Gaucher Disease and Parkinson's Dis

Gaucher Disease and Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, with greater than 1% affected over 65 years of age and more than 4% of the population affected by the age of 85 years [16, 17]. Research indicates that PD likely results from a combination of polygenic inheritance, environmental exposure, and gene-environment interactions. Approximately 20% of PD patients report a family history of the disease [17, 18]. Traditionally, PD has been defined by the presence of classic motor signs: rigidity, tremor, bradykinesia, and postural instability. However, recent evidence indicates that nonmotor characteristics such as autonomic insufficiency, cognitive impairment, olfactory deficits, psychosis, depression, and sleep disturbance are also common occurrences [17]. The first gene (SNCA, PARK1 locus) causally linked to PD was discovered via analysis of a large multigenerational Italian family in which parkinsonism segregated in an autosomal dominant pattern [19, 20]. Subsequently, a total of 18 PD loci (PARK 1-18) have been proposed through linkage analysis and genome-wide association studies [17]. Mutations within genes at six of these loci (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2) have been directly linked to familial parkinsonism [21]. Recently, specific variations in the Gaucher disease-associated gene GBA, which is not assigned to a PARK locus, have been suggested as risk factors for PD, as discussed below [22].

Over the past decade, several lines of evidence have emerged implicating an association between parkinsonism and mutations in the glucocerebrosidase gene. Recognition of the relationship between GBA mutations and PD initially began in the clinic, with the identification of rare Gaucher patients with parkinsonian symptoms appearing in case reports, larger patient series, and prospective studies [22]. Moreover, pedigree analyses indicated an elevated incidence of Parkinson's disease in relatives of Gaucher patients, many of whom were obligate heterozygotes [23, 24]. Additionally, multiple independent studies surfaced reporting an increased frequency of GBA mutations in different cohorts with parkinsonism [25, 26, 27, 28, 29, 30]. Despite this evidence, early studies were often constrained by small sample sizes or evaluation of only a few common GBA mutations [31], complicating a consensus to label GBA mutations as risk factors for typical Parkinson's disease. In 2009, Sidransky et al. [22] published a hallmark study on this topic: a collective analysis of 5691 patients with PD complemented by 4898 controls from 16 centers across 12 countries. For the pool of participants in which the full GBA coding region was screened, loss-of-function mutations were observed in 6.9% of cases and 1.3% of controls (odds ratio, 5.4; 95% CI, 3.9-7.6). Among the Ashkenazi Jewish subset, higher mutation frequencies were seen: 19.3% in cases and 4.1% in controls [17, 22]. The findings were not exclusive to a specific ethnicity, nor associated with any particular GBA mutation. Additional noted trends were: subjects carrying mutations presented an average of four years earlier, were more likely to have a family history of PD, and had less bradykinesia and rest tremor and more cognitive changes described [22]. Other cohort studies have corroborated the results from this collaborative examination, reinforcing mutations in GBA as the number one genetic risk factor for PD

Results (Indonesian) 1:

Gaucher penyakit dan penyakit ParkinsonParkinson's disease (PD) adalah gangguan neurodegeneratif kedua yang paling umum, dengan lebih dari 1% mempengaruhi lebih dari 65 tahun dan lebih dari 4% dari penduduk yang terkena dampak pada usia 85 tahun [16, 17]. Penelitian menunjukkan bahwa PD mungkin hasil dari kombinasi warisan polygenic, lingkungan dan interaksi gen-lingkungan. Sekitar 20% dari pasien PD laporan riwayat keluarga penyakit [17, 18]. Secara tradisional, PD telah ditetapkan oleh adanya tanda motor klasik: kekakuan, getaran, bradykinesia dan ketidakstabilan postural. Namun, bukti baru menunjukkan bahwa nonmotor karakteristik seperti insufisiensi otonom, kerusakan kognitif, defisit penciuman, psikosis, depresi, dan gangguan tidur juga sering terjadi [17]. Gen pertama (SNCA, PARK1 lokus) kausal terhubung ke PD ditemukan melalui analisis keluarga Italia multigenerational besar di mana Parkinsonisme terpisah dalam pola dominan autosomal [19, 20]. Selanjutnya, total 18 PD lokus (PARK 1-18) telah diajukan melalui hubungan analisis dan studi genom-lebar Asosiasi [17]. Mutasi dalam gen di enam dari lokus ini (SNCA, LRRK2, PRKN, DJ1, PINK1, dan ATP13A2) telah terhubung langsung ke keluarga Parkinsonisme [21]. Baru-baru ini spesifik variasi dalam gen terkait penyakit Gaucher GBA, yang tidak ditugaskan untuk lokus PARK, telah diusulkan sebagai faktor risiko untuk PD, seperti yang dibahas di bawah ini [22].Over the past decade, several lines of evidence have emerged implicating an association between parkinsonism and mutations in the glucocerebrosidase gene. Recognition of the relationship between GBA mutations and PD initially began in the clinic, with the identification of rare Gaucher patients with parkinsonian symptoms appearing in case reports, larger patient series, and prospective studies [22]. Moreover, pedigree analyses indicated an elevated incidence of Parkinson's disease in relatives of Gaucher patients, many of whom were obligate heterozygotes [23, 24]. Additionally, multiple independent studies surfaced reporting an increased frequency of GBA mutations in different cohorts with parkinsonism [25, 26, 27, 28, 29, 30]. Despite this evidence, early studies were often constrained by small sample sizes or evaluation of only a few common GBA mutations [31], complicating a consensus to label GBA mutations as risk factors for typical Parkinson's disease. In 2009, Sidransky et al. [22] published a hallmark study on this topic: a collective analysis of 5691 patients with PD complemented by 4898 controls from 16 centers across 12 countries. For the pool of participants in which the full GBA coding region was screened, loss-of-function mutations were observed in 6.9% of cases and 1.3% of controls (odds ratio, 5.4; 95% CI, 3.9-7.6). Among the Ashkenazi Jewish subset, higher mutation frequencies were seen: 19.3% in cases and 4.1% in controls [17, 22]. The findings were not exclusive to a specific ethnicity, nor associated with any particular GBA mutation. Additional noted trends were: subjects carrying mutations presented an average of four years earlier, were more likely to have a family history of PD, and had less bradykinesia and rest tremor and more cognitive changes described [22]. Other cohort studies have corroborated the results from this collaborative examination, reinforcing mutations in GBA as the number one genetic risk factor for PD

Results (Indonesian) 2:

Penyakit Gaucher dan Parkinson Penyakit

Parkinson Penyakit (PD) adalah gangguan neurodegeneratif yang paling umum kedua, dengan lebih dari 1% dipengaruhi lebih dari 65 tahun dan lebih dari 4% dari populasi dipengaruhi oleh usia 85 tahun [16, 17]. Penelitian menunjukkan bahwa PD kemungkinan hasil dari kombinasi warisan poligenik, paparan lingkungan, dan interaksi gen-lingkungan. Sekitar 20% dari pasien PD melaporkan riwayat keluarga penyakit [17, 18]. Secara tradisional, PD telah didefinisikan oleh kehadiran tanda-tanda klasik bermotor: kekakuan, tremor, bradikinesia, dan instabilitas postural. Namun, bukti terbaru menunjukkan bahwa karakteristik nonmotor seperti insufisiensi otonom, gangguan kognitif, defisit penciuman, psikosis, depresi, dan gangguan tidur juga kejadian umum [17]. Gen pertama (SPMB, park1 locus) kausal terkait dengan PD ditemukan melalui analisis dari keluarga Italia multigenerasi besar di mana parkinsonisme dipisahkan secara autosomal dominan pola [19, 20]. Selanjutnya, total 18 PD lokus (PARK 1-18) telah diusulkan melalui analisis linkage dan studi asosiasi genome [17]. Mutasi dalam gen pada enam lokus ini (SPMB, LRRK2, PRKN, DJ1, PINK1, dan ATP13A2) telah secara langsung terkait dengan parkinsonisme keluarga [21]. Baru-baru ini, variasi khusus di GBA gen Gaucher penyakit terkait, yang tidak ditugaskan untuk lokus PARK, telah diusulkan sebagai faktor risiko untuk PD, seperti dibahas di bawah [22].

Selama dekade terakhir, beberapa bukti telah muncul yang melibatkan hubungan antara parkinson dan mutasi pada gen glucocerebrosidase. Pengakuan dari hubungan antara mutasi GBA dan PD awalnya dimulai di klinik, dengan identifikasi pasien Gaucher langka dengan gejala parkinsonian muncul dalam laporan kasus, seri pasien yang lebih besar, dan studi prospektif [22]. Selain itu, silsilah analisis menunjukkan kejadian peningkatan penyakit Parkinson pada keluarga pasien Gaucher, banyak di antaranya adalah heterozigot wajib [23, 24]. Selain itu, beberapa studi independen muncul melaporkan peningkatan frekuensi mutasi GBA di kohort berbeda dengan parkinsonisme [25, 26, 27, 28, 29, 30]. Meskipun bukti ini, studi awal sering dibatasi oleh ukuran sampel yang kecil atau evaluasi dari hanya beberapa mutasi GBA umum [31], rumit konsensus untuk label mutasi GBA sebagai faktor risiko untuk penyakit khas Parkinson. Pada tahun 2009, Sidransky et al. [22] menerbitkan sebuah studi ciri tentang topik ini: analisis kolektif 5.691 pasien dengan PD dilengkapi dengan 4898 kontrol dari 16 pusat di 12 negara. Untuk kolam peserta di mana GBA wilayah coding penuh diputar, kehilangan-of-fungsi mutasi diamati pada 6,9% kasus dan 1,3% dari kontrol (rasio odds, 5,4; 95% CI, 3,9-7,6). Di antara Ashkenazi bagian Yahudi, frekuensi mutasi yang lebih tinggi terlihat: 19,3% dalam kasus dan 4,1% di kontrol [17, 22]. Temuan itu tidak eksklusif untuk etnis tertentu, atau terkait dengan mutasi GBA tertentu. Tren mencatat tambahan adalah: subyek membawa mutasi disajikan rata-rata empat tahun sebelumnya, lebih mungkin untuk memiliki riwayat keluarga PD, dan memiliki kurang bradikinesia dan tremor istirahat dan perubahan kognitif lebih dijelaskan [22]. Penelitian kohort lain telah dikuatkan hasil dari pemeriksaan kolaboratif, memperkuat mutasi di GBA sebagai nomor satu faktor risiko genetik untuk PD