Abstract
BackgroundThe 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.MethodsCurrent 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).ResultsThe 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.ConclusionsConsidering early, but less specific neuropsychiatric signs may accelerate the path to diagnosing NP-C in a patient.
Highlights
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
Generation of the NP-C clinical database (NPC-cdb) With the aim to establish a comprehensive repository (NPC-cdb) to store, share and analyze diagnostic and clinical findings in NP-C patients, we queried the literature for symptoms of direct and possible disease-relevance
Diagnostic findings in 42 patients support the heterogeneous nature of NP-C To test the applicability of NPC-cdb, we obtained diagnostic and longitudinal clinical findings from the majority of NP-C families in Germany and Switzerland
Summary
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. The variable clinical picture, manifestation at different ages and diverse patterns of disease progression may delay the diagnosis NP-C for several years. An early diagnosis necessitates a better understanding of which clinical signs occur early and at which sequence in the course of disease. This is true for neurological symptoms as the major determinant of disease progression [4] and response to treatment [8,9,10]. Due to the rarity of NP-C, individual studies typically miss the statistical power to allow for generalization of their respective findings
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