Foot Drop Dystonia Resulting from parkin (PARK2) Mutation.
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ABSTRACT:
SUBMITTER: de Schipper LJ
PROVIDER: S-EPMC6353316 | biostudies-literature | 2015 Sep
REPOSITORIES: biostudies-literature
Publications
Foot Drop Dystonia Resulting from <i>parkin</i> (PARK2) Mutation.
de Schipper Laura J LJ Boon Agnita J W AJW Munts Alexander G AG
Movement disorders clinical practice 20150604 3
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Project description:The most common presentation of foot dystonia in patients with Parkinson's disease (PD) or dystonia is inversion of the foot accompanied by flexion of the toes, with or without extension of the hallux. Less commonly, foot dystonia may mimic foot drop, as occurs with weakness of the dorsiflexors muscles, resulting in a pseudo foot drop. This has rarely been reported in the literature and has been poorly recognized, often leading to misdiagnosis and unnecessary investigations and treatment. We report 5 patients with dystonic pseudo foot drop, one of them diagnosed with early-onset PD, 2 with sporadic PD, and 2 with dystonia. Despite the steppage gait, their physical exam revealed normal strength, and no other explanation for a "foot drop" was found. It is important to recognize this phenomenology, which can be a clue to the diagnosis of early-onset PD, and may be responsive to levodopa in selected patients.
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Project description:In this study, we used patient-specific and isogenic PARK2-induced pluripotent stem cells (iPSCs) to show that mutations in PARK2 alter neuronal proliferation. The percentage of TH(+) neurons was decreased in Parkinson's disease (PD) patient-derived neurons carrying various mutations in PARK2 compared with an age-matched control subject. This reduction was accompanied by alterations in mitochondrial:cell volume fraction (mitochondrial volume fraction). The same phenotype was confirmed in isogenic PARK2 null lines. The mitochondrial phenotype was also seen in non-midbrain neurons differentiated from the PARK2 null line, as was the functional phenotype of reduced proliferation in culture. Whole genome expression profiling at various stages of differentiation confirmed the mitochondrial phenotype and identified pathways altered by PARK2 dysfunction that include PD-related genes. Our results are consistent with current model of PARK2 function where damaged mitochondria are targeted for degradation via a PARK2/PINK1-mediated mechanism.
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Project description:Robotic technologies are being employed increasingly in the treatment of lower limb disabilities. Individuals suffering from stroke and other neurological disorders often experience inadequate dorsiflexion during swing phase of the gait cycle due to dorsiflexor muscle weakness. This type of pathological gait, mostly known as drop-foot gait, has two major complications, foot-slap during loading response and toe-drag during swing. Ankle foot orthotic (AFO) devices are mostly prescribed to resolve these complications. Existing AFOs are designed with or without articulated joint with various motion control elements like springs, dampers, four-bar mechanism, series elastic actuator, and so forth. This paper examines various AFO designs for drop-foot, discusses the mechanism, and identifies limitations and remaining design challenges. Along with two commercially available AFOs some designs possess promising prospective to be used as daily-wear device. However, the design and mechanism of AFO must ensure compactness, light weight, low noise, and high efficiency. These entailments present significant engineering challenges to develop a new design with wide consumer adoption.
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Project description:Mutations in PINK1 and PARK2/Parkin are a main risk factor for familial Parkinson disease. While the physiological mechanism of their activation is unclear, these proteins have been shown in tissue culture cells to serve as a key trigger for autophagy of depolarized mitochondria. Here we show that ablation of the mitochondrial rhomboid protease PARL leads to retrograde translocation of an intermembrane space-bridging PINK1 import intermediate. Subsequently, it is rerouted to the outer membrane in order to recruit PARK2, which phenocopies mitophagy induction by uncoupling agents. Consistent with a role of this retrograde translocation mechanism in neurodegenerative disease, we show that pathogenic PINK1 mutants which are not cleaved by PARL affect PINK1 kinase activity and the ability to induce PARK2-mediated mitophagy. Altogether we suggest that PARL is an important intrinsic player in mitochondrial quality control, a system substantially impaired in Parkinson disease as indicated by reduced removal of damaged mitochondria in affected patients.
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Project description:Controversy exists regarding the timing and outcome of surgery for lumbar degenerative disease (LDD) associated with foot drop. In this work, we report the results of a retrospective observational study from our center. We had a sample size of 26 patients with a minimum follow-up of 6 months. Of the 26 patients, 88% improved, with complete recovery observed in 61%. Thus, our data support the view that there is good recovery from operative management of foot drop secondary to LDD. Adjusting for preoperative strength, preoperative duration of weakness was a significant predictor of extent of recovery (odds ratio = 0.93; 95% confidence interval 0.88 to 0.98; p = 0.019). The model explained 50% of the variance in outcome in this study.
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Project description:BackgroundMalakoplakia is a rare condition characterized by inflammatory masses with specific histological characteristics. These soft tissue masses can mimic tumors and tend to develop in association with chronic or recurrent infections, typically of the urinary tract. A specific defect in innate immunity has been described. In the absence of randomized controlled trials, management is based on an understanding of the biology and on case reports.Case presentationHere we describe a case of presacral malakoplakia in a British Indian woman in her late 30s, presenting with complex unilateral foot drop. Four years earlier, she had suffered a protracted episode of intrapelvic sepsis following a caesarean delivery. Resection of her presacral soft tissue mass was not possible. She received empiric antibiotics, a cholinergic agonist, and ascorbic acid. She responded well to medical management both when first treated and following a recurrence of symptoms after completing an initial 8 months of therapy. Whole exome sequencing of the patient and her parents was undertaken but no clear causal variant was identified.ConclusionsMalakoplakia is uncommon but the diagnosis should be considered where soft tissue masses develop at the site of chronic or recurrent infections. Obtaining tissue for histological examination is key to making the diagnosis. This case suggests that surgical resection is not always needed to achieve a good clinical and radiological outcome.
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Project description:BackgroundOne of the causes of Parkinson's disease is mutations in the PARK2 gene. Deletions and duplications of single exons or exon groups account for a large proportion of the gene mutations. Direct detection of these mutations can be used for the diagnosis of Parkinson's disease.MethodsTo detect these mutations, we developed an effective technique based on the real-time TaqMan PCR system, which allows us to evaluate the copynumbers of the PARK2 gene exons by comparing the intensity of the amplification signals from some exon of this gene with that of the beta-globin gene (the internal control).ResultsWe analyzed rearrangements in exons 1-12 of the PARK2 gene in 64 patients from Russia with early-onset Parkinson's disease. The frequency of these mutations in our patients was 14%.ConclusionWe have developed a simple, accurate, and reproducible method applicable to the rapid detection of exon rearrangements in the PARK2 gene. It is suitable for the analysis of large patient groups, and it may become the basis for a diagnostic test.
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Project description: Not available
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Project description:Skeletal muscle atrophy is thought to result from hyperactivation of intracellular protein degradation pathways, including autophagy and the ubiquitin-proteasome system. However, the precise contributions of these pathways to muscle atrophy are unclear. Here, we show that an autophagy deficiency in denervated slow-twitch soleus muscles delayed skeletal muscle atrophy, reduced mitochondrial activity, and induced oxidative stress and accumulation of PARK2/Parkin, which participates in mitochondrial quality control (PARK2-mediated mitophagy), in mitochondria. Soleus muscles from denervated Park2 knockout mice also showed resistance to denervation, reduced mitochondrial activities, and increased oxidative stress. In both autophagy-deficient and Park2-deficient soleus muscles, denervation caused the accumulation of polyubiquitinated proteins. Denervation induced proteasomal activation via NFE2L1 nuclear translocation in control mice, whereas it had little effect in autophagy-deficient and Park2-deficient mice. These results suggest that PARK2-mediated mitophagy plays an essential role in the activation of proteasomes during denervation atrophy in slow-twitch muscles.
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Project description:PARK2, a gene associated with Parkinson disease, is a tumor suppressor in human malignancies. Here, we show that c.823C>T (p.Arg275Trp), a germline mutation in PARK2, is present in a family with eight cases of lung cancer. The resulting amino acid change, p.Arg275Trp, is located in the highly conserved RING finger 1 domain of PARK2, which encodes an E3 ubiquitin ligase. Upon further analysis, the c.823C>T mutation was detected in three additional families affected by lung cancer. The effect size for PARK2 c.823C>T (odds ratio = 5.24) in white individuals was larger than those reported for variants from lung cancer genome-wide association studies. These data implicate this PARK2 germline mutation as a genetic susceptibility factor for lung cancer. Our results provide a rationale for further investigations of this specific mutation and gene for evaluation of the possibility of developing targeted therapies against lung cancer in individuals with PARK2 variants by compensating for the loss-of-function effect caused by the associated variation.
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