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Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson’s disease: mutational spectrum and clinical features

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

GBA variants are associated with increased risk and earlier onset of Parkinson’s disease (PD), and more rapid disease progression especially with “severe” variants typified by p.L483P. GBA mutation screening studies from South-East Asia, with > 650 million inhabitants of diverse ancestries, are very limited. We investigated the spectrum of GBA variants, and associated clinico-demographic features, in a multi-ethnic PD cohort in Malaysia. Patients (n = 496) were recruited from seven centres, primarily of Chinese (45%), Malay (37%), and Indian (13%) ethnicities. All GBA coding exons were screened using a next-generation sequencing-based PD gene panel and verified with Sanger sequencing. We identified 14 heterozygous GBA alleles consisting of altogether 17 missense variants (8 classified as pathogenic or likely pathogenic for PD) in 25 (5.0%) patients, with a substantially higher yield among early (< 50 years) vs. late-onset patients across all three ethnicities (9.1–13.2% vs. 1.0–3.2%). The most common variant was p.L483P (including RecNciI, n = 11, 2.2%), detected in all three ethnicities. Three novel variants/recombinant alleles of uncertain significance were found; p.P71L, p.L411P, and p.L15S(;)S16G(;)I20V. The common European risk variants, p.E365K, p.T408M, and p.N409S, were not detected. A severe disease course was noted in the majority of GBA-variant carriers, across a range of detected variants. We report a potentially novel observation of spine posture abnormalities in GBA-variant carriers. This represents the largest study on GBA variation from South-East Asia, and highlights that these populations, especially those with EOPD, would be relevant for studies including clinical trials targeting GBA pathways.

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All data generated or analyzed during this study are included in this published article and additional files. Further anonymised data from this published article are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by a grant awarded to AAA from the Ministry of Higher Education Malaysia (FRGS/1/2018/SKK08/UM/02/3). SYL and AHT are supported by the University of Malaya Parkinson’s Disease and Movement Disorder Research Program (PV035-2017). CK and KL are supported by the DFG (FOR2488). The authors gratefully acknowledge the patients for their consent and participation in this report, including publication of the videos. Gene panel testing was provided as an in-kind contribution from CENTOGENE, Rostock, Germany.

Funding

The Ministry of Higher Education Malaysia Fundamental Research Grant Scheme (FRGS/1/2018/SKK08/UM/02/3) and University of Malaya Parkinson’s Disease and Movement Disorders Research Program (PV035-2017).

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Authors and Affiliations

  1. Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Jia Lun Lim, Yi Wen Tay & Azlina Ahmad-Annuar

  2. The Mah Pooi Soo and Tan Chin Nam Centre for Parkinson’s and Related Disorders, University of Malaya, Kuala Lumpur, Malaysia

    Jia Lun Lim, Ai Huey Tan, Yi Wen Tay & Shen-Yang Lim

  3. Institute of Neurogenetics, University of Luebeck, Luebeck, Germany

    Katja Lohmann & Christine Klein

  4. Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Ai Huey Tan & Shen-Yang Lim

  5. Department of Medicine, Hospital Sultanah Nur Zahirah, Kuala Terengganu, Malaysia

    Khairul Azmi Ibrahim & Zariah Abdul Aziz

  6. Department of Neurology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia

    Ahmad Shahir Mawardi & Santhi Datuk Puvanarajah

  7. Island Hospital, Penang, Malaysia

    Thien Thien Lim

  8. Penang General Hospital, Penang, Malaysia

    Thien Thien Lim

  9. Department of Medicine and Clinical Research Centre, Hospital Seberang Jaya, Penang, Malaysia

    Irene Looi

  10. Department of Neurology, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia

    Joshua Chin Ern Ooi & Yuen Kang Chia

  11. Division of Neurosurgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Kalai Arasu Muthusamy

  12. Centogene AG, Am Strande 7, 18057, Rostock, Germany

    Peter Bauer & Arndt Rolfs

Authors
  1. Jia Lun Lim
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  2. Katja Lohmann
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  3. Ai Huey Tan
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  18. Shen-Yang Lim
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Contributions

Conceptualization: S-YL, AA-A, CK; Design: S-YL, AA-A; funding acquisition: AHT, AA-A, S-YL, CK; sample acquisition: S-YL, AHT, JLL, KAI, ZAA, ASM, SDP, TTL, IL, JCEO, YKC, KAM; laboratory investigations: JLL, YWT, AA-A, KL, PB; statistical analysis: JLL; manuscript preparation—writing of first draft: JLL, AAA, S-YL; manuscript preparation—review, critique and approval: all authors.

Corresponding authors

Correspondence to Azlina Ahmad-Annuar or Shen-Yang Lim.

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Conflict of interest

The authors have no conflict of interest.

Ethics approval

This study was approved by the University of Malaya Medical Research and Ethics Committee (MREC) and the Malaysian Ministry of Health National Medical Research Register (NMRR).

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Written informed consent was obtained from all participants included in this study.

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The participants have consented to the submission of video recordings to the journal.

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Supplementary Information

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MOESM1 (2 March 2010; aged 45 years, 9 years after PD diagnosis). 2.5 h post-levodopa. Moderate-to-severe generalized choreiform (although at times jerky) dyskinesias. The patient is able to walk well. Speech is moderately hypophonic (MP4 54,974 KB)

MOESM2 (3 September 2013). 2 h post-levodopa (ON-medication state). Disabling truncal extension dyskinesias requiring close supervision to stand and to walk; speech moderate-to-severely hypophonic (MP4 54,974 KB)

MOESM3 (5 May 2015). 1 h post-levodopa. Dyskinesias somewhat improved on low-dose clozapine treatment 25 mg bid (MP4 72,618 KB)

MOESM4 10 January 2014 (aged 50 years, 11 years after PD diagnosis). 2 h post-levodopa (ONmedication condition). Generalized dyskinesias including frequent truncal flexion movements, which contibute to him falling (MP4 82,650)

MOESM5 6 October 2020 (aged 71 years, 19 years after PD diagnosis). Speech is moderately slurred. There is a mild-to-moderate lean of the body to the right whilst seated. She has intermittent tremor in the upper limbs, more on the right (also an obvious dependent tremor when standing). She has difficulty obeying even simple verbal and gestural commands to hold both arms outstretched or to perform finger-to-nose testing (not shown). She requires two-person assistance to stand and to take a few small steps (MP4 90,598 KB)

MOESM6 4 September 2009 (aged 54 years, 18 years after PD diagnosis). ON-medication and ONDBS condition, during the course of a post-DBS Core Assessment Program for Surgical Interventional Therapies (CAPSIT) evaluation showing severe dysarthria and hypophonia, postural instability, and significant gait difficulty. Limb bradykinesia was however well-controlled (MP4 54,974 KB)

MOESM7 18 September 2020 (aged 61 years, 20 years or more after PD diagnosis). 3.5 h postlevodopa (OFF-medication state), with severe axial and appendicular parkinsonism. There is severe facial masking, speech is moderately hypophonic and slurred, and there is a moderate-to-severe stoop and body lean to the left. Movements are severely bradykinetic. Two-person assistance is needed to stand and to take a few very small steps (MP4 109,746 KB)

MOESM8 (21 October 2016; aged 59 years, 16 years after PD diagnosis). Patient complaining of stooped posture and lateral flexion of the trunk, which progressively worsens the longer she sits or stands, but mostly resolves upon lying down. This first developed two years prior (MP4 76,687 KB)

MOESM9 (18 Jan 2019). The abnormal posture has become more marked with camptocormia Pisa syndrome (with moderate lean of the trunk to the right). Her speech is still quite clear (MP4 51,315 KB)

Supplementary file10 (DOCX 154 KB)

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Lim, J.L., Lohmann, K., Tan, A.H. et al. Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson’s disease: mutational spectrum and clinical features. J Neural Transm 129, 37–48 (2022). https://doi.org/10.1007/s00702-021-02421-0

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