Grünert Orphanet Journal of Rare Diseases 2014, 9:117 http://www.ojrd.com/content/9/1/117 RESEARCH Open Access Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency Sarah C Grünert Abstract Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder caused by deficiency of electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase. The clinical picture of late-onset forms is highly variable with symptoms ranging from acute metabolic decompensations to chronic, mainly muscular problems or even asymptomatic cases. Methods: All 350 cases of late-onset MADD reported in the literature to date have been analyzed and evaluated with respect to age at presentation, diagnostic delay, biochemical features and diagnostic parameters as well as response to treatment. Results: Mean age at onset was 19.2 years. The mean delay between onset of symptoms and diagnosis was 3.9 years. Chronic muscular symptoms were more than twice as common as acute metabolic decompensations (85% versus 33% of patients, respectively). 20% had both acute and chronic symptoms. 5% of patients had died at a mean age of 5.8 years, while 3% of patients have remained asymptomatic until a maximum age of 14 years. Diagnosis may be difficult as a relevant number of patients do not display typical biochemical patterns of urine organic acids and blood acylcarnitines during times of wellbeing. The vast majority of patients carry mutations in the ETFDH gene (93%), while mutations in the ETFA (5%) and ETFB (2%) genes are the exceptions. Almost all patients with late-onset MADD (98%) are clearly responsive to riboflavin. Conclusions: Late-onset MADD is probably an underdiagnosed disease and should be considered in all patients with acute or chronic muscular symptoms or acute metabolic decompensation with hypoglycemia, acidosis, encephalopathy and hepatopathy. This may not only prevent patients from invasive diagnostic procedures such as muscle biopsies, but also help to avoid fatal metabolic decompensations. Keywords: Glutaric aciduria type 2, Lipid storage myopathy, Muscle weakness, Metabolic decompensation, Riboflavin, ETFDH, ETFA, ETFB Background Inheritance follows an autosomal recessive trait [1]. Multiple acyl-CoA dehydrogenase deficiency (MADD, The metabolic defects result in impaired adenosine MIM #231680), also called glutaric aciduria type 2 (GA2), triphosphate (ATP) biosynthesis, excessive lipid accumula- is an inborn error of metabolism affecting the oxidation of tion in different organs and insufficient gluconeogenesis fatty acids as well as the catabolism of branched-chain [1]. The clinical phenotype is heterogeneous and has been amino acids, lysine and tryptophan. MADD is caused by classified into three groups: neonatal onset with congenital deficiency of either an electron-transfer flavoprotein anomalies (type 1), neonatal onset without anomalies (ETF, encoded by ETFA and ETFB) or an electron-transfer (type 2), and mild and/or later onset (type 3) [1,2]. flavoprotein dehydrogenase (ETFDH, encoded by ETFDH). While neonates usually present with severe metabolic decompensations including metabolic acidosis, non- Correspondence: [email protected] ketotic hypoglycemia, hyperammonemia, hypotonia, coma Center of Pediatrics and Adolescent Medicine, University Hospital Freiburg, and cardiomyopathy, the course and age at presentation Freiburg, Germany © 2014 Grünert; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data made available in this article, unless otherwise stated. Grünert Orphanet Journal of Rare Diseases 2014, 9:117 Page 2 of 8 http://www.ojrd.com/content/9/1/117 of later-onset forms is extremely variable. In adolescents Table 1 Clinical information on 350 patients with and adults, muscular or cardiac symptoms or episodic late-onset MADD published in the literature vomiting are usually first features suggestive for MADD Sex Female n = 144, male n = 177, [1,3-9]. Therapeutic management mostly comprises a not reported n = 29 diet restricted in fat and protein and the avoidance of Identified by newborn screening 2.0% (7/350) patients fasting. The majority of patients respond well to riboflavin Identified by family screening 1.4% (5/350) patients therapy. Acute symptoms 33.1% (111/335) of patients Diagnosis is based on both the urinary organic acid Chronic symptoms 85.3% (291/341) of patients profile and the acylcarnitine pattern in dried blood/ Acute and chronic symptoms 20.4% (68/333) of patients plasma. The characteristic urinary organic acid pattern comprises elevated levels of glutaric, ethylmalonic, Mean age at onset of symptoms 19.2 years (n = 273) 3-hydroxyisovaleric, 2-hydroxyglutaric, 5-hydroxyhexanoic, Mean diagnostic delay 3.9 years (0-29 years) adipic, suberic, sebacic, and dodecanedioic acid without Asymptomatic 2.6% (9/349) of patients relevant ketonuria, especially if combined with glycine Deceased patients 5.2% (18/349) of patients conjugates of C4 and C5 acids [1]. Acylcarnitine analysis Riboflavin responsiveness 98.4% (256/260) of patients usually reveals increased concentrations of several short-, medium- and long-chain acylcarnitines, such as C4, C5, C5-DC, C6, C8, C10, C12, C14:1, C16, C18:1 [10]. How- was only made post mortem. Mean age at diagnosis of ever, the diagnosis may be challenging in late-onset cases symptomatic patients was 17.6 years (n = 111, median since the biochemical abnormalities may be mild, atypical 14.0 years, range 0.13-69 years). The mean delay between or only detectable during metabolic decompensations. This onset of symptoms and diagnosis was 3.9 years (n = 93, report aims at providing a comprehensive description of range 0-29 years). If only patients without acute late-onset MADD in its clinical and genetic heterogeneity decompensations were considered (n = 38), the mean by analysis of all cases published to date. latency was 3.7 years (range 0-29 years). 33.1% of patients (111/335) displayed acute signs and symptoms, i.e., meta- Methods bolic decompensations with hypoglycemia and acidosis, A systematic literature search in PubMed was performed while chronic features were reported in 85.3% (291/341) of using the terms “multiple acyl-CoA dehydrogenase patients. Chronic manifestations mainly comprised muscu- deficiency”, “glutaric aciduria type 2”, “glutaric acidemia lar weakness, exercise intolerance and muscle pain. 20.4% type 2”, “ETFDH”, “ETFA” and “ETFB” in order to obtain (68/333) had both, acute episodes and chronic symptoms. comprehensive information on the clinical course of 5.2% (18/349) of patients had already died when reported MADD patients with late onset of the disease (type 3). in the literature (mean age at death 5.8 years, range 0.2-20 Late onset was defined as onset beyond the neonatal years). Among those only the minority (4/14, 28.6%) period (>28 days). The search was performed in January deceased during the initial metabolic crisis. In 5 of 11 2014. 350 cases of late-onset MADD published between patients with fatal outcome of whom detailed data were 1979 and 2014 were identified (for detailed data and available, the diagnosis was known before the life-ending references see Additional file 1: Table S1). All cases were event. Three of those had been identified by newborn evaluated and analyzed with a special focus on the patients’ screening or early neonatal screening due to an affected age at onset, age at diagnosis, symptoms, biochemical older sibling while two patients had been diagnosed abnormalities, affected genes and response to riboflavin symptomatically in infancy/childhood. In the remaining 6 treatment. Riboflavin responsiveness was defined as a patients the diagnosis was only made during the fatal positive clinical response to treatment with improvement metabolic decompensation or post mortem. 2.6% (9/349) of symptoms, not only biochemical parameters. of patients have remained asymptomatic until a mean age of 6.15 years (0.5-14.0 years). Results Results of organic acid analysis in urine were available in 350 cases of late-onset MADD were reviewed. Detailed 258 patients. A typical metabolite pattern was detected at information on all patients is displayed in the Additional least once in 236/258 patients (91.5%) while only file 1: Table S1 as well as in Table 1. 144 patients were unremarkable organic acid results were reported in female, 177 male, the sex of 29 individuals was not 22/258 individuals (8.5%). In some cases, elevated signals of reported. Mean age at onset was 19.2 years (n = 273, only single metabolites such as ethylmalonic acid or glutaric range 0.13-68 years) (Figure 1). Seven patients were acid were detected [11-13]. Some patients displayed a identified by newborn screening, and another 5 patients pathognomonic metabolite pattern only intermittently, were diagnosed by early investigations in the neonatal i.e. during metabolic decompensations. In several patients, period due to an affected sibling. In 2 patients the diagnosis the initially detected biochemical abnormalities disappeared Grünert Orphanet Journal of Rare Diseases 2014, 9:117 Page 3 of 8 http://www.ojrd.com/content/9/1/117 Figure 1 Age at onset in 146 late-onset MADD patients. Age at onset of symptoms ranges from early infancy to late adulthood. The mean age at onset of 146 patients with late-onset MADD of whom detailed information was given in the literature is 14.3 years. Of additional 56 cases reported by Wang et al. [55] and 71 cases reported by Xi et al. [28] only the mean age at onset (24.5 ± 12.6 years with a range from 4 to 55 years and 25.0 ± 13.3 years with a range from 4 to 36 years, respectively) is known. If these cases are also taken into account, the mean age at onset in this study cohort is 19.2 years.