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

Abstract

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.

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

“…Previous results from a controlled clinical trial in adult and juvenile patients with NPC [Patterson et al, 2007] and the pediatric subgroup [Patterson et al, 2010], data from a retrospective clinical study [Pineda et al, 2009] and also from single additional patients on miglustat treatment [Chien et al, 2007;Paciorkowski et al, 2008;Santos et al, 2008;Galanaud et al, 2009] indicated the beneficial effect of miglustat on the progression of neurological manifestations, including dysphagia, although data on improvement of swallowing impairment were limited.…”

“…These results indicate that swallowing ability does not deteriorate in miglustat-treated patients who did not show severe dysphagia before treatment. Improvement of severe dysphagia has been shown by videofluoroscopic swallowing study (VFSS) in a single reported patient following 1 year-miglustat treatment [Chien et al, 2007].…”

Development of targeted therapies for Parkinson's disease and related synucleinopathies

“…The impact on neuronal synuclein levels remains to be established in this disease. In clinical studies, miglustat has been demonstrated to improve symptoms of disease in small open-label studies ( 44 ). In 20 patients treated for 12 months, miglustat improved saccadic eye movement velocity (the primary end point for the study), swallowing, hearing, and walking in these patients ( 45 ).…”

Splenomegaly, hypersplenism, and hereditary disorders with splenomegaly

“…Miglustat now has regulatory approval for the treatment of NP-C in the European Union and several other countries and is in continued clinical trial in the United States. Because the clinical trials focused primarily on the clinically crucial neurological response, there is little information on the effect of miglustat on splenomegaly or bone marrow foam cell infiltration in NP-C. Two case reports suggest that miglustat stabilizes but does not necessarily decrease spleen and liver volume in NP-C patients [64,65]. That observation, if confirmed in larger numbers of patients, might lend credence to a suggestion based on experimentation in NP-C mice, that the clinical benefit observed with imino sugar inhibitors of glucosylceramide synthase such as miglustat might not necessarily be attributable to substrate reduction but rather to some unrelated, off-target effect [66].…”