Disease mechanism
Most research on the disease mechanism of restless legs syndrome has focused on the dopamine and iron system. These hypotheses are based on the observation that iron and levodopa can be used to treat RLS, levodopa being a medicine for treating hypodopaminergic (low dopamine) conditions, and also on findings from functional brain imaging (such as positron emission tomography and functional magnetic resonance imaging), autopsy series and animal experiments. Differences in dopamine- and iron-related markers have also been demonstrated in the cerebrospinal fluid of individuals with RLS. A connection between these two systems is demonstrated by the finding of low iron levels in the substantia nigra of RLS patients, although other areas may also be involved.Underlying disorders
The most commonly associated medical condition is iron deficiency (specifically blood ferritin below 50& µg/L), which accounts for just over 20% of all cases of RLS. Other conditions associated with RLS include varicose vein or venous reflux, folate deficiency, magnesium deficiency, fibromyalgia, sleep apnea, uremia, diabetes, thyroid disease, peripheral neuropathy, Parkinson's disease and certain auto-immune disorders such as Sjögren's syndrome, celiac disease, and rheumatoid arthritis. RLS can also worsen in pregnancy. In a recent study, RLS was detected in 36% of patients attending a phlebology (vein disease) clinic, compared to 18% in a control group.Certain medications may worsen RLS in those who already have it, or cause it secondarily. These include: some antiemetics (the dopaminergic ones), certain antihistamines (often in over-the-counter cold medications), many antidepressants (both older TCAs and newer SSRIs), antipsychotics, and certain anticonvulsants. Treatment of underlying conditions, or cessation of use of the offending drug, often eliminates the RLS. Restless legs syndrome can occur as a result of the benzodiazepine withdrawal syndrome when discontinuing benzodiazepine tranquillisers or sleeping pills. A sedative hypnotic with a short half life may also induce restless legs syndrome when the dose wears off as part of a rebound effect.
Hypoglycemia has also been found to worsen RLS symptoms. Opioid detoxification has also recently been associated with provocation of RLS-like symptoms during withdrawal. For those affected, a reduction or elimination in the consumption of simple and refined carbohydrates or starches (for example, sugar, white flour, white rice and white potatoes) or some hard fats, such as those found in beef or biscuits, is recommended. Some doctors believe it is caused by irregular electrical impulses from the brain.
Both primary and secondary RLS can be worsened by surgery of any kind; however, back surgery or injury can be associated with causing RLS.
Some experts believe RLS and periodic limb movement disorder are strongly associated with ADHD in some children. Dopamine appears to factor into both conditions. In addition, many types of medication for the treatment of both conditions affect dopamine levels in the brain.
The cause vs. effect of certain conditions and behaviors that are observed in some patients (ex. carrying excess weight, lack of exercise, suffering from depression or other mental illnesses) does not appear to be well established. The loss of sleep due to RLS could be the cause of the conditions, or the medication used to treat a condition could be the cause of an individual's RLS.
Genetics
More than 60% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.No one knows the exact cause of RLS at present. Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the substantia nigra (study published in ''Neurology'', 2003). Iron is an essential cofactor for the formation of L-dopa, the precursor of dopamine.
Six genetic loci found by linkage are currently known and are listed below. Other than the first one in this list, the remainder of the linkage loci were discovered using an autosomal dominant model of inheritance.
#The first genetic locus was discovered in one large French Canadian family and maps on chromosome 12q. This locus was discovered, however, using an autosomal recessive inheritance model. Evidence for this locus was also found using a transmission disequilibrium test (TDT) in 12 Bavarian families.
#The second RLS locus maps to chromosome 14q and was discovered in one Italian family. Evidence for this locus was found in one French Canadian family. Also, an association study in a large sample 159 trios of European descent showed some evidence for this locus.
#This locus maps to chromosome 9p and was discovered in two unrelated American families. Evidence for this locus was also found by the TDT in a large Bavarian family, as well as in a German family, in which significant linkage to this locus was found.
#This locus maps to chromosome 20p and was discovered in a large French Canadian family with RLS.
#This locus maps to chromosome 2p and was found in three related families from population isolate in Bolzano-Bozen.
#The sixth locus is located on chromosome 16p12.1 and was discovered by Levchenko et al. in 2008.
Three genes, MEIS1, BTBD9 and MAP2K5, were found to be associated to RLS.
Their role in RLS pathogenesis is still unclear. More recently, a fourth gene, PTPRD was found to be associated to RLS
There is also some evidence that periodic limb movements in sleep (PLMS) are associated with on chromosome 6p21.2.
Adapted from the Wikipedia article Restless legs syndrome, under the G. N. U. Free Documentation License. Please also see http://en.wikipedia.org/wiki
