Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann–Pick disease type C patients treated with miglustat
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Niemann–Pick disease type C (NPC) is a rare neurovisceral disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment available to date is miglustat, an iminosugar inhibiting the accumulation of lipid by-products in neurons. This study explored how changes in cerebellar grey and white matter volumes, and in subcortical volumes, related to patient treatment status and disability and ataxia ratings. Nine adult-onset NPC patients and 17 matched controls underwent T1-weighted MRI. One patient was not receiving miglustat, and pre-treatment data were available for a further patient. Semi-automated cerebellar and subcortical segmentation was undertaken, and the rates of change in putamen, hippocampal, thalamic and caudal volumes, and grey and white matter cerebellar volumes, were compared to rates of change in Iturriaga disability score, Brief Ataxia Rating Scale (BARS), and horizontal saccadic gain. Untreated NPC patients appeared to lose cerebellar grey and white matter, bilateral thalamic volume, and right caudate volume faster than treated patients. Cerebellar grey matter volume loss and volume loss in the left thalamus were significantly correlated with Iturriaga disability scale changes. Change in both cerebellar grey and white matter was correlated with decrease in horizontal saccadic gain, but not with change in BARS. This is the first study to examine longitudinal treatment effects of miglustat on cerebellar and subcortical volumes in patients with adult-onset NPC, and is evidence that miglustat may have a protective effect on cerebellar and subcortical structure and function.
KeywordsCerebellum Niemann–Pick type C Lysosomal Ataxia Thalamus Saccades
The authors would like to acknowledge the support of the patients and their families in providing clinical information for this study.
Conflicts of interest
Elizabeth Bowman has received salary support through an unrestricted educational grant to The University of Melbourne from Actelion Pharmaceuticals Limited. Dennis Velakoulis has received royalties from the publication of Kaplan and Sadock’s Comprehensive Textbook of Psychiatry (Lippincott Williams & Wilkins, 2009) and research support from the NHMRC. Larry Abel has served as a consultant on previous clinical trials and currently as a consultant for and received funding for travel from Actelion. Patricia Desmond serves on the editorial board of the Journal of Clinical Neuroscience and as an Associate Editor of the Journal of Medical Imaging and Radiation Oncology and receives research support from NHMRC, Cancer Australia, the National Health Foundation, and The Royal Melbourne Hospital Neuroscience Foundation. Michael Fahey has served on a scientific advisory board and as a consultant for and received funding for travel from Actelion Pharmaceuticals Ltd.; has received speaker honoraria from the Australian Podiatry Association; receives research support from NHMRC and the NIH (1R03HD058625-01, CI); has held/holds stock in Sigma Pharmaceuticals, LLC, and Peplin, Inc.; and has given expert testimony on behalf of the Therapeutic Goods Administration. Mark Walterfang has served on a scientific advisory board and as a consultant for and received funding for travel from Actelion Pharmaceuticals Ltd. and received royalties from the publication of Kaplan and Sadock’s Comprehensive Textbook of Psychiatry (Lippincott Williams & Wilkins, 2009).
This study was approved by the Melbourne Health Research & Ethics Committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All patients gave their informed consent to participate in this study.
This study was approved by the Melbourne Health Human Research Ethics Comittee (approval codes HREC2004.042 and HREC2005.168). All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration on human experimentation of 1975, as revised in 2000(5). Informed consent was obtained from all patients for being included in the study.
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