Screening for mutations in the MECP2 (Rett syndrome) gene in Gilles de la Tourette syndrome.
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Chromosomal Proteins, Non-Histone↗
Biomedical subjects
Joseph Jankovic
Publications and source records attributed to Joseph Jankovic.
Association study of Parkin gene polymorphisms with idiopathic Parkinson disease.
BACKGROUND: Previously, we detected linkage of idiopathic Parkinson disease (PD) to the region on chromosome 6 that contains the Parkin gene (D6S305; logarithm of odds score, 5.47) in families with at least one individual with age at onset younger than 40 years (families with early-onset disease). Further study demonstrated the presence of Parkin mutations in this data set. However, previous case-control studies have reported conflicting results regarding the role of more common Parkin polymorphisms as susceptibility alleles for idiopathic PD. OBJECTIVE: To investigate the association of 7 previously studied Parkin single-nucleotide polymorphisms (SNPs) throughout the promoter and most of the open reading frame with PD in a large cohort of patients with primarily late-onset PD. METHODS: One promoter, 3 intronic, and 3 exonic Parkin SNPs were genotyped in 1580 individuals belonging to 397 families, and their association with PD was evaluated using family-based association tests. RESULTS: No significant association (P>.05) between PD and any Parkin SNP allele or genotype was detected. Haplotype analysis and stratification by age at onset or family history also failed to produce significant results. CONCLUSIONS: These results suggest that these common variants of Parkin are not associated with PD in white patients, although Parkin mutations are known to cause early- and late-onset PD.
Adolescent↗
Substantia nigra lesions in viral encephalitis.
Post-encephalitic parkinsonism is a well-known entity, but involvement of the basal ganglia is rarely documented. We describe a 21-year-old man who developed parkinsonism following encephalitic illness presumed to be of viral origin with substantia nigra lesions evident on magnetic resonance imaging scan.
Adult↗
Treatment of hypophonia with collagen vocal cord augmentation in patients with parkinsonism.
We conducted structured interviews of patients with Parkinson's disease (PD) and other parkinsonian disorders and their caregivers after augmentation of vocal folds with collagen injections. A total of 12 patients (mean age, 73.7 +/- 8.6 years) completed the questionnaire after an average of 3.0 +/- 1.7 collagen injections, with an average of 13.8 +/- 7.4 weeks between each injection. In addition to improvement in all six voice quality questions, there was significant improvement (P < 0.05) in the Glascow Benefit Inventory (GBI) score. The injection procedure was tolerated well by patients with an average duration of benefit lasting 7.8 +/- 8.5 weeks. Augmentation of vocal folds with collagen provides temporary improvement in voice in patients with parkinsonian hypophonia.
Aged↗
Phenotypic features of Huntington's disease-like 2.
Huntington's disease-like 2 is an autosomal dominantly inherited disorder due to an expansion of trinucleotide repeats. It resembles classic Huntington's disease in clinical phenotype, inheritance pattern, and neuropathological features. We highlight the clinical features of this disorder, including chorea, dystonia, parkinsonism, and cognitive deficits.
Adult↗
Premonitory sensory phenomenon in Tourette's syndrome.
We administered a questionnaire designed to probe for premonitory sensations associated with motor tics to 50 patients with Tourette's syndrome (TS). Premonitory sensations were reported by 46 (92%) patients, and the most common sensation was an urge to move and an impulse to tic ("had to do it"). Intensification of premonitory sensations, if prevented from performing a motor tic, was reported also in 37 patients (74%), 36 patients (72%) reported relief of premonitory sensations after performing the tic, and 27 of 40 (68%) described a motor tic as a voluntary motor response to an involuntary sensation, rather than a completely involuntary movement. The "just right" sensation correlated with the presence of co-morbid obsessive-compulsive disorder. We conclude that premonitory sensations are an important aspect of motor tics and some patients perceive motor tics as a voluntary movement in response to an involuntary sensation.
Adult↗
Soleus H-reflex measures in patients with focal and generalized dystonia.
OBJECTIVE: The purpose of this study was to examine neurophysiological characteristics of dystonia patients using electromyographic soleus H-reflex methods. METHODS: Thirty normal healthy individuals were compared to 27 patients with focal (cervical) or generalized dystonia. Three H-reflex assessment methods were included: the ratio of maximum H-reflex to direct muscle potential (H/M ratio); vibration inhibition (H(v)/H(c) ratio); and H-reflex recovery curves (HRRC). RESULTS: Average H/M ratios between groups were not statistically significant. The average H(v)/H(c) ratio for the generalized dystonia group was significantly greater than the focal dystonia and normal groups. Average values of the HRRC showed the generalized dystonia group had significantly greater disinhibition than the focal dystonia and control groups during the early inhibition phase. The HRRC for the focal dystonia group was greater than normal and more similar to the generalized dystonia group during the late phases of the recovery curve. The average value of the localized late facilitation phase for the focal dystonia group was significantly greater than the control group and less than the generalized dystonia group. No differences were observed between groups for the average localized late inhibition phase of the recovery curve. CONCLUSIONS: Soleus H-reflex measures identified neurophysiologic differences between generalized dystonia, cervical dystonia and normal conditions. SIGNIFICANCE: This methodology enables analysis of the underlying characteristics of dystonic pathologies using soleus H-reflex methods rather than upper extremity H-reflex techniques.
Adult↗
Role of nitric oxide in rotenone-induced nigro-striatal injury.
Rotenone, a widely used pesticide, causes a syndrome in rats that mimics, both behaviorally and pathologically, the symptoms of Parkinson's disease. The present study evaluated the role of nitric oxide in rotenone-induced nigro-striatal injury. After administration of rotenone in rats for 40 days, there was a moderate but significant injury of the nigro-striatal pathway indicated by a 47% decrease in striatal dopamine levels and a 28% loss of substantia nigra tyrosine hydroxylase-immunopositive neurons. Furthermore, a significant (37%) increase in the number of cells positive for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) in the striatum was observed, accompanied by a 83% increase in nitric oxide synthase (NOS) activity and a significant increase in the production of 3-nitrotyrosine (3-NT). There was a significant increase (45%) in the optical density of NADPH-d staining and an increase (72%) in NOS activity in the substantia nigra. Moreover, administration of the neuronal NOS inhibitor 7-nitroindazole significantly attenuated the increased NOS activity and 3-NT production, and provided significant protection against rotenone-induced nigro-striatal injury. Our data suggest that chronic rotenone administration can lead to significant injury to the nigro-striatal system, mediated by increased generation of nitric oxide.
Animals↗
Basal ganglia neuronal discharge in primary and secondary dystonia in patients undergoing pallidotomy.
OBJECTIVE: Basal ganglia neuronal activity in patients undergoing posteroventral pallidotomy (PVP) for the treatment of primary genetic, secondary, or idiopathic dystonia (DYS) was studied to gain a better understanding of the pathophysiology of DYS. METHODS: Intraoperative neurophysiological data recorded from 15 DYS patients were compared with those from 78 patients with Parkinson's disease (PD) who underwent PVP. RESULTS: Putamen neurons in both DYS and PD patients had low discharge rates. Globus pallidus externa (GPe) and globus pallidus interna (GPi) neurons in DYS patients had significantly lower discharge rates and more irregular discharge patterns than in PD patients. GPe and GPi neurons displayed similar discharge rates and patterns in DYS, whereas in PD, the discharge rate of GPe neurons was lower than that of the GPi neurons. The discharge rate and pattern of GPe and GPi neurons in patients whose DYS was ameliorated by PVP were similar to those in DYS patients who did not benefit from PVP. No significant differences in the rate or pattern of neuronal discharge in patients with DYS of different causes were discernible. PVP was most beneficial in patients with primary genetic DYS. Anesthesia with desflurane depressed the discharge rate of the GPe and GPi neurons, particularly in patients with PD. CONCLUSION: Significant differences in the rates and patterns of discharge of GPe and GPi neurons exist in DYS and PD. The findings are discussed with reference to the current model of the functional connections of the basal ganglia.
Adolescent↗
Dopamine agonists in Parkinson's disease.
Levodopa (LD), the immediate precursor of dopamine, is the most effective agent in the treatment of Parkinson's disease (PD). While quite successful in treating the primary motor deficits of PD, most patients eventually develop LD-related motor fluctuation, dyskinesias and other adverse effects associated with chronic LD therapy. There is also concern that LD is neurotoxic, although this has not been demonstrated in any in vivo studies. Dopamine agonists (DAs) have been shown to be about as effective as LD in symptomatic treatment of mild-to-moderate PD. In addition, there is a lower tendency to develop motor fluctuations and dyskinesias with DA treatment than after initiation of therapy with LD. Furthermore, there is preclinical and clinical data to suggest a slowing of neurodegeneration with DAs. The adverse effects of DAs are similar to those experienced with LD, except that the ergot agents are associated with a small risk of tissue fibrosis not noted with the non-ergot DAs.
Clinical Trials as Topic↗
Benefits and risks of pharmacological treatments for essential tremor.
Essential tremor can cause significant functional disability in some patients. The arms are the most common body part affected and cause the most functional disability. The treatment of essential tremor includes medications, surgical options and other forms of therapy. Presently there is no cure for essential tremor nor are there any medications that can slow the progression of tremor. Treatment for essential tremor is recommended if the tremor causes functional disability. If the tremor is disabling only during periods of stress and anxiety, propranolol and benzodiazepines can be used during those periods when the tremor causes functional disability. The currently available medications can improve tremor in approximately 50% of the patients. If the tremor is disabling, treatment should be initiated with either primidone or propranolol. If either primidone or propranolol do not provide adequate control of the tremor, then the medications can be used in combination. If patients experience adverse effects with propranolol, occasionally other beta-adrenoceptor antagonists (such as atenolol or metoprolol) can be used. If primidone and propranolol do not provide adequate control of tremor, occasionally the use of benzodiazepines (such as clonazepam) can provide benefit. Other medications that may be helpful include gabapentin or topiramate. If a patient has disabling head or voice tremor, botulinum toxin injections into the muscles may provide relief from the tremor. Botulinum toxin in the hand muscles for hand tremor can result in bothersome hand weakness and is not widely used. There are other medications that have been tried in essential tremor and have questionable efficacy. These drugs include carbonic anhydrase inhibitors (e.g. methazolamide), phenobarbital, calcium channel antagonists (e.g. nimodipine), isoniazid, clonidine, clozapine and mirtazapine. If the patient still has disabling tremor after medication trials, surgical options are usually considered. Surgical options include thalamotomy and deep brain stimulation of the thalamus. These surgical options provide adequate tremor control in approximately 90% of the patients. Surgical morbidity and mortality for these procedures is low. Deep brain stimulation and thalamotomy have been shown to have comparable efficacy but fewer complications have been reported with deep brain stimulation. In patients undergoing bilateral procedures deep brain stimulation of the thalamus is the procedure of choice to avoid adverse effects seen with bilateral ablative procedures. The use of medication and/or surgery can provide adequate tremor control in the majority of the patients.
Adrenergic Agonists↗
Potential therapeutic properties of green tea polyphenols in Parkinson's disease.
Tea is one of the most frequently consumed beverages in the world. It is rich in polyphenols, a group of compounds that exhibit numerous biochemical activities. Green tea is not fermented and contains more catechins than black tea or oolong tea. Although clinical evidence is still limited, the circumstantial data from several recent studies suggest that green tea polyphenols may promote health and reduce disease occurrence, and possibly protect against Parkinson's disease and other neurodegenerative diseases. Green tea polyphenols have demonstrated neuroprotectant activity in cell cultures and animal models, such as the prevention of neurotoxin-induced cell injury. The biological properties of green tea polyphenols reported in the literature include antioxidant actions, free radical scavenging, iron-chelating properties, (3)H-dopamine and (3)H-methyl-4-phenylpyridine uptake inhibition, catechol-O-methyltransferase activity reduction, protein kinase C or extracellular signal-regulated kinases signal pathway activation, and cell survival/cell cycle gene modulation. All of these biological effects may benefit patients with Parkinson's disease. Despite numerous studies in recent years, the understanding of the biological activities and health benefits of green tea polyphenols is still very limited. Further in-depth studies are needed to investigate the safety and efficacy of green tea in humans and to determine the different mechanisms of green tea in neuroprotection.
Animals↗
Mutations in NR4A2 associated with familial Parkinson disease.
NR4A2, encoding a member of nuclear receptor superfamily, is essential for the differentiation of the nigral dopaminergic neurons. To determine whether NR4A2 is a susceptibility gene for Parkinson disease, we carried out genetic analyses in 201 individuals affected with Parkinson disease and 221 age-matched unaffected controls. We identified two mutations in NR4A2 associated with Parkinson disease (-291Tdel and -245T-->G), which map to the first exon of NR4A2 and affect one allele in 10 of 107 individuals with familial Parkinson disease but not in any individuals with sporadic Parkinson disease (n = 94) or in unaffected controls (n = 221). The age at onset of disease and clinical features of these ten individuals were not different from those of individuals with typical Parkinson disease. The mutations resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals. Additionally, mutations in NR4A2 affect transcription of the gene encoding tyrosine hydroxylase. These data suggest that mutations in NR4A2 can cause dopaminergic dysfunction, associated with Parkinson disease.
Adult↗
Age at onset in two common neurodegenerative diseases is genetically controlled.
To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n=449) and Parkinson disease (PD; n=174). Heritabilities between 40%--60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases.
Age of Onset↗
Levodopa strengths and weaknesses.
Despite clinical experience with levodopa for more than three decades, the role of this agent in the treatment of Parkinson's disease (PD) has not been well defined. Clearly the most effective antiparkinsonian drug, levodopa, is associated with emergence of motor complications, particularly fluctuations and dyskinesias, as well as other side effects. In addition to these limitations, there is an ongoing debate about the potential neurotoxic effects of levodopa, suggested by some in vitro studies. However, there is no support for levodopa-induced neurotoxicity from in vivo studies. This review discusses possible mechanisms of levodopa-related complications and therapeutic strategies for their prevention and management.
Animals↗
Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD.
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Dopamine↗
Exploring the relationship between Parkinson disease and restless legs syndrome.
BACKGROUND: Restless legs syndrome (RLS) and Parkinson disease (PD) are common neurological conditions that respond to dopaminergic therapy. To our knowledge, the relationship between the two has not been thoroughly explored. METHODS: We consecutively queried 303 patients with PD seen in our clinic for the presence of RLS symptoms, and evaluated their condition with the Epworth Sleepiness Scale and other demographic and sleep measures. We then looked for predictors of RLS in these patients with PD. We also compared a larger group of patients with PD/RLS with a group of patients with RLS alone. RESULTS: Of 303 patients with PD, 63 (20.8%) had symptoms of RLS. Neither PD patient demographics nor PD treatments could reliably predict the development of RLS symptoms; however, lower serum ferritin levels were associated with RLS symptoms in our patients with PD (P =.01). In 54 (68%) of the 79 total patients with PD/RLS (including additional patients with PD/RLS seen in the clinic) with reliable age-at-onset data, the PD symptoms preceded the RLS symptoms (chi(2) test, P<.001). Compared with patients with idiopathic RLS (N = 146), patients with PD/RLS (N = 109) were older at RLS onset (P<.001), were less likely to have a family history of RLS (P<.001), and had lower serum ferritin levels (P =.01). CONCLUSIONS: Symptoms of RLS are common in patients with PD; however, except in patients with a family history of RLS, they seem to reflect a secondary phenomenon, perhaps in relation with lower ferritin levels. There is no evidence that RLS symptoms early in life predispose to the subsequent development of PD.
Aged↗
Intrafamilial phenotypic variability of the DYT1 dystonia: from asymptomatic TOR1A gene carrier status to dystonic storm.
When primary torsion dystonia is caused by a GAG deletion in the TOR1A gene (DYT1 dystonia), it typically presents with an early-onset dystonia involving distal limbs, subsequently spreading to a generalized dystonia. We describe a large family with an unusually broad variability in the clinical features of their dystonia both with regard to severity and age of onset. The proband of this family succumbed in his second decade to malignant generalized dystonia, whereas other family members carrying the same mutation are either asymptomatic or display dystonia that may be focal, segmental, multifocal, or generalized in distribution. One family member had onset of her dystonia at age 64 years, probably the oldest reported in genetically confirmed DYT1 dystonia. We conclude that marked phenotypic heterogeneity characterizes some families with DYT1 dystonia, suggesting a role for genetic, environmental, or other modifiers. These findings have implications for genetic testing and counseling.
Adolescent↗