We have developed the NP-C clinical database (NPC-cdb) with the aim to provide a unifying framework for clinical and diagnostic datasets on NP-C from multiple patient cohorts. A detailed, customized questionnaire facilitates to comprehensively obtain current and past medical history of NP-C patients that can be entered as fixed terms and/or quantifiable parameters into a decentralized electronic database. NPC-cdb is intuitive, can be customized to an individual study’s needs and allows for an easy sharing of distinct, anonymized datasets among researchers and clinicians from diverse disciplines. We envision NPC-cdb to become a starting point for large-scale collaborative studies on NP-C pathogenesis and on the efficiency of current and future therapies.
As a proof-of-concept, we applied our infrastructure to retrospectively assess disease progression in 42 NP-C patients of German and Swiss origin, to date the most comprehensive survey on NP-C in these countries. We confirm many of the findings in other cohorts [8, 9, 12–18], among them a delay of several years from neurological onset to diagnosis; difficulties to unambiguously secure NP-C with current diagnostic tools; or a striking influence of the age at onset on disease progression. However, systematic acquisition of the temporal sequence of clinical signs as assisted by NPC-cdb opens perspectives beyond this previous knowledge. For instance, while the frequently insidious onset of NP-C is known among experts [4, 17], our data show for the first time in a larger cohort that unspecific neuropsychiatric signs involving cognitive, behavioral and motor skills are among the first disease indicators. Specifically, subtle signs such as clumsiness or perturbed fine motor skills were noticed in our cohort close to four years before distinct NP-C indicators such as VSGP, cataplexy or ataxia were reported. Certainly, our data do not exclude the possibility that also specific NP-C signs arise early in the course of disease, but are difficult to assess (such as impaired saccadic eye movements; ) and therefore may simply have been overlooked. Moreover, a substantial fraction of our data was acquired in personal interviews with non-expert relatives. As the earliest abnormalities reported by close family members are by nature subjective and often not documented as such in medical records, we can neither exclude a bias towards more familiar symptoms nor an interviewer-bias by retrospectively asking for the presence of a respective symptom. Nevertheless, our finding that less specific neuropsychiatric signs are early indicators of NP-C is supported by (i.) the large number of patients from all age groups with a similar sequence of clinical events and (ii.) a high congruency between interview and chart data for better documented NP-C symptoms (not shown). Importantly, our data also show that the occurrence of certain more specific NP-C signs appeared to pave the way for a diagnosis within less than 1.4 years after onset of the respective symptom. Our study therefore strongly suggests that to accelerate diagnosis, less specific neuropsychiatric signs should receive a higher attention.
This is of particular importance since even latest diagnostic aids to decide which patients should undergo NP-C testing strongly rely on the presence of the most prominent NP-C signs. For instance, a recently published retrospective chart review in a large cohort  revealed that cholestasis, splenomegaly, VSGP, cataplexy, cognitive decline, co-affected relatives and a co-occurrence of symptoms from different disease domains are the strongest NP-C predictors. Consequently, a proposed Suspicion Index (SI) tool weighs these symptoms relatively high, while frequent, but less specific motor coordination, cognitive and behavioral problems are ranked as moderate to low indicators. While also our study shows that the SI tool is very sensitive in identifying patients that have readily apparent disease, it has not been taken into account during the generation how far in the disease process in individual patients had already progressed before diagnostic testing was initiated. Retrospective application of this Suspicion Index tool to our collective revealed that at diagnosis 30% of our patients would not have been considered as among the strongest candidates for NP-C testing, while NP-C would have been regarded even as unlikely in 13%. Importantly, diagnosis in this sub-cohort was secured before or early after onset of first neurological symptoms, which is reflected by a negative correlation between Suspicion Index score and time to diagnosis. With this, our data take into question that the Suspicion Index tool will significantly contribute to identify NP-C patients early in the disease process. Instead, to reduce diagnostic delay and with this raise response to treatment [8–10], we propose that less specific NP-C indicators should be included in a decision to initiate NP-C testing. This is of particular relevance as plasma oxysterols as a rapid and reliable biochemical screening tool may soon enable the cost-efficient identification of putative NP-C patients from larger cohorts with diverse clinical backgrounds.
For studying the temporal development of NP-C we generated the NPC-cdb score, which allowed us to closely monitor disease progression independent from the age of onset. Unlike a similarly comprehensive clinical severity scale , determining the NPC-cdb score for a patient does neither rely on laboratory investigations nor on laborious re-evaluation of distinct clinical sub-domains at each visit. Instead, the sum of all severity-weighted clinical symptoms present at distinct time points during the course of disease is determined once from questionnaire data obtained at one comprehensive data assessment. During follow-up visits, only symptoms that manifested since the previous data entry are to be added. This ease of use should proof useful in clinical settings and with this complement widely used, but less comprehensive scales that only poorly reflect the heterogeneous clinical picture of NP-C [10, 12, 13, 23]. As the NPC-cdb score is in principle open ended, further symptoms of interest can easily be added which may be of particular interest for prospective and interventional studies. Our focus here was on a solid reconstruction of disease history. Interestingly and in seeming conflict with another cohort where NP-C severity progressed in a close to linear fashion , a sizable fraction of our patients (n=6; 14%), among them one sib pair, showed a steep deterioration of abilities after an initially only slowly-progressive disease. In our cohort this deterioration was associated with seizures, onset of which in a patient could signalize progressed neurological state. Alternatively, seizures might as well impair NP-C relevant brain functions, which secondarily accelerates disease progression as reflected by higher NPC-cdb scores. Closer monitoring of clinical events before and after the onset of seizures in future studies may help to distinguish between cause and consequence.
In addition to epilepsy, the existence of further factors impacting on adverse or beneficial clinical outcomes is highly probable, but failed to be demonstrated here due to insufficient patient numbers. Experience from complex diseases propose that much larger, equally well-documented cohorts will be needed to unambiguously identify also factors with more subtle impact on disease expression . This is particularly the case when aiming at the identification of genetic factors or biomarkers as the basis for particular NP-C phenotypes that may explain the heterogeneous nature of the disease. The prospect of Miglustat as a specific treatment option for NP-C  has triggered numerous trials in several national NP-C patient cohorts (e.g., [9, 10, 13–17, 23, 26]). These studies have contributed significantly to our understanding of which symptoms within the NP-C spectrum are frequent and specific. The systematic collection of comprehensive diagnostic and longitudinal clinical information in a central database will further extend and improve the generalizability of findings from individual cohorts. By providing large-enough patient numbers this may allow to precisely characterize the heterogeneous clinical picture and unambiguously test whether existing or future treatment strategies are efficient. We are confident that NPC-cdb may now provide a platform for such initiatives.