Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

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.

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.

Figure 2

Mutated genes in 245 patients with late-onset MADD. The majority of late-onset MADD patients harbor mutations in the ETFDH gene. The frequency of ETFDH, ETFA and ETFB mutations in 245 patients with late-onset MADD is displayed.

Figure 3

Lipid storage myopathy. Histological picture of lipid storage myopathy typical for late-onset MADD. A Oilred stain. B Trichrome stain. C Electron microscopy.