Fast track — ArticlesMiglustat for treatment of Niemann-Pick C disease: a randomised controlled study
Introduction
Niemann-Pick type C disease (NPC) is an autosomal recessive disease linked to dysregulation of intracellular lipid trafficking.1, 2 There is currently no treatment available for this disease aside from palliative care.
The birth incidence of NPC has been estimated at 1 in 150 000 in western Europe,3 with a higher incidence in certain genetically isolated populations.4, 5 Most patients with NPC harbour mutations in the genes encoding the NPC1 (95%) and HE1/NPC2 (5%) proteins.6, 7
Dysregulated lipid transport in NPC is associated with excess accumulation of free cholesterol and glycosphingolipids in many tissues including the brain.2, 8 Raised concentrations of GM2 and GM3 gangliosides are seen in many diseased neurons, by contrast with their virtual absence in healthy mature neurons.9 GM2 ganglioside accumulation is invariably associated with neuron-specific ectopic dendritogenesis.10 Neurons seem selectively vulnerable to NPC1 protein deficiency, although the mechanisms by which NPC1 and NPC2 sustain normal neuronal function are yet to be established.11
Although the lesions of NPC occur throughout the CNS, certain regions are susceptible to early and severe injury. Purkinje cell loss begins early and progresses rapidly, correlating with gait ataxia, dysarthria, and dysphagia.12 Neurofibrillary tangles, ectopic dendritogenesis, and meganeurite formation in the cortex provide an anatomic substrate for dementia and seizures.12 Severe cell loss has also been reported in the rostral interstitial nucleus of the medial longitudinal fasciculus, a crucial premotor area for vertical gaze, with lesser degeneration in the paramedian pontine reticular formation, the corresponding centre for horizontal saccades.13
Neurological findings in NPC include vertical and horizontal supranuclear gaze palsy, ataxia, dysarthria, dysphagia, dystonia, seizures, progressive dementia, psychiatric syndromes, and gelastic cataplexy.14, 15, 16, 17 Hepatosplenomegaly is frequently, but not invariably, present in NPC, and its absence does not exclude the diagnosis, particularly in late-onset cases.18 Vertical supranuclear gaze palsy has been described in all but a handful of cases of NPC, irrespective of the age of onset.
Separate systems control vertical and horizontal saccades, providing an anatomical basis for the onset of vertical before horizontal saccadic palsy in NPC.13, 19 Saccadic recordings in individuals with NPC show an early, marked slowing of vertical saccadic eye movements, followed later by similar changes in horizontal saccadic eye movements (HSEM).13, 19, 20, 21 Vertical saccadic eye movements are often completely lost by the time NPC is diagnosed.
To date, there is no disease-modifying therapy for NPC.22 Substrate reduction therapy is a novel therapeutic strategy for lysosomal storage diseases23 that uses inhibitors, such as miglustat, to diminish glycolipid biosynthesis. Miglustat, a small iminosugar molecule, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis.24 Its ability to cross the blood-brain barrier renders miglustat a suitable agent for treating CNS disease in NPC.25 Administration of miglustat has ameliorated glycosphingolipid accumulation in neurons and prolonged survival in murine models of lysosomal storage disorders,26 including NPC. Miglustat treatment of mice and cats with NPC resulted in reduced ganglioside accumulation, delayed onset of neurological dysfunction, and increased survival.27 In people, depletion of glycosphingolipids by miglustat in an NPC patient reduced pathological lipid storage, improved endosomal uptake, and normalised lipid trafficking in peripheral blood B lymphocytes.28
Miglustat is currently approved for the treatment of selected patients with Type I Gaucher disease, the most prevalent lysosomal storage disorder. The efficacy, safety, and tolerability of miglustat in individuals with Gaucher disease have been shown in several clinical studies.29, 30, 31 Patients with the disease who were treated with miglustat for up to 3 years showed improvement in key clinical markers of the disease.30 The preceding data provided a strong rationale for the investigation of miglustat as a treatment for patients with NPC.
We aimed to assess the effects of miglustat as a treatment for NPC in adult, adolescent, and paediatric patients, over a 24-month treatment period. The first 12 months' data are presented in this report.
Section snippets
Participants
The efficacy, safety, and tolerability of miglustat in NPC were assessed in patients 12 years and older and paediatric patients (age 4–11 years). Patients with NPC confirmed by reduced cholesterol esterification and abnormal filipin staining in cultured fibroblasts who were capable of cooperating with the physical examination and other testing were considered eligible for participation. The major exclusion criteria included clinically significant diarrhoea (more than three liquid stools per day
Results
29 patients aged 12 years or older (20 receiving miglustat, nine receiving standard care) and 12 children were enrolled in the study (table 1). Baseline characteristics were similar for the standard care and miglustat-treated patients. The mean age for patients aged 12 years or older receiving miglustat was 25·4 years (SD 9·8), for those on standard care was 22·9 years (7·5), and for the paediatric group receiving miglustat was 7·2 years (2·5). In the study group aged 12 years or older, three
Discussion
Overall, patients receiving miglustat for treatment of NPC showed consistent improvement or stabilisation in several clinically relevant endpoints compared with standard care. This trial is the first clinical controlled study to our knowledge that has assessed miglustat as a potential treatment for patients with NPC. Patients with progressive neurodegenerative disorders such as NPC might show apparent improvement or stabilisation if manifestations including seizures, malnutrition, and sleep
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