Siong Chi Lin

Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1

Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10−11, OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10−19, OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5′-end of TOX3 and the adjacent non-coding RNA BC034767.

Effect of Pramipexole in Treatment of Resistant Restless Legs Syndrome

OBJECTIVE To report the results of an open-label trial with a dopaminergic agent, pramipexole, in patients with treatment-resistant restless legs syndrome (RLS). MATERIAL AND METHODS We studied the response to pramipexole in a consecutive series of 16 patients with symptomatic RLS who had previously experienced failure with other dopaminergic therapies. Patients assessed their posttreatment change in symptoms of RLS on a visual analog scale and indicated drug-related side effects with use of a checklist. RESULTS With a mean dose of pramipexole of 0.3 mg, most patients reported clinically significant improvement. From 2 to 3 months after initiation of pramipexole therapy, nocturnal leg restlessness, involuntary leg movements, and insomnia had decreased in 12, 10, and 11 patients, respectively. The most frequent adverse effects were fatigue and stiffness, which occurred in a third of the patients. Overall, the drug was well tolerated. CONCLUSION On the basis of these findings, we propose that pramipexole, a D2 subgroup receptor agonist, is an effective agent for treatment of RLS.

The use of electroconvulsive therapy in pain patients

Twenty-one patients with primary chronic pain received electroconvulsive therapy (ECT) for concurrent affective symptoms. Twenty of the 21 patients experienced improvement in the level of their pain. ECT can be an effective treatment modality for patients who have chronic pain complicated by affective symptoms.

Analysis of the C9orf72 repeat in Parkinson's disease, essential tremor and restless legs syndrome

The hexanucleotide expanded repeat (GGGGCC) in intron 1 of the C9orf72 gene is recognized as the most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, as part of the clinical phenotype, some patients present with parkinsonism. The present study investigated the potential expansion or association of the C9orf72 repeat length with susceptibility to Parkinsons disease and related disorders, essential tremor and restless legs syndrome. One restless legs syndrome patient was shown to harbor a repeat expansion, however on clinical follow-up this patient was observed to have developed frontotemporal dementia. There was no evidence of association of repeat length on disease risk or age-at-onset for any of the three disorders. Therefore the C9orf72 hexanucleotide repeat expansion appears to be specific to TDP-43 driven amyotrophic lateral sclerosis and dementia.

Abnormal daytime sleepiness in dementia with Lewy bodies compared to Alzheimer's disease using the Multiple Sleep Latency Test.

IntroductionExcessive daytime sleepiness is a commonly reported problem in dementia with Lewy bodies (DLB). We examined the relationship between nighttime sleep continuity and the propensity to fall asleep during the day in clinically probable DLB compared to Alzheimer’s disease (AD) dementia.MethodsA full-night polysomnography was carried out in 61 participants with DLB and 26 with AD dementia. Among this group, 32 participants with DLB and 18 with AD dementia underwent a daytime Multiple Sleep Latency Test (MSLT). Neuropathologic examinations of 20 participants with DLB were carried out.ResultsAlthough nighttime sleep efficiency did not differentiate diagnostic groups, the mean MSLT initial sleep latency was significantly shorter in participants with DLB than in those with AD dementia (mean 6.4 ± 5 minutes vs 11 ± 5 minutes, P <0.01). In the DLB group, 81% fell asleep within 10 minutes compared to 39% of the AD dementia group (P <0.01), and 56% in the DLB group fell asleep within 5 minutes compared to 17% in the AD dementia group (P <0.01). Daytime sleepiness in AD dementia was associated with greater dementia severity, but mean MSLT latency in DLB was not related to dementia severity, sleep efficiency the night before, or to visual hallucinations, fluctuations, parkinsonism or rapid eye movement sleep behavior disorder. These data suggest that abnormal daytime sleepiness is a unique feature of DLB that does not depend on nighttime sleep fragmentation or the presence of the four cardinal DLB features. Of the 20 DLB participants who underwent autopsy, those with transitional Lewy body disease (brainstem and limbic) did not differ from those with added cortical pathology (diffuse Lewy body disease) in dementia severity, DLB core features or sleep variables.ConclusionsDaytime sleepiness is more likely to occur in persons with DLB than in those with AD dementia. Daytime sleepiness in DLB may be attributed to disrupted brainstem and limbic sleep–wake physiology, and further work is needed to better understand the underlying mechanisms.

Clinical and Genetic Description of a Family With a High Prevalence of Autosomal Dominant Restless Legs Syndrome

OBJECTIVE To conduct clinical and molecular genetic analyses of the members of an extended family in Central Indiana with a high prevalence of restless legs syndrome (RLS). PARTICIPANTS AND METHODS From February 1, 2006, through August 31, 2008, we collected data from members of this family, which is of English descent. Genealogical methods were used to expand the family tree, and family members were screened with an RLS questionnaire. Telephone interviews and personal examinations were performed at Mayo Clinic and during a field trip to Central Indiana. Blood samples were collected for molecular genetic analysis. A follow-up telephone interview was conducted 1 year later. RESULTS The family tree spans 7 generations with 88 living members, 30 of whom meet the criteria for diagnosis of RLS established by the International Restless Legs Syndrome Study Group. Three affected family members also have Parkinson disease or essential tremor. The mode of RLS inheritance is compatible with an autosomal dominant pattern. The affected family members do not exhibit linkage to the 5 known RLS loci or mutations in the RLS susceptibility genes MEIS1 and BTBD9 . CONCLUSION Of 88 members of this single extended family in Central Indiana, 30 were diagnosed as having RLS. Because our analysis shows that the disease is not linked to any of the known RLS loci or risk-associated genes, we postulate that members of this family may carry a gene mutation in a novel genetic locus.

Sleep patterns of cyclic parenteral nutrition, a pilot study: are there sleepless nights?

BACKGROUND Cyclic home parenteral nutrition (HPN) is 1 of the few medical therapies given during normal nocturnal sleep hours, and it is possible that infusion may alter normal sleep patterns. The aim of this pilot study was to evaluate the sleep patterns of 5 patients receiving HPN. METHODS An Epworth sleep questionnaire was completed and wrist Actigraph data were collected before admission to the sleep laboratory. Formal overnight polysomnography was then preformed for 3 consecutive nights. The first night served as the acclimatization period. On the second and third nights, patients were randomized to receive either no infusion or infusion of their standard parenteral nutrition. Results were reported as the median and range and were compared with historical aged-matched controls. RESULTS Five patients (3 women and 2 men) with a mean age of 61 years (40 to 73 years) were studied. Patients had been HPN-dependent for a median of 23 months (4 to 60 months). Patients were receiving HPN because of short bowel syndrome (2), chronic pancreatitis (2), and intestinal pseudoobstruction (1). A 1.5-liter HPN formula, infused over 10 hours, included approximately 25 kcal/kg/d with 30% lipid and 1.0 to 1.5 g/kg/d of protein. All solutions included multiple trace elements and standard multivitamins. During total parenteral nutrition (TPN) infusion, the percent of sleep efficiency was higher than without infusion, 81% versus 72%. Sleep efficiency in age-matched controls was approximately 88%. Sleep latency was longer in patients compared with controls, and longer in patients during infusion than without infusion, 35 versus 28 minutes. During TPN infusion, the percent of stage-1 (2%), stage-2 (52%), slow-wave (24%) and random eye movement (REM) sleep (21%) was similar to values during the night without infusion. Controls had lower slow-wave and REM times. The median Epworth sleep score was 3, which is the normal reported range. CONCLUSIONS Although sleep quality is reduced in patients receiving HPN compared with aged-matched controls, sleep quality does not seem to be negatively effected by cyclic HPN infusion.

Anatomy of Disturbed Sleep in Pallido-Ponto-Nigral Degeneration

Pallido‐ponto‐nigral degeneration (PPND), caused by an N279K mutation of the MAPT gene, is 1 of a family of disorders collectively referred to as frontotemporal dementia and parkinsonism linked to chromosome 17. This study aims to characterize the nature of the sleep disturbance in PPND and compare these findings to those in other progressive neurological illnesses. Pathological findings are also provided.

The impact of gender on alpha-methyl-paratyrosine mediated changes in prolactin secretion and 6-hydroxymelatonin sulfate excretion

Prolactin (PRL) and melatonin (ML) secretion are mediated by dopamine (DA) and norepinephrine (NE), respectively. Alpha-methyl-para-tyrosine (AMPT) inhibits the production of CNS catecholamines (CA). The purpose of the study is to determine: (1) if AMPT inhibition of ML has the same gender-dependent effect as on PRL secretion; (2) if there is a post AMPT-induced NE depletion mood change in men and/or women. In a randomized, double-blind cross-over fashion, five healthy young males and five females were either given five doses of AMPT 1 g (active) or promethazine 50 mg (placebo) over a 28 h period, separated by 4-6 weeks. The PRL and ML concentrations were collected at regular intervals via an indwelling venous catheter and concurrently, two 12 h urinary 6-hydroxymelatonin sulfate (6-MS) measurements were made. Mood and anxiety states of subjects at baseline and post drug were assessed with appropriate rating scales at regular intervals. Light exposure beginning at dusk and lasting until dawn was controlled to no more than 200 lux during all phases of the study. The PRL secretion showed a significant interaction of drug x time (p = .0001) in women and a non-significant trend (p = .056) in men. No difference in PRL secretion was found between the two genders in the placebo condition, whereas the PRL secretion was significantly higher in the AMPT condition in women when compared to men (df 17,119, F = 1.9, p = .021). Total 24 h urinary 6-MS secretion highly correlated with ML secretion expressed as area under the curve (AUC) during both active and placebo experiments (r = 0.8, p < .01) and (r = 0.86, p < or = .01), respectively. The ANOVA reveals a significant interaction of drug x time for 6-SM excretion. There was no gender difference in AMPT suppression of 6-MS excretion. No mood changes were detected in men or women. We conclude that urinary 6-MS is a reliable indirect measure of the degree of AMPT-induced decrease in CNS NE activity as part of overall AMPT-induced reduction of central catecholamine activities. The pre and post AMPT-induced changes in 6-MS are not gender dependent, dissimilar to the AMPT-induced changes in PRL secretion. Therefore, 6-MS, in addition to PRL, should be measured when applying the AMPT paradigm in future research.

The effect of presynaptic catecholamine depletion on 6-hydroxymelatonin sulfate: A double blind study of α-methyl-para-tyrosine

Because it is a competitive inhibitor of tyrosine hydroxylase, alpha-methyl-para-tyrosine (AMPT) is used to study psychiatric disorders. Melatonin serves as a biological marker of catecholamine function since its secretion is regulated by noradrenergic neurons via beta-adrenergic receptors in the pineal gland. Ten healthy volunteers were administered AMPT in a double-blind placebo controlled study. When subjects received AMPT, nocturnal 6-hydroxymelatonin sulfate (6-SM) decreased significantly as compared with promethazine (night 1 P=0.002; and night 2 P=0.001). Urinary MHPG also decreased on both study days (DF1,9 F=9.82, GG=0.0121). Nocturnal 6-SM excretion and melatonin secretion correlated highly (r=0.91, P=0.0007). Behavioral ratings did not reveal a difference in symptomatology and did not correlate with changes in 6-SM or MHPG. This study demonstrates in healthy controls that 6-SM reliably reflects presynaptic catecholamine depletion induced by AMPT without the emergence of behavioral symptoms.