Long-term therapy with miglustat and cognitive decline in the adult form of Niemann-Pick disease type C: a case report.

Niemann-Pick disease type C (NPC) is a recessive lysosomal lipid storage disorder characterized by central nervous system involvement. Miglustat treatment might improve or stabilize neurological manifestations but there is still limited data on the long-term efficacy. The aim of our study was to report a four-year clinical, neuropsychological and electrophysiological follow-up of two sisters under treatment with miglustat. We report data at basal (T0) and after 4 years (T4) of treatment with miglustat from two sisters (P1 and P2) affected by NPC disease. During the follow-up period, P1 was not adherent to treatment. Both patients underwent neurological evaluation, neuropsychological assessment, nerve conduction study and motor (MEP), visual (VEP), somatosensory, and brainstem auditory evoked potentials. In the patient P2, neurological and electrophysiological evaluations at T4 were stable. Instead, the patient P1, with poor adherence to therapy, developed spasticity, psychiatric disturbances, and alterations of MEP and VEP. Neuropsychological examination showed in both patients a worsening of cognitive impairment. Our findings suggest that long-term therapy with miglustat does not arrest cognitive decline; otherwise, it stabilizes other neurological manifestations.

Alteration of cortical excitability and its modulation by Miglustat in Niemann-Pick disease type C.

Niemann-Pick type C (NP-C) is a rare, neurodegenerative, lysosomal storage disease. Cortical excitability using different transcranial magnetic stimulation (TMS) protocols together with clinical and neuropsychological testing was longitudinally assessed in a patient with NP-C. Cerebellar inhibition, a measure for the integrity of the cerebello-thalamo-cortical network, was impaired. Short-latency afferent inhibition, a measure for cholinergic transmission, and cognitive functions were also impaired and improved under Miglustat treatment. Short interval intracortical facilitation, a marker for glutamatergic neurotransmission, was absent initially but increased after treatment with Miglustat. Our results provide new insights into pathophysiological mechanisms of NP-C and the response to Miglustat treatment.

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

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.

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.

BACKGROUND: Niemann-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 PRESENTATION: We 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. CONCLUSIONS: Miglustat 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.

Longitudinal assessment of reflexive and volitional saccades in Niemann-Pick Type C disease during treatment with miglustat.

BACKGROUND: Niemann-Pick Type C disease (NPC), is an autosomal recessive neurovisceral disorder of lipid metabolism. One characteristic feature of NPC is a vertical supranuclear gaze palsy particularly affecting saccades. However, horizontal saccades are also impaired and as a consequence a parameter related to horizontal peak saccadic velocity was used as an outcome measure in the clinical trial of miglustat, the first drug approved in several jurisdictions for the treatment of NPC. As NPC-related neuropathology is widespread in the brain we examined a wider range of horizontal saccade parameters and to determine whether these showed treatment-related improvement and, if so, if this was maintained over time. METHODS: Nine adult NPC patients participated in the study; 8 were treated with miglustat for periods between 33 and 61 months. Data were available for 2 patients before their treatment commenced and 1 patient was untreated. Tasks included reflexive saccades, antisaccades and self-paced saccades, with eye movements recorded by an infrared reflectance eye tracker. Parameters analysed were reflexive saccade gain and latency, asymptotic peak saccadic velocity, HSEM-α (the slope of the peak duration-amplitude regression line), antisaccade error percentage, self-paced saccade count and time between refixations on the self-paced task. Data were analysed by plotting the change from baseline as a proportion of the baseline value at each test time and, where multiple data values were available at each session, by linear mixed effects (LME) analysis. RESULTS: Examination of change plots suggested some modest sustained improvement in gain, no consistent changes in asymptotic peak velocity or HSEM-α, deterioration in the already poor antisaccade error rate and sustained improvement in self-paced saccade rate. LME analysis showed statistically significant improvement in gain and the interval between self-paced saccades, with differences over time between treated and untreated patients. CONCLUSIONS: Both qualitative examination of change scores and statistical evaluation with LME analysis support the idea that some saccadic parameters are robust indicators of efficacy, and that the variability observed across measures may indicate locally different effects of neurodegeneration and of drug actions.

Oxidative stress in Niemann-Pick type C patients: a protective role of N-butyl-deoxynojirimycin therapy.

Niemann-Pick type C (NPC) is a rare neurodegenerative disorder biochemically characterized by the accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes of the affected patients. N-butyl-deoxynojirimycin is the only approved drug for patients with NPC disease. It inhibits glycosphingolipid synthesis, therefore reducing intracellular lipid storage. Although the mechanisms underlying the neurologic damage in the NPC disease are not yet well established, in vitro and in vivo studies suggest an involvement of reactive species in the pathophysiology of this disease. In this work we aimed to evaluate parameters of lipid and protein oxidation, measured by thiobarbituric acid-reactive species (TBA-RS) and protein carbonyl formation, respectively, as well as the enzymatic and non-enzymatic antioxidant defenses in plasma, erythrocytes and fibroblasts from NPC1 patients, at diagnosis and during treatment with N-butyl-deoxynojirimycin. We found a significant increase of TBA-RS in plasma and fibroblasts, as well as increased protein carbonyl formation and decreased total antioxidant status (TAS) in plasma of untreated NPC1 patients as compared to the control group. In addition, erythrocyte glutathione peroxidase (GSH-Px) activity was increased, whereas CAT and SOD activities were normal in these patients. We also observed that patients treated with N-butyl-deoxynojirimycin normalized plasma TBA-RS and TAS, as well as erythrocyte GSH-Px activity. Taken together, the present data indicate that oxidative stress is increased in patients with NPC1 disease and that treatment with N-butyl-deoxynojirimycin is able to confer protection against this pathological process.

Initiation and discontinuation of substrate inhibitor treatment in patients with Niemann-Pick type C disease.

Niemann-Pick type C disease (NP-C) is a lysosomal storage disorder characterized by a progressive neurological deterioration. Different clinical forms have been defined based on patient age at neurological symptoms onset: perinatal, early infantile (EI), late infantile (LI), juvenile and adult. There is no curative treatment for NP-C. Miglustat is the first effective therapy for the neurological manifestations of NP-C patients, as it can slow down the progression of the disease. Our aim is to establish recommendations on the initiation and discontinuations with miglustat therapy based on the modified disability scale scores and describe therapeutic options to prevent treatment-related adverse effects. Four patients with different clinical forms of NP-C are reported. The modified disability scale was applied at baseline and treatment on follow up. Treatment with miglustat was initiated in patient 1 (EI form) at onset of delayed speech. Patient 2 (LI form) who started miglustat therapy in the advanced stage of the disease, died 2 years thereafter. Patient 3 (juvenile form) started treatment with miglustat at diagnosis and remains stable at four years on follow up. Patient 4, asymptomatic, is not currently treated. Miglustat has demonstrated efficacy to slow down the neurological impairment in NP-C patients assessed by the modified disability scale. Miglustat should be initiated at the onset of the first neurological symptoms. Disability scores above 20 reflect an advanced neurological impairment of the disease and miglustat therapy should be discontinued or not initiated. The gastrointestinal adverse effects can be prevented by dose titration and dietary modifications.

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

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal lipid storage disease characterized by progressive neurological deterioration. Published data on the use of miglustat in paediatric patients in clinical practice settings are limited. We report findings from a prospective open-label study in the French paediatric NP-C cohort. METHODS: Data on all paediatric NP-C patients treated with miglustat in France between October 2006 and December 2010 were compiled. All patients had a confirmed diagnosis of NP-C, and received miglustat therapy according to manufacturer's recommendations. Pre-treatment and follow-up assessments were conducted according to a standardized protocol. RESULTS: Twenty children were enrolled; 19 had NPC1 gene mutations and 1 had NPC2 gene mutations. The median age at diagnosis was 1.5 years, and the median age at miglustat initiation was 6.0 years. Eight NPC1 patients had the early-infantile, eight had the late-infantile, and three had the juvenile-onset forms of NP-C. A history of hepatosplenomegaly and/or other cholestatic symptoms was recorded in all 8 early-infantile onset patients, 3/8 late-infantile patients, and 1/3 juvenile onset patients. Brain imaging indicated white matter abnormalities in most patients. The median (range) duration of miglustat therapy was 1.3 (0.6-2.3) years in early-infantile, 1.0 (0.8-5.0) year in late-infantile, and 1.0 (0.6-2.5) year in juvenile onset patients. NP-C disability scale scores indicated either stabilization or improvement of neurological manifestations in 1/8, 6/8, and 1/3 NPC1 patients in these subgroups, respectively. There were no correlations between brain imaging findings and disease course. Mild-to-moderate gastrointestinal disturbances were frequent during the first 3 months of miglustat therapy, but were easily managed with dietary modifications and/or anti-propulsive medication. CONCLUSIONS: Miglustat can improve or stabilize neurological manifestations in paediatric patients with the late-infantile and juvenile-onset forms of NP-C. Among early-infantile onset patients, a shorter delay between neurological disease onset and miglustat initiation was associated with an initial better therapeutic outcome in one patient, but miglustat did not seem to modify overall disease course in this subgroup. More experience is required with long-term miglustat therapy in early-infantile onset patients treated from the very beginning of neurological manifestations.

The videofluoroscopic swallowing study shows a sustained improvement of dysphagia in children with Niemann-Pick disease type C after therapy with miglustat.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder characterized by defective intracellular lipid trafficking, with secondary accumulation of free cholesterol, sphingosine, and glycosphingolipids. NPC is clinically characterized by a wide spectrum of manifestations with progressive visceral and neurological involvement, including dysphagia. Neurological manifestations represent the most debilitating findings. Swallowing impairment is a frequent cause of morbidity and disability in NPC patients and progressive dysphagia may be considered a marker of neurological progression. Recently substrate reduction therapy with miglustat has been proposed for the treatment of neurological manifestations in NPC patients. This observational study reports on the long-term use of miglustat in four pediatric patients with NPC and shows the efficacy of the treatment to improve or prevent dysphagia, and persistence after 3 years of treatment or more. We used a videofluoroscopic analysis of liquid barium swallowing to provide additional information on patterns of impairment of the swallowing mechanism and to detect aspiration. In three patients showing dysphagia and aspiration we observed the improvement of the swallowing function and the sustained absence of barium aspiration in the airways after miglustat treatment, while the patient with normal swallowing function at baseline did not show any deterioration. We suggest that the videofluoroscopic study of swallowing should be routinely used to monitor the effects of treatment on swallowing ability in NPC patients.

Oxidative stress in Niemann-Pick disease, type C.

Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder due to impaired intracellular cholesterol and lipid transport. Increased oxidative stress has been reported in human NPC1 mutant fibroblasts and in tissues from Npc1 mutant mice. However, oxidative stress in NPC patients has not been established. In this study, we demonstrated increased oxidative stress in NPC patients. Evaluation of serum from 37 NPC patients, compared to control values, showed significant decreases (p<.01) in both the fraction of reduced coenzyme Q10 (CoQ10) and trolox equivalent antioxidant capacity (TEAC). Both findings are consistent with increased oxidative stress in NPC. Supplementation with CoQ10 was not effective in correcting the decreased fraction of reduced CoQ10. Increased oxidative stress may be a contributing factor to the pathology of NPC, and demonstration of increased oxidative stress in NPC patients provides both a rationale and the biomarkers necessary to test the efficacy of antioxidant therapy in NPC.

Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study.

BACKGROUND: Niemann-Pick type C disease (NPC) is an inherited neurodegenerative disorder characterised by an intracellular lipid-trafficking defect with secondary accumulation of glycosphingolipids. Miglustat, a small iminosugar, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis. Miglustat is able to cross the blood-brain barrier, and is thus a potential therapy for neurological diseases. We aimed to establish the effect of miglustat on several markers of NPC severity. METHODS: Patients aged 12 years or older who had NPC (n=29) were randomly assigned to receive either miglustat 200 mg three times a day (n=20) or standard care (n=9) for 12 months. 12 children younger than 12 years of age were included in an additional cohort; all received miglustat at a dose adjusted for body surface area. All participants were then treated with miglustat for an additional year in an extension study. The primary endpoint was horizontal saccadic eye movement (HSEM) velocity, based on its correlation with disease progression. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN26761144. FINDINGS: At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028). Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years. The safety and tolerability of miglustat 200 mg three times a day in study participants was consistent with previous trials in type I Gaucher disease, where half this dose was used. INTERPRETATION: Miglustat improves or stabilises several clinically relevant markers of NPC. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit.

Treatment of Niemann-Pick disease type C in two children with miglustat: initial responses and maintenance of effects over 1 year.

Niemann-Pick disease type C (NP-C) is a lipid storage disorder characterized by the accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system of certain cells in the central nervous system (CNS) and visceral organs. Clinical symptoms include progressive neurological deterioration and visceral organomegaly. Miglustat, a small iminosugar molecule approved for the treatment of Gaucher disease, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step in glycosphingolipid synthesis. The physicochemical properties of miglustat allow it to cross the blood-brain barrier and suggest possible benefits in lysosomal storage diseases affecting the CNS. Here, we present findings in two children with NP-C, aged 14 years (patient 1) and 9 years (patient 2), treated with miglustat for 1 year. Before treatment, patient 1 presented with severe difficulties in swallowing and walking, and patient 2 with problems mostly affecting communication and social interaction. Videofluoroscopic studies in patient 1 demonstrated a substantial improvement in swallowing by month 6 of treatment, and ambulation index measurements indicated improved walking. Mini Mental-State Examination (MMSE) assessments in patient 2 showed cognitive improvement by month 6, which was sustained up to month 12. Liver/spleen volume and plasma chitotriosidase activities were stabilized in both cases. There was no weight loss during treatment. Patient 1 experienced severe but self-limiting paresthesia, which was not associated with peripheral neuropathy. We conclude that miglustat can provide therapeutic benefits in CNS symptoms and allows stabilization of systemic disease in childhood-onset NP-C. Further follow-up is crucial to determine the long-term maintenance of these effects.