As NPC is a rare disease, patient population sizes are limited and tracking the natural history of the disease and enrolling patients for a clinical study is very challenging. The INPDR is a patient centric registry designed to: a) better understand the natural history of Niemann-Pick disease worldwide; b) provide an inventory of patients for recruitment to observational and interventional studies; c) establish genotype-phenotype correlations; d) provide support for education of health professionals and empowerment of patients. Data from 203 NPC patients from 6 countries were available for analysis, forming one of the largest cohorts of patients with NPC reported to date.
The p.I1061T variant was the most common variant in this population, with detection in 28.6% of patients. This aligns with previous research, where p.I1061T is most common in Western European decent populations (10) with varied frequency as reported in cohort studies from the United Kingdom (7), Spain (11), the Czech Republic (12), and Italy (13)
Disease classification based on the age of onset of the first neurological symptoms has been accepted as a guide to clinicians in providing day to day care, genetic counselling and estimate the trajectory of the disease course (10). The proportion of participants at each age category based on neurological onset was relatively consistent; 24.2% early infantile, 26.4% late infantile, 23.0% juvenile and 20.8% adult patients. These findings are in line with the previously reported observational studies (7, 9). The type and onset of visceral symptoms varied across the age groups with decreased occurrence with an increasing age. Neonatal jaundice and hepatomegaly were most prevalent in early infantile and late infantile patients. As has been reported in a prior NPC cohort study, splenomegaly is the most consistent observation across the age spectrum and was recorded in 80% of adult patients (6, 7, 9, 13).
Neurological signs such as ataxia, dysphagia, dysarthria and cognitive impairment were the most common, being reported in over two thirds of patients from all age categories. Similar to visceral manifestations, some of the neurological findings vary with age at disease onset. It is notable that the frequency of seizure and cataplexy is most common in infantile and juvenile onset and less so in adult. Developmental milestones delays were the most commonly reported neurological observation in early and late infantile forms. In contrast, psychiatric manifestations and hearing impairments are more common in adult onset. These observations are in agreement with previous observations (14). Neuroimaging data gathered primarily from juvenile and adult individuals showed a variable pattern, with some being normal, while most patients imaging results demonstrate cortical and cerebellar atrophy as the most common changes. These changes have been reported to correlate with measures of ataxia and ocular-motor function (15).
Clinical assessment of disease burden and rate of progression in time or regression with disease modifying therapy is challenging when dealing with progressive diseases such as NPC. We used a modified 6-domain functional disability score (6) as calculated by combing ambulation, manipulation, speech, swallowing, eye movement and seizure scores. The composite disability scores were notably higher in patients with an early onset neurological signs, particularly in late infantile patients. This is consistent with the natural history of the disease, which has more severe presentation and rapid progression of the disease in patients whose neurological manifestations appear at a younger age (2). On the other hand, juvenile and adult-onset patients had fewer ‘normal’ individual disability scores for ambulation, manipulation and language domains. Eye movements and seizure seem to show the least variability indicating as less sensitive indicators to assess disease progression.
Mortality data was available for 59 patients and the duration of survival after disease onset varies with age spectrum of the disease. As expected, death on average resulted in less than one year of onset with the neonatal rapidly fatal forms. Interestingly, we observed a unique pattern with the other three age category of the disease as follow: early infantile, late infantile and juvenile form, where the mean rate of survival in years doubles for each category of NPC forms. In addition, similar longer survival trend was noted in adult forms. The lack of doubling effect in adult may well be due to long delayed diagnosis which in turn hampers the recognition and/or association of early subtle NPC related neuropsychiatric signs. The pattern of disease onset and survival observed in this study is largely in agreement with study from the French cohort (4). This observation can be used to council patients and families about the disease course and prognosis at the time of diagnosis.
Use of various therapeutic modalities was reported in this registry. The mean total number of therapies used by each patient was 1.84. The most common therapy was Miglustat, a potential disease modifying therapy specifically indicated for NPC, reported in 85 (62.4 %) patients, with a mean duration of just over 4 years. Other symptomatic therapies were antiepileptic (32.94%), antidepressants (11.76%) and antacids (9.41%). These levels of therapeutic intervention in NPC are in line with the current NPC international clinical management guidelines (16).
This study has some limitations: 1) Being an observational, non-interventional real-world study the dataset had some gaps in data points which may reflect variation in standard of care practice and needs of the patient. Therefore, some parameters were analysed with the denominator as “n” rather than 203 patients. 2) The data is a snapshot of the registry, with baseline data reported. Therefore longitudinal follow-up data should be considered to investigate the possible changes in disability score or neurological manifestations in line with existing and future disease modifying treatment. 3) Data reported is from 6 European countries, and may reflect the disease characteristics of patients from those countries rather than being representative of patients globally. The capturing of clinical data from patients beyond these 6 countries may indicate differences to the findings of this analysis. The strength of our study lies on the use of the second largest number of NPC patients studied to date and its international scope. Above all, we have developed an exemplar patient led, independent international registry capable of delivering the unmet need of not only Niemann-Pick Disease but also serves as a model for other rare and neglected disorders.
In summary, the data of 203 NPC patient records captured via the INPDR highlights key patient and disease characteristics that can be tracked for future international studies. To our knowledge, this is the first patient led registry of such international reach. Long term longitudinal data utilising the INPDR on a larger international cohort is currently underway.