The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease

Hendriksz, Christian J.; Anheim, Mathieu; Bauer, Péter; Bonnot, Olivier; Chakrapani, Anupam; Corvol, Jean‐Christophe; Koning, Tomas J. De; Degtyareva, Anna; Dionisi‐Vici, Carlo; Doss, Sarah; Duning, Thomas; Giunti, Paola; Iodice, Rosa; Johnston, Tracy; Kelly, Dierdre; Klünemann, Hans-Hermann; Lorenzl, Stefan; Padovani, Alessandro; Pocovı́, Miguel; Synofzik, Matthis; Terblanche, Alta J.; Bergh, Florian Then; Topçu, Meral; Tranchant, Christine; Walterfang, Mark; Velten, Christian; Kolb, Stefan

doi:10.1080/03007995.2017.1294054

Cited by 27 publications

(22 citation statements)

References 198 publications

(401 reference statements)

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“…Because of reports suggesting changes in body and spleen weights (correlated with inflammatory signals), and the development of frailty in age-related dementias, such as AD [ 35 , 78 , 81 , 96 , 106 ], we evaluated the impact of stroke on these physiological parameters in aged hAPP-SL mice. However, we did not detect a significant difference in the body weights of both the stroke- and sham-operated hAPP-SL mice at pre- and post-surgery timepoints (Fig.…”

Section: Resultsmentioning

confidence: 99%

Alzheimer’s associated amyloid and tau deposition co-localizes with a homeostatic myelin repair pathway in two mouse models of post-stroke mixed dementia

Nguyen

Hayes

Zbesko

et al. 2018

acta neuropathol commun

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The goal of this study was to determine the chronic impact of stroke on the manifestation of Alzheimer’s disease (AD) related pathology and behavioral impairments in mice. To accomplish this goal, we used two distinct models. First, we experimentally induced ischemic stroke in aged wildtype (wt) C57BL/6 mice to determine if stroke leads to the manifestation of AD-associated pathological β-amyloid (Aβ) and tau in aged versus young adult wt mice. Second, we utilized a transgenic (Tg) mouse model of AD (hAPP-SL) to determine if stroke leads to the worsening of pre-existing AD pathology, as well as the development of pathology in brain regions not typically expressed in AD Tg mice. In the wt mice, there was delayed motor recovery and an accelerated development of cognitive deficits in aged mice compared to young adult mice following stroke. This corresponded with increased brain atrophy, increased cholinergic degeneration, and a focal increase of Aβ in areas of axonal degeneration in the ipsilateral hemisphere of the aged animals. By contrast, in the hAPP-SL mice, we found that ischemia induced aggravated behavioral deficits in conjunction with a global increase in Aβ, tau, and cholinergic pathology compared to hAPP-SL mice that underwent a sham stroke procedure. With regard to a potential mechanism, in both models, we found that the stroke-induced Aβ and tau deposits co-localized with increased levels of β-secretase 1 (BACE1), along with its substrate, neuregulin 1 (NGR1) type III, both of which are proteins integral for myelin repair. Based on these findings, we propose that the chronic sequelae of stroke may be ratcheting-up a myelin repair pathway, and that the consequent increase in BACE1 could be causing an inadvertent cleavage of its alternative substrate, AβPP, resulting in greater Aβ seeding and pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Alzheimer’s associated amyloid and tau deposition co-localizes with a homeostatic myelin repair pathway in two mouse models of post-stroke mixed dementia

Nguyen

Hayes

Zbesko

et al. 2018

acta neuropathol commun

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“… The clinical manifestations of NP-C may be nonspecific (e.g., ataxia), implying that patients with NP-C may be “hidden” within larger at-risk clinical patient cohorts, termed here and elsewhere 14 as clinical niches, who also present with nonspecific signs and symptoms. 14 NP-C should therefore be considered as a differential diagnosis for patients in these at-risk groups. We defined several at-risk clinical patient groups, detailed below and summarized in table 1 .…”

Section: Differential Diagnosis and Initial Detectionmentioning

confidence: 99%

“…Increased availability of next-generation sequencing (NGS) (e.g., phenotype-specific gene panels 13 ) may widen the application of genetic testing in clinical practice, particularly in at-risk patient cohorts. 14 …”

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confidence: 99%

Recommendations for the detection and diagnosis of Niemann-Pick disease type C

et al. 2017

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Purpose of review:Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice.Recent findings:New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C. Most diagnoses can now be confirmed by combination of biomarker and genetic analyses. Filipin staining may facilitate diagnosis in uncertain cases. Recommendations are provided for psychiatrists, neuro-ophthalmologists, and radiologists, and on screening within specific at-risk patient cohorts. The NP-C diagnostic algorithm has been updated and simplified.Summary:This publication provides expert recommendations for clinicians who may see patients presenting with the signs and symptoms of NP-C, including general practitioners, pediatricians, neurologists, and psychiatrists.

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“…Future studies could investigate the utility of eye tracking data to screen for NP-C in populations of patients that present with symptoms that are associated NP-C, for example, in patients with early-onset ataxia and / or frontotemporal dementia. It is thought that NP-C may be undiagnosed in some patient groups that display symptoms associated with NP-C, but where the symptoms are not diagnostic on their own [26][27][28] . Eye-tracking measures could contribute to identify those patients that warrant further follow-up investigation.…”

Section: Discussionmentioning

confidence: 99%

Oculomotor abnormalities in children with Niemann-Pick type C

Blundell

Frisson

Chakrapani

et al. 2018

Molecular Genetics and Metabolism

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Niemann-Pick type C (NP-C) is a rare recessive disorder associated with progressive supranuclear gaze palsy. Degeneration occurs initially for vertical saccades and later for horizontal saccades. There are studies of oculomotor degeneration in adult NP-C patients [1, 2] but no comparable studies in children. We used high-resolution video-based eye tracking to record monocular vertical and horizontal eye movements in 2 neurological NP-C patients (children with clinically observable oculomotor abnormalities) and 3 pre-neurological NP-C patients (children without clinically observable oculomotor abnormalities). Saccade onset latency, saccade peak velocity and saccade curvature were compared to healthy controls (N=77). NP-C patients had selective impairments of vertical saccade peak velocity and vertical saccade curvature, with slower peak velocities and greater curvature. Changes were more pronounced in neurological than pre-neurological patients, showing that these measures are sensitive to disease progress, but abnormal curvature and slowed downward saccades were present in both groups, showing that eye-tracking can register disease-related changes before these are evident in a clinical exam. Both slowing, curvature and the detailed characteristics of the curvature we observed are predicted by the detailed characteristics of RIMLF population codes. Onset latencies were not different from healthy controls. High-resolution video-based eye tracking is a promising sensitive and objective method to measure NP-C disease severity and neurological onset. It may also help evaluate responses to therapeutic interventions.

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The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease

Abstract: Several clinical niches have been identified that harbor patients at increased risk of NP-C.

Cited by 27 publications

References 198 publications

Alzheimer’s associated amyloid and tau deposition co-localizes with a homeostatic myelin repair pathway in two mouse models of post-stroke mixed dementia

Alzheimer’s associated amyloid and tau deposition co-localizes with a homeostatic myelin repair pathway in two mouse models of post-stroke mixed dementia

Recommendations for the detection and diagnosis of Niemann-Pick disease type C

Oculomotor abnormalities in children with Niemann-Pick type C

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