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LETTER TO THE EDITOR |
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| Ahead of print
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| A patient with Parkinson’s disease carrying a rare variant in the kinase domain of LRRK2 |
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Halil Onder1, Vehap Topcu2, Selcuk Comoglu1
1 Neurology Clinic, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
2 Medical Genetics, Ankara City Hospital, Ankara, Turkey
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| Date of Submission | 01-Apr-2022 |
| Date of Decision | 01-Aug-2022 |
| Date of Acceptance | 20-Aug-2022 |
| Date of Web Publication | 31-Jan-2023 |
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How to cite this URL:
Onder H, Topcu V, Comoglu S. A patient with Parkinson’s disease carrying a rare variant in the kinase domain of LRRK2. Ann Mov Disord [Epub ahead of print] [cited 2023 Mar 23]. Available from: https://www.aomd.in/preprintarticle.asp?id=368613 |
A 47-year-old male patient visited our outpatient polyclinic for modification of Parkinson’s disease (PD) therapy. The patient had presented with slowness of movement and shaking of his right hand that had started insidiously and progressively worsened over the past 8 years. He was on levodopa/benserazide 100 mg 4 times a day, pramipexole 1.5 mg, and rasagiline 1 mg once daily. He had no constipation or rapid eye movement sleep behavior disorder. However, he had been suffering from anosmia for many years. Interrogation of his medical history revealed that his uncle had also been diagnosed with PD, which had started in his 60s [Figure 1]. A neurological exam showed severely disabling resting tremor in his right hand and generalized slowness of movements, which was more prominent on the right side. The patient was evaluated as being at stage 3 on the Modified Hoehn and Yahr scale. The Movement Disorder Society–Sponsored Revision of the Unified Parkinson’s Disease Rating Scale part III score during the “off” condition was 40 points (after overnight therapy withdrawal), and it was 18 points at the “best on condition.” The levodopa/benserazide dose was increased to 150/37.5 mg 4 times a day, and the pramipexole dose was increased to a daily dosage of 3 mg. After 2 weeks on these doses, substantial improvement was achieved in the patient’s clinical course and daily activities. Slight orofacial and right arm peak-dose dyskinesias were observed in the “on” condition, which did not disturb the patient. A detailed investigation revealed mild compulsive behaviors and increment in sexual drive after the increase in dosages. Therefore, pramipexole was decreased to 2.25 mg, which provided relief from these symptoms. Whole exome sequencing yielded a heterozygote novel missense variant in exon 43 of the leucine-rich repeat kinase 2 (LRRK2; c.6304G>A:p.Ala2102Thr), a susceptibility gene for PD. This variant was classified as a variant of uncertain significance according to the ACMG/AMP 2015 guidelines, applying PM1, PM2, and BP4 criteria. To classify this variant as needed, a familial segregation study was suggested. However, the family did not agree to further investigations. The Ala2102Thr variant was located in a protein kinase domain (PM1) and was absent (PM2) in the gnomAD database. Although the Ala2102 position is not a highly conserved position, this variant has occurred in the kinase domain of the LRRK2 protein (dardarin) and is extremely rare (never reported in gnomAD). We suggest a contributory role of the Ala2102Thr variant in the disease course and consider this patient as having LRKK2-related PD. | Figure 1: III, Case 3 is our index case (47-year-old male patient). II, Case 4 is the uncle of the index patient (a 75-year-old male patient) who was diagnosed with Parkinson’s disease at the age of 60 years. Genetic investigation for this patient is unavailable.
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| Discussion | |  |
In a small percentage of PD patients, the disease may be hereditary. Mutations in the parkin gene are the major cause of early-onset autosomal recessive PD.[1] On the other hand, LRRK2 (PARK8) mutations are the most frequent cause of autosomal dominant (AD) PD known to date.[2] Furthermore, the LRRK2 G2019S mutation is also found in 1% to 2% of apparently sporadic PD cases in Europe and North America.[2] Based on the high frequency of these mutations in PD patients of AD inheritance and the presence of this variant in sporadic PD cases, it is crucial to investigate LRRK2 mutations clinically. However, these mutations are rather uncommon in Turkey.[3] In a recent study including a sample of 91 patients with Parkinsonism compatible with AD inheritance, only 1 patient was found to harbor the LRRK2 G2019S mutation.[4] Of note, the authors reported 3 rare coding variants of unknown significance (LRRK2: A211V, R1067Q, T2494I).[4] They also identified the LRRK2 R1067Q variant as a possible pathogenic substitution in 1 family and emphasized that the unclassified variants of LRRK2 mutations demand further investigation in terms of functional studies and epidemiological investigations, with proper samples sizes and statistical methods.[4] We agree with the authors’ judgment and consider that the detection of an extremely rare variant (Ala2102Thr) in our patient is more than a coincidence; this merits attention and needs to be studied to illustrate the nature of rare variants in LRRK2-related PD. There is evidence that pathogenic LRRK2 variants exhibit incomplete and age-dependent penetrance. The reported age of disease onset for Gly2019Ser-associated LRRK2 PD is slightly lower than that for idiopathic PD,[5] and onset is frequently before the age of 40 years. However, clinical features may vary according to the variants, and another group has reported a higher mean age of disease onset (59.5 ± 6.6 years) in 4 PD patients with LRKK-2 mutation.[6] Therefore, the phenotype can vary according to the variant responsible. Supporting this view, whereas various studies indicate that cognitive changes are milder in LRRK2 PD,[5] some authors have reported lower cognitive assessment scores in patients with G2019S (c.6055G ˃A) mutations when compared with other PD patients.[6] The results of the neuropathology studies may also provide substantial contributions in this regard. Remarkably, in addition to typical Lewy-type pathology, nonspecific cell loss without protein aggregates, and abundant tau pathology, on rare occasions, TAR DNA-binding protein 43 (TDP43) aggregates have also been seen in LRRK2-related PD patients. It should be emphasized that various LRRK2 variants, including R1441C/G/H and N1437H in the ROC domain, Y1699C in the COR domain, and G2019S and I2020T in the kinase domain, are pathogenic.[7] However, the underlying pathological process may vary depending on the unique genomic variant responsible, even between family members with the same disease-causing variant.[8] In rodent models, it has been demonstrated that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity.[5] Genetic and biochemical data show that PD-linked pathogenic LRRK2 mutations cause a toxic gain-of-function increase in LRRK2 kinase activity.[8] However, the distinct mutations may result in various biochemical alterations, including alterations in vesicular trafficking, cytoskeleton dynamics, autophagy, lysosomal function, neurotransmission, and mitochondrial function.[8] Similar to the G2019S mutation, the gene variant that we found in this case is located in the kinase domain of LRRK2. Therefore, it is likely that this variant has the potential to disturb protein function, thus causing PD.
Reporting of novel variants in LRRK2 mutations may aid in a more precise understanding of unknown aspects of the inheritance pattern, factors affecting the penetrance, and the varying phenotypic features of LRKK2-related PD. This could, in turn, potentially aid in understanding the mechanisms underlying the pathogenic effects corresponding to mutations of distinct localizations in this gene. Therefore, we believe that the novel LRKK2 variant in our patient is an important finding to report. However, the main limitation is that neither causal association nor diagnostic certainty could be established, because genetic studies of the other affected family member (uncle) and unaffected family members could not be carried out. Future studies of the c.6304G>A:p.Ala2102Thr mutations in LRKK2-related PD patients could contribute substantially to overcoming the limitations of our study.
Acknowledgments
We thank our assistant doctors for their help during evaluation of this patient. We have no financial and material support to disclose for this report.
Authors’ contributions
Concept – H.O.; Design – H.O.; Supervision – S.C.; Materials – H.O, V.T., S.C.; Data Collection and/or Processing – H.O.; Analysis and/or Interpretation – HO., V.T., S.C.; Literature Search – H.O; Writing Manuscript – H.O. Critical Review – S.C.
Compliance with ethical standards
The manuscript has been prepared in accordance with Helsinki Declaration of Principles
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Klein C, Lohmann K. Parkinson disease(s): Is “Parkin disease” a distinct clinical entity? Neurology 2009;72:106-7.  |
| 2. | Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, et al A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005;365:415-6. |
| 3. | Hanagasi HA, Lohmann E, Dursun B, Honore A, Lesage S, Dogu O, et al LRRK2 mutations are uncommon in Turkey. Eur J Neurol 2011;18:e137. |
| 4. | Kessler C, Atasu B, Hanagasi H, Simon-Sanchez J, Hauser AK, Pak M, et al Role of LRRK2 and SNCA in autosomal dominant Parkinson’s disease in Turkey. Parkinsonism Relat Disord 2018;48:34-9. |
| 5. | Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, et al Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: A case-control study. Lancet Neurol 2008;7:583-90. |
| 6. | Lesage S, Leclere L, Lohmann E, Borg M, Ruberg M, Durr A, et al Frequency of the LRRK2 G2019S mutation in siblings with Parkinson’s disease. Neurodegener Dis 2007;4:195-8. |
| 7. | Islam MS, Moore DJ. Mechanisms of LRRK2-dependent neurodegeneration: Role of enzymatic activity and protein aggregation. Biochem Soc Trans 2017;45:163-72. |
| 8. | Tolosa E, Vila M, Klein C, Rascol O. LRRK2 in Parkinson disease: Challenges of clinical trials. Nat Rev Neurol 2020;16:97-107. |
Correspondence Address:
Halil Onder,
Neurology Clinic, Diskapi Yildirim Beyazit Training and Research Hospital, Şehit Ömer Halisdemir Street. No: 20 Altındag, Ankara
Turkey
 Source of Support: None, Conflict of Interest: None
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