Adult Niemann-Pick disease type C in France: clinical phenotypes and long-term miglustat treatment effect

Abstract

Background: Niemann-Pick disease type C (NP-C) is a neurodegenerative lysosomal lipid storage disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes. The clinical presentation and evolution of NP-C and the effect of miglustat treatment are described in the largest cohort of patients with adolescent/adult-onset NP-C studied to date.

Methods: Observational study based on clinical chart data from adult patients with NP-C (> 18 year old) diagnosed in France between 1990 and 2015. Retrospective data from patients at diagnosis, onset of miglustat therapy (if applicable), and last follow up were analysed.

Results: In France, patients with an adolescent-adult neurological form constituted approximately 25% of all NP-C cases diagnosed during the study period. Forty-seven patients (46 with NP-C1 and one with NP-C2; 53% female) were included. Mean ± SD (range) ages at neurological onset and diagnosis were 23.9 ± 12.5 (8-56) years and 34 ± 13.5 (15-65) years, respectively. At presentation, patients mainly had 1) impaired gait due to cerebellar ataxia and/or dystonia, 2) and/or cognitive/behavioural manifestations, 3) and/or psychotic signs. Initially, almost half of patients had only one of the above three neuro-psychiatric manifestations. Vertical supranuclear gaze palsy, usually occurring without patient complaint, was only detected on careful clinical examination and was recorded in most patients (93%) at the time of diagnosis, several years after neurological onset. Thirty-seven patients (79%) received miglustat, among whom seventeen (46%) continued beyond 2 years (at last follow up) to a maximum of 9.8 years. Eight patients (22%) discontinued treatment early due to side effects (n = 3) or perceived lack of efficacy (n = 5).Miglustat treatment duration correlated significantly with reduced neurological worsening (p < 0.001). Treatment for≥2 years was associated with improved patient survival (p = 0.029). Good responses to miglustat were associated with less severe neurological disability at the start of miglustat treatment (p = 0.02).

Conclusion: The proportion of adolescent/adult-onset NP-C cases diagnosed in France increased 2.5-fold since 2009 compared with the 2000-2008 period due to improved awareness. Adolescent/adult-onset NP-C frequently presented initially with a non-specific isolated neuro-psychiatric manifestation (motor, cognitive or psychotic). Patients with less severe neurological disability responded better to miglustat therapy.

Keywords: Adult-onset; Efficacy; Epidemiology; France; Miglustat; Niemann-pick disease type C; Safety.

Fig. 1

Schematic overview of the NP-C cohort with adolescent/adult neurological onset. Patients were divided in three categories : untreated (a), miglustat-treated for < 2years (b), miglustat-treated for > 2 years (c). See Additional file 1: Table S1 for details and further information

Fig. 2

Frequencies and timings of key neurological symptoms. Color-coded bars represent symptom occurrence (% patients) as initial isolated neurological symptoms, initial neurological symptoms (not isolated), or appearance during the course of neurological deterioration. This classification did not take into account vertical supranuclear gaze palsy (VSGP), cognitive developmental symptoms, or hearing loss (except for the hearing loss item). Cognitive and psychiatric symptoms were considered as a single category as they frequently overlap, and separating them according to age at onset can be arbitrary. Psychosis is contained within the Cognitive/Psychiatric category, but is also shown as a separate item due to its particular importance among adult/adolescent patients. N numbers above each bar are total numbers of patients analysed for each symptom. Mean ± SD ages at onset of each symptom are shown above each bar

Fig. 3

Changes in total NP-C disability score for each patient from baseline (diagnosis) to last follow up. Each point represents change in total disability score in individual patients according to delay between diagnosis and last follow up. A positive change in disability score indicates clinical worsening. Patients who discontinued miglustat after < 2 years due to neurological worsening were excluded (n = 4). For three patients (2, 6, and 16), change in disability score was measured between age at miglustat onset and age at last examination, as delay between diagnosis and miglustat onset exceeded 1 year. The period between diagnosis and last follow up and the duration of miglustat treatment were associated with change in disability score from baseline (p < 0.001 for both variables). Clinical score at diagnosis and age at neurological onset did not show any statistically significant relationship (p = 0.34 and 0.30, respectively)

Fig. 4

Change in individual NP-C disability subscores for each patient from baseline (diagnosis) to last follow up. Changes in gait (panel a; p < 0.001), manipulation (panel b; p = 0.016), speech (panel c; p < 0.001) and swallowing subscores (panel d; p = 0.0176) were statistically significantly associated with duration of miglustat treatment

Fig. 5

Time-to-event analysis of period from diagnosis to death in patients treated with miglustat for > 2 years (n = 17) versus untreated patients and those who received miglustat for < 2 years (n = 26). Patients who discontinued miglustat after < 2 years of treatment because of neurological worsening were excluded (n = 4). The Kaplan Meier curves for this analysis were truncated when approximately 10% of patients were still under observation in each group, due to low relevance of graphical representation based on limited patient numbers beyond this time point. For patient 6 who was diagnosed in early infancy, time-to-event analysis began from start of miglustat treatment. Mean clinical scores at diagnosis were not different between the two groups (9.4 in patients treated for > 2 years versus 9.1 in untreated patients and those receiving miglustat for < 2 years). A statistically significant delay to death was noted in patients treated with miglustat for > 2 years versus untreated patients and those receiving miglustat for < 2 years (p = 0.029; log-rank test)

Fig. 6

Time-to-severe-event analysis for: a) impaired gait (need for wheelchair), b) manipulation (severe dysmetria); c) speech (non-verbal communication); and d) swallowing (need for gastrostomy) subscores in patients treated with miglustat for > 2 years versus untreated patients and those receiving miglustat for < 2 years. N₁, number of patients untreated or receiving miglustat for ≤2 years; N₂, number of patients treated with miglustat for > 2 years; y, years