A mutation noted above that has received attention has been in LRRK2 (leucine-rich repeat kinase 2) because it is implicated in both genetic and sporadic forms of the disease, particularly among those of Ashkenazic Jewish or North African origin. The LRRK2 protein (dardarin) is a cytoplasmic component that is widely distributed in the brain and peripheral nerves. It has been estimated that mutations in the gene (mainly one common one, G20195) are responsible for 1 percent of sporadic cases and are found in 5 to 8 percent of individuals with a first-degree relative who has the disease. The gene acts as a dominant trait but penetrance of the defect increases with age, being 85 percent at 70 years. Therefore, there may not be an obvious family history. The clinical syndrome in most respects simulates the sporadic form of the disease according to Papapetropoulos and colleagues, but several other series have noted the absence of tremor. The genetics of this disorder, also called Park8, have been reviewed by Brice.
Several other gene defects are of interest in familial parkinsonism. One is a dominantly inherited mutation in the gene Nurr1, whose normal function is to specify the identity of dopaminergic neurons. Another is in recessively inherited parkinsonism caused by defects in the gene DJ-1, a protein that is essential for the normal neuronal response to oxidative stress. Also, a disease-causing mutation in the gene termed PINK, corresponding to Park6, codes for a mitochondrial kinase, therefore implicating this cellular structure in some forms of Parkinson disease (Valente et al). Presumably, dopaminergic neurons are compromised in some manner by these defects.
There has also been emphasis on mutations on 1 of 12 exons in the so-called Park2 gene, which codes for the protein parkin (see Table 38-3). The most common types are point mutations or deletions in exon 7, but abnormalities of the other exons evince similar syndromes. Homozygous mutations generally give rise to early-onset disease, but certain hemizygous changes (in exon 7) are associated with a later onset. The resultant syndromes have been termed parkin disease to distinguish them from the idiopathic variety. It has been estimated by Khan and colleagues that 50 percent of families that display an early onset of Parkinson disease and 18 percent of sporadic cases with early onset (before age 40 years) harbor mutations in this gene. Perhaps of greater clinical interest is finding that up to 2 percent of late-onset cases are associated with parkin mutations, and 1 percent due to changes in the aforementioned LRRK2 gene. Sequencing of these genes is now available in commercial laboratories for the purposes of detecting mutations and polymorphisms.
From a clinical perspective, the presentation of the late-onset cases with parkin mutations has been quite variable. Collectively, they can often be identified by an extreme sensitivity to l-dopa, maintaining an almost complete suppression of symptoms over decades with only small doses of medication; also, they have a low threshold for dyskinesias induced by l-dopa. We can also corroborate from experience with our own patients an excellent response of tremor, postural changes, and bradykinesia to anticholinergic drugs. A second feature has been that most of these patients may enjoy a remarkable restorative benefit from sleep, which creates a diurnal pattern of symptoms. Several series, particularly those of Lohmann and associates and of Khan and colleagues, have indicated that there may be a wide variety of additional features: hyperreflexia, cervical, foot, or other focal dystonias, sometimes induced by exercise; and, less often, autonomic dysfunction, peripheral neuropathy, and psychiatric symptoms. The sensitivity to medication and sleep benefit have long been known as the distinguishing components of juvenile-onset parkinsonism with dopa-responsive dystonia (Segawa disease), which is discussed later in the chapter.