Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C

Héron, Bénédicte; Valayannopoulos, Vassili; Baruteau, Julien; Chabrol, B.; Ogier, H.; Latour, Philippe; Dobbelaere, Dries; Eyer, Didier; Labarthe, François; Maurey, Hélène; Cuisset, Jean‐Marie; Villemeur, Thierry Billette de; Sedel, Frédéric; Vanier, Marie T.

doi:10.1186/1750-1172-7-36

Cited by 74 publications

(105 citation statements)

References 34 publications

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“…A systematic review on later findings of clinical trials [21] revealed that miglustat can slow down the progression of neurologic symptoms in all NPC patients, yet the therapeutic benefit is greater in those with a late diagnosis compared with early childhood onset. Although miglustat provided the proof-of-principle for the efficacy of substrate reduction strategies, miglustat still has its limitations, which are mostly related to unwanted side effects including visceromegaly, hematologic abnormalities, diarrhea, intestinal carbohydrate malabsorption and weight loss [6,10,30,31,32,33]. However, our treated mice did not show any obvious gastrointestinal symptoms.…”

Section: Discussionmentioning

confidence: 87%

Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice

Schlegel

Thieme

Holzmann

et al. 2016

IJMS

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Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1nihNpc1−/− mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1−/− animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.

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Section: Discussionmentioning

confidence: 87%

Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice

Schlegel

Thieme

Holzmann

et al. 2016

IJMS

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“…Miglustat was approved in Europe in 2009, and has since been approved in a number of other countries. As a result, clinical experience with this drug is increasing [7,8,16,21]. …”

Section: Introductionmentioning

confidence: 99%

Disease and patient characteristics in NP-C patients: findings from an international disease registry

Patterson

Mengel²,

Wijburg

et al. 2013

Orphanet J Rare Dis

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BackgroundNiemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterized by progressive neurodegeneration and premature death. We report data recorded at enrolment in an ongoing international NP-C registry initiated in September 2009 to describe disease natural history, clinical course and treatment experience of NP-C patients in clinical practice settings.MethodsThe NPC Registry is a prospective observational cohort study. Participating sites are encouraged to evaluate all consecutive patients with a confirmed diagnosis of NP-C, regardless of their treatment status. All patients undergo clinical assessments and medical care as determined by their physicians. Data are collected through a secure internet-based data collection system.ResultsAs of 19th March, 2012, 163 patients have been enrolled in centres across 14 European countries, Australia, Brazil and Canada. The mean (SD) age at enrolment was 19.6 (13.0) years. In general there was a long lag time between the mean (SD) age at neurological onset (10.9 (9.8) years) and age at diagnosis (15.0 (12.2) years). Among all enrolled patients, 107 were diagnosed based on combined genetic testing and filipin staining. Sixteen (11%) out of 145 patients with available age-at-neurological-onset data had early-infantile neurological onset, 45 (31%) had late-infantile onset; 45 (31%) had juvenile onset and 39 (27%) had adolescent/adult onset. The frequencies of neonatal jaundice, hepatomegaly and/or splenomegaly during infancy were greatest among early-infantile patients, and decreased with increasing age at neurological onset. The most frequent neurological manifestations were: ataxia (70%), vertical supranuclear gaze palsy (VSGP; 70%), dysarthria (66%), cognitive impairment (62%), dysphagia (52%). There were no notable differences in composite NP-C disability scores between age-at-neurological-onset groups. Miglustat therapy at enrolment was recorded in 117/163 (72%) patients.ConclusionsApproximately two-thirds of this NP-C cohort had infantile or juvenile onset of neurological manifestations, while the remaining third presented in adolescence or adulthood. While systemic symptoms were most common among patients with early-childhood onset disease, they were also common among patients with adolescent/adult onset. The profiles of neurological manifestations in this Registry were in line with previous publications.

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“…While neurological deterioration was seen to commence in one patient at the time his seizures became refractory to antiepileptic medication, pre-existing epilepsy (before miglustat therapy) or the onset of epilepsy during miglustat therapy did not appear to affect neurological outcomes in cases where seizure control was maintained using antiepileptic medications [11]. In our patient, the antiepileptic therapy using valproate and lamotrigine showed no efficacy for more than 1 year; however, our patient’s condition dramatically improved after miglustat therapy was started and he became seizure free 4 months after its introduction.…”

Section: Discussionmentioning

confidence: 99%

Impact of miglustat on evolution of atypical presentation of late-infantile-onset Niemann–Pick disease type C with early cognitive impairment, behavioral dysfunction, epilepsy, ophthalmoplegia, and cerebellar involvement: a case report

et al. 2016

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BackgroundNiemann–Pick disease type C is a rare inherited neurodegenerative disease involving impaired intracellular lipid trafficking and accumulation of glycolipids in various tissues, including the brain. Miglustat, a reversible inhibitor of glucosylceramide synthase, has been shown to be effective in the treatment of progressive neurological manifestations in pediatric and adult patients with Niemann–Pick disease type C, and has been used in that indication in Europe since 2010.Case presentationWe describe the case of a 16-year-old white French boy with late-infantile-onset Niemann–Pick disease type C who had the unusual presentation of early-onset behavioral disturbance and learning difficulties (aged 5) alongside epileptic seizures. Over time he developed characteristic, progressive vertical ophthalmoplegia, ataxic gait, and cerebellar syndrome; at age 10 he was diagnosed as having Niemann–Pick disease type C based on filipin staining and genetic analysis (heterozygous I1061T/R934X NPC1 mutations). He was commenced on miglustat therapy aged 11 and over the course of approximately 3 years he showed a global improvement as well as improved cognitive and ambulatory function. During this period he remained seizure free on antiepileptic therapy, using valproate and lamotrigine.ConclusionsMiglustat improved the neurological status of our patient, including seizure control. Based on our findings in this patient and previous published data, we discuss the importance of effective seizure control in neurological improvement in Niemann–Pick disease type C, and the relevance of cerebellar involvement as a possible link between these clinical phenomena. Thus the therapeutic efficacy of miglustat could be hypothesized as a substrate reduction effect on Purkinje cells.

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Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C

Cited by 74 publications

References 34 publications

Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice

Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice

Disease and patient characteristics in NP-C patients: findings from an international disease registry

Impact of miglustat on evolution of atypical presentation of late-infantile-onset Niemann–Pick disease type C with early cognitive impairment, behavioral dysfunction, epilepsy, ophthalmoplegia, and cerebellar involvement: a case report

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