ObjectiveThere currently is no disease-modifying therapy for spinocerebellar ataxia type 1 (SCA1). Genetic interventions, such as RNA-based therapies, are being developed but those currently... Show moreObjectiveThere currently is no disease-modifying therapy for spinocerebellar ataxia type 1 (SCA1). Genetic interventions, such as RNA-based therapies, are being developed but those currently available are very expensive. Early evaluation of costs and benefits is, therefore, crucial. By developing a health economic model, we aimed to provide first insights into the potential cost-effectiveness of RNA-based therapies for SCA1 in the Netherlands.MethodsWe simulated disease progression of individuals with SCA1 using a patient-level state-transition model. Five hypothetical treatment strategies with different start and endpoints and level of effectiveness (5-50% reduction in disease progression) were evaluated. Consequences of each strategy were measured in terms of quality-adjusted life years (QALYs), survival, healthcare costs, and maximum costs to be cost effective.ResultsMost QALYs (6.68) are gained when therapy starts during the pre-ataxic stage and continues during the entire disease course. Incremental costs are lowest (- euro14,048) if therapy is stopped when the severe ataxia stage is reached. The maximum costs per year to be cost-effective are euro19,630 in the "stop after moderate ataxia stage" strategy at 50% effectiveness.DiscussionOur model indicates that the maximum price for a hypothetical therapy to be cost-effective is considerably lower than currently available RNA-based therapies. Most value for money can be gained by slowing progression in the early and moderate stages of SCA1 and by stopping therapy upon entering the severe ataxia stage. To allow for such a strategy, it is crucial to identify individuals in early stages of disease, preferably just before symptom onset. Show less
Garrelfs, M.R.; Takada, S.; Kamsteeg, E.J.; Pegge, S.; Mancini, G.; Engelen, M.; ... ; Willemsen, M.A. 2020
Background: We aimed to expand the number of currently known pathogenic PNKP mutations, to study the phenotypic spectrum, including radiological characteristics and genotype-phenotype correlations,... Show moreBackground: We aimed to expand the number of currently known pathogenic PNKP mutations, to study the phenotypic spectrum, including radiological characteristics and genotype-phenotype correlations, and to assess whether immunodeficiency and increased cancer risk are part of the DNA repair disorder caused by mutations in the PNKP gene.Methods: We evaluated nine patients with PNKP mutations. A neurological history and examination was obtained. All patients had undergone neuroimaging and genetic testing as part of the prior diagnostic process. Laboratory measurements included potential biomarkers, and, in the context of a DNA repair disorder, we performed a detailed immunologic evaluation, including B cell repertoire analysis.Results: We identified three new mutations in the PNKP gene and confirm the phenotypic spectrum of PNKP-associated disease, ranging from microcephaly, seizures, and developmental delay to ataxia with oculomotor apraxia type 4. Irrespective of the phenotype, alpha-fetoprotein is a biochemical marker and increases with age and progression of the disease. On neuroimaging, (progressive) cerebellar atrophy was a universal feature. No clinical signs of immunodeficiency were present, and immunologic assessment was unremarkable. One patient developed cancer, but this was attributed to a concurrent von Hippel-Lindau mutation.Conclusions: Immunodeficiency and cancer predisposition do not appear to be part of PNKP-associated disease, contrasting many other DNA repair disorders. Furthermore, our study illustrates that the previously described syndromes microcephaly, seizures, and developmental delay, and ataxia with oculomotor apraxia type 4, represent the extremes of an overlapping spectrum of disease. Cerebellar atrophy and elevated serum alpha-fetoprotein levels are early diagnostic findings across the entire phenotypical spectrum. (C) 2020 The Author(s). Published by Elsevier Inc. Show less
Dool, J. van den; Postma, M.; Hilten, J.J. van; Warrenburg, B. van de; Koelman, J.H.T.M.; Visser, B.; ... ; Zoons, E. 2013
