International Journal of Neonatal Screening

Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids. The clinical presentation is highly variable, ranging from life-threatening metabolic crises with metabolic acidosis and hyperammonemia to a clinically asymptomatic only biochemical phenotype. Newborn screening for IVA has been established in many countries. Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes. Still, evidence-based recommendations for the diagnosis and management of IVA patients with various phenotypes are lacking. Therefore, a systematic search and review of the literature was conducted to make suggestions for the care of patients with IVA based on both the available scientific evidence and consensus-derived expert conclusions. Based on a comprehensive set of literature data published between 1966 and 2024, 15 statements were phrased on the presentation, diagnosis, management, and outcome of IVA involving clinical, biochemical, and nutrition expertise. These statements can serve as a basis for more standardized care for IVA.

Neonatal screening programs for inborn errors of metabolism are essential for early diagnosis and intervention. However, false-positive results can cause unnecessary psychological stress for caregivers. This study investigated the emotional impact on a small number of caregivers in Oita Prefecture in Japan, whose infants received false-positive screening results for very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Particular attention was given to caregivers’ concerns regarding episodes of transient fasting suggestive of nutritional deficiency, as well as their perspectives on appropriate feeding practices for newborns. Nineteen infants in Oita Prefecture were identified as having elevated acylcarnitines, which were later confirmed as false positives. Of these cases, 11 mothers consented to participate in a survey and long-term growth evaluation using health check records. Thirty children with normal screening results were included as controls. While no differences in physical growth were found between groups by 3.5 years of age, some mothers of false-positive infants reported persistent anxiety. Their concerns included regret for inadequate breastfeeding and latent adverse effects on long-term growth or development. Conversely, caregivers’ anxiety diminished over time as they directly observed their infants’ normal growth and development. No regret was expressed regarding breastfeeding, and concerns about VLDCAD were not observed. Caregivers’ responses may help reduce their psychological burden.

Clinical trials in spinal muscular atrophy (SMA) have shown that early treatment improves outcomes, prompting inclusion in newborn screening (NBS) programs worldwide. The province of Quebec launched its SMA NBS program in October 2023, with a rapidly progressive implementation. We describe the program’s first-year experience, focusing on screening yield, birth prevalence, clinical outcomes, and challenges. In the first year, 6 of 67,933 newborns screened positive for SMA, all subsequently confirmed by diagnostic testing. Of these, 4 newborns (67%) had two SMN2 copies and 2 newborns (33%) had four copies. Additionally, one symptomatic compound heterozygote infant presented during this period, indicating a provincial birth prevalence of 1 in 9705 live births (95% CI: 1:20,032–1:4701). Two newborns with two SMN2 copies were symptomatic at initial consultation; one transitioned to palliative care and died at 43 days of life. Surviving newborns initiated treatment at a median age of 30 days (range: 9–103 days), with four receiving onasemnogene abeparvovec and one nusinersen. Motor outcomes at three or six months were stable or improved among treated infants. Overall, the Quebec SMA NBS pilot program successfully identified affected newborns, facilitated early access to therapy, and provided the first provincial estimate of SMA birth prevalence. Improved sample shipping and processing times are needed to maximize the program’s impact, which is expected with full automation.