Krabbe disease (KD) is a rapidly progressive neurodegenerative disorder caused by β-galactocerebrosidase deficiency. While KD has been added to the Recommended Uniform Screening Panel (RUSP), only 15 states have an active KD newborn screening (NBS) program. It is uncertain at what rate states will adopt RUSP recommendations, with a frequently cited barrier being the absence of investigations addressing the impact of hematopoietic stem cell transplantation (HSCT) on quality-of-life. We developed a 90-minute caregiver interview to gather qualitative and quantitative data (including the validated Leukodystrophy Quality-of-Life Assessment – LQLA) evaluating patient/family-centered outcomes of HSCT. The interview was designed to explore the following: 1) disease burden on the patient; 2) physical burden on the caregiver; and 3) emotional/social burden on the caregiver. Comparisons were made between children not transplanted/transplanted late and children transplanted early. Infantile KD (IKD) and late infantile KD (LIKD) were analyzed independently. Forty caregivers participated (non-transplanted/transplanted late: IKD = 19, LIKD = 7; transplanted early: IKD = 10, LIKD = 4). Analysis of the LQLA revealed a relative reduction in disease burden in both IKD and LIKD groups who were transplanted early. Specifically, the early transplanted cohorts achieved statistically significant higher overall scores on the LQLA, as well as better scores in various subcategories in comparison to their non-transplanted/transplanted late counterparts. For IKD, analysis of Likert scale and weighted analysis demonstrated a tendency towards decreased physical burden on caregivers of children transplanted early. Although all groups experienced significant social/emotional burdens, caregivers of IKD transplanted early benefitted from improved sleep, mental health, and familial/spousal relationships compared to IKD non-transplanted/transplanted late. This study provides convincing evidence that HSCT improves quality-of-life and reduces caregiver burden in IKD. The evidence is somewhat less clear for LIKD due to the small LIKD sample size. This data will be critical in the decision-making process for states not currently screening for KD but debating the addition of KD to their NBS panels. Lastly, it will allow families to weigh the risks and benefits of HSCT more confidently when contemplating the life-altering decision of whether to proceed with transplantation.

Krabbe disease is a rare and severe lysosomal disorder affecting the white matter of the central and peripheral nervous system. It is characterized by neurodegeneration, with the most common form being infantile Krabbe disease, typically diagnosed within the first year of life. This autosomal-recessive disease is caused by mutations in the GALC gene, which encodes the lysosomal enzyme β-galactocerebrosidase. This study focuses on a β-galactocerebrosidase variant, with Thr112Ala identified as a homozygous mutation in a patient with infantile Krabbe disease. To understand the structural effects of this mutation, we conducted all-atom molecular dynamics simulations of both the mutant and wild-type (wt) enzymes at cytosolic (pH 7.0) and lysosomal pH (pH 4.5), as β-galactocerebrosidase is localized in the lysosome. The results showed differences in protein flexibility, the hydrogen bond network, and the stability of secondary structure elements between the wild type and mutant enzymes. Additionally, the mutation affected the size of the substrate-binding pocket at lysosomal pH, even though the mutation site is not part of the active/binding site of the enzyme. These findings provide valuable insights into how the mutation impacts the structure of β-galactocerebrosidase in the lysosomal environment, contributing to the understanding of Krabbe disease's molecular mechanisms.

Infantile Krabbe disease (IKD) is a severe, progressive neurological disorder that was recently added to the Recommended Uniform Screening Panel in the United States. IKD is a critical condition that requires a hematopoietic stem cell transplant, preferably by 30 days of age. This study examines whether the 2-tier newborn screening (NBS) strategy (psychosine [PSY] analysis when enzyme activity is low) causes clinically relevant delays compared with PSY measured at a first clinical follow-up visit. We reviewed the PSY analyses performed over a 6-year period on dried blood spots on infants < 28 days old. Results were sorted by the ordering site and final diagnosis. On average, infants with a positive NBS for IKD that included abnormal PSY received their diagnosis 7 days sooner than whose PSY testing was initiated during follow-up. Hematopoietic stem cell transplant occurred by the 36th day of life, on average, for cases with IKD detected by 2-tiered NBS. Effective NBS for Krabbe disease requires the use of PSY as a second-tier test, allowing for timely initiation of treatment while virtually eliminating false-positive results. PSY should be included in NBS algorithms for Krabbe disease, and timeliness metrics need to be adjusted.

Krabbe disease (KD), which affects 0.3-2.6 per 100 000 live births, is an autosomal recessive lysosomal disorder caused by variants in the GALC gene that reduce galactosylceramidase (GALC) activity, leading to psychosine accumulation, cerebral white matter degeneration, and peripheral neuropathy. The most common form, infantile KD (IKD), has onset by 12 months with irritability, feeding difficulty, neurologic regression, and, when untreated, death in early childhood. Hematopoietic stem cell transplantation (HSCT) for IKD approximately 1 month after birth can improve long-term survival but has about a 10% risk of mortality within 100 days, and affected individuals can still have significant functional impairment. Newborn screening for KD is based on low GALC levels in dried-blood spots. Second-tier testing to assess whether an elevated psychosine concentration is present in the same dried-blood spot improves the specificity of screening for IKD. Without newborn screening, diagnosis of IKD is generally made after significant clinical symptoms develop, past when HSCT can be effective. The benefit of newborn detection of later-onset phenotypes of KD is uncertain. In 2024, the US Secretary of Health and Human Services added IKD to the Recommended Uniform Screening Panel after a recommendation by the Advisory Committee on Heritable Disorders in Newborns and Children. For IKD newborn screening to be as effective as possible, it is important to have systems in place to support families in making challenging decisions soon after diagnosis about whether to pursue HSCT and to ensure rapid access to HSCT if chosen.