Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease.

BACKGROUND: Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly refer infants for human stem cell transplantation within the first few weeks of life. After 11 years of active screening in New York and the introduction of Krabbe disease newborn screening in other states, new information has been gained which can inform the design of newborn screening programs to improve infantile Krabbe disease outcomes. FINDINGS: Recent information relevant to Krabbe disease screening, diagnosis, and treatment were assessed by a diverse group of public health, medical, and advocacy professionals. Outcomes after newborn screening may improve if treatment for infantile disease is initiated before 30 days of life. Newer laboratory screening and diagnostic tools can improve the speed and specificity of diagnosis and help facilitate this early referral. Given the rarity of Krabbe disease, most recommendations were based on case series or expert opinion. CONCLUSION: This report updates recommendations for Krabbe disease newborn screening to improve the timeliness of diagnosis and treatment of infantile Krabbe disease. In the United States, several states have begun or are considering Krabbe disease newborn screening. These recommendations can guide public health laboratories on methodologies for screening and inform clinicians about the need to promptly diagnose and treat infantile Krabbe disease. The timing of the initial referral after newborn screening, the speed of diagnostic confirmation of infantile disease, and the transplantation center's experience and ability to rapidly respond to a suspected patient with newly diagnosed infantile Krabbe disease are critical for optimal outcomes.

Lysosomal storage disorder screening implementation: findings from the first six months of full population pilot testing in Missouri.

OBJECTIVE: To evaluate the performance of a statewide full-population pilot study in Missouri on newborn blood spots for screening of lysosomal storage disorders (LSDs) using digital microfluidics. STUDY DESIGN: A full-population pilot study using a multiplexed fluorometric enzymatic assay to detect Pompe disease, Fabry disease, Gaucher disease, and mucopolysaccharidosis type I (MPS I) in the Missouri newborn population is ongoing. Provisional cutoff values were determined during a prepilot study. All newborn dried blood spots received at the Missouri State Public Health Laboratory for routine newborn screening were screened for the 4 LSDs during the pilot study. Newborns determined to be screen-positive were referred for confirmatory testing. RESULTS: The study commenced on January 11, 2013; during the first 6 months, 43,701 specimens were screened, and 27 newborns with a confirmed diagnosis of an LSD genotype (8 with Pompe disease, 1 with Gaucher disease, 15 with Fabry disease, and 3 with MPS I) were identified. These numbers correspond to detection rates of 1:5463 for Pompe disease, 1:43,701 for Gaucher disease, 1:2913 for Fabry disease, and 1:14,567 for MPS I. The positive predictive values were 47% for Pompe disease with 1 lost to follow-up, 10% for Gaucher disease, 58% for Fabry disease with 2 lost to follow-up, and 11% for MPS I with 4 pending. CONCLUSION: The first 6 months of the Missouri LSD pilot study provided the opportunity to validate the effectiveness of the digital microfluidic screening method, refine the cutoffs for detection of these LSDs, and test the entire system of infant referral, follow-up, confirmation, treatment, and screening program communication.