Alex Desautels

Narcolepsy is strongly associated with the T-cell receptor alpha locus

Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10−21, 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA–TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.

Identification of a Major Susceptibility Locus for Restless Legs Syndrome on Chromosome 12q

Restless legs syndrome (RLS) is a neurological disorder characterized by leg paresthesia associated with an irresistible urge to move that often interferes with nocturnal sleep, leading to chronic sleep deprivation. To map genes that may play a role in the vulnerability to RLS, a genomewide scan was conducted in a large French-Canadian family. Significant linkage was established on chromosome 12q, for a series of adjacent microsatellite markers with a maximum two-point LOD score of 3.42 (recombination fraction.05; P=6x10(-4); autosomal recessive mode of inheritance), whereas multipoint linkage calculations yielded a LOD score of 3.59. Haplotype analysis refined the genetic interval, positioning the RLS-predisposing gene in a 14.71-cM region between D12S1044 and D12S78. These findings represent the first mapping of a locus conferring susceptibility to RLS.

Polysomnographic diagnosis of idiopathic REM sleep behavior disorder

The presence of either excessive tonic chin EMG activity during REM sleep, or excessive phasic submental or limb EMG twitching is required to diagnose REM sleep behavior disorder (RBD). The aim was to identify cut‐off values and to assess the sensitivity and specificity of these values taken separately or combined to diagnose idiopathic RBD patients. Eighty patients presenting with a clinical diagnosis of idiopathic RBD and 80 age‐ and gender‐matched normal controls were studied in the sleep laboratory. Receiver operating characteristic curves were drawn to find optimal cut‐off values for three REM sleep EMG parameters. Tonic and phasic EMG activity were measured in the chin, but not in the limbs. Videos were examined during the recording but were not systematically reviewed by the authors. Total correct classification of 81.9% was found for tonic chin EMG density ≥30%; 83.8% for phasic chin EMG density ≥15% and 75.6% for ≥24 leg movements per hour of REM sleep. Five patients did not fulfill any of these three polysomnographic (PSG) criteria. Conversely, one subject of the control group met the PSG criteria for RBD. This study estimates the diagnostic value of a visual scoring method for the diagnosis of idiopathic RBD and establishes cut‐off values to be used in clinical and research set‐ups. For the five RBD patients who did not show chin EMG abnormalities, it cannot be excluded that they had increased phasic EMG activity in the upper limbs and presented visible motor activity.

Common variants in P2RY11 are associated with narcolepsy

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10−10, odds ratio = 1.28, 95% CI 1.19–1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8+ T lymphocytes (72% reduced, P = 0.003) and natural killer (NK) cells (70% reduced, P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.

ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

Sleep Laboratory Diagnosis of Restless Legs Syndrome

Polysomnographic recordings and the Suggested Immobilization Test (SIT) are frequently used to support the clinical diagnosis of restless legs syndrome (RLS). The present study evaluated the discriminant power of 5 different parameters: (1) index of periodic leg movements during sleep (PLMS), (2) index of PLMS with an associated microarousal (PLMS-arousal), (3) index of PLM during nocturnal wakefulness (PLMW), (4) SIT PLM index and (5) mean subjective leg discomfort score during the SIT (SIT MDS) in 100 patients with idiopathic RLS and 50 healthy control subjects. Both groups differed significantly on each parameter studied. Furthermore, while the SIT PLM, the PLMS and the PLMS-arousal indices revealed a poor ability to discriminate patients from controls, the PLMW index and the MDS both showed high sensitivity (87 ± 7 and 82 ± 8, respectively) and specificity (80 ± 11 and 84 ± 10, respectively) for diagnosing RLS. The combination of these 2 parameters correctly classified 88% of all subjects with a sensitivity of 82% and a specificity of 100%.

A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13

The authors investigated genetic factors contributing to restless legs syndrome (RLS) by performing a 10-cM genome-wide scan in a large French-Canadian pedigree. They detected an autosomal-dominant locus mapping to chromosome 20p13, with a maximum multipoint lod score of 3.86 at marker D20S849. This is the third reported autosomal-dominant locus for RLS and the first autosomal-dominant RLS locus in the French-Canadian population.

Effects of immobility on sensory and motor symptoms of restless legs syndrome

Restless legs syndrome (RLS) is defined by an irresistible need to move associated with leg paresthesia. Two additional features are essential for diagnosis: (1) worsening of symptoms at rest with temporary relief by activity, and (2) worsening of symptoms during the evening and/or during the night. The suggested immobilization test (SIT) has been developed to evaluate the presence of these criteria. This test quantifies leg movements and leg discomfort during a 1‐hour period of immobility prior to bedtime. We used the SIT to evaluate the effects of immobility on leg discomfort and leg movements experienced by 19 patients with RLS and 19 control subjects. Results show that immobility significantly worsens both leg discomfort and periodic leg movements (PLM) in patients with RLS but not in controls. Patients with RLS showed a higher leg discomfort score (32.6 ± 15.1 mm vs. 5.7 ± 7.9 mm; P < 0.00001), a greater maximum leg discomfort value (63.4 ± 27.4 mm vs. 13.7 ± 23.0 mm; P < 0.00001) and a greater PLM index (88.4 ± 62.6 vs. 10.4 ± 20.6; P < 0.00004) than control subjects. These results further validate the use of the SIT as a diagnostic and research tool for RLS and confirm the contention of the International RLS study group that RLS symptoms worsen at rest.

Evidence for a genetic association between monoamine oxidase A and restless legs syndrome

Background Impairment in the central dopaminergic system has been consistently suggested as an etiologic factor in restless legs syndrome (RLS). Objective To investigate a possible role for the MAOA and MAOB genes in RLS using a population-based association study. Methods In addition to a dinucleotide repeat located within the second intron of the MAOB gene, a functional variable number of tandem repeat (VNTR) polymorphism recently identified in the MAOA gene promoter region was examined, using 96 extensively characterized patients and 200 control subjects matched for ethnic background. The relationship between variation at these loci and several clinical features was also considered. Results Pertaining to the MAOA gene, females with the high activity allele had a greater risk (OR: 2.0; 95% CI: 1.06 to 3.77) of being affected with RLS than females carrying the low activity alleles. The authors did not observe this association among the male subjects (OR: 0.98; 95% CI: 0.31 to 3.14). Interestingly, females carrying the high transcription alleles showed a longer sleep onset latency (U = 163.5;p = 0.015) and exhibited a higher movement index during the Suggested Immobilization Test (Student’s t-test = −2.02;p = 0.048). No differences were observed regarding the MAOB gene in our sample. Conclusions The high activity allele of the MAOA gene may represent a modifying factor involved in the severity of RLS manifestations in females.

Somnambulism: clinical aspects and pathophysiological hypotheses

Somnambulism, or sleepwalking, can give rise to a wide range of adverse consequences and is one of the leading causes of sleep-related injury. Accurate diagnosis is crucial for proper management and imperative in an ever-increasing number of medicolegal cases implicating sleep-related violence. Unfortunately, several widely held views of sleepwalking are characterised by key misconceptions, and some established diagnostic criteria are inconsistent with research findings. The traditional idea of somnambulism as a disorder of arousal might be too restrictive and a comprehensive view should include the idea of simultaneous interplay between states of sleep and wakefulness. Abnormal sleep physiology, state dissociation, and genetic factors might explain the pathophysiology of the disorder.