These observations come from an international registry population of 163 patients, which represents the largest cohort of living NP-C patients reported to date. As such, the findings reported in this paper provide an important contribution to existing knowledge regarding both disease and patient characteristics. This Registry population also comprises appreciable numbers of patients across all age-at-neurological-onset categories (early-infantile, late-infantile, juvenile and adolescent/adult). Notably, adolescent/adult onset patients make up almost one-third of the Registry population.
As has been reported in previous NP-C patient cohorts, a high proportion of early-infantile and late-infantile onset patients had a history of neonatal jaundice, hepatomegaly and/or splenomegaly [2, 9]. This confirms the importance of these symptoms as tangible clues toward a possible diagnosis of NP-C in new-borns, although it should be borne in mind that they are often transient manifestations [11, 12].
Interestingly, a notable proportion of adolescent/adult-onset patients in the NPC Registry also had a record of neonatal jaundice and/or hepatosplenomegaly during infancy. Despite memory bias, hepatosplenomegaly in older-onset patients often goes unrecognised . Abdominal ultrasound examination and/or a detailed investigation of patients’ medical histories with regard to previous liver disease may help to detect systemic NP-C symptoms during diagnostic work up in adolescent/adult cases [10, 22].
The profile of neurological symptoms in this Registry was consistent with data from previous large cohort studies [2, 5, 6, 9]. In particular, VSGP was confirmed as a frequent finding across all age-at-onset categories. Saccadic eye movement abnormalities are known to be one of the earliest specific signs of neurological deterioration in NP-C, progressing over time to full VSGP in most cases [10, 23, 24]. These data therefore support existing knowledge and underline the importance of systematic examination of saccades and vergence movements as well as pursuit movements in the detection of possible NP-C [10, 25–27].
The common occurrence of cataplexy and seizures in late-infantile and juvenile-onset NP-C patients, with lower levels seen in early-infantile and adolescent/adult-onset patients, is also in close agreement with existing reports [2, 10]. These manifestations impair patient quality of life and in some severe cases, prognosis. Treatment directed toward achieving adequate control of cataplexy and seizures is essential .
Cognitive impairment was one of the most consistent neurological findings, reported in 60–70% of patients across all age-at-onset categories. While progressive cognitive decline eventually affects most, if not all, patients with NP-C, it is generally less commonly recognised during early childhood. Impaired cognition frequently manifests as poor school performance in juveniles and adolescents, and as NP-C progresses patients experience a general decline, leading to frank dementia in many cases [10, 15, 28, 29]. In younger-onset patients it is more likely to be recognised initially as developmental delay .
Similar to cognitive decline, previous studies have reported psychiatric manifestations more frequently among adolescent/adult-onset NP-C patients compared with younger-onset patients [2, 14, 15]. In the Registry population 40% of adolescent/adult-onset patients had psychiatric manifestations, although this value might have been artificially high due to ‘cognitive decline’ having been recorded as a psychiatric manifestation; this was certainly the case in the early- and late-infantile groups. Nevertheless, schizophrenia-like psychosis has previously been reported in up to 25% of NP-C patients, and other major psychiatric illnesses reported in association with NP-C include depression, bipolar disorder and obsessive-compulsive disorder . The frequency of NP-C in patients diagnosed with psychiatric disorders is an important aspect because in some patients, psychiatric manifestations can overshadow systemic symptoms and subtle neurological signs of NP-C, which leads to significant delays in the detection and diagnosis of NP-C [30, 31]. Studies are currently ongoing to further establish the frequency of NP-C among psychiatric patients .
Analysis of patient age milestones illustrated that early-infantile patients have a greater tendency to be diagnosed before the onset of neurological manifestations compared with late-infantile, juvenile and adolescent/adult-onset patients, who are diagnosed after neurological onset. This is likely due to the greater prominence of systemic symptoms in very young patients. Overall, there were long delays between the onset of neurological manifestations and confirmation of the diagnosis of NP-C. This finding is consistent with data from previous studies [10, 18, 33], and highlights this major problem in NP-C.
Delayed diagnosis can have a considerable impact on quality of life for patients and/or their family and primary caregivers. In addition, it has been recommended that disease-specific therapy with miglustat should be started as early as possible in the course of neurological disease in order to stabilise neurological function [1, 10]. Possible measures that might enhance the detection of NP-C and expedite future diagnoses include the use of novel screening tools such as the NP-C suspicion index , increased vigilance for early systemic symptoms, and the development of potential new disease biomarkers such as plasma oxysterols .
The composite disability scores among patients in the Registry at enrolment were comparable with baseline scores reported in previous cohort studies that utilised this disability scale [7, 18, 35]. It is notable that there were no significant differences in composite scores between age-at-onset categories among the Registry patients. The 95% CIs of the mean composite scores all overlapped. It also remains to be seen whether changes in composite scores over time in this Registry reflect previously observed differences in the rates of disease progression between the age-at-onset categories.
It is not possible to state whether any single disability scale measure (ambulation, manipulation, language or swallowing) was statistically more affected than others at enrolment based on the current categorical analysis. However, the distribution of scores for each disability parameter in the Registry appeared comparable with those seen at baseline during a previous cohort study based on the same disability scale .
The data summarised in this report should be interpreted with the awareness that disease registries come with a number of inherent limitations. As with all disease registries, the integrity and comparability of the NPC Registry data relies on the accurate entry of patient information by the treating physicians and other nominated staff at each participating centre. The potential for ascertainment bias (also present to some extent in all published NP-C cohorts) should be recognised. Registries can also suffer from selection bias. In the former case, the inclusion of all consecutive patients (both incident and prevalent) who present for outpatient and/or inpatient visits irrespective of treatment status is one measure stipulated in the NPC Registry protocol to minimise selection bias. Finally, most patients with a confirmed diagnosis of NP-C are currently being treated with miglustat, and there are only a few treatment-naïve patients available for study within the Registry population. At this point in time, this precludes meaningful comparisons between treated and untreated patients.
In summary, these data derived from the largest NP-C Registry cohort reported to date, provide a useful overall snapshot of patient and disease characteristics that can be considered alongside epidemiological data from previous large cohort studies. Our findings confirm that systemic symptoms are common among patients with early-childhood onset of neurological manifestations but are also a common finding among patients with adolescent/adult onset disease. The profiles of neurological manifestations seen among all age-at-onset categories in the Registry are in line with previous publications. Longitudinal data from follow up assessments are required to discern any differences in disease progression and degrees of neurological stability between early-infantile, late-infantile, juvenile and adolescent/adult-onset groups, and will be reported in future publications.