Restless Legs Syndrome and Sleep-Related Movement Disorders.

PURPOSE OF REVIEW: This article provides an update on six sleep-related movement disorders: restless legs syndrome (RLS), periodic limb movement disorder, sleep-related leg cramps, bruxism, rhythmic movement disorder, and propriospinal myoclonus, with an emphasis on RLS. RECENT FINDINGS: RLS is a common sensorimotor disorder that impairs quality of life. RLS is frequently comorbid to neurologic, psychiatric, vascular, and inflammatory diseases. Accumulating evidence implicates the pathophysiology of RLS as a state of dopamine dysfunction and iron deficiency that occurs on a background of genetic susceptibility conferred by 6 gene polymorphisms. Multiple treatments approved by the US Food and Drug Administration (FDA) are available. Dopamine agonists and α2δ calcium channel ligands are considered first-line treatments, but these treatments have very different side effect profiles that should be taken into consideration. SUMMARY: Sleep-related movement disorders are frequently encountered in clinical practice. For some disorders, particularly RLS and periodic limb movement disorder, our understanding of biology, epidemiology, and treatment is advanced. For others, much work is needed to determine optimal treatment strategies.

Periodic leg movements during sleep: phenotype, neurophysiology, and clinical significance.

Periodic leg movements during sleep (PLMS) are the most important objective finding in restless legs syndrome (RLS). During the last decade, PLMS have been very important for the assessment and comprehension of their pathophysiological correlates, which have been paralleled by the emergence of new computer-assisted and data-driven rules for their identification, scoring, and analysis. The present article focused on the most relevant PLMS-related findings of the last decade, and sought to provide a coherent and comprehensive overview on this enigmatic motor phenomenon. First, a clear description was made on the identification, quantification, and scoring of PLMS and their associated events. This was followed by a description of the current knowledge of their neurophysiologic aspects. Then, the typical phenotype of genuine PLMS in RLS and other clinical conditions was described, allowing for their careful separation from other sleep leg motor activities. In addition, the most recent findings on the genetics of PLMS were briefly summarized, followed by the current evidence on their clinical correlates, which is another rapidly advancing field of research. The description of the specific aspects of PLMS in children was also carefully reported, with important clues on their evaluation in this age group. Finally, further research was proposed, which may lead to consideration of PLMS as a clinically significant concern, independent of the association with RLS.

Prevalence and determinants of periodic limb movements in the general population.

OBJECTIVE: Periodic limb movements during sleep (PLMS) are sleep phenomena characterized by periodic episodes of repetitive stereotyped limb movements. The aim of this study was to describe the prevalence and determinants of PLMS in a middle to older aged general population. METHODS: Data from 2,162 subjects (51.2% women, mean age = 58.4 ± 11.1 years) participating in a population-based study (HypnoLaus, Lausanne, Switzerland) were collected. Assessments included laboratory tests, sociodemographic data, personal and treatment history, and full polysomnography at home. PLMS index (PLMSI) was determined, and PLMSI > 15/h was considered as significant. RESULTS: Prevalence of PLMSI > 15/h was 28.6% (31.3% in men, 26% in women). Compared to subjects with PLMSI ≤ 15/h, subjects with PLMSI > 15/h were older (p < 0.001), were predominantly males (p = 0.007), had a higher proportion of restless legs syndrome (RLS; p < 0.001), had a higher body mass index (p = 0.001), and had a lower mean glomerular filtration rate (p < 0.001). Subjects with PLMSI > 15/h also had a higher prevalence of diabetes, hypertension, and beta-blocker or hypnotic treatments. The prevalence of antidepressant use was higher, but not statistically significant (p = 0.07). Single nucleotide polymorphisms (SNPs) within BTBD9 (rs3923809), TOX3 (rs3104788), and MEIS1 (rs2300478) genes were significantly associated with PLSMI > 15/h. Conversely, mean hemoglobin and ferritin levels were similar in both groups. In the multivariate analysis, age, male gender, antidepressant intake, RLS, and rs3923809, rs3104788, and rs2300478 SNPs were independently associated with PLMSI > 15/h. INTERPRETATION: PLMS are highly prevalent in our middle-aged European population. Age, male gender, RLS, antidepressant treatment, and specific BTBD9, TOX3, and MEIS1 SNP distribution are independent predictors of PLMSI > 15/h.

Genetic associations of periodic limb movements of sleep in the elderly for the MrOS sleep study.

OBJECTIVE: The objective of this study was to assess the relationship between single-nucleotide polymorphisms associated with restless legs syndrome and periodic limb movements of sleep in a population cohort of elderly individuals. METHODS: Single-nucleotide polymorphisms previously associated with periodic limb movements of sleep or restless legs syndrome were analyzed in 2356 white male participants in the Osteoporotic Fractures in Men Sleep Study cohort. The associations between single-nucleotide polymorphisms and polysomnographically measured periodic limb movement index ≥15 were examined with logistic regression adjusted for age, ancestry markers, and periodic limb movements of sleep risk factors. RESULTS: Of the men in this cohort, 61% had a periodic limb movement index ≥15. Significant associations were observed between a periodic limb movement index ≥15 and the number of risk alleles for the two BTBD9 single-nucleotide polymorphisms (rs9357271[T], odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.20-1.58; and rs3923809[A], OR = 1.43, 95% CI 1.26-1.63), one of the MEIS1 single-nucleotide polymorphisms (rs2300478[G], OR = 1.31, 95% CI 1.14-1.51) and the mitogen-activated protein kinase kinase 5 (MAP2K5)/Ski family transcriptional corepressor 1 (SKOR1) single-nucleotide polymorphism (rs1026732[G], OR = 1.16, 95% CI 1.02-1.31). In a multivariable model controlling for each of the two MEIS1 single-nucleotide polymorphisms, the rs6710341[A] single-nucleotide polymorphism became a significant risk allele (OR = 1.59, 95% CI 1.26-2.00). CONCLUSIONS: Our findings confirm an association between the BTBD9, MEIS1, and MAP2K5/SKOR1 single-nucleotide polymorphisms and periodic limb movements of sleep in an elderly cohort not selected for the presence of restless legs syndrome.

Genetic variants associated with sleep disorders.

OBJECTIVE: The diagnostic boundaries of sleep disorders are under considerable debate. The main sleep disorders are partly heritable; therefore, defining heritable pathophysiologic mechanisms could delineate diagnoses and suggest treatment. We collected clinical data and DNA from consenting patients scheduled to undergo clinical polysomnograms, to expand our understanding of the polymorphisms associated with the phenotypes of particular sleep disorders. METHODS: Patients at least 21 years of age were recruited to contribute research questionnaires, and to provide access to their medical records, saliva for deoxyribonucleic acid (DNA), and polysomnographic data. From these complex data, 38 partly overlapping phenotypes were derived indicating complaints, subjective and objective sleep timing, and polysomnographic disturbances. A custom chip was used to genotype 768 single-nucleotide polymorphisms (SNPs). Additional assays derived ancestry-informative markers (eg, 751 participants of European ancestry). Linear regressions controlling for age, gender, and ancestry were used to assess the associations of each phenotype with each of the SNPs, highlighting those with Bonferroni-corrected significance. RESULTS: In peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B), rs6888451 was associated with several markers of obstructive sleep apnea. In aryl hydrocarbon receptor nuclear translocator-like (ARNTL), rs10766071 was associated with decreased polysomnographic sleep duration. The association of rs3923809 in BTBD9 with periodic limb movements in sleep was confirmed. SNPs in casein kinase 1 delta (CSNK1D rs11552085), cryptochrome 1 (CRY1 rs4964515), and retinoic acid receptor-related orphan receptor A (RORA rs11071547) were less persuasively associated with sleep latency and time of falling asleep. CONCLUSIONS: SNPs associated with several sleep phenotypes were suggested, but due to risks of false discovery, independent replications are needed before the importance of these associations can be assessed, followed by investigation of molecular mechanisms.

Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.

STUDY OBJECTIVES: To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS). SETTING: Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research. PATIENTS: Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012). DESIGN AND INTERVENTIONS: A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P < 8.3 × 10(-3)). RLS symptoms were categorized into four groups: likely, possible, no symptoms, and unknown based on a mailed survey response. MEASUREMENTS AND RESULTS: Prevalence of PLMI ≥ 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI > 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations. CONCLUSIONS: Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.

Clinical and polysomnographic features of a large Turkish pedigree with restless leg syndrome and periodic limb movements.

PURPOSE: Restless leg syndrome (RLS) and periodic limb movements (PLMS) are common neurological diseases often associated with insomnia. A familial aggregation in RLS has been identified since it was first described; however, inheritance patterns of RLS/PLMS are poorly understood and their exact pathophysiology is not well-known. We have identified a Turkish pedigree with RLS/PLMS, which is a rare condition, in five generations of a family, including nine affected family members. METHODS: A detailed clinical evaluation of the family was conducted with the help of polysomnographic recording, electrophysiological findings, and biochemical parameters. RESULTS: The proband is a 38-year-old male member of the family who first started to show symptoms at the age of 29. All the patients from this family have been diagnosed with RLS, according to the criteria of the International RLS Study Group. Disease onset was early in all cases and even earlier in the younger generation. Three affected individuals also had PLMS on polysomnographic recordings. CONCLUSION: To our knowledge, this is the first Turkish family in which nine individuals in five generations are affected. We suggest an important effect of anticipation and genetic impact of the diseases and describe specific clinical features. Further investigation of clinical, genetic, and biochemical similarities between PLMS and RLS may yield important clues, adding to our understanding of the pathophysiology of these common diseases.

Polysomnographic characteristics of a referred sample of children with sickle cell disease.

STUDY OBJECTIVES: To describe polysomnographic parameters and their clinical correlates in a referred sample of children with sickle cell disease (SCD). METHODS: This was a retrospective medical record review of 55 consecutive children aged 2-18 years with SCD (hemoglobin [Hb] SS and Hb SC genotypes) undergoing polysomnography for evaluation of sleep disordered breathing. Polysomnography values were compared between SCD genotypes, 4 age groups, and adenotonsillectomy status using descriptive and nonparametric statistics. RESULTS: Obstructive sleep apnea (OSA) was diagnosed in 38/55 (69%) children. Polysomnographic parameters differed significantly between Hb SS and Hb SC genotypes only on arterial oxyhemoglobin saturation (SpO2; 95.2 +/- 3.8 vs. 98.0 +/- 0.8, respectively, p < 0.01) and percent of sleep time below SpO2 90% (T90; 8.0 +/- 22.0 vs. 0.01 +/- 0.02, respectively, p < 0.05). Increasing age was associated with decreasing SpO2 (rho = -0.282, p < 0.05), obstructive apnea-hypopnea index (OAHI; rho = -0.364, p < 0.01), total arousal index (rho -0.272, p < 0.05) and respiratory arousal index (rho = -0.349, p < 0.01). Periodic limb movements in sleep (PLM) averaged 4.7 +/- 8.8/h, with a PLM index > 5/h in 5/17 children without OSA. Post- adenotonsillectomy, 8/10 children had OSA, but compared to untreated OSA-positive children they had a lower mean OAHI (4.4 +/- 5.5 vs. 8.9 +/- 12.5) and a lower T90 (1.6 +/- 4.2 vs. 9.2 +/- 24.9). CONCLUSIONS: Both OSA and PLMs were common in children with SCD. Children with Hb SS experienced more severe nocturnal oxygen desaturation than did those with Hb SC. Post-adenotonsillectomy, most children had OSA, although they experienced fewer obstructive respiratory events and less severe nocturnal oxygen desaturation than did untreated OSA-positive children.

Diffuse subcortical band heterotopia, periodic limb movements during sleep and a novel "de novo" mutation in the DCX gene.

Mutations of the DCX gene (Xp22.3) cause X-linked lissencephaly in males and double cortex syndrome (DCS) or subcortical band heterotopia (SBH) in females. SBH is characterized by bilateral bands of grey matter interposed in the white matter between the cortex and the lateral ventricles. The main clinical manifestation in patients with SBH is epilepsy, which may be partial or generalized and is intractable in approximately 65% of the patients. An association of periodic limb movements (PLMs) and SBH has not been documented previously. We describe a 2-year-old girl affected by SBH with epilepsy and periodic limb movements (PLMs), in whom a novel "de novo" missense substitution, Met1Val (M1V), was identified in the DCX gene. Physiopathological links between PLMs and SBH are discussed.

Association of intronic variants of the BTBD9 gene with Tourette syndrome.

OBJECTIVE: To test the association between Tourette syndrome (TS) and genetic variants in genomic loci MEIS1, MAP2K5/LBXCOR1, and BTBD9, for which genome-wide association studies in restless legs syndrome and periodic limb movements during sleep revealed common risk variants. DESIGN: Case-control association study. SETTING: Movement disorder clinic in Montreal. Subjects We typed 14 single-nucleotide polymorphisms spanning the 3 genomic loci in 298 TS trios, 322 TS cases (including 298 probands from the cohort of TS trios), and 290 control subjects. MAIN OUTCOME MEASURES: Clinical diagnosis of TS, obsessive-compulsive disorder, and attention-deficit disorder. RESULTS: The study provided 3 single-nucleotide polymorphisms within BTBD9 associated with TS (chi(2) = 8.02 [P = .005] for rs9357271), with the risk alleles for restless legs syndrome and periodic limb movements during sleep overrepresented in the TS cohort. We stratified our group of patients with TS according to presence or absence of obsessive-compulsive disorder and/or attention-deficit disorder and found that variants in BTBD9 were strongly associated with TS without obsessive-compulsive disorder (chi(2) = 12.95 [P < .001] for rs9357271). Furthermore, allele frequency of rs9357271 inversely correlated with severity of obsessive-compulsive disorder as measured by the Yale-Brown Obsessive Compulsive Scale score. CONCLUSION: Variants in BTBD9 that predispose to restless legs syndrome and periodic limb movements during sleep are also associated with TS, particularly TS without obsessive-compulsive disorder.

Pediatric restless legs syndrome and periodic limb movement disorder: parent-child pairs.

OBJECTIVE: Although recent publications have reported the occurrence of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) in children and adolescents, the literature is relatively limited. The goals of this retrospective study were to (1) apply the recent International Classification of Sleep Disorders 2nd edition (ICSD-2) diagnostic criteria for RLS and PLMD in pediatric cases where periodic limb movements in sleep (PLMS) 5 per hour were found; (2) review parental history of RLS; and (3) further define the clinical characteristics of RLS and PLMD in a pediatric subgroup where each child had a parent with clinically assessed RLS. METHODS: This was a retrospective analysis of consecutive polysomnograms (PSGs) with PLMS >5 per hour in patients 19 years of age from a single pediatric sleep/neurology practice over 11 years. Excluded were cases with sleep apnea, narcolepsy, or medication that might induce or aggravate PLMS or RLS. ICSD-2 diagnostic criteria for definite RLS and PLMD were applied to the pediatric cases, and parental history for RLS was assessed. A subset of cases was included for detailed review if the child or adolescent had RLS or PLMD and a biological parent met RLS criteria and had a formal sleep evaluation. RESULTS: There were 204 cases that met the initial inclusion criteria. A positive parental history of RLS was found in 53% of pediatric RLS cases and in 52% of pediatric PLMD cases. A subset of 37 children or adolescents and 36 biological parents, from 33 different families, met full inclusion criteria and are presented in detail. Of these 37, 10 had a diagnosis of RLS and 27 a diagnosis of PLMD. Over this same period of time, PLMS >5 per hour were found in 74% of pediatric definite RLS cases assessed by PSG. CONCLUSIONS: This case series adds to the growing literature describing RLS and PLMD in children and adolescents using recently revised diagnostic criteria. The similar prevalence of parental RLS in both pediatric RLS and pediatric PLMD cases suggests a close association between PLMD and RLS in some cases. This supports the emerging view that PLMS may be a marker or endophenotype for a specific, common RLS genotype.

Rapid eye movement sleep disturbances in Huntington disease.

BACKGROUND: Sleep disorders including insomnia, movements during sleep, and daytime sleepiness are common but poorly studied in Huntington disease (HD). OBJECTIVE: To evaluate the HD sleep-wake phenotype (including abnormal motor activity during sleep) in patients with various HD stages and the length of CAG repeats. Because a mild hypocretin deficiency has been found in the brains of some patients with HD (hereinafter referred to as HD patients), we also tested the HD patients for narcolepsy. DESIGN AND PATIENTS: Twenty-five HD patients (including 2 premanifest carriers) underwent clinical interview, nighttime video and sleep monitoring, and daytime multiple sleep latency tests. Their results were compared with those of patients with narcolepsy and control patients. RESULTS: The HD patients had frequent insomnia, earlier sleep onset, lower sleep efficiency, increased stage 1 sleep, delayed and shortened rapid eye movement (REM) sleep, and increased periodic leg movements. Three HD patients (12%) had REM sleep behavior disorders. No sleep abnormality correlated with CAG repeat length. Reduced REM sleep duration (but not REM sleep behavior disorders) was present in premanifest carriers and patients with very mild HD and worsened with disease severity. In contrast to narcoleptic patients, HD patients had no cataplexy, hypnagogic hallucinations, or sleep paralysis. Four HD patients had abnormally low (< 8 minutes) daytime sleep latencies, but none had multiple sleep-onset REM periods. CONCLUSIONS: The sleep phenotype of HD includes insomnia, advanced sleep phase, periodic leg movements, REM sleep behavior disorders, and reduced REM sleep but not narcolepsy. Reduced REM sleep may precede chorea. Mutant huntingtin may exert an effect on REM sleep and motor control during sleep.

Are there distinctive sleep problems in Angelman syndrome?

Angelman syndrome is a neurogenetic condition characterized by developmental delay, absence of speech, motor impairment, epilepsy and a peculiar behavioral phenotype that includes sleep problems. It is caused by lack of expression of the UBE3A gene on the maternal chromosome 15q11-q13. Although part of the diagnostic description, 'sleep problems' are not well characterized. A pattern emerges from the available reports. It includes reduced total sleep time, increased sleep onset latency, disrupted sleep architecture with frequent nocturnal awakenings, reduced rapid eye movement (REM) sleep and periodic leg movements. Poor sleep does not significantly interfere with daytime alertness and sleep problems commonly diminish by late childhood, with continuing improvement through adolescence and adulthood. Sleep problems in Angelman syndrome reflect abnormal neurodevelopmental functioning presumably involving dysregulation of GABA-mediated inhibitory influences in thalamocortical interactions. Management may be difficult, particularly in young children; it primarily involves behavioral approaches, though pharmacological treatment may be required. The relationship between sleep and seizure disorder, and between sleep and learning raises critical questions, but more studies are needed to address these relationships adequately.

A genetic risk factor for periodic limb movements in sleep.

BACKGROUND: The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. METHODS: To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. RESULTS: In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). CONCLUSIONS: We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.

Familial benign neonatal sleep myoclonus.

Benign neonatal sleep myoclonus is a nonepileptic syndrome characterized by myoclonic jerks during sleep. It occurs in the first weeks of life and disappears, in most cases, within 3 months. There are no sequelae, and psychomotor and cognitive development are normal. The syndrome is usually sporadic; only a few familial cases have been reported in the literature. This case report describes three members of a single family with benign neonatal sleep myoclonus and discusses its differentiation from other types of myoclonus.

Undiagnosed individuals with first-degree relatives with restless legs syndrome have increased periodic limb movements.

BACKGROUND AND PURPOSE: To evaluate periodic limb movements during sleep (PLMS) in first-degree relatives of both restless legs syndrome (RLS) patients and matched controls without RLS in order to analyze patterns of this motor sign of RLS. PATIENTS AND METHODS: First-degree relatives of a consecutive case series of RLS patients and matched community controls without RLS were evaluated for diagnosis of primary RLS and for PLMS as determined by a leg activity meter. The data were analyzed to determine whether or not PLMS rates are higher than expected for RLS subjects in these families, who have mostly milder disease, and family members of early-onset RLS patients not themselves diagnosed with RLS. RESULTS: PLMS activity in family members was significantly higher for those diagnosed as RLS compared to those diagnosed as not-RLS. This difference was greater for older than younger subjects. In family members older than the median study age (52 years old) who were diagnosed as not-RLS, PLMS were significantly more frequent in those related to an early-onset RLS proband than in those related to either a control or late-onset RLS proband. CONCLUSIONS: PLMS are elevated even in those with mild RLS and reveal an age-related worsening of the motor component of RLS. PLMS may represent an incomplete expression of RLS tendencies in families of patients with early-onset RLS, but this needs to be confirmed in future longitudinal studies. The increase in PLMS with age, reported in healthy controls, may in fact occur in part as a partial expression of familial or genetic factors associated with RLS.

Disturbance of rapid eye movement sleep in spinocerebellar ataxia type 2.

Five genetically confirmed spinocerebellar ataxia type 2 (SCA2) patients were admitted to our sleep laboratory for two all-night video-polysomnographies. A standard montage was used, including electroencephalography, vertical and horizontal electrooculography, electromyography of mental, submental, and tibialis anterior muscles, and respiratory monitoring. Four of five SCA2 patients had insufficient muscle atonia during rapid eye movement (REM) sleep. All patients exhibited myoclonic jerks during REM sleep, while elaborated behavior was not observed in the video. Abnormal motor control during sleep with periodic leg movements and REM sleep without atonia occurs frequently in SCA2. This finding may reflect a dysfunction of dopaminergic and/or brainstem and cerebellar outflow pathways.

Autosomal dominant nocturnal frontal lobe epilepsy--a critical overview.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic epilepsy, with a spectrum of clinical manifestations, ranging from brief, stereotyped, sudden arousals to more complex dystonic-dyskinetic seizures. Video-polysomnography allows a correct differential diagnosis. There is no difference between sporadic nocturnal frontal lobe epilepsy (NFLE) and ADNFLE in the clinical and neurophysiological findings. ADNFLE is the first idiopathic epilepsy for which a genetic basis has been identified. Mutations have been found in two genes (CHRNA4 and CHRNB2) coding for neuronal nicotinic receptor subunits (alpha4 and beta2, respectively). Contrasting data have been reported on the effect of these mutations on the functionality of the receptor.Moreover, the incomplete data on the neuronal network/s in which this receptor is involved, make difficult the understanding of the genotype-phenotype correlation. This is an overview on the clinical and genetic aspects of ADNFLE including a discussion of some open questions on the role of the neuronal nicotinic receptor subunit mutations in the pathogenesis of this form of epilepsy.