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

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.

The Spectrum of Niemann-Pick Type C Disease in Greece

“…In our cohort of patients the mutation was also identified either in homozygosity or heterozygosity in three patients all with the variant filipin staining pattern. In homozygosity it was associated with the adult form of the disease in siblings #12 and #13, in good accordance with other studies (Ribeiro et al 2001;Stampfer et al 2013) whereas in heterozygosity with the missense mutation p.S940L(c.2819C>T) (Greer et al 1999) it was associated with juvenile onset of disease (Patient #11). Patient #14 was shown to be homozygous for the mutation IVS2+5G>A (c.190+5G>A) in the NPC2 gene.…”

“…Furthermore, 2 maternal first cousins of patient 14 are also reported to have died with clinical symptoms compatible with NPC disease. Also, only two siblings presented with an adult neurological onset, making the contribution of this disease form much lower than described in recent large cohorts from three countries (Jahnova et al 2014;Stampfer et al 2013;Imrie et al 2015). This strongly suggests decreased awareness regarding NPC among adult neurologists, which is in good agreement with probable underdiagnosis of mild and late-onset forms (Wassif et al 2016).…”

Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann–Pick disease type C in a retrospective study

“…The test can lead to non-conclusive results, particularly for adult and juvenile patients. NPC1 and NPC2 gene sequencing would appear in the current age to offer a less fallible means of testing, however it failed to identify 14% patients in a recent study [8] and many physicians still favour biochemical confirmation through the filipin test. Recently, the levels of two oxysterol molecules in plasma have been shown to have excellent specificity and sensitivity in differentiating NP-C patients from controls [9,10].…”

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

“…In the NPC murine model, an increase of two oxysterols, cholestane-3 b ,5 a ,6 b -triol (CT) and 7-ketocholesterol (7-KC), has been observed ( 8 ). This evidence was later confi rmed in NPC patients (8)(9)(10)(11)(12)(13), showing a correlation between the oxysterol profi le and the age of onset and severity of the disease ( 8,14 ). Moreover, CT specifi cally has been found to be increased in NPC disease compared with other lysosomal and neurodegenerative diseases ( 8 ).…”