scholarly journals Rare PSAP variants and possible interaction with GBA in REM sleep behavior disorder

2021 ◽  
Author(s):  
Yuri L. Sosero ◽  
Eric Yu ◽  
Mehrdad A. Estiar ◽  
Kheireddin Mufti ◽  
Uladzislau Rudakou ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Genetic Interaction ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Motor Dysfunction ◽  
Clinical Markers ◽  
Loss Of Function ◽  
Sleep Behavior ◽  
Saposin C

PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. Since GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy, we examined the role of PSAP mutations in iRBD. We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p=0.018). Two variants were stop mutations, p.Gln260Ter p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria was 98% or more. These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

scholarly journals Motor Dysfunction in REM Sleep Behavior Disorder: A Rehabilitation Framework for Prodromal Synucleinopathy

2021 ◽  
pp. 154596832110112
Author(s):  
Rebekah L. S. Summers ◽  
Miriam R. Rafferty ◽  
Michael J. Howell ◽  
Colum D. MacKinnon
Keyword(s):  
Rem Sleep ◽  
Motor System ◽  
Clinical Care ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Sleep Behavior ◽  
Early Exercise ◽  
Extrapyramidal Signs

Parkinson disease (PD) and other related diseases with α-synuclein pathology are associated with a long prodromal or preclinical stage of disease. Predictive models based on diagnosis of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) make it possible to identify people in the prodromal stage of synucleinopathy who have a high probability of future disease and provide an opportunity to implement neuroprotective therapies. However, rehabilitation providers may be unaware of iRBD and the motor abnormalities that indicate early motor system dysfunction related to α-synuclein pathology. Furthermore, there is no existing rehabilitation framework to guide early interventions for people with iRBD. The purpose of this work is to (1) review extrapyramidal signs of motor system dysfunction in people with iRBD and (2) propose a framework for early protective or preventive therapies in prodromal synucleinopathy using iRBD as a predictive marker. Longitudinal and cross-sectional studies indicate that the earliest emerging motor deficits in iRBD are bradykinesia, deficits performing activities of daily living, and abnormalities in speech, gait, and posture. These deficits may emerge up to 12 years before a diagnosis of synucleinopathy. The proposed rehabilitation framework for iRBD includes early exercise-based interventions of aerobic exercise, progressive resistance training, and multimodal exercise with rehabilitation consultations to address exercise prescription, progression, and monitoring. This rehabilitation framework may be used to implement neuroprotective, multidisciplinary, and proactive clinical care in people with a high likelihood of conversion to PD, dementia with Lewy bodies, or multiple systems atrophy.

scholarly journals A comprehensive analysis of dominant and recessive parkinsonism genes in REM sleep behavior disorder

2020 ◽  
Author(s):  
Kheireddin Mufti ◽  
Uladzislau Rudakou ◽  
Eric Yu ◽  
Jennifer A. Ruskey ◽  
Farnaz Asayesh ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Copy Number Variants ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
European Ancestry ◽  
Compound Heterozygous ◽  
Sleep Behavior ◽  
Targeted Next Generation Sequencing ◽  
Variants Of Unknown Significance

AbstractObjectiveTo examine the role of autosomal dominant (AD) and recessive (AR) Parkinsonism genes in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).MethodsTen genes implicated in AD and AR Parkinsonism were fully sequenced using targeted next-generation sequencing in 1,039 iRBD patients and 1,852 controls of European ancestry. These include the AR genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7 and PLA2G6, and the AD genes LRRK2, GCH1 and VPS35. To examine the role of rare heterozygous variants in these genes, burden test and SKAT-O analyses were performed. The contribution of homozygous and compound heterozygous variants was further examined in the AR genes. Copy number variants (CNVs) in PRKN were tested in a subset of samples (n=374) using multiplex ligation-dependent probe amplification followed by analysis of all samples using ExomeDepth.ResultsWe found no association between rare heterozygous variants in the tested genes and risk for iRBD. Several homozygous and compound heterozygous carriers were identified with variants of unknown significance, yet there was no overrepresentation in iRBD patients versus controls.ConclusionOur results do not support a major role for variants in PRKN, PARK7, PINK1, VPS13C, ATP13A2, FBXO7, PLA2G6, LRRK2, GCH1 and VPS35 in the risk of iRBD.

scholarly journals The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

2016 ◽  
Vol 43 ◽  
pp. 180.e7-180.e13 ◽  
Author(s):  
Ziv Gan-Or ◽  
Noreen Mohsin ◽  
Simon L. Girard ◽  
Jacques Y. Montplaisir ◽  
Amirthagowri Ambalavanan ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Rem Sleep ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Sleep Behavior

Differential diagnosis of sporadic adult-onset ataxia: The role of REM sleep behavior disorder

2015 ◽  
Vol 21 (6) ◽  
pp. 640-643 ◽  
Author(s):  
Hélio A.G. Teive ◽  
Walter O. Arruda ◽  
Adriana Moro ◽  
Mariana Moscovich ◽  
Renato P. Munhoz
Keyword(s):  
Differential Diagnosis ◽  
Rem Sleep ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Adult Onset ◽  
Sleep Behavior

scholarly journals GBA variants in REM sleep behavior disorder

Neurology ◽  
2020 ◽  
Vol 95 (8) ◽  
pp. e1008-e1016 ◽  
Author(s):  
Lynne Krohn ◽  
Jennifer A. Ruskey ◽  
Uladzislau Rudakou ◽  
Etienne Leveille ◽  
Farnaz Asayesh ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Sanger Sequencing ◽  
Age At Onset ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Sleep Behavior ◽  
Conversion Rates ◽  
Molecular Inversion Probes ◽  
Healthy Carriers

ObjectiveTo study the role of GBA variants in the risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.MethodsA total of 4,147 individuals were included: 1,061 patients with iRBD and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk of iRBD, age at onset (AAO), and conversion rates.ResultsGBA variants were found in 9.5% of patients with iRBD compared to 4.1% of controls (odds ratio, 2.45; 95% confidence interval [CI], 1.87–3.22; p = 1 × 10−10). The estimated OR for mild p.N370S variant carriers was 3.69 (95% CI, 1.90–7.14; p = 3.5 × 10−5), while for severe variant carriers it was 17.55 (95% CI, 2.11–145.9; p = 0.0015). Carriers of severe GBA variants had an average AAO of 52.8 years, 7–8 years earlier than those with mild variants or noncarriers (p = 0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% of noncarriers (p = 0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be interpreted with caution.ConclusionsGBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.

The role of REM sleep without atonia in the diagnosis of REM sleep behavior disorder: past errors and new challenges

2014 ◽  
Vol 15 (9) ◽  
pp. 1007-1008 ◽  
Author(s):  
Raffaele Ferri ◽  
Maria Livia Fantini ◽  
Carlos H. Schenck
Keyword(s):  
Rem Sleep ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Sleep Behavior ◽  
Rem Sleep Without Atonia ◽  
New Challenges

The role of tissue biopsy as a biomarker in REM sleep behavior disorder

2020 ◽  
Vol 51 ◽  
pp. 101283
Author(s):  
Jennifer Zitser ◽  
Christopher Gibbons ◽  
Mitchell G. Miglis
Keyword(s):  
Rem Sleep ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Sleep Behavior ◽  
Tissue Biopsy
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