Niemann-Pick disease type C clinical database: cognitive and coordination deficits are early disease indicators

Abstract

Background: The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NP-C) is characterized by a broad clinical variability involving neurological, psychiatric and systemic signs. Diverse patterns of disease manifestation and progression considerably delay its diagnosis. Here we introduce the NP-C clinical database (NPC-cdb) to systematically obtain, store and analyze diagnostic and clinical findings in patients with NP-C. We apply NPC-cdb to study NP-C temporal expression in a large German-Swiss patient cohort.

Methods: Current and past medical history was systematically acquired from 42 patients using tailored questionnaires. Manifestation of 72 distinct neuropsychiatric signs was modeled over the course of disease. The sequence of disease progression was re-constructed by a novel clinical outcome scale (NPC-cdb score).

Results: The efficiency of current clinical diagnostic standards negatively correlates with duration of disease (p<3.9x10(-4)), suggesting insufficient sensitivity in patients early in the disease process. Neurological signs considered as typical for NP-C were frequent (e.g., cognitive impairment 86%, ataxia 79%, vertical supranuclear gaze palsy 76%) and their presence co-occurred with accelerated diagnosis. However, less specific neuropsychiatric signs were reported to arise considerably more early in the disease process (e.g., clumsiness -4.9±1.1 y before diagnosis). Most patients showed a steady disease progression that correlated with age at neurological onset. However, a distinct subcohort (n=6) with initially steadily progressing disease later showed a 2.9-fold accelerated progression that was associated with the onset of seizures (p<7x10(-4)), suggesting seizures as predictive for a poor prognosis.

Conclusions: Considering early, but less specific neuropsychiatric signs may accelerate the path to diagnosing NP-C in a patient.

Figure 1

Diagnostic findings in studied NP-C patient cohort (n=42).* NP-C Suspicion Index (acc. to Wijburg et al., 2012): <40, NP-C unlikely; 40-69, NP-C follow up advised; ≥70, NP-C likely; na, not available; NAD, nothing abnormal detected; cl., classic; var., variant; indiff., indifferent; Cys-rich, cystein-rich loop (aa 855-1098); SSD, sterol sensing domain (aa 615-797), normal range: 3β,5α,6β-triol: 29-152; 7-KC: 78-390.

Figure 2

Spectrum of disease presentation in studied neurological NP-C patient cohort (n=38). Horizontal bars show disease duration (in years) in individual patients (represented by NPC-cdb no.; see Figure 1) from the onset of neurological symptoms until the age at data assessment. Dark blue, timespan from first reported neurological sign until diagnosis NP-C. Light blue, timespan from diagnosis until data assessment. In four patients NP-C was diagnosed prior to the onset of neurological signs (narrow bars). Deceased patients are highlighted by crosses. Patients are aligned according to age at diagnosis.

Figure 3

Sequence of most frequent neuropsychiatric symptoms during disease course. Estimated median time until presentation (±95%CI) of the 21 most frequent neurological signs present in >40% of studied neurological patients (n=38), normalized to the relative age at neurological disease onset (x=0). Symptoms are aligned in order of appearance (bottom to top). VSGP, vertical supranuclear gaze palsy.

Figure 4

Manifestation of 10 characteristic neurological NP-C signs relative to diagnosis. Sequence of occurrence of 10 selected neurological symptoms with diagnostic importance (acc. to Wijburg et al., 2012, [8]), normalized to the relative age at diagnosis (y=0). Each dot represents one patient. Medians are indicated by grey bars. Symptoms are aligned in order of appearance (bottom to top). VSGP, vertical supranuclear gaze palsy.

Figure 5

Symptoms considered for NP-C clinical database (NPC-cdb) score. Colored areas represent different subject categories in NPC-cdb questionnaire and database (Additional file 1 and Additional file 2).

Figure 6

Disease progression in 38 NP-C patients with neurological disease. (A) Occurrence of disease symptoms over time (in years) was scored for each of the 38 patients (colored lines) individually with both, the NPC-cdb score (large graph) and the NIH clinical severity scale (Yanyanin et al., 2010, [17]; inset), each normalized to the age at neurological disease onset (x=0). Higher score values (y-axis) reflect higher number of symptoms. Standard deviations around mean values (reflecting the normal range) are represented by yellow clouds. (B) Examples for patients with particular types of disease progression. Top, steady disease course; center, rapid degenerative course; bottom, initial steady progression is followed by acceleration.