Juvenile Parkinsonism Research Articles

Juvenile Parkinsonism Associated With Dihydropyrimidinase Deficiency.

Juvenile parkinsonism is an exceedingly rare condition in which clinical signs of parkinsonism manifest before 21 years of age. Although the genetic underpinnings of this disorder are increasingly recognized, the full range of inherited metabolic contributors remains undefined. We present the first case of levodopa-responsive juvenile parkinsonism associated with dihydropyrimidinase deficiency caused by a novel DPYS variant. A 13-year-old patient presented with rapid progression of dysphagia, dysarthria, and loss of ambulation over 18 months. Whole-exome sequencing revealed compound heterozygous variants in the DPYS gene (NM_001385: c.1393C>T, p.R465X, and c.905G>A, p.R302Q). In silico analysis predicted both variants to be pathogenic. Further urinary metabolome analysis demonstrated markedly elevated dihydrouracil and dihydrothymine levels, confirming impaired pyrimidine metabolism. Levodopa treatment effectively relieved the patient's motor symptoms. This report identifies DPYS as a novel genetic cause of juvenile parkinsonism and underscores the potential efficacy of levodopa therapy in managing motor dysfunction in DYPS-related parkinsonism.

Parkin paves the path to antitumor immunity: Expanding Parkin's role as a tumor suppressor.

Parkin, a ring-between-ring-type E3 ubiquitin ligase, first shown to play a critical role in autosomal recessive juvenile Parkinsonism, has recently emerged as a key player in cancer biology. Parkin is now known to serve as a tumor suppressor, and its deregulation frequently promotes tumorigenesis. In this issue of the JCI, Perego et al. expand that role by showing that Parkin expression stimulated an interferon (IFN) response to modulate CD8+ T cell activity. These findings suggest that, in addition to directly inhibiting tumor progression, Parkin enhances antitumor immune responses, highlighting it as a promising therapeutic target for cancer treatment.

Cooperative Substructure and Energetics of Allosteric Regulation of the Catalytic Core of the E3 Ubiquitin Ligase Parkin by Phosphorylated Ubiquitin.

Mutations in the parkin gene product Parkin give rise to autosomal recessive juvenile parkinsonism. Parkin is an E3 ubiquitin ligase that is a critical participant in the process of mitophagy. Parkin has a complex structure that integrates several allosteric signals to maintain precise control of its catalytic activity. Though its allosterically controlled structural reorganization has been extensively characterized by crystallography, the energetics and mechanisms of allosteric regulation of Parkin are much less well understood. Allostery is fundamentally linked to the energetics of the cooperative (sub)structure of the protein. Herein, we examine the mechanism of allosteric activation by phosphorylated ubiquitin binding to the enzymatic core of Parkin, which lacks the antagonistic Ubl domain. In this way, the allosteric effects of the agonist phosphorylated ubiquitin can be isolated. Using native-state hydrogen exchange monitored by mass spectrometry, we find that the five structural domains of the core of Parkin are energetically distinct. Nevertheless, association of phosphorylated ubiquitin destabilizes structural elements that bind the ubiquitin-like domain antagonist while promoting the dissociation of the catalytic domain and energetically poises the protein for transition to the fully activated structure.

Dopamine neuron dysfunction and loss in the PrknR275W mouse model of juvenile parkinsonism.

Mutations in the PRKN gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP). Harnessing this mutation to create an early-onset Parkinson's disease mouse model would provide a unique opportunity to clarify the mechanisms involved in the neurodegenerative process and lay the groundwork for the development of neuroprotective strategies. To this end, we created a knock-in mouse carrying the homozygous PrknR275W mutation, which is the missense mutation with the highest allelic frequency in PRKN patients. We evaluated the anatomical and functional integrity of the nigrostriatal dopamine (DA) pathway, as well as motor behaviour in PrknR275W mice of both sexes. We report here that PrknR275W mice show early DA neuron dysfunction, age-dependent loss of DA neurons in the substantia nigra, decreased DA content and stimulus-evoked DA release in the striatum, and progressive motor impairment. Together, these data show that the PrknR275W mouse recapitulates key features of ARJP. Thus, these studies fill a critical need in the field by introducing a promising new Parkinson's disease model in which to study causative mechanisms of the disease and test therapeutic strategies.

A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism.

Biallelic variants in PTRHD1 have been associated with autosomal recessive intellectual disability, spasticity, and juvenile parkinsonism, with few reported cases. Here, we present the clinical and genetic findings of a female of Austrian origin exhibiting infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, consistent with the established phenotypic spectrum. Notably, she developed genetic generalized epilepsy at age 4, persisting into adulthood. Using diagnostic exome sequencing, we identified a homozygous missense variant (c.365G > A, p.(Arg122Gln)) in PTRHD1 (NM_001013663). In summary, our findings not only support the existing link between biallelic PTRHD1 variants and parkinsonism with neurodevelopmental abnormalities but also suggest a potential extension of the phenotypic spectrum to include generalized epilepsy.

A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism.

Biallelic variants in PTRHD1 have been associated with autosomal recessive intellectual disability, spasticity, and juvenile Parkinsonism, with few reported cases. Here, we present the clinical and genetic findings of a female of Austrian origin exhibiting infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, consistent with the established phenotypic spectrum. Notably, she developed genetic generalized epilepsy at age 4, persisting into adulthood. Using diagnostic exome sequencing, we identified a homozygous missense variant (c.365G > A, p.(Arg122Gln)) in PTRHD1 (NM_001013663). In summary, our findings not only support the existing link between biallelic PTRHD1 variants and Parkinsonism with neurodevelopmental abnormalities but also suggest a potential extension of the phenotypic spectrum to include generalized epilepsy.

Design and high-throughput implementation of MALDI-TOF/MS-based assays for Parkin E3 ligase activity

Parkinson's disease (PD) is a progressive neurological disorder that manifests clinically as alterations in movement as well as multiple non-motor symptoms including but not limited to cognitive and autonomic abnormalities. Loss-of-function mutations in the gene encoding the ubiquitin E3 ligase Parkin are causal for familial and juvenile PD. Among several therapeutic approaches being explored to treat or improve the prognosis of patients with PD, the use of small molecules able to reinstate or boost Parkin activity represents a potential pharmacological treatment strategy. A major barrier is the lack of high-throughput platforms for the robust and accurate quantification of Parkin activity invitro. Here, we present two different and complementary Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF/MS)-based approaches for the quantification of Parkin E3 ligase activity invitro. Both approaches are scalable for high-throughput primary screening to facilitate the identification of Parkin modulators.

Psychopathological disorders at the onset of juvenile parkinsonism in childhood

The article presents a case of a teenage female patient illustrating the difficulties of diagnosis and treatment of mental pathology at the onset of juvenile parkinsonism, which developed as a result of compound heterozygous mutations and proceeds with moderate akinetic-rigid and pseudopyramidal syndromes and combined tremor. It is shown that before the appearance of distinct symptoms of parkinsonism and the genetic study that confirmed the diagnosis, the patient had been observed for several years with various psychiatric diagnoses and received psychotropic therapy. This case demonstrates the difficulties of differential diagnosis of juvenile parkinsonism in children at the initial stage due to multiple comorbid motor, affective and behavioral disorders. When neurological symptoms appear in patients, a multidisciplinary approach is required, including joint diagnostics by psychiatrists and neurologists to establish an accurate diagnosis and select the optimal therapy. The introduction of principles of interdisciplinary interaction in the management of such patients will improve the timeliness of diagnosis and pathogenetically based therapy.

Catecholamines and Parkinson's disease: tyrosine hydroxylase (TH) over tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GCH1) to cytokines, neuromelanin, and gene therapy: a historical overview.

The author identified the genes and proteins of human enzymes involved in the biosynthesis of catecholamines (dopamine, norepinephrine, epinephrine) and tetrahydrobiopterin (BH4): tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine β-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT), and GTP cyclohydrolase I (GCH1). In Parkinson's disease (PD), the activities and levels of mRNA and protein of all catecholamine-synthesizing enzymes are decreased, especially in dopamine neurons in the substantia nigra. Hereditary GCH1 deficiency results in reductions in the levels of BH4 and the activities of TH, causing decreases in dopamine levels. Severe deficiencies in GCH1 or TH cause severe decreases in dopamine levels leading to severe neurological symptoms, whereas mild decreases in TH activity in mild GCH1 deficiency or in mild TH deficiency result in only modest reductions in dopamine levels and symptoms of DOPA-responsive dystonia (DRD, Segawa disease) or juvenile Parkinsonism. DRD is a treatable disease and small doses of L-DOPA can halt progression. The death of dopamine neurons in PD in the substantia nigra may be related to (i) inflammatory effect of extra neuronal neuromelanin, (ii) inflammatory cytokines which are produced by activated microglia, (iii) decreased levels of BDNF, and/or (iv) increased levels of apoptosis-related factors. This review also discusses progress in gene therapies for the treatment of PD, and of GCH1, TH and AADC deficiencies, by transfection of TH, AADC, and GCH1 via adeno-associated virus (AAV) vectors.

GENETIC STUDY OF KRABBE LYSOSOME METABOLIC DISEASE

We studied blood samples of identical twins who are girls suspicious of the lysosome metabolic disease. For diagnostics goal we used New Generation Sequencing – NGS method and diagnostic amplicon panel. Diagnostic panel represents primers for the following diseases: Krabbe disease, mucopolysaccharidosis Type II (Hanter disease), Niemann-Pick disease, mucopolysaccharidosis Type IV (Morquio disease), Fabry disease, multiple sulfatase deficit, Gaucher disease, gangliosidase, mucopolysaccharidosis Type 1 (Gurler disease), mucopolysaccharidosis Type VII (Leya disease), and juvenile Parkinson disease. In studied material when analyzing GALC gene with molecular-genetic methods there was substitution of one nucleotide fragment GTCAG of c.1834 in intron 15 with another nucleotide fragment AGTCAC and that was identified (c.1834 GTCAG>AGTCAC). There is no information about this mutation in the world scientific literature. This is for the first time that this mutation of GALC gene was found in Azerbaijani children.

The Ameliorative Effect of Ashwagandha- Withania somnifera (L.) Dunal on park25 Induced Neurodegeneration in Drosophila melanogaster Parkinson’s Disease Model

Ashwagandha - Withania somnifera (L.) Dunal is a perennial shrub belonging to the family Solanaceae. Ashwagandha has been used for over 3000 years in traditional Indian Ayurveda for treatment of various neurological, and stress disorders. The root of Ashwagandha (ASH) is regarded as a tonic, aphrodisiac, narcotic, diuretic, anthelmintic, astringent, thermogenic and stimulant. Ashwagandha with other herbal decoctions was recognized to treat Kampavatha (Parkinson’s Disease) since 18th century. With this wide array of ethnopharmacological relevance, Ashwagandha has been recognized as one of the prominent complementary and alternative medicine to treat many neurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s disease (PD). There is a prominent increase in the cases of AD and PD all over the world and it demands the requirement of complementary and alternative herbal remedies with no/minimal side effects. Many genetic factors are responsible for the onset and progression of PD. Loss-of-function mutations in the parkin gene are a major cause of early onset of autosomal recessive juvenile parkinsonism (AR-JP). Drosophila park25 loss of function mutants exhibit significantly increased number of mitochondria-endoplasmic reticulum contacts and a significantly decreased number of dopaminergic neurons in the adult brain which is the main cause of PD condition. Several studies have demonstrated the ability of Ashwagandha in imparting neuroprotection, improved locomotory ability, memory and learning abilities. The challenge lies in scrutinizing the mechanism and the pathways involved in the neuroprotective properties of this well-known herb. Here in our study, we test the possible neuroprotective effect of Ashwagandha on park25 mutants of Drosophila using lifespan analysis and climbing disability as a disease marker. Parkinson’s mimicking flies were administered with aqueous extraction of Ashwagandha-root mixed with the fly food and subjected to negative geotaxis assay. We observed that there is a prominent increase in the climbing ability in park25 treated flies compared to its age-matched untreated flies. This is the first report showing that, aqueous extraction of Ashwagandha-root extract was able to ameliorate the disease phenotype in the park25 Drosophila Parkinson’s disease model.

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.

Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10-15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism.

Enhanced IRE1α Phosphorylation/Oligomerization-Triggered XBP1 Splicing Contributes to Parkin-Mediated Prevention of SH-SY5Y Cell Death under Nitrosative Stress.

Mutations in parkin, a neuroprotective protein, are the predominant cause of autosomal recessive juvenile Parkinson's disease. Neuroinflammation-derived nitrosative stress has been implicated in the etiology of the chronic neurodegeneration. However, the interactions between genetic predisposition and nitrosative stress contributing to the degeneration of dopaminergic (DA) neurons remain incompletely understood. Here, we used the SH-SY5Y neuroblastoma cells to investigate the function of parkin and its pathogenic mutants in relation to cell survival under nitric oxide (NO) exposure. The results showed that overexpression of wild-type parkin protected SH-SY5Y cells from NO-induced apoptosis in a reactive oxygen species-dependent manner. Under nitrosative stress conditions, parkin selectively upregulated the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) signaling axis, an unfolded protein response signal through the sensor IRE1α, which controls the splicing of XBP1 mRNA. Inhibition of XBP1 mRNA splicing either by pharmacologically inhibiting IRE1α endoribonuclease activity or by genetically knocking down XBP1 interfered with the protective activity of parkin. Furthermore, pathogenic parkin mutants with a defective protective capacity showed a lower ability to activate the IRE1α/XBP1 signaling. Finally, we demonstrated that IRE1α activity augmented by parkin was possibly mediated through interacting with IRE1α to regulate its phosphorylation/oligomerization processes, whereas mutant parkin diminished its binding to and activation of IRE1α. Thus, these results support a direct link between the protective activity of parkin and the IRE1α/XBP1 pathway in response to nitrosative stress, and mutant parkin disrupts this function.

Juvenile Parkinson's disease and 22q11.2 microdeletion syndrome

Juvenile Parkinson's disease and 22q11.2 microdeletion syndrome

Relevance of Fluorodopa PET Scan in Dopamine Responsive Dystonia and Juvenile Parkinsonism: A Systematic Review.

Dopamine Responsive Dystonia (DRD) and Juvenile Parkinsonism (JP) are two diseases commonly presenting with parkinsonian symptoms in young patients. Current clinical guidelines offer a diagnostic approach based on molecular analysis. However, developing countries have limitations in terms of accessibility to these tests. We aimed to assess the utility of imaging equipment, usually more available worldwide, to help diagnose and improve patients' quality of life with these diseases. We performed a systematic literature review in English using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and meta-analysis of observational studies in epidemiology (MOOSE) protocols. We only used human clinical trials about dopamine responsive dystonia and juvenile parkinsonism patients in which a fluorodopa (FD) positron emission tomography (PET) scan was performed to identify its use in these diseases. We included six studies that fulfilled our criteria. We found a clear pattern of decreased uptake in the putamen and caudate nucleus in JP cases. At the same time, the results in DRD were comparable to normal subjects, with only a slightly decreased marker uptake in the previously mentioned regions by the FD PET scan. We found a distinctive pattern for each of these diseases. Identifying these findings with FD PET scans can shorten the delay in making a definitive diagnosis when genetic testing is unavailable, a common scenario in developing countries.

Young-Onset Dementia and Neurodegenerative Disorders of the Young With an Emphasis on Clinical Manifestations.

Young-onset dementia (YOD) refers to a neurological ailment primarily affecting people below 65 years of age in roughly about 8% of cases found through various researches.The high rate of prevalence of secondary dementias among older patients proves that younger people show a better prognosis of the conditions causing dementia than older people. However, effective interventions have to be usually provided early in the course of cognitive decline to help facilitate cognitive improvement. The risk of development of prodromal dementia is high if there is a development of psychoses in middle-aged or older people.When there is a development of psychoses in middle to late life, the likelihood of this indicates prodromal dementia is high. The clinical presentation is quite variable and often subtle in frontotemporal dementia (FTD) but may be dominated by personality change, behavioral disturbances, motivation, or the loss of empathy. There is great heterogeneity in the probable causes of dementia in young age as compared to dementia in old age, and some observed differences also existin the course and characteristicsof the disease. These causes may range from the most probable cause such as Alzheimer's disease (AD) to causes with low probability, such as metabolic disorders and prion diseases. The symptoms of young-onset dementia include a gradual development of personality and behavioral changes over a period of years. However, in the initial stages of young-onset dementia, this change can be attributed to various issues, such as depression, marital problems, and menopause. Other neurodegenerative diseases such as Huntington's disease show presentations such aschanges in personality, chorea, and depression that can be observed in patients in their early adulthood. A few other neurodegenerative disorders are myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with presentations such as characterized muscle weakness, poor growth, problems with vision and hearing, and the involvement of the multi-organ system, including the central nervous systemto name a few. There is also the prevalence of juvenile parkinsonism in the community, which represents a group of clinicopathological entities present before the age of 21. Young-onset Parkinson's disease (PD) (YOPD) appears to have the same pathological presentation as late-onset Parkinson's disease (LOPD). Recent researches have proved that "gene therapy" can be useful in the treatment and in preventing the progression of symptoms in cases of neurodegenerative diseases.

TU-155. Bradykinesia in juvenile Parkinsonism due to monoamine neurotransmitters disorders

TU-155. Bradykinesia in juvenile Parkinsonism due to monoamine neurotransmitters disorders

Neurophysiological assessment of juvenile parkinsonism due to primary monoamine neurotransmitter disorders

No studies have investigated voluntary movement abnormalities and their neurophysiological correlates in patients with parkinsonism due to inherited primary monoamine neurotransmitter (NT) disorders. Nine NT disorders patients and 16 healthy controls (HCs) were enrolled. Objective measurements of repetitive finger tapping were obtained using a motion analysis system. Primary motor cortex (M1) excitability was assessed by recording the input/output (I/O) curve of motor-evoked potentials (MEP) and using a conditioning test paradigm for short-interval intracortical inhibition (SICI) assessment. M1 plasticity-like mechanisms were indexed according to MEPs amplitude changes after the paired associative stimulation protocol. Patient values were considered abnormal if they were greater or lower than two standard deviations from the average HCs value. Patients with aromatic amino acid decarboxylase, tyrosine hydroxylase, and 6-pyruvoyl-tetrahydropterin synthase defects showed markedly reduced velocity (5/5 patients), reduced movement amplitude, and irregular rhythm (4/5 patients). Conversely, only 1 out of 3 patients with autosomal-dominant GTPCH deficiency showed abnormal movement parameters. Interestingly, none of the patients had a progressive reduction in movement amplitude or velocity during the tapping sequence (no sequence effect). Reduced SICI was the most prominent neurophysiological abnormality in patients (5/9 patients). Finally, the I/O curve slope correlated with movement velocity and rhythm in patients. We provided an objective assessment of finger tapping abnormalities in monoamine NT disorders. We also demonstrated M1 excitability changes possibly related to alterations in motor execution. Our results may contribute to a better understanding of the pathophysiology of juvenile parkinsonism due to dopamine deficiency.

19. Phase determination and demonstration of parental mosaicism of intragenic PRKN deletions initially identified by chromosomal microarray analysis

Biallelic variants in PRKN are associated with autosomal recessive (AR) juvenile Parkinson disease. Various PRKN mutation types cause disease, however deletions are frequent due to its large size (∼1.4Mb) and its localization within a common fragile site. Here we present a case with biallelic intragenic PRKN deletions identified using chromosomal microarray (CMA) in a newborn. CMA was performed on a six-day old female with a family history of a 17q12 duplication. This maternal 1.5 Mb duplication was observed, along with two non-overlapping intragenic deletions encompassing exons 2 (227 Kb) and 7 (140 Kb) of PRKN.