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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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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.
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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.

Mentions: As the early diagnosis and start of treatment is believed to benefit treatment outcome in NP-C [8-10], we determined the manifestation of selected neuropsychiatric signs relative to the time point of diagnosis (Figure 4). Notably, once symptoms considered as typical for NP-C were observed in a patient, the delay until diagnosis was short (mean delay from manifestation to diagnosis: VSGP -1.4±0.7 y, cataplexy 0.3±1.0 y, dysarthria 0.0±0.7 y). This indicated that the presence of such “classical” NP-C symptoms either succesfully initiates the right path to diagnosis, or that these signs are recognized immediately following the diagnosis NP-C in a patient. By contrast, delay from onset to diagnosis was long for less specific neuropsychiatric signs affecting cognition and coordination that in the vast majority of patients (>79%; Additional file 5: Table S1) was noticed considerably more early during disease course (e.g., clumsiness (-4.9±1.1 y), cognitive impairment (-3.6±1.1 y), impaired fine motor skills (-2.2±0.9 y), balance problems (-1.4±1.1 y) (Figure 4). These findings strongly propose that less specific neuropsychiatric signs are frequent and early indicators of NP-C, and that raising the awareness of this may help to substantially reduce the timespan until a patient is diagnosed.


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)

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

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

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.
Mentions: As the early diagnosis and start of treatment is believed to benefit treatment outcome in NP-C [8-10], we determined the manifestation of selected neuropsychiatric signs relative to the time point of diagnosis (Figure 4). Notably, once symptoms considered as typical for NP-C were observed in a patient, the delay until diagnosis was short (mean delay from manifestation to diagnosis: VSGP -1.4±0.7 y, cataplexy 0.3±1.0 y, dysarthria 0.0±0.7 y). This indicated that the presence of such “classical” NP-C symptoms either succesfully initiates the right path to diagnosis, or that these signs are recognized immediately following the diagnosis NP-C in a patient. By contrast, delay from onset to diagnosis was long for less specific neuropsychiatric signs affecting cognition and coordination that in the vast majority of patients (>79%; Additional file 5: Table S1) was noticed considerably more early during disease course (e.g., clumsiness (-4.9±1.1 y), cognitive impairment (-3.6±1.1 y), impaired fine motor skills (-2.2±0.9 y), balance problems (-1.4±1.1 y) (Figure 4). These findings strongly propose that less specific neuropsychiatric signs are frequent and early indicators of NP-C, and that raising the awareness of this may help to substantially reduce the timespan until a patient is diagnosed.

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