Orsini, Joseph J

Krabbe disease is an autosomal recessive leukodystrophy caused by a deficiency of the lysosomal enzyme galactosylceramidase (GALC), responsible for the degradation of galactolipids, resulting in toxic psychosine accumulation and progressive demyelination of the central and peripheral nervous systems. Newborn screening (NBS) has increased recognition of later-onset Krabbe disease, although interpretation of complex GALC genotypes remains challenging, particularly in the presence of “pseudodeficiency” and modifier alleles. In this case report, we describe a child with late-infantile Krabbe disease identified through NBS with markedly reduced GALC activity and a homozygous GALC haplotype containing c.956A>G (p.Tyr319Cys; Y319C) and c.1685T>C (p.Ile562Thr; I562T), in addition to other benign variants. Retrospective analysis of the newborn screening specimen demonstrated mild psychosine elevation. Despite preserved neurodevelopment, longitudinal surveillance demonstrated progressive cerebral white matter abnormalities by 3 years and 9 months of age and psychosine elevation in erythrocytes (14 pmol/g Hb; controls < 5), prompting umbilical cord blood transplantation (UCBT). Following transplantation, GALC enzyme activity normalized, psychosine levels decreased, and serial neuroimaging demonstrated radiographic stability without neurologic regression at last follow-up (9 years old). This case expands the phenotypic spectrum associated with homozygosity for the p.Tyr319Cys variant and highlights the role of p.Ile562Thr in amplifying the pathogenic potential when in cis with p.Tyr319Cys. This GALC haplotype illustrates how “pseudodeficiency” and modifier alleles may collectively influence biochemical, radiologic, and clinical disease expression. These findings emphasize the importance of integrating genotype, psychosine, enzyme activity, and longitudinal neuroimaging when evaluating infants with NBS results positive for Krabbe disease.

COASY-related disorders (CRDs) are a spectrum of autosomal recessive conditions caused by the dysfunction of CoA synthase, an enzyme responsible for the final steps of CoA synthesis. Clinical manifestations of CRDs are highly variable, ranging from perinatal lethal pontocerebellar hypoplasia to childhood-onset neurodegenerative brain iron accumulation, which is often recognized after clinical regression. Recent reports have described a few individuals with CRD who screened positive for carnitine palmitoyltransferase-I deficiency by newborn screening (NBS). However, heterogeneous clinical presentations, conflicting biochemical/molecular sequencing of CPT1A, and a lack of metabolic characterization have led to lengthy, costly diagnostic journeys. To address some of these aspects, this investigation retrospectively evaluated NBS acylcarnitine patterns in five CRD cases using Collaborative Laboratory Integrated Reports (CLIR). A total of 25 metabolites/ratios were identified to deviate significantly from reference ranges and were primarily composed of elevated free carnitine and reduced long-chain acylcarnitine levels. While low acylcarnitine concentrations are often not reported due to a lack of lower reference cutoffs, ratios involving these metabolites relative to short-chain acylcarnitines could aid in identifying CRD cases via NBS. When comparing this pattern to CPT-Ia cases, we confirmed a nearly identical acylcarnitine pattern between these, and thus support the need to consider CRD in cases with NBS results suggestive of CPT-Ia. This study is the first case series to characterize NBS patterns in patients with CRD and highlights the unique opportunity for early detection, particularly in cases that are neonatally asymptomatic and have unremarkable confirmatory biochemical results.

Krabbe disease (KD) is part of newborn screening (NBS) in 11 states with at least one additional state preparing to screen. In July 2021, KD was re-nominated for addition to the federal Recommended Uniform Screening Panel (RUSP) in the USA with a two-tiered strategy based on psychosine (PSY) as the determinant if an NBS result is positive or negative after a first-tier test revealed decreased galactocerebrosidase activity. Nine states currently screening for KD include PSY analysis in their screening strategy. However, the nomination was rejected in February 2023 because of perceived concerns about a high false positive rate, potential harm to newborns with an uncertain prognosis, and inadequate data on presymptomatic treatment benefit or harm. To address the concern about false positive NBS results, a survey was conducted of the eight NBS programs that use PSY and have been screening for KD for at least 1 year. Seven of eight states responded. We found that: (1) the use of PSY is variable; (2) when modeling the data based on the recommended screening strategy for KD, and applying different cutoffs for PSY, each state could virtually eliminate false positive results without major impact on sensitivity; (3) the reason for the diverse strategies appears to be primarily the difficulty of state programs to adjust screening algorithms due to the concern of possibly missing even an adult-onset case following a change that focuses on infantile and early infantile KD. Contracts with outside vendors and the effort/cost of making changes to a program’s information systems can be additional obstacles. We recommend that programs review their historical NBS outcomes for KD with their advisory committees and make transparent decisions on whether to accept false positive results for such a devastating condition or to adjust their procedures to ensure an efficient, effective, and manageable NBS program for KD.