Clinical and neurophysiological characteristics of heterozygous NPC1 carriers

Abstract Niemann‐Pick disease type C (NPC) is an uncommon lysosomal storage disorder, which is characterized neuropathologically by cholinergic dysfunction and presents clinically with a broad series of neurological signs and symptoms. NPC is inherited as an autosomal recessive trait, caused by muta...

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Main Authors: Alberto Benussi, Maria S. Cotelli, Valentina Cantoni, Valeria Bertasi, Marinella Turla, Andrea Dardis, Jessica Biasizzo, Rosa Manenti, Maria Cotelli, Alessandro Padovani, Barbara Borroni
Format: Article
Language:English
Published: Wiley 2019-09-01
Series:JIMD Reports
Subjects:
Online Access:https://doi.org/10.1002/jmd2.12059
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spelling doaj-9eb176230dde40e694e2e63d6ec831ee2020-11-25T02:32:42ZengWileyJIMD Reports2192-83122019-09-01491808810.1002/jmd2.12059Clinical and neurophysiological characteristics of heterozygous NPC1 carriersAlberto Benussi0Maria S. Cotelli1Valentina Cantoni2Valeria Bertasi3Marinella Turla4Andrea Dardis5Jessica Biasizzo6Rosa Manenti7Maria Cotelli8Alessandro Padovani9Barbara Borroni10Neurology Unit, Department of Clinical and Experimental Sciences University of Brescia Brescia ItalyNeurology Unit Valle Camonica Hospital Brescia ItalyNeurology Unit, Department of Clinical and Experimental Sciences University of Brescia Brescia ItalyNeurology Unit Valle Camonica Hospital Brescia ItalyNeurology Unit Valle Camonica Hospital Brescia ItalyUniversity Hospital “Santa Maria della Misericordia” Udine ItalyUniversity Hospital “Santa Maria della Misericordia” Udine ItalyIRCCS Istituto Centro San Giovanni di Dio Brescia ItalyIRCCS Istituto Centro San Giovanni di Dio Brescia ItalyNeurology Unit, Department of Clinical and Experimental Sciences University of Brescia Brescia ItalyNeurology Unit, Department of Clinical and Experimental Sciences University of Brescia Brescia ItalyAbstract Niemann‐Pick disease type C (NPC) is an uncommon lysosomal storage disorder, which is characterized neuropathologically by cholinergic dysfunction and presents clinically with a broad series of neurological signs and symptoms. NPC is inherited as an autosomal recessive trait, caused by mutations in the NPC1 or NPC2 genes. However, recent reports have raised concerns on heterozygous NPC1 gene mutation carriers, which historically have been considered as clinically unaffected, occasionally presenting with clinical parkinsonian syndromes or dementia. In the present study, we aimed at comprehensively assessing clinical, biochemical, and neurophysiological features in heterozygous NPC1 gene mutation carriers. We assessed cholinergic intracortical circuits with transcranial magnetic stimulation, executive functions and plasma oxysterol levels in two families comprising two monozygotic twins with a homozygous NPC1 p.P888S mutation, four patients with a compound heterozygous p.E451K and p.G992W mutation, 10 heterozygous NPC1 p.P888S carriers, 1 heterozygous NPC1 p.E451K carrier, and 11 noncarrier family members. We observed a significant impairment in cholinergic circuits, evaluated with short‐latency afferent inhibition (SAI), and executive abilities in homozygous/compound heterozygous patients and heterozygous asymptomatic NPC1 carriers, compared to noncarriers. Moreover, we reported a significant correlation between executive functions performances and both plasma oxysterol levels and neurophysiological parameters. These data suggest that heterozygous NPC1 carriers show subclinical deficits in cognition, possibly mediated by an impairment of cholinergic circuits, which in turn may mediate the onset of neurological disorders in a subset of patients.https://doi.org/10.1002/jmd2.12059acetylcholinecognitionexecutive functionsheterozygousNiemann‐Pick disease type Cshort latency afferent inhibition
collection DOAJ
language English
format Article
sources DOAJ
author Alberto Benussi
Maria S. Cotelli
Valentina Cantoni
Valeria Bertasi
Marinella Turla
Andrea Dardis
Jessica Biasizzo
Rosa Manenti
Maria Cotelli
Alessandro Padovani
Barbara Borroni
spellingShingle Alberto Benussi
Maria S. Cotelli
Valentina Cantoni
Valeria Bertasi
Marinella Turla
Andrea Dardis
Jessica Biasizzo
Rosa Manenti
Maria Cotelli
Alessandro Padovani
Barbara Borroni
Clinical and neurophysiological characteristics of heterozygous NPC1 carriers
JIMD Reports
acetylcholine
cognition
executive functions
heterozygous
Niemann‐Pick disease type C
short latency afferent inhibition
author_facet Alberto Benussi
Maria S. Cotelli
Valentina Cantoni
Valeria Bertasi
Marinella Turla
Andrea Dardis
Jessica Biasizzo
Rosa Manenti
Maria Cotelli
Alessandro Padovani
Barbara Borroni
author_sort Alberto Benussi
title Clinical and neurophysiological characteristics of heterozygous NPC1 carriers
title_short Clinical and neurophysiological characteristics of heterozygous NPC1 carriers
title_full Clinical and neurophysiological characteristics of heterozygous NPC1 carriers
title_fullStr Clinical and neurophysiological characteristics of heterozygous NPC1 carriers
title_full_unstemmed Clinical and neurophysiological characteristics of heterozygous NPC1 carriers
title_sort clinical and neurophysiological characteristics of heterozygous npc1 carriers
publisher Wiley
series JIMD Reports
issn 2192-8312
publishDate 2019-09-01
description Abstract Niemann‐Pick disease type C (NPC) is an uncommon lysosomal storage disorder, which is characterized neuropathologically by cholinergic dysfunction and presents clinically with a broad series of neurological signs and symptoms. NPC is inherited as an autosomal recessive trait, caused by mutations in the NPC1 or NPC2 genes. However, recent reports have raised concerns on heterozygous NPC1 gene mutation carriers, which historically have been considered as clinically unaffected, occasionally presenting with clinical parkinsonian syndromes or dementia. In the present study, we aimed at comprehensively assessing clinical, biochemical, and neurophysiological features in heterozygous NPC1 gene mutation carriers. We assessed cholinergic intracortical circuits with transcranial magnetic stimulation, executive functions and plasma oxysterol levels in two families comprising two monozygotic twins with a homozygous NPC1 p.P888S mutation, four patients with a compound heterozygous p.E451K and p.G992W mutation, 10 heterozygous NPC1 p.P888S carriers, 1 heterozygous NPC1 p.E451K carrier, and 11 noncarrier family members. We observed a significant impairment in cholinergic circuits, evaluated with short‐latency afferent inhibition (SAI), and executive abilities in homozygous/compound heterozygous patients and heterozygous asymptomatic NPC1 carriers, compared to noncarriers. Moreover, we reported a significant correlation between executive functions performances and both plasma oxysterol levels and neurophysiological parameters. These data suggest that heterozygous NPC1 carriers show subclinical deficits in cognition, possibly mediated by an impairment of cholinergic circuits, which in turn may mediate the onset of neurological disorders in a subset of patients.
topic acetylcholine
cognition
executive functions
heterozygous
Niemann‐Pick disease type C
short latency afferent inhibition
url https://doi.org/10.1002/jmd2.12059
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