Longitudinal Changes in White Matter Fractional Anisotropy in Adult-Onset Niemann-Pick Disease Type C Patients Treated with Miglustat

Bowman, Elizabeth A.; Velakoulis, Dennis; Desmond, Patricia; Walterfang, Mark

doi:10.1007/8904_2017_42

Cited by 13 publications

(7 citation statements)

References 21 publications

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“…NPC1 −/− mice present accumulation of unesterified cholesterol in different tissues, abnormalities in lysosomal enzyme levels, increased activity of hepatic enzymes and decreased levels of triacylglycerides ( Pentchev et al., 1980 ; Amigo et al., 2002 ; Beltroy et al., 2005 , 2007 ; Kulinski and Vance, 2007 ). At present there is no cure for Niemann-Pick disease, and the only available treatment, Miglustat, can alleviate symptoms but does not cure the disease (( Wraith et al., 2010 ; Bowman et al., 2015 ; Sedel et al., 2016 ; Bowman et al., 2018 ), for review see ( Lyseng-Williamson, 2014 )).…”

Section: Introductionmentioning

confidence: 99%

Hepatic and neuronal phenotype of NPC1−/− mice

Santiago-Mujica¹,

Flunkert²,

Rabl

et al. 2019

Heliyon

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Niemann-Pick type C disease (NPC) is a fatal autosomal recessive disorder characterized by a defect in the intracellular transport of lipoproteins leading to the accumulation of lipids in diverse tissues. A visceral and neuronal phenotype mimicking human NPC1 disease has been described in NPC1 mutant mice. These mice are by now the most widely used NPC1 rodent model to study NPC and developmental compounds against this devastating disease. Here we characterized NPC1−/− mice for their hepatic and neuronal phenotype to confirm the stability of the phenotype, provide a characterization of disease progression and pinpoint the age of robust phenotype onset. Animals of 4–10 weeks of age were analyzed for general health, motor deficits as well as hepatic and neuronal alterations with a special focus on cerebellar pathology.Our results show that NPC1−/− mice have a reduced general health at the age of 9–10 weeks. Robust motor deficits can be observed even earlier at 8 weeks of age. Hepatic changes included increased organ weight and cholesterol levels at 6 weeks of age accompanied by severely increased liver enzyme levels. Analysis of NPC1−/− brain pathology showed decreased cholesterol and increased Aβ levels in the hippocampus at the age of 6 weeks. Further analysis revealed a decrease of the cytokine IL-12p70 in the cerebellum along with a very early increase of astrocytosis. Hippocampal IL-12p70 levels were increased at the age of 6 weeks followed by increased activated microglia levels. By the age of 10 weeks, also cerebellar Aβ levels were increased along with strongly reduced Calbindin D-28k levels.Our results validate and summarize the progressive development of the hepatic and neuronal phenotype of NPC1−/− mice that starts with cerebellar astrocytosis, making this mouse model a valuable tool for the development of new compounds against NPC.

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Section: Introductionmentioning

confidence: 99%

Hepatic and neuronal phenotype of NPC1−/− mice

Santiago-Mujica¹,

Flunkert²,

Rabl

et al. 2019

Heliyon

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“…Bowman et al 14,15 examined longitudinally a collection of nine adult patients in comparison to a healthy person. The MR follow-up showed that the untreated patients had less thalamic and cerebellar gray and white matter volume over time compared with both controls and treated patients.…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of Cerebral Magnetic Resonance Imaging Changes in Nontreated Infantile, Juvenile and Adult Patients with Niemann-Pick Disease Type C

et al. 2019

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Aim The study aims to describe cerebral MRI in different onset forms of Niemann-Pick type C (NPC). Systematic MRI analyses in this rare lysosomal storage disease are lacking in the infantile and juvenile onset forms. Methods Thirty-two cerebral MRI scans from 19 patients with NPC were assessed using a newly established and validated scoring system which addresses white matter changes and supratentorial versus infratentorial atrophy. Results Seven scans were from six NPC patients with early infantile onset (<2 years of age), six scans were from three patients with late infantile onset (2–6 years), six scans from four with juvenile onset (6–15 years), and 13 from six with adult onset (>15 years). While supratentorial atrophy was the leading sign in the infantile groups, the juvenile and adult forms were characterized by both, infra- and supratentorial atrophy. White matter changes were found in nearly every patient; they increased with the disease duration in the earlier forms and were prominent in the later forms already early in the disease course. Conclusion This is the first systematic and comparative MRI analysis in the different onset groups of NPC using a scoring system. Early during disease course, MRI showed different patterns in infantile compared with juvenile and adult onset NPC patients, for example, only supratentorial atrophy in juvenile versus global atrophy in adult onset patients. MRI changes provide an additional, early biomarker for NPC.

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“…Therapeutically, Miglustat (Zavesca) is a targeted treatment for neurological deterioration in NPC [9] and we hope find a therapeutic alternative for systemic signs.…”

Section: Discussionmentioning

confidence: 99%

Niemann-Pick Disease Type C, A Rare Cause of Pancytopenia: A Case Report

Sghaier¹,

Sghaeir²,

Younes³

et al. 2018

IJHT

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Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease where impaired intracellular lipid trafficking leads to excess storage of cholesterol, sphingomyelin, glycosphingolipids, and sphingosine in tissues. The disease is caused by mutations in one of the two genes, NPC1 or NPC2. Lymphadenopathy and hematological especially pancytopenia in newborns or toddlers with NPC have been anecdotally reported, with limited evidence. The association of this two systemic signs must be differentiated from others blood disorders especially hematological malignancy. We report a case of NPC, in a 26-year-old girl, who presented at the age of 16 a cervical bilateral poly-lymphadenopathy, associated with hematological disorder in which all three major formed elements of the blood (red blood cells, white blood cells and platelets) are decreased in number. The case was essentially reported because of its rare occurrence (pancytopenia and poly-lymphadenopathy which are very rare systemic signs or even exceptional), and because it emphasizes the need for further studies in order to understand how defects in lipid metabolism in NPC can lead to hematological defects especially pancytopenia.

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Longitudinal Changes in White Matter Fractional Anisotropy in Adult-Onset Niemann-Pick Disease Type C Patients Treated with Miglustat

Cited by 13 publications

References 21 publications

Hepatic and neuronal phenotype of NPC1−/− mice

Hepatic and neuronal phenotype of NPC1−/− mice

Comparative Analysis of Cerebral Magnetic Resonance Imaging Changes in Nontreated Infantile, Juvenile and Adult Patients with Niemann-Pick Disease Type C

Niemann-Pick Disease Type C, A Rare Cause of Pancytopenia: A Case Report

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