Dysphagia as a risk factor for mortality in Niemann-Pick disease type C: systematic literature review and evidence from studies with miglustat

Abstract

Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological deterioration and premature death, and has an estimated birth incidence of 1:120,000. Mutations in the NPC1 gene (in 95% of cases) and the NPC2 gene (in approximately 4% of cases) give rise to impaired intracellular lipid metabolism in a number of tissues, including the brain. Typical neurological manifestations include vertical supranuclear gaze palsy, saccadic eye movement abnormalities, cerebellar ataxia, dystonia, dysmetria, dysphagia and dysarthria. Oropharyngeal dysphagia can be particularly problematic as it can often lead to food or fluid aspiration and subsequent pneumonia. Epidemiological data suggest that bronchopneumonia subsequent to food or fluid aspiration is a major cause of mortality in NP-C and other neurodegenerative disorders. These findings indicate that a therapy capable of improving or stabilising swallowing function might reduce the risk of aspiration pneumonia, and could have a positive impact on patient survival. Miglustat, currently the only approved disease-specific therapy for NP-C in children and adults, has been shown to stabilise key neurological manifestations in NP-C, including dysphagia. In this article we present findings from a systematic literature review of published data on bronchopneumonia/aspiration pneumonia as a cause of death, and on the occurrence of dysphagia in NP-C and other neurodegenerative diseases. We then examine the potential links between dysphagia, aspiration, pneumonia and mortality with a view to assessing the possible effect of miglustat on patient lifespan.

Figure 1

Prevalence of dysphagia in Niemann-Pick disease type C (NP-C) and other neurodegenerative diseases. *Conditions where data were available from only one study. ALS, amyotrophic lateral sclerosis; MS, multiple sclerosis, PD, Parkinson’s disease; PSP, progressive supranuclear palsy.

Figure 2

Odds ratios for association between dysphagia and aspiration pneumonia in patients with neurodegenerative diseases and stroke. M-H, Mantel-Haenszel fixed effects method. Note: Altman et al. [56] paper excluded.

Figure 3

Odds ratios for association between aspiration pneumonia and mortality outcomes. M-H, Mantel-Haenszel fixed effects method.

Figure 4

Effect of miglustat versus standard care on swallowing ability in adolescent/adult patients over 12 months in a randomised, controlled trial. Reproduced with permission from [25].

Figure 5

Influence of age at neurological onset on patient survival in untreated NP-C patients. Kaplan-Meier log-rank analysis of mortality by age at neurological disease onset in untreated patients.

Figure 6

Influence of miglustat therapy on NP-C patient survival. Kaplan-Meier log-rank analysis of mortality since treatment start for treated patients and since age at neurological disease onset in untreated patients.