Krabbe disease (KD) is a rare and devastating neurodegenerative disorder caused by mutations in the GALC gene, resulting in increased accumulation of galactosylcerebroside in the brain (MIM 24500). Although there are several subtypes of KD, early infantile Krabbe disease (EIKD) is the most severe, resulting in the loss of developmental milestones, weakness, seizures, and death, typically by 2 years of age.1 Later-onset forms are also reported.2
Similar to Tay-Sachs disease and other neurodegenerative lysosomal storage diseases, there is no curative treatment, and patients are almost always diagnosed with a disease too late to benefit from early interventions to attenuate disease progression. When administered within the first month of life, bone marrow or hematopoetic stem cell transplantation has slowed or attenuated disease progression of EIKD in some children (most commonly in individuals diagnosed with the disease prenatally or secondary to affected siblings).3 This finding has led 9 states...
It is not known if neurodegenerative changes occur in utero to determine available perinatal treatment outcomes.
Krabbe Disease is again being considered for addition to the Recommended Panel for Newborn Screening (RUSP). When this expert review is completed and it is determined that KD meets scientific criteria for inclusion on the RUSP, we trust that advocates will help problem solve with the states struggling with equity and funding concerns. "
Vergano highlighted, “the lack of consensus regarding the definition of EIKD and later onset forms", even among KD experts, and ambiguity surrounding the interpretation of screening and case confirmation data” and referenced the consensus guidelines developed by Stone et al (1). However, 10/11 authors reached consensus for the classification of KD. Furthermore, all authors agreed to a classification based on psychosine concentrations where cases with psychosines between 2-10 nmol/L are at high risk for non-infantile forms and those with psychosines >10 nmol/L have IKD. Vergano noted a lack of genotype – phenotype correlation which is why genotyping should not be relied upon for identification of babies with IKD through NBS (2,3).
Vergano asserted that barriers exist for admission of patients to specialized centers. However, with advanced planning, the NBS program can develop roadmaps for rapid referrals to expert centers. Historically, families with newborns with IKD have been able to rapidly access treatment facilities (4,5).
The authors state “Systemically, the minimal criteria for the implementation of a new disorder should require a stable infrastructure to conduct screening with rapid results, availability of sensitive and specific laboratory tests, the institution of equitable follow-up and effective treatment, and adequate funding for the program.” We agree but know that these criteria have already been met in other states where the above-mentioned screening approach has been adopted.
Vergano refer to the use of psychosine as “still investigational,” yet it has been part of routine screening of Kentucky newborns for Krabbe disease since February 2016 (3). Among more than 330,000 newborns, only two had positive screening results to date; both were diagnosed with IKD within days, and both were transplanted out-of-state within 30 days of life. Vergano state that the VA newborn screening program estimated an additional cost of “over $2 million” to add KD to their program. This seems exceedingly high and should be questioned.
Vergano et al end by emphasizing the importance of “understanding the systemic processes and challenges involved in NBS” and then “encourage pediatricians to work together with parents, legislators, and NBS advisory members to accomplish well-versed NBS decisions for their state.” We couldn’t agree more and hope that pediatricians and geneticists will advocate for their patients based on what NBS can be and not accept a status quo that robs newborns of a chance to survive a disease that would otherwise lead to death after suffering a relentlessly brutal neurodegenerative course.
(1) Thompson-Stone R, Ream MA, Gelb M, et al. Consensus recommendations for the classification and long-term follow up of infants who screen positive for Krabbe disease. Mol Genet Metab. 2021;134(1–2):53–59
(2) Guenzel AJ, Turgeon CT, Nickander KK, White AL, Peck DS, Pino GB, Studinski AL, Prasad VK, Kurtzberg J, Escolar ML, Lasio MLD, Pellegrino JE, Sakonju A, Hickey RE, Shallow NM, Ream MA, Orsini JJ, Gelb MH, Raymond K, Gavrilov DK, Oglesbee D, Rinaldo P, Tortorelli S, Matern D. The critical role of psychosine in screening, diagnosis, and monitoring of Krabbe disease. Genet Med. 2020 Jun;22(6):1108-1118.
(3) Basheeruddin K, Shao R, Balster F, Gardley P, Ashbaugh L. Newborn Screening for Krabbe Disease-Illinois Experience: Role of Psychosine in Diagnosis of the Disease. Int J Neonatal Screen. 2021 May 9;7(2):24.
(4) Allewelt H, Taskindoust M, Troy J, Page K, Wood S, Parikh S, Prasad V, Kurtzberg J. Long-term functional outcomes following hematopoietic stem cell transplant for early infantile Krabbe disease. Biol Blood and Marrow Transplant. 24:11; pp 2233-2238. 2018. PMID: 29933067.
(5) Page KM, Ream MA, Rangarajan HG, Galindo R, Mian AY, Ho ML, Provenzale J, Gustafson KE, Rubin J, Shenoy S, Kurtzberg J. Benefits of Newborn Screening and Hematopoietic Cell Transplant in Infantile Krabbe Disease. Blood Adv. 2022 Jan 18:bloodadvances.2021006094