Clinical, biochemical, and molecular spectrum of short/branched-chain acyl-CoA dehydrogenase deficiency: two new cases and review of literature.

Background Short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency is a rare inborn error of metabolism with uncertain clinical significance. As it leads to C5-carnitine (i.e. isovalerylcarnitine, 2methylbutyrilcarnitine, or pivaloylcarnitine) elevation, SBCAD deficiency is detectable at newborn screening, requiring differential diagnosis from isovaleric acidemia and pivalic acid administration. Increased urinary excretion of 2-methylbutyrylglycine (2MBG) is the hallmark of SBCAD deficiency. Methods We report two cases of SBCAD deficiency and provide a review of the available literature on this condition. Results Two siblings newly diagnosed with SBCAD deficiency are reported. Newborn screening allowed the early diagnosis in the second-born (C5=0.5 μmol/L, normal 0.05-0.3 μmol/L) and addressed selective screening in the 5-year asymptomatic brother (C5=1.9 μmol/L). Both patients showed increased urinary excretion of 2MBG and two mutations in the ACADSB gene (c.443C>T/c.1145C>T). Currently, both the patients are asymptomatic. Longitudinal biochemical monitoring of the two patients while on treatment with carnitine (100 mg/kg/day) was provided. Based on our experience and the literature review (162 patients), SBCAD deficiency is symptomatic in about 10% of reported patients. Clinical onset occurs in newborns or later in life with seizures, developmental delay, hypotonia, and failure to thrive. On longitudinal follow-up, epilepsy, developmental delay, microcephaly, and autism can develop. Acute metabolic decompensation due to catabolic stressors can occur, as observed in one newly reported patient. Fifteen mutations in the ACADSB gene are known, including the newly identified variant c.1145C>T (p.Thr382Met), variably associated to the phenotype. In the Hmong population, SBCAD deficiency is highly prevalent, mostly due to the founder mutation c.1165A>G, and is largely asymptomatic. Conclusions Although mostly asymptomatic, considering SBCAD deficiency as a non-disease in non-Hmong subjects appears unsafe. Catabolic situations can precipitate acute metabolic decompensation. Carnitine supplementation and valproate avoidance appear to be indicated. Providing an emergency protocol for the management of acute catabolic episodes seems reasonable in asymptomatic patients with SBCAD deficiency. Longitudinal follow-up is recommended.