Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency

CONTEXT: Short-chain acyl-coenzyme A (CoA) dehydrogenase (SCAD) deficiency (SCADD) is an autosomal recessive, clinically heterogeneous disorder with only 22 case reports published so far. Screening for SCADD is included in expanded newborn screening programs in most US and Australian states. OBJECTIVES: To describe the genetic, biochemical, and clinical characteristics of SCADD patients in the Netherlands and their SCADD relatives and to explore the genotype to phenotype relation. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study involving 31 Dutch SCADD patients diagnosed between January 1987 and January 2006 and 8 SCADD relatives. SCADD was defined by the presence of (1) increased butyrylcarnitine (C4-C) levels in plasma and/or increased ethylmalonic acid (EMA) levels in urine under nonstressed conditions on at least 2 occasions, in combination with (2) a mutation and/or the c.511C>T or c.625G>A susceptibility variants on each SCAD-encoding (ACADS) allele. Patients were included only if the SCAD-encoding (ACADS) was fully sequenced and if current clinical information could be obtained. Relatives were included when they carried the same ACADS genotype as the proband, and had increased C4-C and/or EMA. MAIN OUTCOME MEASURES: Prevalence, genotype (mutation/mutation, mutation/variant, variant/variant), C4-C and EMA levels, clinical signs and symptoms, and clinical course. RESULTS: A birth-prevalence of at least 1:50,000 was calculated. Most patients presented before the age of 3 years, with nonspecific, generally uncomplicated, and often transient symptoms. Developmental delay, epilepsy, behavioral disturbances, and hypoglycemia were the most frequently reported symptoms. The ACADS genotype showed a statistically significant association with EMA and C4-C levels, but not with clinical characteristics. Seven out of 8 SCADD relatives were free of symptoms. CONCLUSIONS: SCADD is far more common than assumed previously, and clinical symptoms in SCADD are nonspecific, generally uncomplicated, often transient, and not correlated with specific ACADS genotypes. Because SCADD does not meet major newborn screening criteria, including a lack of clinical significance in many patients and that it is not possible to differentiate diseased and nondiseased individuals, it is not suited for inclusion in newborn screening programs at the present time