Parkinson's disease type 3 (PD3) is a form of Parkinson's disease that is inherited in an autosomal dominant manner. The underlying mutation has not yet been identified, but PD3 has been related to a 2.5 Mb-locus on the short arm of chromosome 2. To date, PD3 has been diagnosed in distinct families in Europe and North America. Clinically, PD3 resembles the classical sporadic variant of the disease. It is also treated in the same way.
Clinical features of PD3 closely resemble the classical sporadic form of Parkinson's disease . Affected individuals present typical parkinsonism with tremor, muscle rigidity, bradykinesia and impaired postural reflexes . Tremor seems to be the most common presenting symptom in PD3 patients   . PD3 may be associated with dementia, and dementia has been observed in affected families in the absence of parkinsonism .
The intrafamilial variation in clinical presentation is low .
First and foremost, the diagnosis of hereditary Parkinson's disease requires a thorough anamnesis. Familial clustering is an indispensable hint on PD3 and thus, it is essential to assess the patient's medical and family history . Unless the patient is a member of a family known to be affected by PD3, comprehensive linkage studies are required to diagnose a new case of this variant of Parkinson's disease. Less cumbersome, targeted genetic studies such as the sequencing of individual genes may eventually become feasible, but require precise knowledge on the cause of PD3.
Parkinson's disease itself is diagnosed clinically. The vast majority of patients presents at least two out of the three cardinal symptoms, namely rigidity, resting tremor, and bradykinesia. In the absence of these symptoms, the diagnosis of Parkinson's disease poses a major challenge that can hardly be overcome employing additional diagnostic tools. The latter may support but not replace the clinical diagnosis of this neurodegenerative disorder: Magnetic resonance imaging may not yield pathological findings or show moderately enlarged ventricles and cortical atrophy; positron emission tomography may reveal reduced fluorodopa uptake . Results obtained by means of electroencephalography may reveal diffuse encephalopathy but are often normal . Muscle biopsies are not helpful for diagnosing Parkinson's disease although they may allow the exclusion of differential diagnoses. Neither of these findings is specific.
Specific recommendations for the management of PD3 have not yet been published, so affected individuals are essentially treated like those suffering from the classical sporadic disease. PD3 has been described as a levodopa-responsive form of Parkinson's disease  , so dopamine replacement is the mainstay of therapy. But even though it may alleviate the symptoms of Parkinson's disease, it can't halt its progression. Besides levodopa, which is a dopamine precursor, dopamine agonists may be employed in the treatment of Parkinson's disease. Additionally, patients may benefit from the administration of anticholinergics, COMT inhibitors, MAO-B inhibitors, and NMDA receptor antagonists. They should also be offered physical therapy and psychological support.
PD3 patients usually respond well to dopamine replacement therapy. Levodopa is most frequently administered and provides symptom relieve, thereby enabling affected individuals to maintain an acceptable quality of life for prolonged periods of time. Nevertheless, PD3 follows a progressive course and symptomatic treatment may eventually lose its efficacy. Clinical symptoms become more prominent over time. The average duration of PD3 is 25 years .
About 10-20% of patients diagnosed with Parkinson's disease have a positive family history of this neurodegenerative disorder . However, familial accumulation of Parkinson's disease may be due to distinct mechanisms: On the one hand, predisposing sequence anomalies may trigger the disease in the presence of unfavorable environmental factors. On the other hand, pathogenic mutations alone may be sufficient to provoke neurodegeneration. The latter applies to monogenic forms of Parkinson's disease, which are caused by germline mutations and which often manifest earlier than the sporadic disease. Linkage studies may provide valuable information as to the genes involved in etiology and pathogenesis of the disease in individual families, and such a study has been carried out to identify the trigger of PD3 . In this study, PD3 has been linked to chromosomal locus 2p13, which has subsequently been designated PARK3. Later studies achieved to delimit PARK3 to a region comprising approximately 2.5 Mb and 14 genes, some of which have been suggested to be involved in the etiology of PD3 . One of these genes is the SPR gene, which encodes for sepiapterin reductase, an enzyme catalyzing the final step of tetrahydrobiopterin synthesis. But even though SPR-deficient mice showed parkinsonism-like symptoms, population studies didn't yield any evidence of a large-scale association of SPR and Parkinson's disease . Because similar results were obtained for the remaining 13 genes , research efforts were extended to unigene clusters within the region . The SFXN5 gene is located here and has also been discussed in the context of PD3 development. It encodes for sideroflexin 5, a protein with transmembrane transporter activity that has not yet been characterized in detail. However, pathogenic SFXN5 mutations could not be identified . Further analyses are currently undertaken. Regardless of which gene is the key element in PD3 etiology, the penetrance of the causative mutation has been estimated to 40%  .
Sporadic Parkinson's disease is the second most common neurodegenerative disorder, second only to Alzheimer disease. The annual incidence of Parkinson's disease ranges between 10 and 20 per 100,000 inhabitants and it has been estimated that Parkinson's disease affects 1-2% of people aged >65 years and up to 4% of individuals aged >85 years . Symptom onset before the age of 50 is uncommon. In this context, PD3 is not significantly different from the sporadic variant of the disease: PD3 has been diagnosed in patients aged 35-89 years, with their average age at symptom onset being approximately 60 years  . Little is known about the specific incidence and prevalence of PD3.
The two families described in the original report by Gasser and colleagues originated from Northern Germany and Southern Denmark, suggesting a common ancestor and founder effect. However, the results of genetic studies carried out in Northern Germany argue against this hypothesis . Today, members of the affected families live in Canada and the United States, so PD3 patients may present in North America, too . After the initial association of Parkinson's disease with chromosomal locus 2p13, such linkage has been confirmed in independent studies carried out in the United States  .
While the triggers of neurodegeneration remain largely unknown, it is the key process in the pathogenesis of Parkinson's disease. Histological hallmarks of Parkinson's disease comprise the selective loss of dopaminergic neurons in the pars compacta of the substantia nigra, which is accompanied by depigmentation and gliosis. Neuronal loss may also be observed in the locus ceruleus, pedunculopontine nucleus, raphe nucleus, dorsal motor nucleus of the vagal nerve, olfactory bulb, parasympathetic as well as sympathetic post-ganglionic neurons, Mynert nucleus, amygdaloid nucleus and cerebral cortex . These histological features can, however, only be confirmed at autopsy.
It has been hypothesized that the accumulation of dysfunctional, abnormally folded or insufficiently degraded protein leads to nigral degeneration . With regard to hereditary forms of Parkinson's disease, the amassment of such proteins is likely related to the underlying gene defect. For instance, Parkinson's disease type 1 is presumably caused by dysfunctional α-synuclein, subsequent deficiencies in neurotransmitter release, and the intracellular accumulation of aberrant α-synuclein and dopamine-derived neurotoxic metabolites. According to current knowledge, the latter can't be metabolized to non-toxic neuromelanin, which may explain hypopigmentation of the substantia nigra and neuronal death .
The pathogenetic mechanism behind the formation of inclusion bodies in neurons of PD3 patients remains to be clarified. It is known, though, that abnormal protein of as-of-yet unknown composition accumulates and aggregates in so-called Lewy bodies  . These eosinophilic inclusions are also typical of classical sporadic Parkinson's disease. Lewy bodies interfere with neuronal function. For instance, Lewy body infiltration in the olfactory bulb adversely affects the sense of smell. Thus, people with Parkinson's disease frequently suffer from olfactory impairment.
Besides the loss of dopaminergic neurons and the presence of Lewy bodies, neurofibrillary tangles and Alzheimer plaques have been observed in brain tissue samples obtained from PD3 patients  . Considering the facts that PD3 may be associated with dementia and that familial clustering has been observed for both entities in affected families, it becomes tempting to speculate that sequence anomalies of the PARK3 locus may give rise to distinct phenotypes of neurodegenerative disease .
In general, affected families may benefit from genetic counseling. Genealogical analyses may allow for an estimation of the specific PD3 risk of each family member and high-risk individuals may be recommended for regular surveillance from the age of 50. However, such estimates are considerably complicated by the low penetrance and late onset of PD3-associated symptoms. Estimates regarding the individual risk of family members of fertile age are unreliable and without practical relevance for prenatal counseling. This may change as soon as the causative gene is identified.
Parkinson's disease is a neurodegenerative disorder associated with muscle rigidity, tremor, and bradykinesia. The majority of cases is deemed sporadic, but familial clustering and Mendelian inheritance of phenotypic traits is occasionally been observed. Both autosomal dominant and autosomal recessive patterns of inheritance have been observed, and the underlying gene defects could be identified in some of the families affected but remain unknown in others . PD3 is inherited in an autosomal dominant manner and has first been associated with chromosomal locus 2p13 in 1998 . At a later point in time, the locus giving rise to PD3 has been narrowed down to a 2.5 Mb-region containing 14 genes. However, sequence anomalies could not be detected in either one . Other research groups have focused on sequencing DNA segments in close proximity to this locus, but so far, they have neither been able to identify the causative gene defect . Further research is required to this end. Precise knowledge regarding the underlying mutation would greatly facilitate prophylactic screenings of members of affected families, would even allow for prenatal diagnoses. And last but not least, it would enable epidemiologists to revise whether PD3 is indeed a very rare entity affecting only two families of Central European - North American origin, or whether the respective mutation also accounts for other cases of Parkinson's disease. The clinical presentation of PD3 patients doesn't allow for such conclusions because it is very similar to that of patients suffering from the classical sporadic variant of the disease  . The concomitant familial clustering of Alzheimer's disease may hint at PD3, though  .
Parkinson's disease is the second most common neurodegenerative disorder, second only to Alzheimer's disease. Most cases of Parkinson's disease are deemed sporadic. They are assumed to be triggered by environmental factors that exert particularly unfavorable effects in genetically predisposed patients. By contrast, familial clustering is occasionally observed and has been related to mutations passed on from generation to generation, similar to what happens in well-known hereditary disorders. Hereditary Parkinson's disease may then be diagnosed. There are distinct types of hereditary Parkinson's disease and they differ with regards to the underlying mutation. For some types of hereditary Parkinson's disease, the causative genetic defect could not yet be identified. This also applies to Parkinson's disease type 3 (PD3). Clinically, PD3 resembles the classical sporadic variant of the disease. PD3 patients mainly suffer from tremor, muscle rigidity, and slowness of movements. The disease is treated symptomatically, much like the sporadic form of Parkinson's disease. This way, affected individuals are able to maintain an acceptable quality of life for prolonged periods of time, but disease progression can't be halted.