Genetics of progressive supranuclear palsy in a Chinese population

Xiao, Xuewen; Yang, Qingda; Wen, Yafei; Jiao, Bin; Liao, Xinxin; Zhou, Yifei; Weng, Ling; Liu, Hui; Xu, Tianyan; Zhu, Yuan; Guo, Lijia; Zhou, Lu; Wang, Xin; Liu, Xixi; Bi, Xiangyun; Liu, Yingzi; Zhang, Sizhe; Zhang, Weiwei; Li, Jinchen; Tang, Beisha; Shen, Lu

doi:10.1016/j.nbd.2022.105819

Cited by 4 publications

(6 citation statements)

References 57 publications

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“…However, none showed PD-suggestive features in the motor or non-motor domains (e.g., typical parkinsonian resting tremor, dramatic beneficial response to dopaminergic therapy, or levodopa-induced dyskinesias) [13], except for one patient harbouring a pathogenic GBA mutation (who had resting tremors, a history of RBD symptoms and visual hallucinations, as well as a supranuclear downgaze palsy - see Supplementary Video, Patient #18). Although mutations in GBA and SYNJ1 are listed as exclusionary in the MDS-PSP diagnostic scheme (due to their links with PD, as well as DLB in the case of GBA [3]), there is emerging research implicating GBA variants in PSP patients [14,15]. This is perhaps unsurprising, given their role in lysosomal dysfunction involved in various neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

Prospective Characterization of Progressive Supranuclear Palsy in a Multi-Ethnic Asian Cohort

Lim

Closas

Tan

et al. 2022

Preprint

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Background: Progressive supranuclear palsy (PSP) is a rare, disabling, neurodegenerative disease. There are limited studies on the spectrum of PSP predominance-types and their clinico-demographic features among Asian patients. We prospectively characterized the clinical features, disease severity, and caregiver burden in a multi-ethnic Asian PSP cohort. Methods: Consecutively-recruited patients with PSP (n=104, 64.4% male; 67.3% Chinese, 21.2% Indians, 9.6% Malays) were extensively phenotyped by a movement disorders neurologist using the MDS-PSP clinical diagnostic criteria and PSP-Clinical Deficits Scale (PSP-CDS). Caregiver burden was measured using the modified Zarit Burden Interview (ZBI). Investigations were reviewed to help rule out potential PSP mimics. Results: There were 104 patients, consisting of 48.1% Richardson syndrome (PSP-RS), 37.5% parkinsonian phenotype (PSP-P), and 10.6% progressive gait freezing phenotype (PSP-PGF). Mean age at motor onset was 66.3 ± 7.7 years, with no significant differences between the PSP phenotypes. Interestingly, REM-sleep behaviour disorder (RBD) symptoms and visual hallucinations (considered rare in PSP) were reported in 23.5% and 22.8% of patients, respectively, and a family history of possible neurodegenerative or movement disorder in 20.4%. PSP-CDS scores were highest (worst) in PSP-RS; and correlated moderately with disease duration (rs=0.45, P<0.001) and weakly with caregiver burden (rs=0.22, P=0.029) in the overall cohort. Three of 48 (6.3%) patients who had whole-exome sequencing harboured pathogenic/likely pathogenic GBA variants. Conclusions: This prospective characterization of a relatively large cohort of Asian PSP patients depicts significant heterogeneity in clinical features and disease burden. Unexpectedly high rates of RBD symptoms, visual hallucinations, and familial involvement warrant further study.

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Section: Discussionmentioning

confidence: 99%

Prospective Characterization of Progressive Supranuclear Palsy in a Multi-Ethnic Asian Cohort

Lim

Closas

Tan

et al. 2022

Preprint

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“…1,2 Although PSP is generally regarded as sporadic, there have long been reports of familial clustering with other cases of parkinsonism, 3 and there is increasing evidence implicating a role of genetic factors in both the sporadic and familial forms of PSP. 1,2,4,5 To date, more than 10 genes have been reported to be potentially associated with PSP, with some genetic overlap observed, particularly between PSP and frontotemporal dementia (FTD) and Parkinson's disease (PD). 1,2,4,5 These shared genes include MAPT, 1,2,6 LRRK2, 1,2,7 and possibly GBA1.…”

Section: Introductionmentioning

confidence: 99%

“…1,2,4,5 To date, more than 10 genes have been reported to be potentially associated with PSP, with some genetic overlap observed, particularly between PSP and frontotemporal dementia (FTD) and Parkinson's disease (PD). 1,2,4,5 These shared genes include MAPT, 1,2,6 LRRK2, 1,2,7 and possibly GBA1. 4,5,8 Heterozygous GBA1 variants are the most common genetic risk factor for PD worldwide, with increased odds ratios (ORs, ~1.4-30×) for the disease; 9 moreover, there are emerging reports suggesting their involvement in PSP.…”

Section: Introductionmentioning

confidence: 99%

“…1,2,4,5 These shared genes include MAPT, 1,2,6 LRRK2, 1,2,7 and possibly GBA1. 4,5,8 Heterozygous GBA1 variants are the most common genetic risk factor for PD worldwide, with increased odds ratios (ORs, ~1.4-30×) for the disease; 9 moreover, there are emerging reports suggesting their involvement in PSP. 4,5,8 Similar to GBA1, which encodes the lysosomal enzyme glucocerebrosidase, homozygous loss-of-function variants in SMPD1 resulting in deficiency of the lysosomal enzyme acid sphingomyelinase (ASMase) also cause recessive lysosomal lipid storage disorders (Gaucher's disease and Niemann-Pick disease type A/ B).…”

Section: Introductionmentioning

confidence: 99%

“…4,5,8 Heterozygous GBA1 variants are the most common genetic risk factor for PD worldwide, with increased odds ratios (ORs, ~1.4-30×) for the disease; 9 moreover, there are emerging reports suggesting their involvement in PSP. 4,5,8 Similar to GBA1, which encodes the lysosomal enzyme glucocerebrosidase, homozygous loss-of-function variants in SMPD1 resulting in deficiency of the lysosomal enzyme acid sphingomyelinase (ASMase) also cause recessive lysosomal lipid storage disorders (Gaucher's disease and Niemann-Pick disease type A/ B). 9 Niemann-Pick disease type C, another closely related autosomal recessive lipid storage disorder, presents with adult-onset neurological manifestations, including parkinsonism, supranuclear gaze palsy, and cognitive-behavioral deficits and is recognized as a PSP mimic.…”

Section: Introductionmentioning

confidence: 99%

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Loss-of-Function Variant in the SMPD1 Gene in Progressive Supranuclear Palsy-Richardson Syndrome Patients of Chinese Ancestry

Lim,

Tan,

Foo

et al. 2024

JMD

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Lysosomal dysfunction plays an important role in neurodegenerative diseases, including Parkinson’s disease (PD) and possibly Parkinson-plus syndromes such as progressive supranuclear palsy (PSP). This role is exemplified by the involvement of variants in the GBA1 gene, which results in a deficiency of the lysosomal enzyme glucocerebrosidase and is the most frequently identified genetic factor underlying PD worldwide. Pathogenic variants in the SMPD1 gene are a recessive cause of Niemann–Pick disease types A and B. Here, we provide the first report on an association between a loss-of-function variant in the SMPD1 gene present in a heterozygous state (p.Pro332Arg/p.P332R, which is known to result in reduced lysosomal acid sphingomyelinase activity), with PSP-Richardson syndrome in three unrelated patients of Chinese ancestry.

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Identification of Genetic Variants in Progressive Supranuclear Palsy in Southeast Asia

Ng,

Tan,

Tan

et al. 2024

Movement Disorders

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BackgroundProgressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome‐wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations.ObjectivesOur goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients.MethodsNext‐generation sequencing (whole‐exome, whole‐genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients.ResultsWe identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7—genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN.ConclusionsThe genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society.

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Genetics of progressive supranuclear palsy in a Chinese population

Cited by 4 publications

References 57 publications

Prospective Characterization of Progressive Supranuclear Palsy in a Multi-Ethnic Asian Cohort

Prospective Characterization of Progressive Supranuclear Palsy in a Multi-Ethnic Asian Cohort

Loss-of-Function Variant in the SMPD1 Gene in Progressive Supranuclear Palsy-Richardson Syndrome Patients of Chinese Ancestry

Identification of Genetic Variants in Progressive Supranuclear Palsy in Southeast Asia

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