Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database

Abstract

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency can present at various ages from the neonatal period to adulthood, and poses the greatest risk of complications during intercurrent illness or after prolonged fasting. Early diagnosis, treatment, and surveillance can reduce mortality; hence, the disorder is included in the newborn Recommended Uniform Screening Panel (RUSP) in the United States. The Inborn Errors of Metabolism Information System (IBEM-IS) was established in 2007 to collect longitudinal information on individuals with inborn errors of metabolism included in newborn screening (NBS) programs, including VLCAD deficiency. We retrospectively analyzed early outcomes for individuals who were diagnosed with VLCAD deficiency by NBS and describe initial presentations, diagnosis, clinical outcomes and treatment in a cohort of 52 individuals ages 1–18 years. Maternal prenatal symptoms were not reported, and most newborns remained asymptomatic. Cardiomyopathy was uncommon in the cohort, diagnosed in 2/52 cases. Elevations in creatine kinase were a common finding, and usually first occurred during the toddler period (1–3 years of age). Diagnostic evaluations required several testing modalities, most commonly plasma acylcarnitine profiles and molecular testing. Functional testing, including fibroblast acylcarnitine profiling and white blood cell or fibroblast enzyme assay, is a useful diagnostic adjunct if uncharacterized mutations are identified.

Impact of newborn screening for very‐long‐chain acyl‐CoA dehydrogenase deficiency on genetic, enzymatic, and clinical outcomes

“…The prevalence of cardiac disease in our study is low, which is also in line with previous reports . The yield of NBS on cardiac symptoms appears to be minimal, as there was no difference in prevalence between pre‐NBS and NBS patients.…”

“…The most apparent beneficial effect of NBS on outcome in VLCADD patients is the prevention of hypoglycemic events in patients with residual enzyme activity. NBS did not prevent hypoglycemic events in patients with low residual enzyme activity, which is consistent with VLCADD cohorts in the United States and Australia . Comparison of cohort data before and after initiation of screening is challenging due to the difference in duration of follow‐up, in our case 47 vs 11 years and the likelihood of missed pre‐NBS cases.…”

“…This is largely the result of prevention of cerebral damage due to hypoglycemia. However, NBS did not prevent hypoglycemic events and cardiac complications in patients with an LC‐FAO flux <10%, indicating that current therapeutic options are ineffective in these patients (Figure ) . Finally, although myopathy‐related complications in pre‐NBS patients are significantly more prevalent than those in NBS patients, these complications manifested mostly during adolescence, and as the oldest patients identified by NBS in the Netherlands are now 10 years of age, we cannot yet assess the impact of NBS on myopathy.…”

Utilization of archived neonatal dried blood spots for genome-wide genotyping

“…Blood obtained from heel pricks of newborn infants are spotted on Guthrie cards and collected as part of newborn screening (NBS) programs to identify potentially life-threatening metabolic and genetic disorders including sickle cell disease, phenylketonuria, and numerous other conditions associated with long-term morbidity [1][2][3][4][5][6][7]. Many states store excess or residual dried blood spots (DBS) that are not needed for the NBS in long-term repositories.…”

Long-term follow-up in newborn screening: the role of collaboration

“…3 The IBEM-IS database was also used to describe outcomes and genotype-phenotype correlations of individuals with very-long-chain acyl-CoA dehydrogenase deficiency. 4 These are just the beginning; the potential of IBEM-IS to inform NBS practices is substantial. It will be exciting to see the diversity of clinical practices that are currently in use, to discover which are the most effective at improving outcomes, and to objectively determine whether early detection does in fact improve patient outcomes for particular disorders.…”