, Haluk Topaloglu3, Zuhal Akçören2, Ali Dursun4, Hatice Serap Sivri4, Turgay Coşkun4, Ayşegül Tokatlı4. 1. Division of Pediatric Metabolism, Hacettepe University Children's Hospital, Ankara, Turkey. Electronic address: yilmaz.yildiz@hacettepe.edu.tr. 2. Pediatric Pathology Unit, Hacettepe University Children's Hospital, Ankara, Turkey. 3. Division of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey. 4. Division of Pediatric Metabolism, Hacettepe University Children's Hospital, Ankara, Turkey.
Abstract
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.
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 myopathicETFDH 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.
Authors: Gregory McInnes; Andrew G Sharo; Megan L Koleske; Julia E H Brown; Matthew Norstad; Aashish N Adhikari; Sheng Wang; Steven E Brenner; Jodi Halpern; Barbara A Koenig; David C Magnus; Renata C Gallagher; Kathleen M Giacomini; Russ B Altman Journal: Am J Hum Genet Date: 2021-04-01 Impact factor: 11.025