Of similar interest as a modulating factor in the development of the disease is strong association between mutations in the glucocerebrosidase gene (other mutations of which causes Gaucher disease) among Ashkenazi Jews (Sidransky et al), the same population predominantly affected by polymorphisms of LRRK2. Although population studies allow only limited conclusions about clinical correlations, the glucocerebrosidase mutation is present more often in patients with a family history of the disease, have an earlier onset that in patients with a normal gene and a lower incidence of resting tremor. Mutations have been present in 7 percent of Parkinson patients who had their genes fully sequenced, making it a common genetic factor for the disease, particularly in this ethnographic population.
It is hoped that the genetic mutations that give rise to Parkinson disease will expose the molecular pathophysiology of the disease. As discussed earlier, several sites are implicated in the familial forms of Parkinson disease, some related to the gene that codes for synuclein, the main component of the Lewy body.
Although there is no current treatment that clearly halts or reverses the neuronal degeneration underlying Parkinson disease, methods are now available that afford considerable relief from symptoms. Treatment can be medical or surgical, although reliance is placed mainly on drugs, particularly on l-dopa (Table 38-4). The following sections are necessarily detailed so as to give the clinician a full comprehension of the use and side effects and interactions of these drugs.
l-dopa and l-dopa–modifying drugs At present, l-dihydroxyphenylalanine (l-dopa) is the most effective agent for the treatment of Parkinson disease and the therapeutic results, even in those with far advanced disease, are consistently better than have been obtained with other drugs. The drug has an interesting history that includes many early trials that failed to persuade neurologists of its effectiveness; Barbeau’s paper on this historical subject may be consulted by the interested reader. Most patients tolerate the drug initially, experiencing few serious adverse effects and showing various degrees of improvement, sometimes dramatic, especially in hypokinesia and tremor after several days or sooner. However, the side effects and limitations of l-dopa become considerable as the drug therapy continues and the disease progresses, as discussed below.
The levodopa, or a dopamine agonist preparation as described below, is introduced when the symptoms begin to interfere with work and social life or falling becomes a threat, and then these drugs are used at the lowest effective dose. The theoretical basis for the use of this compound rests on the observation that striatal dopamine is depleted in patients with Parkinson disease but that the remaining diseased nigral cells are still capable of producing some dopamine by taking up its precursor, l-dopa. The number of neurons in the striatum is not diminished and they remain receptive to ingested dopamine acting through the residual nigral neurons. Over time, however, the number of remaining nigral neurons becomes inadequate and the receptivity to dopamine of the striatal target neurons becomes excessive, possibly as a result of denervation hypersensitivity; this results in both a reduced response to l-dopa and to paradoxical and excessive movements (dyskinesias) with each dose.