Isobutyryl‐CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: A case report

Abstract

Background Isobutyryl‐CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched‐chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl‐CoA dehydrogenase deficiency (IBDD), which is identified by increased C4‐acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. Methods Here, we review all previously published IBDD patients and describe a girl diagnosed with IBDD who was presenting with autism as the main disease feature. Results To assess whether a phenotype‐genotype correlation exists that could explain the development or absence of clinical symptoms in IBDD, we compared CADD scores, in silico mutation predictions, LoF tolerance scores and C4‐acylcarnitine levels between symptomatic and asymptomatic individuals. Statistical analysis of these parameters did not establish significant differences amongst both groups. Conclusion As in our proband, trio whole exome sequencing did not establish an alternative secondary genetic diagnosis for autism, and reported long‐term follow‐up of IBDD patients is limited, it is possible that autism spectrum disorders could be one of the disease‐associated features. Further long‐term follow‐up is suggested in order to delineate the full clinical spectrum associated with IBDD.

Combined isobutyryl‐CoA and multiple acyl‐CoA dehydrogenase deficiency in a boy with altered riboflavin homeostasis

“…Only a few patients, who were not diagnosed from a newborn screening program, as our patient was, had anemia, dilated cardiomyopathy, ketotic hypoglycemia, and asthma. 18,43,47 In agreement with ACAD8 deficiency, in acylcarnitine profiles of our patient the levels of C4 and C4 related ratios are significantly altered, reaching values more pronounced than in a large cohort of IBDD subjects, recently described, 44 and even higher than the levels of the other MADD specific acylcarnitines (see Mereis et al 16 ). If actually due to a reduction in IBD activity, this complex biochemical phenotype might be explained by the speculation, which is still a matter of debate, that IBD might overlap SCAD functionality.…”

“…Indeed, its increase was not always reported, as in the case of severalrecently described patients. 43,44 Interestingly ETF/ETF:QO, IBD, and other ACADs requires FAD for their enzymatic activities; it is noteworthy that we revealed in our patient a disturbance of flavin cofactor availability, presumably due to fasting, as revealed by EGRAC and HPLC measurements. FAD scarcity is expected to induce defects in downstream enzymes.…”

“…Indeed, its increase was not always reported, as in the case of severalrecently described patients. 43 , 44 …”

“…Treatment with l ‐carnitine was beneficial. Since then, patients with inherited IBDD have mostly been diagnosed through newborn screening programs due to elevated C4‐acylcarnitine levels and have appeared clinically asymptomatic, though a few patients have shown speech delay and neurodevelopmental delay/intellectual disability, hypotonia, emesis, failure to thrive (see Sass and colleagues 42 , 43 , 44 , 45 , 46 and references therein). Only a few patients, who were not diagnosed from a newborn screening program, as our patient was, had anemia, dilated cardiomyopathy, ketotic hypoglycemia, and asthma.…”

“…Only a few patients, who were not diagnosed from a newborn screening program, as our patient was, had anemia, dilated cardiomyopathy, ketotic hypoglycemia, and asthma. 18 , 43 , 47 …”