Young-onset Parkinson's Disease Research Articles

Generation of induced pluripotent stem cells (NIMHi015-A) from a Parkinson’s Disease patient harbouring a homozygous Exon 3 deletion in the PRKN gene

The Parkin (PRKN) gene mutation is prevalent in young-onset Parkinson's disease (PD), typically emerging before age 30, accompanied by early motor symptoms. Induced pluripotent stem cells (iPSCs) were derived from peripheral blood mononuclear cells of a PD patient with an exon 3 deletion in PRKN using Sendai-virus reprogramming. PD diagnosis was confirmed via the Unified Parkinson's Disease Rating Scale (UPDRS). Characterization of the iPSC line ensured self-renewal and pluripotency. This resource serves as a valuable platform for drug screening and elucidating the pathophysiology of this mutation, facilitating advancements in PD research.

Usage of modern technologies like VR therapy, physio therapy along with levodopa in Young-Onset Parkinson's disease patients

Usage of modern technologies like VR therapy, physio therapy along with levodopa in Young-Onset Parkinson's disease patients

Pathogenesis of Parkinson's disease: from hints from monogenic familial PD to biomarkers.

Twenty-five years have passed since the causative gene for familial Parkinson's disease (PD), Parkin (now PRKN), was identified in 1998; PRKN is the most common causative gene in young-onset PD. Parkin encodes a ubiquitin-protein ligase, and Parkin is involved in mitophagy, a type of macroautophagy, in concert with PTEN-induced kinase 1 (PINK1). Both gene products are also involved in mitochondrial quality control. Among the many genetic PD-causing genes discovered, discovering PRKN as a cause of juvenile-onset PD has significantly impacted other neurodegenerative disorders. This is because the involvement of proteolytic systems has been suggested as a common mechanism in neurodegenerative diseases in which inclusion body formation is observed. The discovery of the participation of PRKN in PD has brought attention to the involvement of the proteolytic system in neurodegenerative diseases. Our research group has successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system, and prosaposin (PSAP), which is involved in the lysosomal system, in this Parkin mechanism. Hereditary PD is undoubtedly an essential clue to solitary PD, and at least 25 or so genes and loci have been reported so far. This number of genes indicates that PD is a very diverse group of diseases. Currently, the diagnosis of PD is based on clinical symptoms and imaging studies. Although highly accurate diagnostic criteria have been published, early diagnosis is becoming increasingly important in treatment strategies for neurodegenerative diseases. Here, we also describe biomarkers that our group is working on.

Effects of STN-DBS on cognition and mood in young-onset Parkinson's disease: a two-year follow-up.

The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on the cognition and mood of patients with PD are still not uniformly concluded, and young-onset Parkinson's disease (YOPD) is even less explored. To observe the effectiveness of STN-DBS on the cognition and mood of YOPD patients. A total of 27 subjects, with a mean age at onset of 39.48 ± 6.24 and age at surgery for STN-DBS of 48.44 ± 4.85, were followed up preoperatively and for 2 years postoperatively. Using the Unified Parkinson disease rating scale (UPDRS), H&Y(Hoehn and Yahr stage), 39-Item Parkinson's Disease Questionnaire (PDQ-39), Mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), Hamilton depression scale (HAMD), Hamilton anxiety scale (HAMA) to assess motor, cognition, and mood. At the 2-year follow-up after STN-DBS, YOPD patients showed significant improvements in motor and quality of life (UPDRS III: p < 0.001, PDQ-39: p < 0.001); overall cognition was not significantly different from preoperative (MMSE: p = 0.275, MoCA: p = 0.913), although language function was significantly impaired compared to preoperative (MMSE: p = 0.004, MoCA: p = 0.009); depression and anxiety symptoms also improved significantly (HAMD: p < 0.001, HAMA: p < 0.001) and the depression score correlated significantly with motor (preoperative: r = 0.493, p = 0.009), disease duration (preoperative: r = 0.519, p = 0.006; postoperative: r = 0.406, p = 0.036) and H&Y (preoperative: r = 0.430, p = 0.025; postoperative: r = 0.387, p = 0.046); total anxiety scores were also significantly correlated with motor (preoperative: r = 0.553, p = 0.003; postoperative: r = 0.444, p = 0.020), disease duration (preoperative: r = 0.417, p = 0.031), PDQ-39 (preoperative: r = 0.464, p = 0.015) and H&Y (preoperative: r = 0.440, p = 0.022; postoperative: r = 0.526, p = 0.005). STN-DBS is a safe and effective treatment for YOPD. The mood improved significantly, and overall cognition was not impaired, were only verbal fluency decreased but did not affect the improvement in quality of life.

Sexual dysfunction in men with young onset Parkinson's disease.

Sexual dysfunction (SD) is a common, yet under-reported non-motor symptom of PD. Common sexual symptoms among male PD patients include erectile dysfunction, premature ejaculation, and decreased sexual desire. Few research papers have examined sexual dysfunction in PD, especially in YOPD male patients, and there is no Indian research study on sexual dysfunction in YOPD. In this study, we determined the frequency of sexual dysfunction in men with YOPD, and its correlation with other motor and NMS. This prospective cross-sectional study was conducted on YOPD males who presented to the Department of Neurology, NIMHANS, Bangalore, India, from May 2021 to April 2023. The diagnosis of YOPD was made based on MDS criteria for IPD 2015. Sexual functions were evaluated by ASEX, PEDT, QUIP-RS, and sex hormone assay. The patients also underwent other motor and non-motor assessments. Statistical analysis was done using SPSS version 22.0. The study was funded by the PDMD fund. This study included 62 male YOPD patients. The mean age of cases was 44.74 ± 8.54years. The mean duration of symptoms was 8.45 ± 6.23years. 43.5% of the cases of PD were Akinetic rigid type. By ASEX Score grading, 46.8% of the cases had erectile dysfunction and 71% of the cases of YOPD had premature ejaculation by PEDT Score grading. 9.7% of the cases had hypersexuality by QUIP-RS.Duration of YOPD was a better predictor of Erectile Dysfunction and premature ejaculation when compared with other variables. SD was related to anxiety and depression and it had a negative impact on the patient's health-related quality of life (HR-QoL). SD should be investigated and treated as an integral part of the neurological assessment in YOPD.

Pramipexole induced syndrome of inappropriate antidiuretic hormone secretion in a patient with young onset Parkinson’s disease

Abstract Pramipexole, a dopaminergic agonist, has rarely been implicated as a cause of hyponatremia in patients with Parkinson’s disease (PD). Pramipexole-induced stimulation of anti-diuretic hormone results in euvolemic hyponatremia. This is often neglected, and hyponatremia may lead to worsening of the motor symptoms with PD and an unnecessary increase in dopaminergic medications, causing disabling dyskinesias. This case report describes a patient with young-onset PD who developed new-onset hyponatremia due to pramipexole-induced syndrome of inappropriate anti-diuretic hormone within 3 months of starting the drug.

Response to: 'Adult-onset Leigh's syndrome: a rare cause of young-onset parkinsonism with dystonia' by Saluja etal.

Response to: 'Adult-onset Leigh's syndrome: a rare cause of young-onset parkinsonism with dystonia' by Saluja etal.

DNAJC12 in Monoamine Metabolism, Neurodevelopment, and Neurodegeneration.

Recent studies show that pathogenic variants in DNAJC12, a co-chaperone for monoamine synthesis, may cause mild hyperphenylalaninemia with infantile dystonia, young-onset parkinsonism, developmental delay and cognitive deficits. DNAJC12 has been included in newborn screening, most revealingly in Spain, and those results highlight the importance of genetic diagnosis and early intervention in combating human disease. However, practitioners may be unaware of these advances and it is probable that many patients, especially adults, have yet to receive molecular testing for DNAJC12. Hence, this review summarizes genotype-phenotype relationships and treatment paradigms for patients with pathogenic variants in DNAJC12. It provides an overview of the structure of DNAJC12 protein, known genetic variants, domains, and binding partners, and elaborates on its role in monoamine synthesis, disease etiology, and pathogenesis. © 2023 International Parkinson and Movement Disorder Society.

Adult-onset Leigh's syndrome: a rare cause of young-onset parkinsonism with dystonia.

Adult-onset Leigh's syndrome: a rare cause of young-onset parkinsonism with dystonia.

Long-Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease.

Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants. To identify complex structural variants in PRKN using long-read sequencing. We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole-genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP-PD) and United Kingdom (UK)-Biobank datasets. Multiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long-read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression. This is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long-read sequencing for structural variant analysis in unresolved young-onset PD cases. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Novel RAB39B variant associated intellectual disability and levodopa-responsive young-onset parkinsonism

We report a 37-year-old Caucasian male with history of developmental delay, childhood onset Intellectual Disability (ID) and attention deficit hyperactivity disorder (ADHD) who presented at the age of 34 with tremor-dominant parkinsonism. Next Generation Sequencing (NGS) revealed pathogenic hemizygous sequence variant, c.200G > T, in the RAB39B gene. This report expands the number of described individuals with young onset PD associated with RAB39B mutation.

A new genetic variant, presenting as young onset rapidly progressive dementia and parkinsonism

There are various neurodegenerative or hereditary causes of Parkinsonism. Therefore, clinicians should consider an increasing range of differential diagnoses when facing a patient with Parkinsonism, especially when associated with additional clinical features. Young-onset Parkinsonism, especially when accompanied by features uncommon in idiopathic Parkinson's disease raises the possibility of genetic etiology.Herein, we present a case of a 40-year-old man with genetic Parkinson's disease, presenting with rapidly progressive dementia. This round will describe our approach to this clinical presentation and the unveiling of a rare genetic condition.

Cognitive impairment and dementia in young onset Parkinson's disease.

Patients with young-onset Parkinson's disease (YOPD) have a slower progression. Our aim was to analyze the change in cognitive function in YOPD compared to patients with a later onset and controls. Patients with Parkinson's disease (PD) and controls from the COPPADIS cohort were included. Cognitive function was assessed with the Parkinson's Disease Cognitive Rating Scale (PD-CRS) at baseline (V0), 2-year ± 1month (V2y), and 4-year ± 3months follow-up (V4y). Regarding age from symptoms onset, patients were classified as YOPD (< 50years) or non-YOPD (≥ 50). A score in the PD-CRS < 81 was defined as cognitive impairment (CI): ≤ 64 dementia; 65-80 mild cognitive impairment (MCI). One-hundred and twenty-four YOPD (50.7 ± 7.9years; 66.1% males), 234 non-YOPD (67.8 ± 7.8years; 59.3% males) patients, and 205 controls (61 ± 8.3years; 49.5% males) were included. The score on the PD-CRS and its subscore domains was higher at all visits in YOPD compared to non-YOPD patients and to controls (p < 0.0001 in all analysis), but no differences were detected between YOPD patients and controls. Only non-YOPD patients had significant impairment in their cognitive function from V0 to V4y (p < 0.0001). At V4y, the frequency of dementia and MCI was 5% and 10% in YOPD compared to 25.2% and 22.3% in non-YOPD patients (p < 0.0001). A lower score on the Parkinson's Disease Sleep Scale at baseline was a predictor of CI at V4y in YOPD patients (Adjusted R2 = 0.61; OR = 0.965; p = 0.029). Cognitive dysfunction progressed more slowly in YOPD than in non-YOPD patients.

Experiences of Health Service Access and Use for People Living with Parkinson’s Disease in Ireland: A National Survey

Background. Despite the growing prevalence of Parkinson’s disease (PD) and the need to plan for future health service provision, little is known in the Irish context about PD patients’ experiences of service access/use. Methods. A cross-sectional survey, with multiple formats, i.e., online, pen-and-paper, and telephone. Data were collected from May 2020 to July 2021 using a multipronged recruitment strategy. The survey was completed by people with PD alone or with the support of a carer/support person. Results. A total of 1402 responses were included. Over half (53%) were male. Approx. 10% were diagnosed with young-onset PD. A minority (6%) reported attending only their GP to manage their PD, with the rest attending a generic or specialist outpatient clinic. Almost 1-in-5 reported it took more than 12 months to obtain the diagnosis. Most were diagnosed by neurologists (84%), followed by GPs (8%) and geriatricians (7%); 1% indicated “other.” Of those diagnosed privately, 37% of these patients subsequently switched to the public system for ongoing management. The majority (97%) reported currently taking PD medications, but just 52% believed these were working effectively. Access to the range of health and social care professionals, including PD nurse specialists and clinical therapies is universally poor. Conclusions. A number of significant gaps in PD care are discussed, which require urgent attention. A reconfigured model of PD care is necessary to accommodate the growing need for specialist, integrated care at the population level. Specifically, more PD nurse specialists are needed within the public health system.

Effect of Shashti Shali Pinda Swedan and Sahchar Tail Matra Basti in the management of Young Onset of Parkinson Disorder (YOPD) - A Case Report

The young onset Parkinson disease is a progressive neurodegenerative disease characterized by both motor and non motor features. The diseases affect families and caregivers through its progressive degenerative effect on mobility and the muscle control.[1] The main difference between young onset of Parkinson disorder (YOPD)and the late onset of Parkinson disorder (LOPD) is genetic etiology and clinical symptoms e.g., dystonia and levodopa induced per dyskinesia are common in YOPD. YOPD person carrying a greater social economic burden compared to late onset of Parkinson disease due to age factor. YOPD Patients more prone to levodopa related motor complication. Parkinson’s disease is referred to in the ancient Indian medical system of Ayurveda under the name Kampavata which is characterized by Kampa (Tremors), Stambha (Rigidity), Chesthahani (Akinesia) &amp; Gativikriti (Gait Disorders). The case study is of a 45 years old male who has been diagnosed with early stage idiopathic Parkinson’s disease. No satisfactory treatment is seen in contemporary system of medicine so treatment is planned in here study.

Frequency and Clinical Characteristics of Young Onset Parkinson’s Disease at Chandka Medical College Hospital Larkana

Background: One of the most prevalent forms of neurodegenerative illness, Parkinson's is characterised by a loss of postural response, stiffness, and tremor at rest. Young-onset Parkinson's disease occurs between the ages of 21 and 50 on average, however it begins much younger in 3 to 5 percent of people. Objective: To determine frequency of Young onset Parkinson’s disease in Parkinson’s patients. Methodology: This research was conducted from May 2022 and October 2022 at the Chandka Medical College Hospital in Larkana. The World Health Organization's online calculator determined that 73 people would be used for the study. Permission and ethical review forms were filled out. The data was analysed using SPSS. The significance level of 0.05 was considered crucial. Results: The total number of female patients were 31(42.5%) while male were 42(57.5%) The duration of disease was from 6 months to 22 years. Majority of the patients were in stage 2 and 3 according to Hoehn and Yahr rating scale. The frequency of Young Onset Parkinson’s disease in Parkinson’s patients is 24.7%. Overall prevalence of Parkinson’s disease was seen more in male patients, this even increases in YOPD, (38% VS 62%).Almost all patients in both age categories have bradykinesia and rigidity while 6 patients out of 73 have absent tremors. Loss of postural reflex was seen in 33 patients, every second (51%) patient in idiopathic Parkinson’s disease and every third (38%) in YOPD. Dystonia was seen more in YOPD, total 8 patients have dystonia, 4(28%) in YOPD and 4(8%) in Idiopathic Parkinson’s disease. Dyskinesia was not seen in YOPD while it was frequent in Idiopathic Parkinson’s disease. Family history was positive in total 9 patients, 50% of cases YOPD, while it was positive 5.8% in idiopathic Parkinson’s disease. Conclusion: YOPD is unique subgroup among patients of Parkinson’s disease, it burden is much more than ever reported, this calls for shared decision making , the possibility of genetic counseling and appropriate multidisciplinary treatment options. Keywords: Parkinson’s disease, YOPD (Young onset Parkinson’s disease, bradykinesia, rigidity, tremor, dystonia, postural reflex. Dyskinesia.

A homozygous PRKN-associated juvenile Parkinson's disease with pregnancy in China.

Although Parkinson's disease (PD) is the second most common neurodegenerative disorder, pregnancy in patients with PD is a relatively rare occurrence because the most common age of onset of PD is beyond the childbearing age, except in patients with Young-Onset PD (YOPD) caused by parkin RBR E3 ubiquitin protein ligase (PRKN) mutations. In this study, we report the case of a 30-year-old Chinese woman who was affected by PRKN-associated YOPD and was treated with levodopa/benserazide during pregnancy. She gave birth to a healthy baby boy with an Apgar score of 9 through an uncomplicated vaginal delivery. This case further suggests that levodopa/benserazide during pregnancy is safe in the treatment of PRKN-associated YOPD.

Constructing the detecting stage: Social processes and the diagnostic journey of early onset Parkinson's disease.

Parkinson's is a neurodegenerative disorder that mostly affects people over the age of 65; however, a significant number (10%) of the diagnosed cases are under the age of 50 (Young Onset Parkinson's disease). It has multiple symptoms; it is difficult to diagnose and its progression cannot be intercepted. This article focuses on the experience of the diagnostic process as narrated by individuals who were under the age of 50 when diagnosed. Analysis of in-depth interviews with 17 individuals with Parkinson's disease inductively reveals a 'detecting stage', a period during which they visit different doctors, undertake many examinations and experience bodily symptoms with impacts on their mental health. The diagnostic process, which usually lasts over 2years, often leads to misdiagnosis and or late diagnosis (a) on account of the individual's young age and social meanings attached to it, usually by doctors, whose discourse appears to be rather psychologised and (b) is perceived as disruptive to individuals' biographies. Due to the tendency to over-attribute bodily symptoms to psychological problems, accurate diagnosis is experienced as redemption.

Generation of feeder-independent transgene-free iPSC lines from a young-onset Parkinson’s disease (YOPD) patient with a homozygous PLA2G6: c.2222G>A (p. Arg741Gln) mutation (NCBSi003-A) and unaffected heterozygous parent (NCBSi004-A)

Phospholipase A2 group 6 (PLA2G6, iPLA2β or PARK14) gene encodes a calcium-independent group 6 phospholipase A2 enzyme and is associated with young-onset autosomal recessive Parkinson’s disease (PD). We generated human induced pluripotent stem cell (iPSC) lines from a patient with young-onset PD carrying a homozygous PLA2G6: c.2222G>A (p. Arg741Gln) mutation (NCBSi003-A) and unaffected heterozygous parent (NCBSi004-A). These iPSC lines will be used for investigating the key molecular signatures of young-onset PD (YOPD), and to understand the predictive phenotypes of the disease.

Time trends in demographic characteristics of participants and outcome measures in Parkinson’s disease research: A 19-year single-center experience

BackgroundFemales, people with young-onset PD and older individuals, and non-white populations are historically underrepresented in clinical Parkinson’s disease (PD) research. Furthermore, research traditionally focused predominantly on motor symptoms of PD. Including a representative and diverse group of people with PD and also studying non-motor symptoms is warranted to better understand heterogeneity in PD and to generalize research findings. ObjectiveThis project aimed to determine whether, within a consecutive series of PD studies performed within a single center in the Netherlands: (1) the proportion of included females, mean age and proportion of native Dutch people changed over time; and 2) reports of the ethnicity of participants and the proportion of studies with non-motor outcomes changed over time. MethodsCharacteristics of participants and non-motor outcomes were analyzed using a unique dataset of summary statistics of studies with a large number of participants conducted at a single center during a 19-year period (2003–2021). ResultsResults indicate no relationship between calendar time and proportion of females (mean 39 %), mean age (66 years), proportion of studies that reported ethnicity, and proportion of native Dutch people in studies (range 97–100 %). The proportion of participants in whom non-motor symptoms were assessed increased, but this difference was consistent with chance. ConclusionStudy participants in this center reflect the PD population in the Netherlands in terms of sex, but older individuals and non-native Dutch individuals are under-represented. We have still a lot to do in ensuring adequate representation and diversity in PD patients within our research.