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Parkinson's Disease Type 3

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.


Presentation

Clinical features of PD3 closely resemble the classical sporadic form of Parkinson's disease [1]. Affected individuals present typical parkinsonism with tremor, muscle rigidity, bradykinesia and impaired postural reflexes [2]. Tremor seems to be the most common presenting symptom in PD3 patients [2] [3] [4]. PD3 may be associated with dementia, and dementia has been observed in affected families in the absence of parkinsonism [3].

The intrafamilial variation in clinical presentation is low [2].

Fatigue
  • Choose a weight that you can push or lift without pain or fatigue for an easy 10 repetitions. Only increase the weight once you can comfortably perform three sets of 10 repetitions.[betterhealth.vic.gov.au]
  • Non-motor symptoms include: problems with smell anxiety depression vision problems fatigue cognitive changes, such as memory loss or slow thinking insomnia problems with speech constipation difficulty swallowing It is usual for the symptoms of Parkinson's[medicalnewstoday.com]
  • Though the symptoms experienced by Type 1 Gaucher patients may vary, some of the most common include: low red blood cell counts, enlarged liver, osteoporosis, and bruising. 3 In contrast, Parkinson’s disease has notably different symptoms including fatigue[rarediseasereview.org]
  • Nonmotor symptoms include: cognitive changes, such as difficulties with memory or planning, or slowing of thought mood disorders such as anxiety and depression sleep disorders such as insomnia fatigue constipation vision problems speech and swallowing[healthline.com]
  • Cramping of the hand during writing or fatigue during walking or other manual activities may indicate limb dystonia. Dystonia is also variable in its progression. For some patients, the disease steadily worsens; for others, it plateaus.[aans.org]
Difficulty Walking
  • Understanding Parkinson's Symptoms Some people with Parkinson’s will first notice a sense of weakness, difficulty walking, and stiff muscles. Others may notice a tremor of the head or hands.[webmd.com]
  • Fluctuations in cognition, attention or alertness; Problems with movement including tremors, stiffness, slowness and difficulty walking Visual hallucinations (seeing things that are not present) Sleep disorders, such as acting out one’s dreams while asleep[lbda.org]
  • Difficulties walking may develop or increase, and the person’s posture may start to change. People at this stage feel symptoms on both sides of the body (though one side may only be minimally affected) and sometimes experience speech difficulties.[healthline.com]
  • Parkinson’s can ultimately cause muscle rigidity and difficulty walking, poor posture, loss of muscle control, hallucinations, and dementia.[healthline.com]
  • Other symptoms may include difficulty walking, talking, eating, or carrying out other simple tasks.[sleepfoundation.org]
Asymptomatic
  • Three subjects with clinical evidence of parkinsonism carried the L444P allele, while two asymptomatic subjects did not. Thus, in the paternal lineage, parkinsonism appeared to be associated with heterozygosity for a mutation in glucocerebrosidase.[jmg.bmj.com]
  • We have also found that, in contrast to previous suggestions, heterozygosity for a non-neuropathic GBA mutation is not an absolutely asymptomatic state.[nejm.org]
Hypophonia
  • There was asymmetric bradykinesia and rigidity associated with hypomimia and hypophonia. Gait had a normal base and stride length, with reduced swing and flexed posture of the right arm (Additional file 2: Video S2).[clinicalmovementdisorders.biomedcentral.com]
  • In addition, individuals with depression may present signs and symptoms that occur frequently in PD, including masking of facial expression, bradykinesia, hypophonia, apathy, motor retardation, cognitive dysfunction, and in some cases, increased muscle[scielo.br]
  • Treatment of Parkinson hypophonia with percutaneous collagen augmentation. Laryngoscope. 1999 Aug. 109(8):1295-9. [Medline]. Kim HJ, Jeon BS, Paek SH. Effect of deep brain stimulation on pain in Parkinson disease.[emedicine.medscape.com]
Anosmia
  • […] and inflexible muscles A person with Parkinson's disease can also experience a wide range of other physical and psychological symptoms, including: depression and anxiety balance problems – this may increase the chance of a fall loss of sense of smell (anosmia[nhs.uk]
  • GD-PD patients have a high prevalence of non-motor symptoms, most commonly anosmia and dysautonomia [ 7 ]. Cognitive impairment with a more rapid cognitive decline is common [ 7 ].[clinicalmovementdisorders.biomedcentral.com]
  • These earliest signs include: decreased ability to smell (anosmia) constipation small, cramped handwriting voice changes stooped posture The four major motor problems seen are: tremor (shaking that occurs at rest) slow movements stiffness of arms, legs[healthline.com]
Muscle Rigidity
  • Parkinson's disease is a neurodegenerative disorder associated with muscle rigidity, tremor, and bradykinesia.[symptoma.com]
  • The drugs L- dopa and baclofen may relieve muscle rigidity and spasticity. Individuals with at least one family member who has been diagnosed with this disease should consider genetic counseling.[rarediseases.org]
  • NMS causes severe fever, muscle rigidity and breakdown that can lead to kidney failure.[lbda.org]
  • Called the “shaking palsy” by Parkinson, PD is diagnosed when a person shows at least two of these three symptoms: slowed movements (bradykinesia), muscle rigidity, and tremor (at rest).[brightfocus.org]
  • Parkinson’s can ultimately cause muscle rigidity and difficulty walking, poor posture, loss of muscle control, hallucinations, and dementia.[healthline.com]
Drooling
  • Images 1 of 9 Tremor - One of the most noticeable signs of Parkinson's is a tremor that often starts in the hands or fingers when they are relaxed Other symptoms include erectile dysfunction, dizziness, blurred vision or fainting, excessive sweating and drooling[express.co.uk]
Short Arm
  • 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.[symptoma.com]
  • Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11.[rarediseases.org]
Blepharospasm
  • Eye irritation, excessive sensitivity to bright light and increased blinking may be an indication of blepharospasm. Subtle facial spasms, difficulty chewing or changes in speech cadence may indicate oromandibular dystonia.[aans.org]
Suggestibility
  • 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.[symptoma.com]
  • Some findings have suggested a greater risk for PD in people with diabetes but this link has not been consistently seen in all studies.[michaeljfox.org]
  • The benefit persisted even when the drug had not been taken for 12 weeks, suggesting it might be helping to slow the progression of the disease.[theguardian.com]
  • Exercise and Parkinson’s disease Evidence suggests that regular exercise can improve some symptoms of Parkinson’s disease and improve your quality of life.[betterhealth.vic.gov.au]
Hypomimia
  • Known as “hypomimia,” the condition has some connection with bradykinesia.[aging.com]
  • There was asymmetric bradykinesia and rigidity associated with hypomimia and hypophonia. Gait had a normal base and stride length, with reduced swing and flexed posture of the right arm (Additional file 2: Video S2).[clinicalmovementdisorders.biomedcentral.com]
Tremor
  • 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.[symptoma.com]
  • See your GP if you're concerned you may have symptoms of Parkinson's disease NHS Tremors Tremors refer to shaking, usually in the hands or arms. Tremors are more likely to occur when the limb is relaxed and resting.[express.co.uk]
  • Tremor Involuntary shaking of the hands, arms, legs, jaw or tongue. The typical Parkinson’s tremor is “pill-rolling” – it looks like holding a pill between thumb and forefinger and continuously rolling it around.[parkinson.org]
  • The predominant initial motor symptoms include rigidity and painful cramps which may be followed by tremor, bradykinesia, gait complaints and falls.[orpha.net]
  • Symptoms at stage one may include tremor , such as intermittent tremor of one hand, rigidity , or one hand or leg may feel more clumsy than another, or one side of the face may be affected, impacting the expression.[parkinsonsdisease.net]
Bradykinesia
  • Parkinson's disease is a neurodegenerative disorder associated with muscle rigidity, tremor, and bradykinesia.[symptoma.com]
  • Parkinsonism is the umbrella term given to a group of conditions that feature Parkinson’s-type symptoms: slowness of movement (bradykinesia), tremor and stiffness of muscles.[epda.eu.com]
  • Known as “hypomimia,” the condition has some connection with bradykinesia.[aging.com]
  • Some patients with type 3 disease — specifically, six of the 12 — passed age 40 without developing additional symptoms (i.e, parkinsonism, a clinical syndrome characterized by tremors; bradykinesia, a slowness of movement, rigidity, and postural instability[gaucherdiseasenews.com]
  • The predominant initial motor symptoms include rigidity and painful cramps which may be followed by tremor, bradykinesia, gait complaints and falls.[orpha.net]
Resting Tremor
  • The vast majority of patients presents at least two out of the three cardinal symptoms, namely rigidity, resting tremor, and bradykinesia.[symptoma.com]
  • Most Parkinson’s tremor is “resting tremor,” which lessens during sleep and when the body part is actively in use. and other movement symptoms occur on one side of the body only. Changes in posture, walking and facial expressions occur.[parkinson.org]
  • The cardinal features of Parkinson’s disease are the slowing down of motor function, resting tremor, muscular rigidity, gait disturbances, and postural reflex impairment.[coffeeandhealth.org]
  • Keywords: Parkinson disease/ultrasonography; Ultrasonography, doppler, transcranial; Diagnosis, differential INTRODUCTION Parkinson's disease (PD) is a common neurodegenerative disease, clinically characterized by cog-wheel rigidity, rest tremor (most[scielo.br]
  • His 42 year old father developed a resting tremor at age 34 and had asymmetrical reduced arm swing on exam.[jmg.bmj.com]
Dystonia
  • […] face (oromandibular dystonia), vocal cords (laryngeal dystonia) or arms/legs (limb dystonia).[aans.org]
  • Some with type 3 disease showed a never-before-reported phenomenon of rapid and repetitive dystonia-like hyperkinetic movement disorder.[gaucherdiseasenews.com]
  • Compared to PD, a lower risk of developing falls and freezing of gait but a higher risk of dystonia, motor fluctuations, and levodopa induced dyskinesia (LID) have been reported.[orpha.net]
  • They may include severe weakness in the arms and legs (dystonia), spasticity or muscle rigidity, (hypertonia), awkward body movements (ataxia) often involving a slow, staggering, lurching gait (athetosis) that may be mistaken for drunkenness, slurred[rarediseases.org]
  • “Off” period dystonia may respond to lithium therapy and can be relieved by botulinum toxin injections into dystonic muscles.[pmj.bmj.com]
Postural Instability
  • Some patients with type 3 disease — specifically, six of the 12 — passed age 40 without developing additional symptoms (i.e, parkinsonism, a clinical syndrome characterized by tremors; bradykinesia, a slowness of movement, rigidity, and postural instability[gaucherdiseasenews.com]
  • Drug-induced parkinsonism may be difficult to distinguish from Parkinson’s disease, but the symptoms of tremors and postural instability will generally improve in the weeks or months after use of the medication has stopped.[parkinsonsnewstoday.com]
  • Parkinson's symptom pattern known as postural instability and gait disturbance (PIGD), which includes "freezing" in mid-step, difficulty initiating movement, shuffling, problems with balance and falling.[alz.org]
  • On the other hand, characteristic signs of atypical parkinsonian syndromes, such as postural instability, signs of frontal lobe dysfunction and autonomic dysfunction may also be found in PD (10) .[scielo.br]
  • Other characteristic symptoms of Parkinson disease include rigidity or stiffness of the limbs and torso, slow movement (bradykinesia) or an inability to move (akinesia), and impaired balance and coordination (postural instability).[ghr.nlm.nih.gov]
Sexual Dysfunction
  • Other physical symptoms can include: Sexual dysfunction Excessive sweating Constipation Incontinence Blurred vision Emotional symptoms such as depression , anxiety and memory problems can also affect people with Parkinson’s.[diabetes.co.uk]
  • Parkinson’s patients also suffer incontinence, constipation, and sexual dysfunction and are at higher risk for developing depression, anxiety, memory, and emotional problems.[sleepfoundation.org]
  • dysfunction, seborrheic dermatitis) A general feeling of weakness, malaise, or lassitude Depression or anhedonia Slowness in thinking Onset of motor signs include the following: Typically asymmetric The most common initial finding is a resting tremor[emedicine.medscape.com]

Workup

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 [5]. 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 [3]. Results obtained by means of electroencephalography may reveal diffuse encephalopathy but are often normal [4]. 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.

Gliosis
  • 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.[symptoma.com]
  • Initially, 17 subjects were identified with Gaucher disease and l -DOPA refractory parkinsonian manifestations that included tremor, bradykinesia, rigidity, and often cognitive decline. 1 Several of the subjects had Lewy bodies and gliosis specifically[jmg.bmj.com]
  • A decreased angle of the corpus callosum in the coronal plane ( The FLAIR sequence is useful for the evaluation of tissue loss and gliosis commonly seen in vascular brain damage, which can support the diagnosis of vascular parkinsonism [20–22].[journalofparkinsonsdisease.com]
Neurofibrillary Tangle
  • 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.[symptoma.com]
Diffuse Encephalopathy
  • 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.[symptoma.com]

Treatment

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 [2] [4], 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.

Prognosis

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 [4].

Etiology

About 10-20% of patients diagnosed with Parkinson's disease have a positive family history of this neurodegenerative disorder [6]. 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 [1]. 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 [7]. 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 [8]. Because similar results were obtained for the remaining 13 genes [7], research efforts were extended to unigene clusters within the region [9]. 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 [9]. 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% [1] [7].

Epidemiology

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 [6]. 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 [3] [10]. 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 [11]. Today, members of the affected families live in Canada and the United States, so PD3 patients may present in North America, too [9]. 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 [12] [13].

Sex distribution
Age distribution

Pathophysiology

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 [10]. 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 [10]. 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 [14].

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 [1] [3]. 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 [3] [4]. 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 [3].

Prevention

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.

Summary

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 [6]. PD3 is inherited in an autosomal dominant manner and has first been associated with chromosomal locus 2p13 in 1998 [1]. 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 [7]. 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 [9]. 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 [2] [3]. The concomitant familial clustering of Alzheimer's disease may hint at PD3, though [3] [4].

Patient Information

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.

References

Article

  1. Gasser T, Muller-Myhsok B, Wszolek ZK, et al. A susceptibility locus for Parkinson's disease maps to chromosome 2p13. Nat Genet. 1998; 18(3):262-265.
  2. Wszolek ZK, Cordes M, Calne DB, Münter MD, Cordes I, Pfeifer RF. [Hereditary Parkinson disease: report of 3 families with dominant autosomal inheritance]. Nervenarzt. 1993; 64(5):331-335.
  3. Denson MA, Wszolek ZK. Familial parkinsonism: Our experience and review. Parkinsonism Relat Disord. 1995; 1(1):35-46.
  4. Wszolek ZK, Gwinn-Hardy K, Wszolek EK, et al. Neuropathology of two members of a German-American kindred (Family C) with late onset parkinsonism. Acta Neuropathol. 2002; 103(4):344-350.
  5. Klein C, Schlossmacher MG. The genetics of Parkinson disease: Implications for neurological care. Nat Clin Pract Neurol. 2006; 2(3):136-146.
  6. Schulte C, Gasser T. Genetic basis of Parkinson's disease: inheritance, penetrance, and expression. Appl Clin Genet. 2011; 4:67-80.
  7. West AB, Zimprich A, Lockhart PJ, et al. Refinement of the PARK3 locus on chromosome 2p13 and the analysis of 14 candidate genes. Eur J Hum Genet. 2001; 9(9):659-666.
  8. Sharma M, Maraganore DM, Ioannidis JP, et al. Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease. Neurobiol Aging. 2011; 32(11):2108.e2101-2105.
  9. Lockhart PJ, Holtom B, Lincoln S, et al. The human sideroflexin 5 (SFXN5) gene: sequence, expression analysis and exclusion as a candidate for PARK3. Gene. 2002; 285(1-2):229-237.
  10. Hatano T, Kubo S, Sato S, Hattori N. Pathogenesis of familial Parkinson's disease: new insights based on monogenic forms of Parkinson's disease. J Neurochem. 2009; 111(5):1075-1093.
  11. Klein C, Vieregge P, Hagenah J, et al. Search for the PARK3 founder haplotype in a large cohort of patients with Parkinson's disease from northern Germany. Ann Hum Genet. 1999; 63(Pt 4):285-291.
  12. DeStefano AL, Lew MF, Golbe LI, et al. PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study. Am J Hum Genet. 2002; 70(5):1089-1095.
  13. Pankratz N, Uniacke SK, Halter CA, et al. Genes influencing Parkinson disease onset: replication of PARK3 and identification of novel loci. Neurology. 2004; 62(9):1616-1618.
  14. Kazantsev AG, Kolchinsky AM. Central role of alpha-synuclein oligomers in neurodegeneration in Parkinson disease. Arch Neurol. 2008; 65(12):1577-1581.

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Last updated: 2019-07-11 20:29