Atypical presentation of VLCAD deficiency associated with a novel ACADVL splicing mutation

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive inborn error of metabolism characterized by impaired mitochondrial beta-oxidation of fatty acids with a chain length between 14 and 18 carbons. While expansion of newborn screening has improved our ability to detect VLCAD deficiency in early childhood, the late-onset form of the disease still presents a significant diagnostic challenge. We report a 20-year-old female with VLCAD deficiency who first presented in infancy with hypoketotic hypoglycemia. In childhood the patient developed complex partial seizures that were aggravated by Lamotrigine treatment. The clinical course in early adulthood was complicated by recurrent, often unprovoked, episodes of rhabdomyolysis and myoglobinuria. In addition, she suffered from chronic myalgia, muscle weakness, and diffuse abdominal tenderness. A muscle biopsy revealed accumulation of fat droplets. Her acylcarnitine profile showed significantly elevated C14, C14:1, C16, and C18-carnitines. Sequence analysis of ACADVL revealed a heterozygous recurrent mutation c.848T>C (p.V283A) and a heterozygous novel splice mutation c.879-8T>A that results in the inclusion of six nucleotides from intron 9 into the transcript sequence. The molecular characterization of this novel mutation and its correlation with the clinical phenotype are discussed.