Clinico-genetic profile of seven patients with PARK-PINK1: A case series from a tertiary care centre from India and review of literature.

Background: Recessive variants in the PINK1 gene is a known cause of early-onset Parkinson's disease (EOPD). Objective: To describe the clinical features and genetic profile of patients of PARK-PINK1. Methods: Retrospective chart review of demographic, clinical and genetic details of patients carrying biallelic PINK1 variants from our database. Result: Seven cases were recruited with median age at onset 33 years (Range: 20-49). All had asymmetrical onset, tremor in four, abnormal posturing in two and slowness in one patient. Parkinsonism phenotype was noted in six patients (with dystonia in four) and isolated dystonia in one. Among 6 patients with parkinsonism, five had rest tremor, all had good levodopa-response, and four had motor-fluctuation with choreiform-dyskinesia. Exome-sequencing revealed bi-allelic pathogenic/likely pathogenic variants in all of which five were novel. Conclusion: PARK-PINK1 presents as an EOPD with tremor-predominant phenotype, good levodopa-responsiveness, early motor fluctuation and dyskinesia. We describe five novel variants in PINK1 gene.

The Clinical, Radiological and Genetic Spectrum of PLA2G6-Associated Neurodegeneration: An Experience From a Tertiary Center.

Background: Despite being the second most common type of neurodegeneration with brain iron accumulation, there is limited literature on PLA2G6-associated neurodegeneration (PLAN) within the Asian ethnicity, particularly in the Indian context. Methods: We conducted a retrospective observational study on patients with pathogenic/likely pathogenic PLA2G6 variants based on exome sequencing. Results: We identified 26 patients (22 families, 15 males) of genetically-confirmed PLAN with a median age of 22.5 years and age at onset of 13.0 years, encompassing various subtypes: infantile neuroaxonal dystrophy (5/26;19.2%), atypical neuroaxonal dystrophy (3/26;11.5%), dystonia-parkinsonism (5/26;19.2%), dystonia-parkinsonism-myoclonus (n = 4, 15.38%), early-onset Parkinson's disease (2/26;7.7%), complex dystonia (2/26;7.7%), and complicated hereditary spastic paraparesis (cHSP; 5/26;19.2%). The common initial symptoms included walking difficulty (7/26;26.9%), developmental regression (6/26;23.1%), and slowness (4/26;15.4%). Dystonia (14/26;53.8%), followed by parkinsonism (11/26; 42.3%), was the most common motor symptom. Non-motor symptoms included cognitive decline (12/26;46.2%) and behavioral changes (6/26;23.1%). Neuroimaging revealed cerebellar atrophy in 23/26 (88.5%) patients and claval hypertrophy in 80% (4/5) of INAD patients. Levodopa responsiveness was noted in 12 of 14 patients with parkinsonism/dystonia who received levodopa, and dyskinesia was noted in 10/11 patients. Genetic analysis revealed a total of 19 unique variants in PLA2G6 gene, of which 11 were novel. Twelve patients harbored the c.2222G>A variant, which is predominantly seen in Asian subpopulations. Conclusions: The study introduces 26 new patients of PLAN and 12 patients associated with the c.2222G>A variant, potentially forming the most extensive single center series to date. It also expands the phenotypic, neuroimaging, and genotypic spectrum of PLAN.

The Utility of Long-Read Sequencing in Diagnosing Genetic Autosomal Recessive Parkinson's Disease: a genetic screening study.

Background: Mutations within the genes PRKN and PINK1 are the leading cause of early onset autosomal recessive Parkinson's disease (PD). However, the genetic cause of most early-onset PD (EOPD) cases still remains unresolved. Long-read sequencing has successfully identified many pathogenic structural variants that cause disease, but this technology has not been widely applied to PD. We recently identified the genetic cause of EOPD in a pair of monozygotic twins by uncovering a complex structural variant that spans over 7 Mb, utilizing Oxford Nanopore Technologies (ONT) long-read sequencing. In this study, we aimed to expand on this and assess whether a second variant could be detected with ONT long-read sequencing in other unresolved EOPD cases reported to carry one heterozygous variant in PRKN or PINK1. Methods: ONT long-read sequencing was performed on patients with one reported PRKN/PINK1 pathogenic variant. EOPD patients with an age at onset younger than 50 were included in this study. As a positive control, we also included EOPD patients who had already been identified to carry two known PRKN pathogenic variants. Initial genetic testing was performed using either short-read targeted panel sequencing for single nucleotide variants and multiplex ligation-dependent probe amplification (MLPA) for copy number variants. Results: 48 patients were included in this study (PRKN "one-variant" n = 24, PINK1 "one-variant" n = 12, PRKN "two-variants" n = 12). Using ONT long-read sequencing, we detected a second pathogenic variant in six PRKN "one-variant" patients (26%, 6/23) but none in the PINK1 "one-variant" patients (0%, 0/12). Long-read sequencing identified one case with a complex inversion, two instances of structural variant overlap, and three cases of duplication. In addition, in the positive control PRKN "two-variants" group, we were able to identify both pathogenic variants in PRKN in all the patients (100%, 12/12). Conclusions: This data highlights that ONT long-read sequencing is a powerful tool to identify a pathogenic structural variant at the PRKN locus that is often missed by conventional methods. Therefore, for cases where conventional methods fail to detect a second variant for EOPD, long-read sequencing should be considered as an alternative and complementary approach.

Contribution of testosterone and estradiol in sexual dimorphism of early-onset Parkinson's disease.

Early-onset Parkinson's disease (EOPD) occurs during the fertile life, when circulating neuroactive sex hormones might enhance the sexual dimorphism of the disease. Here, we aimed to examine how sex hormones can contribute to sex differences in EOPD patients. A cohort of 34 EOPD patients, 20 males and 14 females, underwent comprehensive clinical evaluation of motor and non-motor disturbances. Blood levels of estradiol, total testosterone, follicle-stimulating hormone, and luteinizing hormone were measured in all patients and correlated to clinical features. We found that female patients exhibited greater non-motor symptoms and a relatively higher rate of dystonia than males. In females, lower estradiol levels accounted for higher MDS-UPDRS-II and III scores and more frequent motor complications, while lower testosterone levels were associated with a major occurrence of dystonia. In male patients, no significant correlations emerged. In conclusion, this study highlighted the relevance of sex hormone levels in the sexual dimorphism and unique phenotype of EOPD.

Empowering the management of early-onset Parkinsons' disease: The role of technology.

Early-onset Parkinson's disease (EOPD) is defined as PD with an age of onset after 21 years of age but before 50 years. It displays many important differences to late-onset PD in terms of its pathology, phenotype, presentation and disease course, all of which have consequences for achieving a definitive diagnosis, the choice of therapy and approach to management. Studies show that this younger population is keen to embrace digital technologies as part of PD care, being familiar with using digital tools in their daily lives. Although most of the literature relating to the use of technology in PD applies to the broad population, this review focuses on evidence and potential benefits of the use of digital technologies to support clinical management in EOPD as well as its value in empowering patients to achieve self-management and in improving their quality of life. Digital technologies also have important and increasing roles in providing telehealth, including rehabilitation strategies for motor and non-motor PD symptoms. EOPD is known to be associated with a higher risk of motor fluctuations, so technologies such as wearable sensors have a valuable role for monitoring symptoms, providing timely feedback, and informing treatment decisions. In addition, digital technologies allow easy provision and equitable access to education and networking opportunities that will enable patients to have a better understanding of their condition.

Reproductive life factors and estro-progestin exposure in women with early-onset Parkinson's disease compared to late-onset disease and controls: A retrospective cohort study.

BACKGROUND: Parkinson's disease (PD) is more common in men than women. Although hormonal factors may partially explain this difference, there are no studies evaluating reproductive life factors and exogenous estroprogestin exposure in women with Early Onset Parkinson Disease (EOPD). OBJECTIVE: To compare reproductive life factors and exogenous estroprogestin exposure among female patients with EOPD, late-onset Parkinson's disease (LOPD), and EOPD-matched unaffected controls. METHODS: We identified female patients with EOPD from 1989 to 2021, defining EOPD as PD with motor-symptoms onset before age 50 and LOPD as PD with motor onset after 50. We paired EOPD patients to age-matched, unaffected controls. We reviewed medical records to determine demographic characteristics, clinical history, and reported reproductive menopausal history (reviewing medical records). RESULTS: We included 87 EOPD patients, 84 LOPD patients, and 91 unaffected controls with information about reproductive life factors and exogenous estroprogestin exposure in their medical records. There were no significant differences in race, ethnicity, or BMI between the three groups. EOPD patients were more likely to have used hormonal contraception than LOPD patients (23/49 (47 %) vs 0/84 (0 %), p < 0.001). LOPD patients had higher numbers of pelvic surgeries (48/84 [57 %] in LOPD, 23/87 [26 %] in EOPD, p < 0.001) and higher usage of perimenopausal hormonal therapy (52/84 [62 %] in LOPD, 10/87 [11 %] in EOPD, p < 0.001) in LOPD than EOPD. CONCLUSIONS: Our study reports no significant difference in reproductive life factors and exogenous estroprogestin exposure between controls and EOPD patients, except for higher exposure to hormonal contraception in EOPD. There was no apparent difference in reproductive life factors and exogenous estroprogestin exposure between EOPD and LOPD patients. Our findings therefore do not observe that hormonal exposure is different between earlier onset of female EOPD compared to female LOPD patients, or between female EOPD patients and unaffected female controls.

Early-onset Parkinson's disease with mutations in both the PRKN gene and the APOB gene: A case report. / PRKNåŸºå› åˆå¹¶APOBåŸºå› çªå˜çš„æ—©å‘åž‹å¸•é‡‘æ£®ç— 1例.

The incidence rate of Parkinson's disease ranks the second among degenerative diseases of the nervous system, only lower than Alzheimer's disease. Early-onset Parkinson's disease (EPOD) refers to Parkinson's disease with initial symptoms appearing before the age of 50. EOPD is associated with certain genetic mutations and has distinct clinical features. This study reports a case of EOPD with mutations in both the PRKN and the APOB genes. The patient presented with the initial symptom of unstable walking at the age of 28, followed by bradykinesia, limb tremors, masked face, shuffling gait, and cogwheel rigidity in both upper limbs. The blood lipid test showed total cholesterol of 6.48 mmol/L and low-density lipoprotein cholesterol of 4.13 mmol/L. Genetic testing showed a deletion in exon 5 and a point mutation [c.850G>C(p.Gly284Arg)] in exon 7 of the PRKN gene, as well as a point mutation [c.10579C>T(p.Arg3527Trp)] in exon 26 of the APOB gene. Based on these clinical manifestations and examination results, the patient was diagnosed with EOPD. The compound heterozygous mutations in the PRKN gene, as well as the combined mutations in the PRKN and APOB genes, are both reported for the first time, expanding the spectrum of genetic mutations associated with EOPD.

Impulse control disorders and use of dopamine agonists in early onset Parkinson's disease.

Introduction: Impulse control disorders (ICDs) are defined as excessive and repetitive behaviors that may affect Parkinson's disease (PD) patients exposed to dopamine agonists. Current data on ICDs in patients with early-onset Parkinson's disease (EOPD) is lacking. In this study we aim to assess the frequency of use of dopamine agonists, the prevalence of ICDs, and to explore potential factors associated with their development in patients with EOPD. Methods: We used the Mayo Clinic Data Explorer system to investigate a population-based cohort of EOPD patients between 1990 and 2022 at Mayo Clinic, Rochester, MN. We used ICD coding for parkinsonism; then, we reviewed all the clinical records and included only those patients with a clinical diagnosis of PD with symptoms onset at or before the age of 50, and who developed ICDs after using therapeutic doses of dopamine agonists. Results: A total of 831 (513 males and 318 females) patients with EOPD were included with a median age at symptom onset of 42 years of age (CI: 37-46). Dopamine agonists were used in 49.7% of all patients; of these, only 14.5% developed symptoms of one or more ICDs. Hypersexuality was the most commonly observed ICD (38.3%), and the only one having a statistically significant male predominance (p = 0.011). Conclusion: ICDs are common in EOPD, particularly when associated with the use of dopamine agonists.

Are rare heterozygous SYNJ1 variants associated with Parkinson's disease?

Previous studies have suggested that rare biallelic SYNJ1 mutations may cause autosomal recessive parkinsonism and Parkinson's disease (PD). Our study explored the impact of rare SYNJ1 variants in non-familial settings, including 8,165 PD cases, 818 early-onset PD (EOPD, <50 years) and 70,363 controls. Burden meta-analysis using optimized sequence Kernel association test (SKAT-O) revealed an association between rare nonsynonymous variants in the Sac1 SYNJ1 domain and PD (Pfdr=0.040). Additionally, a meta-analysis focusing on patients with EOPD demonstrated an association between all rare SYNJ1 variants and PD (Pfdr=0.029). Rare SYNJ1 variants may be associated with sporadic PD, and more specifically with EOPD.

Co-occurrence of PRKN and SYNJ1 variants in Early-Onset Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease globally, with a fast-growing prevalence. The etiology of PD exhibits a multifactorial complex nature and remains challenging. Herein, we described clinical, molecular, and integrative bioinformatics findings from a Brazilian female affected by Early-Onset PD (EOPD) harboring a recurrent homozygous pathogenic deletion in the parkin RBR E3 ubiquitin protein ligase gene (PRKN; NM_004562.3:c.155delA; p.Asn52Metfs*29; rs754809877), along with a novel heterozygous variant in the synaptojanin 1 gene (SYNJ1; NM_003895.3:c.62G > T; p.Cys21Phe; rs1486511197) found by Whole Exome Sequencing. Uncommon or unreported PRKN-related clinical features in the patient include cognitive decline, auditory and visual hallucinations, REM sleep disorder, and depression, previously observed in SYNJ1-related conditions. Moreover, PRKN interacts with endophilin A1, which is a major binding partner of SYNJ1. This protein plays a pivotal role in regulating the dynamics of synaptic vesicles, particularly in the context of endocytosis and recycling processes. Altogether, our comprehensive analyses underscore a potential synergistic effect between the PRKN and SYNJ1 variants over the pathogenesis of EOPD.

Role of ATP10B in Parkinson disease in a cohort from southern Spain.

The ATP10B gene has been proposed to play an important role in the development of early-onset Parkinson's disease (PD). Nevertheless, various studies have presented controversial conclusions regarding the involvement of this gene in PD. Here, we screened 1162 patients with PD, employing a targeted resequencing approach to investigate the putative relevance of this gene in a large independent cohort of these patients from southern Spain. Variations were classified according to the American College of Medical Genetics and Genomics criteria. Association studies were performed using data of a representative healthy Spanish population from the Medical Genome Project. Frequent variants were excluded. A total of 68 variants (rare or very rare) were detected in our cohort. Among ATP10B variant carriers, 12.9 % were putative compound heterozygous carriers; of these, 25 % were patients with early-onset PD. No evidence of a relation between any rare variants of ATP10B and PD risk was observed. Therefore, our results do not support a role for ATP10B in the onset of PD, or in the risk of developing it.

Novel RAB39B loss-of-function mutation in patient with typical early-onset Parkinson's disease.

RAB39B mutations have been identified in X-linked developmental delays. Recently, RAB39B mutations were identified in males with early-onset parkinsonism and intellectual disability. A novel loss-of-function RAB39B mutation was found in a female patient with typical early-onset Parkinson's disease (EOPD). RAB39B mutations may cause EOPD, potentially due to a-synuclein homeostasis disruption.

Impact of Non-Motor Symptoms on Quality of Life in Patients with Early-Onset Parkinson's Disease.

BACKGROUND: Early-onset Parkinson's disease (EOPD) refers to patients with Parkinson's disease (PD) whose age at disease onset is less than 50 years. Literature on the non-motor symptoms (NMS) in these patients is very limited in the Indian context. We aimed to study the NMS in patients with EOPD and its impact on the quality of life (QoL). METHODS: We included 124 patients with EOPD with a mean age at disease onset between 21 and 45 years and 60 healthy controls (HC). NMS were assessed using validated scales, and the QoL domains were evaluated using the PD QoL-39 scale (PDQ-39). RESULTS: The mean age at disease onset in EOPD patients was 37.33 ± 6.36 years. Majority of the patients were male (66.12%). The average disease duration was 6.62 ± 5.3 years. EOPD patients exhibited a significantly higher number of NMS per patient (7.97 ± 4.69) compared to HC (1.3 ± 1.39; p < 0.001). The most common NMS reported were urinary dysfunction, body pain, poor sleep quality, constipation, anxiety, depression, cognitive impairment, and REM sleep behavior disorder. The total NMS burden correlated with the QoL measures. Distinctive patterns of QoL subdomain involvement were identified, with sleep/fatigue, mood/cognition, and urinary dysfunction independently influencing QoL metrics. CONCLUSIONS: Our study provides valuable insights into the NMS profile and its impact on QoL in patients with EOPD, addressing an important knowledge gap in the Indian context. By understanding the specific NMS and their influence on QoL, healthcare professionals can develop targeted interventions to address these symptoms and improve the overall QoL.

Rare variant analysis of UQCRC1 in Chinese patients with early-onset Parkinson's disease.

Mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene has been identified as a causative gene for autosomal dominant Parkinson's disease (PD), with the p.Y314S variant potentially associated with polyneuropathy in PD patients. The objectives of our study were to screen for UQCRC1 variants in Chinese patients with early-onset PD (EOPD) and explore the role of UQCRC1 in EOPD. We investigated the rare variants in 913 EOPD patients in our cohort using whole-exome sequencing, assessing their link to PD at both allele and gene levels. A total of 7 rare variants (minor allele frequency < 0.1%) of UQCRC1 were identified. However, no excessive burden of rare UQCRC1 variants was suggested in the EOPD patients. Further analysis with larger sample size and diverse regions is needed to determine the role of UQCRC1 in PD.

A molecular simulation study of the clinical G409V mutant in PINK1 associated with early-onset Parkinson's disease.

The serine/threonine kinase PINK1 is responsible for phosphorylating a ubiquitin (Ub)-like domain in an E3 Ub ligase Parkin protein and a Parkin-bound Ub. PINK1 works as a mitochondrial quality control by phosphorylating and activating the E3 ubiquitin ligase Parkin. Recent medicinal study has reported that mutations of Parkin and PINK1 cause defects in mitophagy and induce early-onset Parkinson's disease (EOPD). In this study, we conducted molecular dynamics simulations to investigate the structural discrepancy caused by a clinical G409V mutation in PINK1 kinase domain's A-loop. The Ub phosphorylation begins with PINK1 D362 deprotonating the hydroxyl group of the substrate Ub's S65' and PINK1's A-loop is responsible for coordinating S65'. On contrary to G409 offering structural plasticity, the replaced, bulky V409 interferes with the alignment of D362-S65', seriously hampering Ub phosphorylation, leading to the accumulation of damaged mitochondria, and ultimately EOPD. In this study, we predicted the hPINK1WT-UbWT binding mode and detected the structural impact brought by G409V replacement. It is expected the concluded remarks to be beneficial for developing cures to alleviate structural interference and restore PINK1 function.

Pregnancy, fertile life factors, and associated clinical course in PRKN early-onset Parkinson's disease.

INTRODUCTION: As the most common cause of autosomal recessive early onset Parkinson's disease (EOPD), parkin type Parkinson's disease (PRKN-PD) may affect female patients in childbearing age. Accordingly, issues related to fertility must be adequately addressed. Here, we landscaped fertile life factors and pregnancy course of a PRKN-PD cohort, including both novel cases directly observed at our center and published ones. METHODS: Six patients with confirmed PRKN-PD were examined by a structured interview on reproductive factors and associated modifications of PD disturbances, including one case followed up throughout pregnancy which was described in greater detail. Six studies reporting fertile life factors of nine PRKN-PD patients were reviewed collecting homogeneous data on fertile life and pregnancy course. RESULTS: PRKN-PD female patients experienced motor fluctuations with the menstrual cycle, pregnancy, and puerperium, which suggests a role for sex hormones in PD clinical burden. In some cases, abortion and miscarriages occurred during the organogenesis phase in patients receiving oral antiparkinsonian therapy; however, levodopa/benserazide monotherapy resulted to be the safest choice in pregnancy. CONCLUSION: Collectively these data disclose the importance of pre-conception counseling in childbearing age PRKN-PD patients and EOPD in general.

Motor cortex transcranial direct current stimulation improves non-motor symptoms in early-onset Parkinson's disease: a pilot study.

Early-onset Parkinson's Disease (EOPD) demands tailored treatments. The younger age of patients might account for a higher sensitivity to transcranial direct current stimulation (tDCS) based non-invasive neuromodulation, which may raise as an integrative therapy in the field. Accordingly, here we assessed the safety and efficacy of the primary left motor cortex (M1) anodal tDCS in EOPD. Ten idiopathic EOPD patients received tDCS at 2.0 mA per 20 min for 10 days within a crossover, double-blind, sham-controlled pilot study. The outcome was evaluated by measuring changes in MDS-UPDRS part III, Non-Motor Symptoms Scale (NMSS), PD-cognitive rating scale, and PD Quality of Life Questionnaire-39 scores. We showed that anodal but not sham tDCS significantly reduced the NMSS total and "item 2" (sleep/fatigue) scores. Other parameters were not modified. No adverse events occurred. M1 anodal tDCS might thus evoke plasticity changes in cortical-subcortical circuits involved in non-motor functions, supporting the value as a therapeutic option in EOPD.

Corrigendum: Characteristics and influencing factors of 11C-CFT PET imaging in patients with early and late onset Parkinson's disease.

[This corrects the article DOI: 10.3389/fneur.2023.1195577.].

Surface-Based Functional Alterations in Early-Onset and Late-Onset Parkinson's Disease: A Multi-Modal MRI Study.

This study used a surface-based method to investigate brain functional alteration patterns in early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD) to provide more reliable imaging indicators for the assessment of the two subtypes. A total of 58 patients with Parkinson's disease were divided into two groups according to age at onset: EOPD (≤50 years; 16 males and 15 females) and LOPD (>50 years; 17 males and 10 females) groups. Two control groups were recruited from the community: young adults (YC; ≤50 years; 8 males and 19 females) and older adults (OC; >50 years; 12 males and 10 females). No significant differences were observed between the EOPD and YC groups or the LOPD and OC groups in terms of age, sex, education, and MMSE scores (p > 0.05). No statistically significant differences were observed between the EOPD and LOPD groups in terms of education, H-Y scale, UPDRS score, or HAMD score (p > 0.05). Data preprocessing and surface-based regional homogeneity (2D-ReHo) calculations were subsequently performed using the MATLAB-based DPABIsurf software. The EOPD group showed decreased 2D-ReHo values in the left premotor area and right dorsal stream visual cortex, along with increased 2D-ReHo values in the left dorsolateral prefrontal cortex. In patients with LOPD, 2D-ReHo values were decreased in bilateral somatosensory and motor areas and the right paracentral lobular and mid-cingulate. The imaging characterization of surface-based regional changes may serve useful as monitoring indicators and will help to better understand the mechanisms underlying divergent clinical presentations.