Purpose Infants admitted to a level IV neonatal intensive care unit (NICU) who do not survive early childhood represent a population likely enriched for rare genetic disease; we therefore characterized their genetic diagnostic evaluation. Methods This is a retrospective analysis of infants admitted to our NICU between January 1, 2011 and December 31, 2015 who were deceased at the time of records review with an age at death of less than five years. Results 2,670 infants were admitted; 170 later died. 106/170 (62%) had an evaluation for a genetic or metabolic disorder. 47/170 (28%) had laboratory-confirmed genetic diagnoses made, though 14/47 (30%) diagnoses were made postmortem. Infants who were evaluated for a genetic disorder spent more time in the NICU (median 13.5 vs. 5.0 days, p = 0.003), were older at death (median 92.0 vs. 17.5 days p < 0.001), and had similarly-high rates of redirection of care (86% vs. 79%, p = 0.28). Conclusion Genetic disorders were suspected in many infants but found in a minority. Approximately one-third of diagnosed infants died prior to a laboratory-confirmed genetic diagnosis being made. This highlights the need to improve the genetic diagnostic evaluation in the NICU, particularly to aid in end-of-life decision-making.

Progressive multifocal leukoencephalopathy (PML) induced by JC virus (JCV) is a risk for natalizumab-treated multiple sclerosis (MS) patients. Here we characterize the JCV-specific T cell responses in healthy donors and natalizumab-treated MS patients to reveal functional differences that may account for the development of natalizumab-associated PML. CD4 and CD8 T cell responses specific for all JCV proteins were readily identified in MS patients and healthy volunteers. The magnitude and quality of responses to JCV and cytomegalovirus (CMV) did not change from baseline through several months of natalizumab therapy. However, the frequency of T cells producing IL-10 upon mitogenic stimulation transiently increased after the first dose. In addition, MS patients with natalizumab-associated PML were distinguished from all other subjects in that they either had no detectable JCV-specific T cell response or had JCV-specific CD4 T cell responses uniquely dominated by IL-10 production. Additionally, IL-10 levels were higher in the CSF of individuals with recently diagnosed PML. Thus, natalizumab-treated MS patients with PML have absent or aberrant JCV-specific T cell responses compared with non-PML patients, and changes in T cell-mediated control of JCV replication may be a risk factor for developing PML. Our data suggest further approaches to improved monitoring, treatment and prevention of PML in natalizumab-treated patients.