Genotype–phenotype correlations: sudden death in an infant with very-long-chain acyl-CoA dehydrogenase deficiency

Very-long-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. The phenotype of VLCADD is heterogeneous, and patients are typically classified into three categories based upon onset of symptoms and clinical findings. As a result of early diagnosis and treatment, many patients with VLCADD have remained asymptomatic. A general genotype–phenotype correlation has been elicited. A genotype that is associated with residual enzyme activity is more likely to present with an attenuated phenotype. One prevailing mutation, the c.848T>C (p.V283A), has been associated with residual enzyme activity and has been identified in many asymptomatic individuals diagnosed through either newborn or family screening. We present a patient who died as a result of fatal hypoglycemia at 38 h of life before diagnosis of VLCADD could be established by newborn screening. Despite the early onset of the disease, the patient was found to have a missense mutation within the ACADVL gene with a c.848T>C, c.342+1G>C genotype. Genotype alone remains limited in its predictive ability to determine which affected individuals are at risk for fatal complications.