alpha-synuclein and Restless-Legs-Syndrome

Brain iron disequilibrium and dopaminergic dysfunction are key pathophysiological features of Restless Legs Syndrome (RLS). Rep1 polymorphism in the promotor region of SNCA is associated with risk of Parkinson's disease, however its association with RLS and iron status is unclear.. To investigate SNCA-Rep1 polymorphism in RLS and its phenotypes.. We recruited RLS patients as well as age and gender matched healthy controls. Demographic information and clinical features of RLS were recorded. Laboratory examinations were performed to exclude possible secondary causes.. 215 RLS patients and 369 healthy controls were included. We found that the Rep1 allele 0 homozygosity significantly decreased RLS risk (OR: 0.345; P < 0.0001, and remained significant after the Bonferroni correction). Phenotypic analysis demonstrated that longer Rep1 alleles were associated with increased susceptibility to iron deficiency (53.0% vs 36.1%, P = 0.017), however had no phenotypic significant effects on age, gender, onset age, duration, RLS family history, severity, laterality, extra body involvement and seasonal fluctuation. Multivariate logistic regression analyses confirmed long Rep1 allele was associated with higher risk of iron deficiency in RLS after adjusting for potential confounding factors. In detail, Rep1 allele 2 homozygosity was prone to a higher risk of peripheral iron deficiency in RLS (OR: 4.550, P = 0.006, remained significant after the Bonferroni correction).. The SNCA-Rep1 variability modified RLS risk and influenced peripheral iron deficiency in this group of Chinese RLS patients. Rep1 allele 0 homozygosity decreased the risk of RLS, while homozygous allele 2 increased the risk of nonanemic iron deficiency in RLS.

Topics: Adult; Aged; Alleles; alpha-Synuclein; Anemia, Iron-Deficiency; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Humans; Iron Deficiencies; Iron Metabolism Disorders; Logistic Models; Male; Middle Aged; Multivariate Analysis; Phenotype; Restless Legs Syndrome

Gain-of-function mutations of alpha-synuclein (SNCA) are known to trigger Parkinson's disease (PD) with striatal dopaminergic deficits and a reduction of spontaneous movements. The longest size variant (allele 2) of the complex microsatellite repeat Rep1 within the SNCA gene promoter is known to confer a PD risk. We now observed this Rep1 allele 2 to show significantly decreased frequency in restless legs syndrome (RLS) in a genotyping study of 258 patients versus 235 healthy controls from Germany. Given that RLS is a disease with increased spontaneous movements and with increased striatal dopamine signaling, these novel data appear plausible. The scarcity of this alpha-synuclein gain-of-function variant in RLS might suggest that a low alpha-synuclein function via the SNARE complex in presynaptic vesicle release and neurotransmission of the striatum contributes to RLS pathogenesis.

Topics: Adult; Aged; Aged, 80 and over; Alleles; alpha-Synuclein; Gene Frequency; Humans; Microsatellite Repeats; Middle Aged; Parkinson Disease; Promoter Regions, Genetic; Restless Legs Syndrome

Previous epidemiologic and genetic studies have suggested a link between Parkinson disease (PD), essential tremor (ET), and restless legs syndrome (RLS).. We describe the clinical, PET, and pathologic characteristics of an extensive kindred from Arkansas with hereditary PD, ET, and RLS. The pedigree contains 138 individuals. Sixty-five family members were examined neurologically up to 3 times from 2004 to 2010. Clinical data were collected from medical records and questionnaires. Genetic studies were performed. Five family members underwent multitracer PET. Two individuals with PD were examined postmortem.. Eleven family members had PD with generally mild and slowly progressive symptoms. Age at onset was between 39 and 74 years (mean 59.1, SD 13.4). All individuals treated with l-dopa responded positively. Postural or action tremor was present in 6 individuals with PD, and in 19 additional family members. Fifteen persons reported symptoms of RLS. PET showed reduced presynaptic dopamine function typical of sporadic PD in a patient with PD and ET, but not in persons with ET or RLS. The inheritance pattern was autosomal dominant for PD and RLS. No known pathogenic mutation in PD-related genes was found. Fourteen of the family members with PD, ET, or RLS had depression. Neuropathologic examination revealed pallidonigral pigment spheroid degeneration with ubiquitin-positive axonal spheroids, TDP43-positive pathology in the basal ganglia, hippocampus, and brainstem, and only sparse Lewy bodies.. Familial forms of PD, ET, RLS, and depression occur in this family. The genetic cause remains to be elucidated.

Topics: Adult; Aged; alpha-Synuclein; Brain; Depression; DNA-Binding Proteins; Dynactin Complex; Essential Tremor; Eukaryotic Initiation Factor-4G; Family Health; Female; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Longitudinal Studies; Male; Mental Status Schedule; Microtubule-Associated Proteins; Middle Aged; Parkinsonian Disorders; Positron-Emission Tomography; Protein Serine-Threonine Kinases; Restless Legs Syndrome

We examined 7 patients from a family harboring a novel mutation in the alpha-synuclein gene (E46K) that segregated with a phenotype of parkinsonism and dementia with Lewy bodies. An abnormal restless sleep was the presenting symptom in 2 of them. Polysomnographic (PSG) studies were performed in 4 of the 7 patients and in 2 asymptomatic carriers of the mutation. A severe loss of both rapid eye movement (REM) and non-REM sleep was observed in 2 patients complaining of insomnia and in a third parkinsonian member of the family who did not complain of trouble with sleeping. Another parkinsonian family member had a mild disorganization of the sleep architecture. The 2 asymptomatic carriers also had minor changes in the PSG findings. Episodes of bizarre behavior at night were reported historically in the 2 symptomatic patients, but we did not observed the behaviors during the PSG studies. REM sleep behavior disorder could not be recorded in any case. Our findings expand the spectrum of sleep disorders reported in synucleinopathies whether sporadic or familial.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Diagnosis, Differential; DNA Mutational Analysis; Electroencephalography; Electromyography; Electrooculography; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinsonian Disorders; Pedigree; Point Mutation; Polysomnography; REM Sleep Behavior Disorder; Restless Legs Syndrome; Sleep Initiation and Maintenance Disorders

The neuroanatomical substrate for restless legs syndrome (RLS) is unknown. We identified 4 patients with idiopathic RLS who came to post-mortem examination, where brain and spinal cord tissue were available for neuropathological assessment. Lewy bodies were not identified and alpha-synuclein immunohistochemistry was uniformly negative. Neurofibrillary tangle pathology was variable and nonspecific. These findings suggest that tau- or alpha-synuclein brain pathology is not a component of primary RLS. Although chronic ischemic changes were found in all 4 cases, these were probably incidental. The absence of diagnostic microscopic brain or spinal cord pathology suggests that the pathologic substrate may be neurochemical or receptor based.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Female; Humans; Immunohistochemistry; Male; Middle Aged; Nerve Tissue Proteins; Neurofibrillary Tangles; Restless Legs Syndrome; Spinal Cord; Synucleins; tau Proteins