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

Stampfer M, Theiss S, Amraoui Y, Jiang X, Keller S, Ory DS, Mengel E, Fischer C, Runz H - Orphanet J Rare Dis (2013)

Bottom Line: The sequence of disease progression was re-constructed by a novel clinical outcome scale (NPC-cdb score).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany.

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.

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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).
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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).

Mentions: NP-C manifestation and course appeared to vary considerably within our cohort (Figure 1, Figure 2). Several scoring systems have been developed to monitor disease progression in NP-C [10,13,17,23]. However, none of the existing tools covered the comprehensive patient-specific clinical information available through NPC-cdb. Moreover, previous scales quantify deterioration or improvement within defined symptom domains, which necessitates complete evaluation of all such domains at each visit. To ease the acquisition and documentation of comprehensive longitudinal data, we therefore established a novel clinical outcome scale (NPC-cdb score). Unlike previous tools, the NPC-cdb score represents the sum of all past and current symptoms present in a patient at a given time point, with each symptom (as listed in Figure 5) contributing a severity-weighted summand (for guidelines on how to apply the NPC-cdb score, see Additional file 3). For 10 patients in which plasma oxysterol levels were measured at visits for which scoring could be performed, scores correlated well with mean 3β,5α,6β-triol and 7-KC levels, which supports the hypothesis that the NPC-cdb score is a reliable indicator of NP-C severity (Additional file 4: Figure S1).


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

Stampfer M, Theiss S, Amraoui Y, Jiang X, Keller S, Ory DS, Mengel E, Fischer C, Runz H - Orphanet J Rare Dis (2013)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3649939&req=5

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).
Mentions: NP-C manifestation and course appeared to vary considerably within our cohort (Figure 1, Figure 2). Several scoring systems have been developed to monitor disease progression in NP-C [10,13,17,23]. However, none of the existing tools covered the comprehensive patient-specific clinical information available through NPC-cdb. Moreover, previous scales quantify deterioration or improvement within defined symptom domains, which necessitates complete evaluation of all such domains at each visit. To ease the acquisition and documentation of comprehensive longitudinal data, we therefore established a novel clinical outcome scale (NPC-cdb score). Unlike previous tools, the NPC-cdb score represents the sum of all past and current symptoms present in a patient at a given time point, with each symptom (as listed in Figure 5) contributing a severity-weighted summand (for guidelines on how to apply the NPC-cdb score, see Additional file 3). For 10 patients in which plasma oxysterol levels were measured at visits for which scoring could be performed, scores correlated well with mean 3β,5α,6β-triol and 7-KC levels, which supports the hypothesis that the NPC-cdb score is a reliable indicator of NP-C severity (Additional file 4: Figure S1).

Bottom Line: The sequence of disease progression was re-constructed by a novel clinical outcome scale (NPC-cdb score).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany.

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.

Show MeSH
Related in: MedlinePlus