Ethical issues with testing and treatment for Krabbe disease

Ehmann, Paul; Lantos, John D.

doi:10.1111/dmcn.14258

Cited by 20 publications

(16 citation statements)

References 9 publications

(20 reference statements)

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“…The workflow in the IDPH laboratory of holding Krabbe screening results until sequencing results are received is beneficial for families. As a result, Krabbe screening in Illinois had a low impact on families, and affected infants presumed to have IKD were detected and treated in a timely manner [17,18].…”

Section: Discussionmentioning

confidence: 99%

Newborn Screening for Krabbe Disease—Illinois Experience: Role of Psychosine in Diagnosis of the Disease

Basheeruddin

Shao

Balster

et al. 2021

IJNS

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Population-based newborn screening for Krabbe disease was initiated by measurement of galactocerebrosidase (GALC) activity in the state of Illinois in December 2017. Due to the poor specificity of GALC for the diagnosis of Krabbe disease, second-tier testing services were provided to reduce the false positive rates for disease monitoring. Using ultra-pressure liquid chromatography coupled to mass spectrometry assay, a total of 497,147 newborns were screened. In total, 288 infants’ specimens (0.06%) having reduced GALC activity were sent out for second-tier testing to a reference laboratory. All newborns’ reduced GALC specimens were tested for psychosine levels, the presence of a 30-kb deletion and GALC sequencing. The results showed that two infants had elevated psychosine levels (10 and 35 nM) and were referred immediately for evaluation and treatment for Infantile Krabbe disease, and six infants had intermediate PSY levels (≥2 to 5 nM) and are under observation as suspected candidates for late-onset Krabbe disease. In addition, 178 infants had pseudodeficiency alleles, all having psychosine levels < 2.0 nM. Our data show that a high percentage of reduced GALC activity (62%) was due to the presence of pseudodeficiency alleles in the GALC gene. In conclusion, incorporation of psychosine measurements can identify infants with infantile Krabbe disease and probable late-onset Krabbe infants. Furthermore, Krabbe disease screening can be achieved at public health laboratories, and infants with infantile Krabbe disease can be diagnosed in timely manner for better outcome.

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Section: Discussionmentioning

confidence: 99%

Newborn Screening for Krabbe Disease—Illinois Experience: Role of Psychosine in Diagnosis of the Disease

Basheeruddin

Shao

Balster

et al. 2021

IJNS

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“…KD disease is subdivided into sub-categories based on the age at presentation of symptoms. It is possible to screen newborns for KD, but current tests to identify which children are likely to develop the disease are inadequate (Kwon et al, 2018;Ehmann and Lantos, 2019). HSPC transplantation is the only available treatment for early infantile KD and should be performed before the onset of symptoms to be effective (Ehmann and Lantos, 2019).…”

Section: Krabbe Disease (Kd)mentioning

confidence: 99%

Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

Jensen

Gøtzsche

Woldbye

2021

Front. Mol. Neurosci.

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In recent years, gene therapy has been raising hopes toward viable treatment strategies for rare genetic diseases for which there has been almost exclusively supportive treatment. We here review this progress at the pre-clinical and clinical trial levels as well as market approvals within diseases that specifically affect the brain and spinal cord, including degenerative, developmental, lysosomal storage, and metabolic disorders. The field reached an unprecedented milestone when Zolgensma® (onasemnogene abeparvovec) was approved by the FDA and EMA for in vivo adeno-associated virus-mediated gene replacement therapy for spinal muscular atrophy. Shortly after EMA approved Libmeldy®, an ex vivo gene therapy with lentivirus vector-transduced autologous CD34-positive stem cells, for treatment of metachromatic leukodystrophy. These successes could be the first of many more new gene therapies in development that mostly target loss-of-function mutation diseases with gene replacement (e.g., Batten disease, mucopolysaccharidoses, gangliosidoses) or, less frequently, gain-of-toxic-function mutation diseases by gene therapeutic silencing of pathologic genes (e.g., amyotrophic lateral sclerosis, Huntington's disease). In addition, the use of genome editing as a gene therapy is being explored for some diseases, but this has so far only reached clinical testing in the treatment of mucopolysaccharidoses. Based on the large number of planned, ongoing, and completed clinical trials for rare genetic central nervous system diseases, it can be expected that several novel gene therapies will be approved and become available within the near future. Essential for this to happen is the in depth characterization of short- and long-term effects, safety aspects, and pharmacodynamics of the applied gene therapy platforms.

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“…Long before this became recognizable and other important facts being also unknown, newborn screening for Krabbe disease was enthusiastically introduced in the state of New York in 2006. This project has been associated with many false hopes and binding of enormous resources (19).…”

Section: Experimental Therapies Outside Clinical Trialsmentioning

confidence: 99%

Ethical Issues in Care and Treatment of Neuronal Ceroid Lipofuscinoses (NCL)–A Personal View

Kohlschütter

2021

Front. Neurol.

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The management of Neuronal Ceroid Lipofuscinoses (NCL), a group of genetic neurodegenerative disorders mainly affecting brain and retinas, raises difficult questions for physicians and other professionals in research, pharmaceutical industry, and public health. Ethical problems in medicine cannot be solved by rational deliberation or by following formal rules. Two topics of ethical issues in the field of NCL are presented here. One group relates to the care of individual patients and centers on a life with dementia at a young age. Advanced care planning for the end of life and the use of life-prolonging measures require challenging assumptions in the best interest of a patient. A second group of questions relates to new treatments. Impressive novel putative causal therapies, such as enzyme replacement for CLN2 disease, may be only disease-modifying and carry the risk of changing a deadly disease of short duration into one with prolonged survival and poor quality of life. The wish for better therapeutic interventions in life-limiting diseases has to take such risks, but more experience is needed before definite conclusions can be drawn. The appropriateness of presymptomatic screening for a severe disease, e.g., must be carefully evaluated to avoid the disastrous experience made with the rash start of newborn screening for Krabbe disease. The ethical issues described and commented in the article reflect the personal experience of a pediatrician who has studied clinical and research questions in NCL for four decades. They should alert various professionals to the necessity of taking their own decisions in situations that are caused by rare progressive brain diseases of young persons, as typified by the NCL.

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Ethical issues with testing and treatment for Krabbe disease

Cited by 20 publications

References 9 publications

Newborn Screening for Krabbe Disease—Illinois Experience: Role of Psychosine in Diagnosis of the Disease

Newborn Screening for Krabbe Disease—Illinois Experience: Role of Psychosine in Diagnosis of the Disease

Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

Ethical Issues in Care and Treatment of Neuronal Ceroid Lipofuscinoses (NCL)–A Personal View

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