Developmental outcomes of cord blood transplantation for Krabbe disease

Wright, Matthew; Poe, Michele D.; DeRenzo, Anthony; Haldal, Shilpa; Escolar, Maria L.

doi:10.1212/wnl.0000000000004418

Cited by 81 publications

(99 citation statements)

References 13 publications

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“…Even so, at present, harms (including costs of all kinds) seem likely to outweigh the slender benefits. Other papers attest to this, showing improved survival, but ongoing significant disability in most if not all presymptomatically-treated patients [20]. This is a disorder that possibly should not be screened for at present.…”

Section: Newborn Screening For Krabbe Disease (Globoid-cell Leukodystmentioning

confidence: 87%

Newborn Screening for Lysosomal Disease: Mission Creep and a Taste of Things to Come?

Wilcken

2018

IJNS

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Newborn screening for several lysosomal disorders can now be accomplished successfully for case finding. However, many cases identified do not require immediate intervention and it is not yet clear, for some disorders, if there is a benefit in early diagnosis for those cases, or what should be called a benefit. Diagnosing adult-onset cases, especially when there are quite imperfect genotype-phenotype correlations, represents a significant expansion of what has heretofore been considered the aim of newborn screening. This mission creep should be carefully discussed, and certain aspects of newborn screening strengthened. We should all proceed with caution in this field.

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Section: Newborn Screening For Krabbe Disease (Globoid-cell Leukodystmentioning

confidence: 87%

Newborn Screening for Lysosomal Disease: Mission Creep and a Taste of Things to Come?

Wilcken

2018

IJNS

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“…But the New York State data show that many children who are identified as being ‘at risk’ for EIKD remain asymptomatic for years. So, should asymptomatic children undergo a transplant? If yes, then it seems possible that at least some children will undergo a dangerous transplant that they do not need. If no, then we will never transplant asymptomatic children and outcomes for children who do go on to develop EIKD will be worse than they might have been.…”

Section: Discussionmentioning

confidence: 99%

Ethical issues with testing and treatment for Krabbe disease

Ehmann

Lantos

2019

Develop Med Child Neuro

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Early‐infantile Krabbe disease (EIKD) is an autosomal recessive, progressive, neurodegenerative disorder that usually leads to death in infancy. A study published in 2005 indicated that hematopoietic stem‐cell transplantation (HSCT) was effective in the treatment for EIKD when used before the onset of symptoms. This finding suggested that newborn screening for EIKD, which would allow earlier diagnosis, might lead to earlier treatment and better outcomes. In 2006, New York was the first state to implement newborn screening for Krabbe disease; however, the results were not as good as proponents had hoped. In this paper, we present the history of efforts to diagnose and treat EIKD. Based on our findings, we question the efficacy of newborn screening for Krabbe disease. We present two arguments. First, testing itself is too imprecise. Even with the most rigorous testing standards, such as those used in New York, many of the children who are identified as being ‘at risk’ for EIKD remain asymptomatic. It is unclear if they will remain asymptomatic forever and, thus, whether the tests should be considered ‘false positives’, or whether they will eventually develop the disease. Second, we question the efficacy of early HSCT. We recommend placing a moratorium on mandatory newborn screening for EIKD. What this paper adds Current tests to identify which children are likely to develop Krabbe diseased are inadequate. Many children identified as being ‘at risk’ for early infantile Krabbe disease remain asymptomatic. Psychosine appears to be more specific than low galactosylceramidase levels for diagnosing early infantile Krabbe disease.

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“…In addition, it was particularly intriguing that the residual GALC was unable to cross-correct affected tissues, as deduced from the severe phenotype. This result may correlate with deteriorative moribund pathology of HSCT-treated twitcher and KD patients despite the increased GALC activity 25,26,27,28 , emphasizing the importance of providing GALC at a specific developmental period.…”

Section: The Cag-cre/er T Transgene Recombines Efficiently With Tamoxmentioning

confidence: 92%

“…In fact, most children who develop KD in infancy die before the age of 2, often from respiratory failure 51 and suspected autonomic dysfunction. In addition, even pre-symptomatic KD infants treated with HSCT continue to develop substantial motor impairments because of brainstem dysfunction involving corticospinal tract pathology 27 . Therefore, we suspect that GALC-dependent brainstem dysfunction may directly influence KD pathogenesis.…”

Section: Cell and Region-specific Requirement For Galc In Brain Develmentioning

confidence: 99%

Brainstem development requires galactosylceramidase and is critical for the pathogenesis of Krabbe Disease

Weinstock

Kreher

Favret

et al. 2020

Preprint

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Krabbe disease (KD) is caused by a deficiency of galactosylceramidase (GALC), which induces demyelination and neurodegeneration due to accumulation of cytotoxic psychosine. Hematopoietic stem cell transplantation (HSCT) improves clinical outcomes in KD patients only if delivered pre-symptomatically. We hypothesized that the restricted temporal efficacy of HSCT reflects a requirement for GALC in early brain development. Using a novel Galc floxed allele, we induced ubiquitous GALC ablation (Galc-iKO) at various postnatal timepoints and identified a critical period of vulnerability to GALC ablation between P4-6. Early Galc-iKO induction caused a worse KD phenotype, higher psychosine levels, and a significantly shorter life-span. Intriguingly, GALC expression peaks during this critical developmental period. Further analysis revealed a novel cell autonomous role for GALC in the development and maturation of immature T-box-brain-1 positive brainstem neurons. These data identify a perinatal developmental period, in which neuronal GALC expression influences brainstem development that is critical for KD pathogenesis.

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Developmental outcomes of cord blood transplantation for Krabbe disease

Abstract: This study provides Class IV evidence that for children with early-infantile Krabbe disease, early HSCT improves lifespan and functional abilities.

Cited by 81 publications

References 13 publications

Newborn Screening for Lysosomal Disease: Mission Creep and a Taste of Things to Come?

Newborn Screening for Lysosomal Disease: Mission Creep and a Taste of Things to Come?

Ethical issues with testing and treatment for Krabbe disease

Brainstem development requires galactosylceramidase and is critical for the pathogenesis of Krabbe Disease

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