Alteration of cortical excitability and its modulation by Miglustat in Niemann-Pick disease type C

Hassan, Shady Safwat; Trenado, Carlos; Elben, Saskia; Schnitzler, Alfons; Groiss, Stefan Jun

doi:10.1016/j.jocn.2017.10.011

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…ERT and SRT methods are approved for these diseases in Europe, United States, and other countries ( Beck, 2018 ). The previously described drug Zavesca ® is also used for the treatment of Niemann-Pick disease type C ( Hassan et al, 2018 ; Pineda et al, 2018 ) and GM1-gangliosidosis ( Deodato et al, 2017 ). It is worth mentioning that, similarly to TSD, early diagnosis is necessary for successful LSD therapy in order to prevent organ damage that aggravates the disease progression ( Wasserstein et al, 2018 ).…”

Section: Treatment Strategies For Lysosomal Storage Disordersmentioning

confidence: 99%

New Approaches to Tay-Sachs Disease Therapy

et al. 2018

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Tay-Sachs disease belongs to the group of autosomal-recessive lysosomal storage metabolic disorders. This disease is caused by β-hexosaminidase A (HexA) enzyme deficiency due to various mutations in α-subunit gene of this enzyme, resulting in GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Tay-Sachs disease is characterized by acute neurodegeneration preceded by activated microglia expansion, macrophage and astrocyte activation along with inflammatory mediator production. In most cases, the disease manifests itself during infancy, the “infantile form,” which characterizes the most severe disorders of the nervous system. The juvenile form, the symptoms of which appear in adolescence, and the most rare form with late onset of symptoms in adulthood are also described. The typical features of Tay-Sachs disease are muscle weakness, ataxia, speech, and mental disorders. Clinical symptom severity depends on residual HexA enzymatic activity associated with some mutations. Currently, Tay-Sachs disease treatment is based on symptom relief and, in case of the late-onset form, on the delay of progression. There are also clinical reports of substrate reduction therapy using miglustat and bone marrow or hematopoietic stem cell transplantation. At the development stage there are methods of Tay-Sachs disease gene therapy using adeno- or adeno-associated viruses as vectors for the delivery of cDNA encoding α and β HexA subunit genes. Effectiveness of this approach is evaluated in α or β HexA subunit defective model mice or Jacob sheep, in which Tay-Sachs disease arises spontaneously and is characterized by the same pathological features as in humans. This review discusses the possibilities of new therapeutic strategies in Tay-Sachs disease therapy aimed at preventing neurodegeneration and neuroinflammation.

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Section: Treatment Strategies For Lysosomal Storage Disordersmentioning

confidence: 99%

New Approaches to Tay-Sachs Disease Therapy

et al. 2018

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“…vs. healthy controls ( N = 22) 35 (25–57) yrs • TMS • Cog. function (MMSE, other) 1.0 (NA) yr • Improved LTP-like cortical plasticity • Improved short-latency afferent inhibition • Improved/stabilised movement Hassan et al (2017) [ 93 ] Single-pt. case report in a pt.…”

Section: Clinical Efficacy Studiesmentioning

confidence: 99%

“…However, the control population for this study was not well matched, and these findings should be interpreted with caution. In a further case report relating to longitudinal TMS evaluations during 15 months of miglustat therapy, cerebellar inhibition, TMS-derived short-latency afferent inhibition – a measure for cholinergic transmission – and short-interval intracortical facilitation – a marker for glutamatergic neurotransmission – both showed improvement during miglustat therapy [ 93 ].…”

Section: Clinical Efficacy Studiesmentioning

confidence: 99%

Miglustat in Niemann-Pick disease type C patients: a review

Pineda

Walterfang

Patterson

2018

Orphanet J Rare Dis

142

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ObjectiveNiemann-Pick disease type C (NP-C) is a rare, autosomal recessive, neurodegenerative disease associated with a wide variety of progressive neurological manifestations. Miglustat is indicated for the treatment of progressive neurological manifestations in both adults and children. Since approval in 2009 there has been a vast growth in clinical experience with miglustat. The effectiveness of miglustat has been assessed using a range of measures.MethodsComprehensive review of published data from studies of cellular neuropathological markers and structural neurological indices in the brain, clinical impairment/disability, specific clinical neurological manifestations, and patient survival.ResultsCranial diffusion tensor imaging and magnetic resonance spectroscopy studies have shown reduced levels of choline (a neurodegeneration marker), and choline/N-acetyl aspartate ratio (indicating increased neuronal viability) in the brain during up to 5 years of miglustat therapy, as well as a slowing of reductions in fractional anisotropy (an axonal/myelin integrity marker). A 2-year immunoassay study showed significant reductions in CSF-calbindin during treatment, indicating reduced cerebellar Purkinje cell loss. Magnetic resonance imaging studies have demonstrated a protective effect of miglustat on cerebellar and subcortical structure that correlated with clinical symptom severity. Numerous cohort studies assessing core neurological manifestations (impaired ambulation, manipulation, speech, swallowing, other) using NP-C disability scales indicate neurological stabilization over 2–8 years, with a trend for greater benefits in patients with older (non-infantile) age at neurological onset. A randomized controlled trial and several cohort studies have reported improvements or stabilization of saccadic eye movements during 1–5 years of therapy. Swallowing was also shown to improve/remain stable during the randomized trial (up to 2 years), as well as in long-term observational cohorts (up to 6 years). A meta-analysis of dysphagia – a potent risk factor for aspiration pneumonia and premature death in NP-C – demonstrated a survival benefit with miglustat due to improved/stabilized swallowing function.ConclusionsThe effects of miglustat on neurological NP-C manifestations has been assessed using a range of approaches, with benefits ranging from cellular changes in the brain through to visible clinical improvements and improved survival.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0844-0) contains supplementary material, which is available to authorized users.

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“…Neuropathologically, an interesting parallelism has been observed between NPC and Alzheimer's disease, with both disorders sharing pathological features as the aggregation of amyloid‐β and tau tangles . This resemblance transcends the pathological aspects of the disease to neurophysiological measures, with the impairment of long‐term dependent (LTP)‐like synaptic plasticity and cholinergic dysfunction observed in both disorders …”

Section: Introductionmentioning

confidence: 96%

“…8 This resemblance transcends the pathological aspects of the disease to neurophysiological measures, with the impairment of longterm dependent (LTP)-like synaptic plasticity and cholinergic dysfunction observed in both disorders. [9][10][11][12][13] Historically, NPC has been considered as an autosomal recessive disease; nevertheless, several reports have now shown that heterozygous NPC carriers harbor subclinical abnormalities in cholesterol metabolism [14][15][16] and in neuronal functions resulting in neurodegeneration. 17,18 Moreover, various heterozygous NPC mutations have been observed in patients with Parkinson's disease, 19,20 corticobasal syndrome and progressive supranuclear palsy.…”

Section: Introductionmentioning

confidence: 99%

Clinical and neurophysiological characteristics of heterozygous NPC1 carriers

Benussi

Cotelli²,

Cantoni

et al. 2019

JIMD Reports

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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.

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Alteration of cortical excitability and its modulation by Miglustat in Niemann-Pick disease type C

Cited by 7 publications

References 28 publications

New Approaches to Tay-Sachs Disease Therapy

New Approaches to Tay-Sachs Disease Therapy

Miglustat in Niemann-Pick disease type C patients: a review

Clinical and neurophysiological characteristics of heterozygous NPC1 carriers

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