Clinical experience with miglustat therapy in pediatric patients with Niemann–Pick disease type C: A case series

Abstract

Niemann–Pick disease type C (NP-C) is an inherited neurovisceral lysosomal lipid storage disease characterized by progressive neurological deterioration. Different clinical forms have been defined based on patient age at onset: perinatal, early-infantile (EI), late-infantile (Li), juvenile and adult. We evaluated the efficacy and tolerability of miglustat in 16 symptomatic NP-C patients, with comparative reference to one neurologically asymptomatic, untreated patient. All patients were categorized according to age at neurological disease onset, and were assessed using a standardized clinical assessment protocol: disability and cognitive function scales, positron emission tomography (PET), and biochemical markers. PET and disability scale evaluations indicated that cerebral hypometabolism and neurological symptoms were stabilized during treatment in juvenile-onset NP-C patients. EI and Li NP-C patients, who had higher disease severity at baseline (treatment start), showed increased disability scores and progressive cerebral hypometabolism during follow up. Similarly, while cognitive scale scores remained relatively stable in patients with juvenile NP-C, cognition deteriorated in EI and Li patients. Plasma chitotriosidase (ChT) activity was lower in the juvenile NP-C subgroup than in EI and Li patients, and generally increased in patients who discontinued treatment. Plasma CCL18/PARC and ChT activities indicated greater macrophagic activity in EI and Li patients versus juveniles. Miglustat was generally well tolerated; frequent adverse events included diarrhea and flatulence, which were managed effectively by dietary modification and loperamide. Overall, miglustat appeared to stabilize neurological status in juvenile-onset NP-C patients, but therapeutic benefits appeared smaller among younger patients who were at a more advanced stage of disease at baseline.

Introduction

Niemann–Pick disease type C (NP-C) is a neurovisceral lysosomal lipid storage disease characterized by progressive neurological deterioration. NP-C is caused by mutations in either one of the two genes, NPC1 or NPC2, which encode proteins involved in the regulation of normal intracellular lipid trafficking through sequential activities within a common pathway [1], [2], [3], [4]. Expression of the mutant genes leads to severely impaired intracellular lipid transport and marked accumulation of both unesterified cholesterol and several glycosphingolipids in a variety of tissues and organs, in particular the brain [2], [3], [5], [6].

NP-C has a highly variable clinical presentation. The symptomatology and rate of disease progression are strongly influenced by age at disease onset [7], [8], and different clinical forms have been described on this basis. In the perinatal form, patients die from liver failure within the first months of life. Other forms are defined based on the following ages at onset: early-infantile (EI) form, <2 years; late-infantile (Li) form, 3–5 years; juvenile form, 5–16 years; adult form, >16 years. Clinical symptoms include progressive neurological deterioration and visceral organomegaly. Neurodegeneration begins with clumsiness and progressive ataxia followed by a range of symptoms that can generally include dysmetria, vertical supranuclear ophthalmoplegia, cataplexy, seizures, dystonia, pyramidal signs, dysphagia and dementia [8], [9].

The biochemical diagnosis of NP-C is currently based on the demonstration of impaired low-density lipoprotein (LDL) cholesterol trafficking in cultured fibroblasts from patients, by cytochemical visualization of accumulated free cholesterol after filipin staining [9]. Recently, CCL18 pulmonary and activation-regulated chemokine (PARC), termed hereinafter as ‘CCL18’, has been reported as a potential new surrogate marker for monitoring symptomatic patients with Gaucher disease (GD) [10]. On average, this protein is elevated 29-fold in GD patients, without overlap between patient and control values. Chitotriosidase (ChT) is a human chitinase that shows markedly elevated activity in a variety of lysosomal storage disorders [11]. It is secreted by activated macrophages and is thought to play a role in defense against chitin-containing pathogens, in tissue remodeling and cell migration, as well as during atherogenesis. Plasma ChT is considered a useful surrogate marker in the lysosomal work-up of GD and NP-C patients with organomegaly, as it is relatively inexpensive and is easily assayed [12]. However, the use of plasma ChT as a marker of disease progression can be problematic in some patients who have no ChT activity due to possession of a 24-base pair (bp) duplication in the ChT gene; this mutation is inherited as an autosomal recessive trait [11]. Nevertheless, plasma ChT is considered also to be of possible use as a screening marker in pediatric patients [12].

Currently, there is no cure for NP-C, although palliative therapy can alleviate some symptoms of the disease [13]. Miglustat (N-butyldeoxynojirimycin; NB-DNJ; OGT-918) is a small iminosugar molecule that reversibly inhibits glucosylceramide synthase, the enzyme that catalyses the first committed step in glycosphingolipid synthesis [14]. The ability of miglustat to cross the blood–brain barrier indicated its potential use as a therapy for lysosomal storage diseases affecting the central nervous system. In animal NP-C models, miglustat delayed the onset of neurological symptoms and increased life span [15]. Evidence suggests that miglustat might also have beneficial effects on pathogenetic NP-C cellular pathways associated with calcium homeostasis [16]. Based on findings from a randomized, controlled clinical trial and a retrospective observational cohort study [17], [18], miglustat was approved in the European Union for the treatment of progressive neurological manifestations in adult patients and pediatric patients with NP-C in January 2009.

We report an evaluation of 17 patients with NP-C (16 symptomatic and one neurologically asymptomatic) from Spain and Portugal who were treated with miglustat for up to 4 years. We applied a standardized clinical, biochemical and neuroimaging protocol in order to establish the effect of miglustat on several markers of NP-C severity.