Genetics of Restless Legs Syndrome

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Chapter 8 Genetics of Restless Legs Syndrome

Lan Xiong, Gustavo Turecki, Anastasia Levchenko, Claudia Gaspar, Wayne A. Hening, Jacques Montplaisir, Guy A. Rouleau

Clinical Genetics of Restless Legs Syndrome

Data from epidemiological and family studies clearly indicate that a genetic component plays an important role in the pathogenesis of restless legs syndrome (RLS).

Restless Legs Syndrome is a Common Neurological Disorder with Variable Prevalence in Different Populations

Although RLS was first systematically described by Ekbom,¹ a Swedish neurologist, in 1945, accurate estimates of population incidence and prevalence only started to emerge in the late 1990s, following the first large-scale population survey by Montplaisir and associates.² Numerous recent epidemiological studies further confirmed that RLS is a very prevalent disorder in the population (see Chapter 7), with a prevalence around 10% to 15% in Western populations,³^–⁹ which is equivalent to the sum of prevalences for epilepsy (≈1%),¹⁰ Parkinson’s disease (≈1%),^11,¹² Alzheimer’s disease (≈1%),¹³ schizophrenia (≈1%),^14,¹⁵ and other neuropsychatric disorders, and only comparable with a few common prevalent diseases, such as depression (≈10%),¹⁶ hypertension (≈20%),¹⁷ and obesity (≈16%).¹⁸ Further studies suggest that there are substantial prevalence variations of RLS in different populations and racial groups. The prevalence was estimated higher in certain geographically or socially isolated populations, such as the French Canadians in Quebec compared with those in other provinces of Canada.² Conversely, RLS prevalence seems to be lower in Asian and African American populations compared with whites based on some preliminary results.¹⁹^–²⁴ However, one more recent survey of an adult community sample from east Baltimore suggests that there may be no appreciable difference of RLS prevalence between whites and African Americans.²⁵ Further large-scale population studies with validated diagnostic instruments will be needed to clarify the racial difference in RLS. Although both genetic and environmental factors may account for the divergence of prevalence in different populations, significant variations in disease incidence and prevalence among different racial/ethnic groups are usually an indicator of a strong genetic effect at the population level, especially when different ethnic groups show variable disease frequencies within a similar environment. Certainly, the discrepancy of prevalence difference between studies may also have derived from the sensitivity and specificity of the different diagnostic instruments used in the different studies, as well as ascertainment bias and population substratification due to geographical or cultural reasons.

Familiality

RLS is not only prevalent in the general population but also aggregates in families. The familial character of RLS has long been recognized since its first clinical description,¹ and it has been consistently reported by experienced clinicians.^2,²⁶^–³¹ Family history has been recognized as a significant risk factor for RLS.³² The proportion of familial cases present in the overall RLS patient population has been estimated to be 60%,²⁷^–³⁰ ³³ but it could be as high as 80% to 90% among idiopathic RLS patients.^27,³⁴ In our extensive family studies of 244 probands with idiopathic RLS, only 57 probands do not have a positive family history, which translates into a familial rate of 76.6% in our sample (L. Xiong, G. A. Rouleau, and J. Montplaisir, unpublished data). Family data from the Baltimore group also show that about 70% of their RLS patients have an interviewed first-degree relatives affected by RLS (W. A. Hening, preliminary data, 2006). A sample of RLS Foundation brain bank volunteers (N = 86; 82% women) had an even higher frequency of affected first-degree relatives: 79% (W. A. Hening, preliminary data, 2006).

Several large pedigrees were described in the literature where multiple members were affected with RLS over a span of three to five generations.^28,^31,³⁵^–⁴¹ According to our experience, this phenomenon is quite common in the general population, at least in French Canadians, further confirming its genetic nature.

Heritability

Adequate clinical data strongly indicate that RLS has an important genetic component. However, a crucial step before undertaking any molecular genetic studies in RLS is to determine the degree to which the phenotype is determined by the underlying genetic component. Data from population, family, and twin studies usually permit geneticists to estimate the magnitude of the genetic effect on the trait under study. The estimation of heritability is calculated by the expected correlation between family members for the phenotypic trait based on their degree of relationship. The prevalence of RLS in first-degree relatives of affected patients is estimated to be between 20% and 60%.²⁶^–²⁹ ³¹ Montplaisir and colleagues²⁸ examined 133 RLS patients who were studied using a standardized self-report questionnaire. In this sample, 63% had at least one first-degree relative affected with RLS, and 221 of 568 (38.9%) first-degree relatives were reported as affected.

Traditionally, the most powerful way to estimate the genetic and environmental components of phenotypic variance is to study monozygotic (MZ) and dizygotic (DZ) twins. However, due to its recent acceptance as a clinical entity and the development of accurate diagnostic criteria and instruments, there are few papers reporting limited data on twin studies about RLS that are up to date. One is from the Ondo group,⁴² which reported 12 pairs of MZ twins, among them 10 pairs concordant, 1 pair probably concordant, and 1 pair discordant on RLS symptoms. There were no concomitant data on DZ twins, making it impossible to differentiate the relative proportions and magnitude of genetic and environmental factors. The other large-scale population-based twin studies of RLS symptoms included 933 MZ and 1004 DZ twins who have completed two questions regarding their restless legs symptoms.⁴³ This study showed that the concordance rate of possible RLS symptoms is 61% in MZ and 45% in DZ twins; the concordance rate for “involuntary leg jerks during the night,” a possible metaphor for periodic leg movements during sleep (PLMS), is 69% in MZ and 54% in DZ twins. Further genetic modeling with the same set of data by using the frequencies of disease-concordant and disease-discordant rates and applying to a multifactorial liability threshold model indicates that additive genetic factors and a unique environment best explained the variance in disease liability. However, the critical weakness of this study is that the RLS diagnosis was only based on a simplified two-question self-report survey, which did not include all four essential clinical features. Therefore, they did not study RLS, but rather possibly a component of the disease. Nevertheless, as demonstrated in numerous studies of other genetic disorders, twin studies are powerful genetic tools to quantify and define the genetic contribution, possible mode of inheritance, and potential gene–environment interaction. Our data from a population-based survey of 272 twin pairs from Canada show that the concordant rate of definite RLS is 53.7% and 19.0% in MZ and DZ twins, respectively.⁴⁴ The estimated heritability is 69.4%, confirming the importance of the genetic factor in RLS etiology. However, in the World War II twin cohort (176 MZ and 135 DZ twin pairs), concordance was only slightly higher in MZ twins (23% versus 16%), leading to a much lower estimated heritability of 20%.⁸ This may reflect the much greater influence of environmental factors leading to secondary RLS in this aged, male-only cohort. The information obtained from additional appropriate twin studies will be critical for further molecular genetic studies aimed at identifying underlying causative or susceptibility genes for RLS.

It is well known in the field of genetic studies that the pattern of risk ratio (λ_R) in various degrees of relationship within a family may reflect the underlying genetic mechanism. The magnitude of λ_R can usually be used to predict the statistical power to detect linkage in gene mapping.⁴⁵^–⁴⁷ For a single-locus model and an additive multilocus genetic model, λ_R decreases by a factor of 2 with each degree of relationship. However, for a multiplicative (epistasis) model, λ_R decreases more rapidly than by a factor of 2 with degree of relationship.⁴⁵ For example, λ_R in first-, second-, and third-degree relatives of schizophrenia patients is 6% to 17%, 2% to 6%, and 2%, respectively,⁴⁸ suggesting the presence of multiple interacting loci. Unfortunately, there are very limited data available regarding the prevalence of RLS in more distant relatives other than the first-degree relatives, due to the difficulty in disease ascertainment. In one study of 96 RLS families, Allen and associates³⁰ reported that 19.9% of the first-degree relatives versus 4.1% of the second-degree relatives are affected compared with 3.5% versus 0.5% in 15 non-RLS control subjects.³⁰ Compared with a prevalence of 3.5% in their control group, the relative risk ratio λ_R dropped quickly from 5.7 to 1.2 from the first-degree relatives to the second-degree relatives. In another study of 15 large multiplex families with RLS by the Baylor group, the λ_R for parent-offspring is 10.25 and the λ_R for siblings is 16.23, and the overall heritability in their sample was estimated at 60%.³¹ Undoubtedly, the λ_R estimated in this study will not reflect the relative risk in general population, because the sample is extremely biased toward only the heavily loaded RLS families. In the Johns Hopkins family study, the relative risk for first-degree relatives of RLS probands (N = 134) was 3.6 compared with both the general population figures⁹ and an age- and gender-matched control group (N = 58), with higher figures for younger-onset probands (W. A. Hening and colleagues, preliminary data).

Mode of Inheritance

It is possible for geneticists to propose a genetic model for a given genetic trait, by deriving information from data obtained from population and family studies and by using specific statistical tools. Also, the simpler the underlying genetic structure, the more reliable their prediction becomes. However, the genetic study of RLS is at a very early stage compared with other hereditary forms of neurological and psychiatric disorders, such as epilepsy and schizophrenia, where many population and molecular genetic studies have been undertaken. In RLS, there are very limited reliable data on which to speculate. A few studies have attempted to model the genetic transmission of RLS. In most of the reported pedigrees, vertical transmission is predominant, making RLS mostly compatible with an autosomal dominant mode of inheritance with relatively high penetrance.^31,³⁵^–³⁷ The Winkelmann group from Germany performed complex segregation analyses on 238 families and predicted that a single autosomal allele acting dominantly can explain RLS in families with an early age at onset (AO) of symptoms, but it will not account for RLS with a later onset (>30 years).⁴⁹ However, another recent segregation study by Mathias and coworkers⁵⁰ indicates that a dominant model works for all families, not only younger-onset families. That study also found both a high frequency for the major gene and a high phenocopy rate (14%) fit better with the genetic model. That analysis also showed that there was genetic control of age at RLS onset, but without a major gene effect. Nevertheless, a careful examination of the detailed family histories in RLS pedigrees has always suggested a genetic model more complicated than a classic mendelian inheritance. In some reports, the percentage of RLS in first-degree relatives is greater than 50%^34,³⁷; we have also observed such segregation distortion in some of our collected RLS families (L. Xiong, G. A. Rouleau, and J. Montplaisir, unpublished data). The observed ratio of more than one half of first-degree relatives being affected in some RLS families may be due to an ascertainment bias but warrants further study to either confirm or refute this unusual observation. Some dominant families also showed reduced AO in consecutive generations, indicating possible anticipation.^36,³⁷ Due to the high prevalence of RLS and possible assortative mating in the population, bilinear inheritance is not uncommon. Among 50 familial cases in the Ondo group’s study, three had both parents affected.⁴² In our family studies, we also frequently encounter affected spouses and observe bilinear inheritance (L. Xiong, G. A. Rouleau, and J. Montplaisir, unpublished data). All pedigrees in the published linkage studies reported individuals carrying the predisposing haplotype but without the disease phenotype (nonpenetrants) and individuals without the haplotype but presenting with the disease symptoms (phenocopies).^31,^38,⁴⁰ More surprisingly, our linkage study of one large French-Canadian family showed the most significant results under an autosomal recessive model with an unusually high common disease allele frequency (25%), although the pedigree appears to be dominant³⁸; that is, a pseudodominant inheritance. In the systematic analysis of 15 autosomal dominant–looking multiplex families with 134 affected, 136 founders, and 317 nonfounders, Chen and coworkers³¹ demonstrated that the λ_R is higher in sib-pairs than in parent-offspring pairs (16.23 versus 10.25), which could also be explained by recessively or additively acting disease alleles. In summary, all available evidence suggests that genetic factors play an important role in the etiology of RLS; however, the mode of inheritance is probably more complex than it appears on cursory examination of available pedigrees. Results from complex segregation analysis need to be examined carefully and interpreted with caution because it is known to be problematic when dealing with complex traits.^51,⁵²

Source of Complexity: Phenotypic Definition

The high prevalence of the disease in the general population and several other clinical features strongly suggest that RLS is more likely a complex genetic trait than a classic mendelian trait, which is critical when undertaking molecular genetic studies.

Variable Age at Onset and Bimodal Age at Onset Distribution

In general, RLS is an adult-onset neurological disorder with a prevalence that tends to increase linearly with age.^3,⁷ In Ondo’s twin study, the earliest AO is 3 years of age, whereas the latest is 65 years of age. The AO varied by 40 years in two of the MZ twin pairs.⁴² The clinical manifestations of RLS also slowly progress with age in some patients with a severe form of RLS, which is similar to other late-onset neurodegenerative diseases. However, a certain percentage of patients and their family members may present with only a much milder form of RLS, never seeking medical attention and having a clinical course that is intermittent or waxing and waning. The limited number of neuropathological studies available also indicates that RLS is not caused by a traditional neurodegenerative processes, such as seen in τ- or α-synuclein brain pathologies.^53,⁵⁴

Several studies suggest a bimodal distribution of AO among RLS patients.²⁸^–³⁰ ^,49 ^,55 The younger probands usually have a higher rate of positive family history and slower disease progression rate, suggesting a greater genetic contribution and possibly a distinctive clinical course compared with nongenetic forms of RLS cases.²⁸^–³⁰ ⁵⁵ Many complex and highly prevalent disorders exhibit a wide range of AO due to various genetic and environmental factors that contribute to the same phenotype. An earlier AO is often considered a sign of genetic predisposition in many diseases, such as Alzheimer’s disease,^56,⁵⁷ breast cancer,⁵⁸ prostate cancer,⁵⁹ and Parkinson’s disease.^60,⁶¹ The use of AO information affects the power of gene mapping and identification. Several strategies can be applied to integrate AO information into molecular genetic studies. If a major gene effect is suspected that manifests itself at a specific range of age, the simplest way to use AO information is to stratify patients and families into early- and late-onset subgroups. Hopefully, in this way, the samples can be divided into more homogeneous subgroups to help circumvent the underlying genetic heterogeneity, or to purge the nongenetic cases. In parametric linkage analysis, adjustment of variable AO to different age-dependent liability classes within pedigrees is an important component of effective linkage analysis.⁶²^–⁶⁴ Liability classes are used to define penetrance values for each of the possible genotypes of the trait locus and to classify each individual into different penetrance groups on the basis of their age at investigation. In complex traits, the effects of AO on penetrance model–free analyses are even more complicated and have been further investigated by Li and associates.⁶⁵ These authors suggested that incorporating the AO information into affected sib-pairs (ASP) and transmission disequilibrium (TDT) tests, especially when focusing on sib-pairs both with early AO and TDT with all early AO trios, will greatly improve the power to detect the genetic signals. Alternatively, AO can be treated either as a covariate or quantitative trait by using variance component linkage analysis.⁶⁶ This is usually applied to identify genetic variants that will influence age at disease onset. For example, this method has been successfully applied to map genes modifying disease onset for type 2 diabetes,⁶⁷ Parkinson’s disease,⁶⁸ and Alzheimer’s disease.⁶⁹ Nevertheless, the preliminary data from complex segregation analyses by Mathias and colleagues⁵⁰ suggest that there is complex genetic control of age at onset for RLS in their samples.

Variable Phenotypic Expressivity

One of the most striking features of RLS is the high degree of variable phenotypic expressivity,^35,³⁶ even within MZ twins.⁴² The cardinal clinical symptom of RLS is an imperative urge to move, which is very subjective without any reliable validation and measurement. Misdiagnosis and underdiagnosis are not uncommon in clinical practice. RLS is considered one of the most common and least diagnosed sleep disorders, as well as neurological disorders.^70,⁷¹ Furthermore, as we mentioned earlier, frequently there are even milder forms among family members who never need medical attention and only get ascertained during family studies, quite often through telephone interviews only. We know that RLS can sometimes be very severe, causing intractable insomnia ⁷²; unfortunately, we do not know how mild symptoms should be interpreted, whether as mild RLS or as something completely unrelated. This is critically important in genetic studies. Until more reliable biological markers or laboratory tests become available, in current family linkage studies, different diagnostic criteria schemes can be applied to define the exact phenotype under study, from the most to the least stringent, to accommodate the wide range of phenotypic variations within the pedigree. Because the primary symptom of RLS is an imperative urge to move, other features, such as frequency and intensity of symptoms, can all be considered as measurements of severity. To fully address the phenotypic variations within and between families in gene mapping, the degree of severity, together with variable AO, can also be treated as covariate or quantitative traits by using a variance component method. Nonetheless, all these approaches require a significantly large number of participating families.