Jin Hwangbo; Myung Jun Lee; Sang Jin Kim; Jae‑Hyeok Lee

doi:10.14802/jmd.22191

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Letter to the editor The Frequency of Korean Patients With Parkinson’s Disease Carrying GBA Mutations in a Subgroup With Age at Onset ≤ 55 Years Old: Jin Hwangbo¹, Myung Jun Lee^2,3, Sang Jin Kim⁴, Jae‑Hyeok Lee^1,3; Journal of Movement Disorders 2023;16(2):207-209.
DOI: https://doi.org/10.14802/jmd.22191
Published online: March 7, 2023

¹Department of Neurology, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea

²Department of Neurology, Pusan National University Hospital, Busan, Korea

³Department of Neurology, Pusan National University School of Medicine, Yangsan, Korea

⁴Department of Neurology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea

Corresponding author: Jae-Hyeok Lee, MD, PhD Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan 50612, Korea / Tel: +82-55-360-2453 / Fax: +82-55-360-2152 / E-mail: jhlee.neuro@pusan.ac.kr

• Received: November 3, 2022 • Revised: December 25, 2022 • Accepted: January 10, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Supplementary Material
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REFERENCES

Dear Editor,

Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), represent important genetic risk factors for Parkinson’s disease (PD) [1]. Patients with PD who carry GBA mutations (GBA-PD) have been reported to present an earlier age at onset, faster disease progression, and a greater occurrence of nonmotor symptoms than those without mutations.

The frequency of GBA-PD varies widely between ethnicities, with 7%–10% in most populations, and a relatively lower frequency has been reported in Asians [1]. However, there are few studies on the frequency of GBA-PD in Koreans. A previous study in Korean PD cohorts reported a frequency of 3.2%, which is much lower than the overall frequency [2].

The mean age at onset of GBA-PD is approximately 50–55 years, which is much earlier than that of patients without GBA mutations [1]. Thus, we postulated that a higher detection rate of GBA-PD can be achieved by screening for GBA mutations in a subgroup of patients with PD with earlier onset. We screened for GBA mutations in Korean patients with PD with onset at age 55 years or younger (≤ 55 years).

From April 2021 to April 2022, we recruited 134 patients fulfilling the Movement Disorder Society diagnostic criteria for PD [3] and whose age at onset was ≤ 55 years. Fourteen patients declined to participate. Therefore, 120 patients were enrolled in this study. The mean age of onset was 48.8 ± 5.5 years (range: 31–55 years). The entire GBA gene, including all 11 exons and intron‒exon boundaries, was sequenced using the long-range polymerase chain reaction approach to exclude amplification of its pseudogene. GBA mutations were annotated according to NM_000157.4 and NP_000148.2. GCase activity from fresh blood was assayed in 11 GBA-PD patients using the 4-methylumbelliferylβ-D-glucopyranoside leukocyte assay [4]. GCase activity was expressed as nanomoles of product per hour per milligram (nmol/h/mg) protein. The GCase activity of each GBA-PD patient and three healthy controls was simultaneously measured by a commercial testing laboratory, and the relative ratio (GCase_patient/GCase_controls) was calculated for consistency.

Among 120 patients with early-onset PD, 10 mutations were detected in 13 (10.83%) patients. Eight heterozygous mutations (p.L483P [n = 3, previously known as L444P], including Rec1 [p.L483P, p.A495P, p.V499V; n = 2 ], p.N227S [n = 2, N188S], p.F252I [n =2, F213I], p.N431S [n =1, N392S], p.R159W [n =1, R120W], p.S310G [n =1, S271G], p.D448H [n =1, D409H], c.115+1G>A [n =1, IVS2 + 1]) are known to be associated with Gaucher’s disease and PD and are classified as severe mutations for developing PD [5]. p.N431S (N392S) has already been reported in PD, but the significance of PD remains unknown. One novel variant (p.I442V) that is likely pathogenic was found to have unknown significance based on the American College of Medical Genetics and Genomics guidelines. None of the GBA mutations were homozygous or compound heterozygous. GCase activity was measured in 11 patients with GBA-PD (56.7 ± 18.5% of controls, range 38.4%–96.4%) and was found to be significantly lower in eight patients, approximately half the value measured in normal controls.

The clinical features of the patients with GBA-PD are summarized in Table 1. The mean age at onset was 49.9 ± 4.3 years (range: 43–55 years). The mean disease duration at the time of evaluation was 5.5 ± 4.1 years (range: 2–16 years). There was no significant difference in the mean age at onset, age at evaluation, disease duration, or sex between GBA-PD patients and GBA mutation noncarriers (Supplementary Table 1 in the online-only Data Supplement). The proportion of patients with a positive family history was higher in GBA-PD patients than in GBA mutation noncarriers (15.4% vs. 1.9%). Two patients developed overt dementia 4 and 10 years after onset. Of the 9 patients without dementia who underwent the Seoul neuropsychological screening battery, 8 patients showed mild cognitive impairment. Two other patients had concomitant psychosis prior to PD. Five patients experienced motor complications (3.1 ± 1.7 years after treatment, range: 2–6 years).

We found a higher frequency of GBA mutations among Korean PD patients with onset at age ≤ 55 years compared to a previous report that did not consider age. Recently, a similar frequency was observed in a multiethnic Asian cohort with early-onset PD [6]. We used an age cutoff of 55 years instead of the age criterion for early-onset PD, usually defined as disease onset before the age of 50 years. The incidence of PD was relatively low when the age of onset was limited to 50 years. When expanding the range to ≤ 55 years, the number of PD patients increased significantly [7]. Studies have also shown that the age at onset of GBA mutation carriers is typically in the mid-50s [1]. Therefore, screening for GBA mutations in a subgroup of PD with onset at age ≤ 55 years increased the detection rate in GBAPD patients.

Various GBA mutations were identified in this study. All known GBA mutations have been observed in patients with PD [5]. p.L483P and p.N227S mutations have been reported in diverse ethnic groups [5,6]. p.F252I and p.R159W are more prevalent in Asian populations [6]. The common European risk mutations, i.e., p.E365K (E326K), p.T408M (T369M), and p.N409S (N370K) [5,6] were not detected. The pathogenicity of GBA mutations is often classified as ‘severe’ or ‘mild’ based on the established risks reported for PD [5]. Eight of the nine known mutations in this study were classified as severe mutations, showing an odds ratio of 10–15 for developing PD [5]. Consistent with previous reports [1,4], we also observed lower leukocyte GCase activity, mostly in 1/3–2/3 of normal controls. Generally, patients with GBA-PD have a more severe disease course [1]. Although approximately half of the patients in this study reached significant milestones, including dementia and motor complications, it was difficult to determine the clinical trajectory of GBA-PD patients because of the small number of cases with different disease durations.

The frequency of GBA mutations in a subgroup with age onset ≤ 55 years is up to 10% in Korean patients with PD. GBA-PD is a candidate model for precision medicine in PD. Clinical trials have been in progress to target the GCase pathway [1]. Large-scale GBA gene screening in this subgroup with high prevalence can be used to establish a GBA-PD cohort for targeted therapies.

Supplementary Material

The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.22191.

Supplementary Table 1.

Comparisons between GBA-PD patients and non-carriers of GBA mutation

jmd-22191-Supplementary-Table-1.pdf

Notes

Ethics Statement

This study was approved by the Institutional Review Board of Pusan National University Yangsan Hospital (No. 05-2022-220), and informed consent was obtained in accordance with the recommendations of the Declaration of Helsinki.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This study was supported by the Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital (20-2022-008).

Author contributions

Conceptualization: Jae-Hyeok Lee. Data curation: Jin Hwangbo, Jae-Hyeok Lee. Funding acquisition: Jae-Hyeok Lee. Supervision: Jae-Hyeok Lee, Myung Jun Lee, Sang Jin Kim. Validation: Jae-Hyeok Lee, Jin Hwangbo. Writing—original draft: Jin Hwangbo. Writing—review & editing: Jae-Hyeok Lee, Myung Jun Lee, Sang Jin Kim.

Acknowledgments

We are grateful to Professor Chong Kun Cheon (Pusan National University Children’s Hospital) and Gu-Hwan Kim (Asan Medical Center) for helpful discussions and advice.

Table 1.

Clinical manifestations in GBA-PD patients

Patient number	GBA mutations	Sex	Age at onset (yr)	Disease duration (yr)	FHx.	H&Y stage	Neuropsychological assessment	Motor complications	GCase activity (%)
1	p.L483P	M	46	4	-	2.5	MCI	Y	57.4
2	p.L483P(Rec1)	F	43	16	-	3	PDD	Y	46.2
3	p.L483P(Rec1)	F	53	2	Y	1.5	SMI	-	38.4
4	p.N227S	F	52	7	-	2.5	MCI^*	-	39.3
5	p.N227S	M	53	4	-	2.5	MCI	Y	79.2
6	p.F252I	M	55	3	-	2	NE, not demented	-	NE
7	p.F252I	F	48	2	-	1.5	MCI	-	50.5
8	p.N431S	M	50	4	-	1.5	MCI	-	40.3
9	p.R159W	M	44	9	-	2.5	MCI	Y	71.3
10	p.S310G	M	55	5	-	2.5	PDD	-	96.4
11	p.D448H	F	46	3	Y	2.5	NE, not demented	Y	47.5
12	c.115+1G>A	M	55	2	-	2.5	MCI^*	-	NE
13	p.I442V	F	48	10	-	2	MCI	-	57.4

^* psychiatric disorders prior to Parkinson’s disease (PD).

GBA-PD, patients with PD who carry GBA mutations; M, male; F, female; FHx., family history; H&Y, Hoehn and Yahr stage; Y, present; MCI, mild cognitive impairment; SMI, subjective cognitive impairment; PDD, Parkinson’s disease dementia; NE, not evaluated.

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Clinicogenetic Characterization of Patients with PD and Heterozygous GBA1 Variants in an Indian Cohort
Sneha D Kamath, Vikram V. Holla, Prashant Phulpagar, Nitish Kamble, Ravi Yadav, Babylakshmi Muthusamy, Pramod Kumar Pal
Movement Disorders.2024; 39(3): 628. CrossRef



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