Open access peer-reviewed chapter

Dopamine and Early Onset Parkinson’s Disease

Written By

Katarzyna Wize, Wojciech Kozubski and Jolanta Dorszewska

Submitted: 01 May 2018 Reviewed: 19 July 2018 Published: 31 October 2018

DOI: 10.5772/intechopen.80400

Chapter metrics overview

1,292 Chapter Downloads

View Full Metrics


Parkinson’s disease (PD) is divided into early-onset (EOPD) occurring at the age of fewer than 45 years of age and late-onset PD (LOPD) above 45 years of age. EOPD accounts for 5–10% of all the cases with PD. It is thought that occurrence in this age is connected with genetic factors, mutations in e.g. PRKN, PINK1, DJ-1 and changes in proteins it is encoded. The loss of dopaminergic neurons in the nigrostriatal system leads to decreased dopamine (DA) concentrations. Pathogenic PD proteins may affect the DA level. The lower level of DA may be responsible for movement-related symptoms. EOPDs have a slower progression of the disease and a longer disorder duration but tend to develop dyskinesias and motor fluctuations earlier than LOPD. Currently, the diagnosis of PD is based on clinical criteria, supported neuroimaging like MRI or PET. Understanding the pathogenesis of the EOPD may be contributing to improving diagnostics and effectiveness of pharmacotherapy.


  • molecular factors
  • dopamine
  • Parkinson’s disease of early onset

1. Introduction

Parkinson’s disease (PD) is one of the most common and spontaneous degenerative disease of the central nervous system (CNS) that is characterized by classical motor symptoms like bradykinesia, muscular rigidity, rest tremor, or postural instability [1]. It is estimated that approximately 5 million people worldwide suffer from PD. The frequency of disease increases with age; there are 1% of people older than 60 years and 5% of people over 85 years [2, 3, 4]. It seems that males suffer more often than females [5]. Furthermore, the estimates indicate that the number of PD patients will maintain increase trend because of population aging.

PD usually develops in the fifth or the sixth decade of life and is called late-onset PD (LOPD), but in a small group of patients, it is diagnosed even before the age of 40 years. The definition of early-onset PD (EOPD) is arbitrary. Some authors defined this disorder with an age of onset (AOO) below 40 years, others even below 50 years, but usually, it refers to age less than 45 [6, 7]. According to the literature data, 5–10% patients suffer from EOPD. EOPD can also be subdivided into the group called juvenile PD with AOO less than 21 years [8].

The main factor in PD pathology is loss or degeneration of dopaminergic neurons in the substantia nigra (SN). Although this disease was described more than 200 years ago, its cause is still not fully understood. It is considered that the pathogenesis depends on both genetic and environmental factors, but genetic changes are main causes in about 5–10% of the PD patients [9]. Some genes and its proteins associated with EOPD like PRKN gene and the Parkin protein or PINK1 gene are identified.

The phenotype of PD is various and related to AOO. It includes classical motor symptoms and non-motor symptoms such as disorder of mood, cognitive, behavioral, sensory, and autonomic dysfunctions (e.g., orthostatic hypotension and urogenital dysfunction) [10]. Patients’ characteristic of EOPD and LOPD is summarized in Table 1.The study of Wickremaratchi et al. [7] showed that features like tremor, rigidity, response to most common treatment, or presence of dystonia and dyskinesia’s have linear changes (increasing or decreasing). However, dystonia demonstrates the highest risk of occurrence among EOPD and reduction among LOPD patients.

Features EOPD LOPD
Mean age of onset (years) 44 72
Survival from onset (years) 27 10
Mean age at death (years) 71 82
Tremor at onset, only (%) 45 59
Bradykinesia and tremor at onset (%) 23 9
Bradykinesia at onset, only (%) 32 25
Postural instability at onset (%) 0 7

Table 1.

Patients’ characteristic of EOPD and LOPD [8].

The proper diagnosis of PD is very important. Nowadays, there are a lot of neuroimaging methods that can be used to increase the accuracy of differential diagnosis, but none of them have been endorsed to routine use in clinical practice [11, 12].


2. Dopamine and pathogenesis of Parkinson’s disease

Dopamine (DA) is the organic chemical of the catecholamine family and precursor for noradrenaline. It is synthesized in presynaptic neuron from tyrosine to L-dihydroxyphenylalanine (L-dopa) via tyrosine hydroxylase. Subsequently, aromatic amino acid decarboxylase removes a carboxyl group, form neurotransmitter, which is packed into synaptic vesicles. DA is released into the synapse during stimulation, actives dopaminergic receptors, and evokes a response in the postsynaptic cell [13]. It plays a pivotal role in the generation of normal movements by transmission information from SN to the striatum, where movements are initiated and controlled facility and balance [14].

The pathomechanism of PD is progressive and subsequent degeneration of neurons in SN, which results in the decreased level of DA in the dopaminergic neurons. Further, there is also the presence of Lewy bodies (LBs), intracytoplasmic eosinophilic inclusion bodies, in others neurons in SN. The literature indicates that loss of 60–70% of dopamine neurons in SN is presented as PD motor symptoms [15]. Pathogenesis of PD involves both environmental and genetic factors. It is thought that the pathways involved in PD are impairment of cellular clearance pathways, protein aggregation, oxidative stress, mitochondria dysfunction, and neuroinflammation (Figure 1) [16, 17, 18].

Figure 1.

Association between DA in Parkinson’s disease, EOPD and genetic and biochemical factors. EOPD—early-onset Parkinson’s disease, LB—Lewy bodies, DA—dopamine, ASN—α-synuclein, L-dopa—L-dihydroxyphenylalanine, DAT—dopamine transporter, ROS—reactive oxygen species.

α-Synuclein (ASN) is a major component of LB [19]. Aggregation of ASN is considered to be engaged in the pathogenesis of PD in consequence of the cellular clearance pathway like ubiquitin-proteasome and autophagy-lysosome [20]. The literature indicates that ASN modulates dopamine transporter (DAT) activity. DAT is responsible for removing DA from the synaptic cleft. It is showed that the polymorphisms in gene coding DAT (DAT1) are engaged in the detoxication mechanism and oxidative stress [21]. Membrane depolarization of DAT enhances plasma membrane ASN localization, which subsequently increases DA efflux [22]. The study of Mazzulli et al. [23] shows that the loss of lysosomal enzyme glucocerebrosidase (GBA) causes interference in protein degradation and accumulation of ASN, and GBA substrate is associated with the amyloid formation of purified ASN. On the other hand, GBA activity in neurons of PD brain is inhibited by ASN.

Oxidative stress is a disturbance in the balance between prooxidant and antioxidant homeostasis and production of reactive oxygen species (ROS) [24]. The main mitochondrial site of generation ROS is complex I [25]. There is a direct relationship between mitochondrial dysfunction and decreased activity of complex I among PD patients [26]. Moreover, it is known involvement of such genes like PRKN, PINK1, and DJ1 in mitochondrial PD pathogenesis [18]. One of the causes of the increase of oxidative stress and ROS in dopaminergic neurons is self-oxidation of DA to quinones (DAQs).

DAQs are electrophilic species, very reactive toward cellular nucleophiles, which effect damage of cells. DAQs can bind to Parkin and promote its aggregation. Thus, this protein losses its function. It seems that DAQs are more responsible for inactivation of Parkin than ROS [14]. The study of Bisaglia et al. [27] shows that DAQs interact with ASN by inhibition of ASN fibrilization and stabilizing ASN/DAQ oligomers. It seems that DAQs can also modify the structure of DJ-1 through modifications in cysteine residues of its protein [28].

Kitada et al. [29] show that mutations in PINK1 gene, which is associated with EOPD, and inactivation of encoded protein impair DA release. However, they do not alter the levels of DA, a number of dopaminergic neurons, DA synthesis, and levels of DA receptors. These results indicate that this impairment is sufficient to cause dysfunction of the nigrostriatal circuit by deficits in synaptic plasticity.


3. Genetic risk factors for early-onset Parkinson’s disease

The etiology of EOPD is not completely explained. It seems that genetic factors, environmental factors, or both of them may play an important role in the pathogenesis of this disease. There have been identified several genes and their mutations associated with EOPD, but new loci are still being identified. Most of these genes are inherited autosomal recessive, for example, PRKN, PINK1, or DJ1, but some of them are associated with the autosomal dominant pattern, for example, SNCA [30].

3.1. PRKN gene

One of the most important genes involved in the pathogenesis of EOPD is PRKN (PARK2) that encodes 465 amino acid-long Parkin protein. Parkin is a part of multiprotein E3 ubiquitin ligase complex and is involved in the regulation of mitochondrial quality control pathway and promotion selective autophagy of depolarized mitochondria (mitophagy) [31]. Moreover, overexpression of this protein leads to elevated expression of complex I subunits and decreased the accumulation of ROS [32]. Parkin interacts with other proteins such as PINK1, which promotes the mitochondrial translocation of Parkin [33]. There is also a suggestion about a role in DA utilization in human dopaminergic neurons by controlling the precision of dopaminergic neurotransmission and DA oxidation [34].

PRKN gene is located on chromosome 6q26 and consists of 12 exons. There are various data results about the frequency of mutations in PRKN that implies a possible role of the environment [35]. Some of them indicate that they are responsible for 9% of cases of EOPD, but others suggest even twice higher number—18% among patients with age of onset (AOO) before 45 years and 77% of those with AOO before 20 years. Mutations in PRKN gene are also more frequent in patients with a positive history than in sporadic cases [36, 37]. Pathogenic mutations in PRKN gene cause losing quality control pathway and accumulation of damaged mitochondria, what in consequence leads to elevation of ROS, cell death, and PD [31]. There have been identified more than 100 mutations in PRKN gene, which includes deletions, insertions point mutations, and large arrangements [38]. Some of them seem to be pathogenic like Q171X, R275W, G284R, or T425 N, but another likely to be non-pathogenic, for example, A82Q, L174 L, or L261 L [35, 39]. Hedrich et al. [40] indicate that R275W mutation is the most common point mutation in EOPD and is always combined with other changes in PRKN gene.

3.2. PINK1 gene

Another gene which mutations are involved in the occurrence of EOPD is phosphate and tensin homolog (PTEN)-induced putative kinase 1 (PINK1). It is a 581 amino acid ubiquitously protein kinase, which includes a 34 amino acid mitochondrial targeting motif and a highly conserved protein domain (amino acids 156–509, exons 2–8) showing a high degree of homology to the serine/threonine kinases [38, 41]. It is widely expressed in human brain and plays a role in the mitochondrial response to oxidative stress, degradation of impaired mitochondria by activation this organelle's autophagy (mitophagy) by Parkin, and regulation of Parkin localization [42, 43]. Morais et al. [44] also show that modifications in PINK1 may cause elevated ROS production and impaired DA release.

Mutations in PINK1 (PARK6) gene are the second most common cause of AR EOPD [38]. PINK1 is mapped to chromosome 1p36.12 and contains eight exons. There have been reported more than 100 PINK1 gene mutations including large deletions, frame shift mutations, nonsense, or missense mutations, which cause loss of protein function [45]. It is considered that mutations in this gene are responsible for 14% of EOPD cases, but there is wide variation between different ethnic group [37, 46]. The study of Kilarski et al. [36] indicates that majority of mutations are homozygous and they are more common in Asian populations than in white patients or Latin American. One of the reported mutations in PINK1 was Q456X in exon 7 by Bonifati et al. [46]. It is a nonsense mutation that results in a premature stop codon. The study of Siuda et al. [43] suggests that this mutation leads to complete loss of PINK1 at the RNA level in skin fibroblast derived from a patient, what causes dysfunction of Parkin. Other mutations in this gene associated with EOPD and are likely to be pathogenic Y258X, R276X, M318 L, and A427E [39, 47, 48]. The literature data also indicate occurrence of such mutations that seems to be non-pathogenic or the significance is unknown in EOPD patients like R312R, A339T, D391D, G411S, T420 T, D525N, and S576S [39].

3.3. DJ-1 gene

The third gene associated with EOPD is DJ-1 (PARK7). It encodes a 189 amino acid-long protein, which is a mitochondrial peroxidase. DJ-1 protein has homodimeric structure, which is ubiquitously expressed in brain areas and also in peripheral tissues [49, 50]. The literature indicates multiple functions of this protein-like protection cells against oxidative stress, acting as a chaperone and protease or interactions with other known PD-proteins such as Parkin or PINK1 [51, 52, 53]. Moreover, it plays an important role in the maintenance of mitochondrial complex I activity and defense function against cytotoxicity induced by toxic ion metals like copper or mercury [53, 54]. DJ-1 protects against dopamine toxicity and control the vesicular sequestration of DA [55]. Mutations cause instability of a dimeric structure, which is physiological form, and lack of expression [45]. Modified proteins are not properly folded, unstable, and degraded by the proteasome what results in a reduction of neuroprotective function and antioxidative activity [38].

The DJ-1 gene is located on chromosome 1p36.23 and contains eight exons, where first two of them are noncoding and alternatively spliced in mRNA [56]. The DJ-1 gene mutations in EOPD are rarer than PRKN and PINK1 mutations with overall frequency 0.4%, which increases with familial cases to 0.8% [36]. The DJ-1 locus was identified in a Dutch family with AR EOPD [57] and that led to the identification of mutations in DJ-1 gene of two families [56]. They have been identified in nucleotide substitutions like missense, truncating, spic-site mutations and also large deletions [58]. The study of Abou-Sleiman et al. [59] identified two mutations in DJ-1. The first one was homozygous M26I in an Ashkenazi Jewish patient, which causes substitution of methionine for isoleucine. The second was a substitution at codon 149 in which highly conserved polar aspartate residue exchanges to non-polar alanine (D149A). There have been found another mutation in EOPD like A104T [60] or L10P in Asian populations. The study of Guo et al. [61] also suggests that two identified mutations in the Italian population, D24A and F162 L, may cause PD in the case of presence in homozygous or compound heterozygous state with other mutations. The literature data indicate that there was a considerable reduction of DAT binding in the Turkish patient with an E64D mutation in the homozygous state. These results show a significant decline of presynaptic dopaminergic afferents [62]. Moreover, the clinically unaffected sister of EOPD patient (homozygous for E64D) had demonstrated reduction of DA uptake in comparison with a clinically unaffected brother, who has the heterozygous state for this mutation.

3.4. GBA gene

The GBA gene is mapped to chromosome 1q22 and encodes the lysosomal enzyme GBA. It is β-glucosidase that catalyzes the breakdown of glucose and ceramide, which are a precursor for glycosphingolipids and sphingomyelin occurring in nervous tissues [63, 64]. Mutations in GBA gene play an important role in neurological disorder like PD. They account for 5% of all PD cases, but the frequency of occurrence is ranged from 10.7 to 31.3% of Ashkenazi Jewish patients with PD and from 2.3 to 9.4% in patients of other populations [65]. The most common mutation in the Ashkenazi Jewish is N370S, but in Caucasian populations are N370S and L444P. There have been also identified such mutations in EOPD as H255Q, E326K, D409H, or R329H [66]. The activity of this protein is decreased in heterozygous mutations in PD patients in comparison to non-mutated carriers [67]. It is suggested that they cause dysfunction of the autophagy-lysosome pathway, mainly impairment in macroautophagy and chaperone-mediated autophagy involved in accumulation, aggregation, and transmission of ASN [64].

Moreover, homozygous mutations in GBA gene leads to Gaucher’s disease (GD), the most common lysosomal storage disorder due to deficiency of enzyme GBA [68]. The literature indicates that mutations of GBA, even in the heterozygous state, may be associated with this disorder [69]. Patients with GD have an increased risk of PD and parkinsonism features. It seems that there is no GD genetic variant linked with PD, but N370S is the most frequent mutation detected in American, European, and Ashkenazi Jewish population [65, 68].

3.5. SNCA gene

SNCA (PARK1 and PARK4) gene was the first gene ever identified as causal PD. It is an inherited autosomal dominant pattern and located to chromosome 4q22.1 [30]. SNCA gene encodes ASN, but the functions of its are still not completely understood. It is known that it is the main component of LB [19]. ASN reduces protein kinase C (PKC) activity, which is sensitive to oxidative stress and protects dopaminergic cells against apoptosis [70]. It can also regulate glucose levels by increasing tissue glucose uptake, modulate calmodulin activity, and act as a molecular chaperone and antioxidant by protecting dopaminergic neurons against oxidative stress [71, 72, 73, 74]. Moreover, ASN can decrease the activity of tyrosine hydroxylase and thus regulates the production of DA and control its levels [75]. It also interacts with other proteins including Parkin or DAT by decreasing its activity [76].

One of the most common mutations in SCNA gene associated with EOPD is A53T. It was firstly identified in members of Contursi kindred and three families from Greece, but later A53T was also found, for example, in Sweden and Korean population [77, 78, 79]. They were also described in such mutations as A30P and E46K related to EOPD [37, 80].


4. The phenotype of early-onset Parkinson’s disease

Patients with EOPD are characterized as younger AOO and longer disease duration than patients with LOPD [81]. Some symptoms vary among patients (Table 2), but classical motor symptoms are mainly affected.

Gene (locus) Location Selected mutations in EOPD patients Inheritance Clinical phenotype
PRKN (PARK2) 6q26 Q171X, R275W, G284R, T425N, A82Q, L174L, L261L Recessive Tremor, bradykinesia, urinary dysfunctions
PINK1 (PARK6) 1p36.12 Q456X, Y258X, R276X, M318L, A427E, R312R, A339T, D391D, G411S, T420T, D525N, S576S Recessive Foot dystonia, gait impairment, excellent L-dopa responsiveness
DJ-1 (PARK7) 1p36.23 D149A, A104T, L10P, D24A, F162 L, E64D Recessive Similar to PRKN
GBA 1q22 N370S, L444P, H255Q, E326K, D409H, R329H Recessive Mild Gaucher’s symptoms, cognitive impairment
SNCA (PARK1, PARK4) 4q22.1 A53T, A30P, E46K Dominant Rigidity, rapid progression

Table 2.

Genes implicated in EOPD and its clinical phenotype [30, 39].

EOPD with PRKN mutations is characterized by excellent response to L-dopa treatment and in consequence presence of dose-related fluctuations or dyskinesias after around 7 years of pharmacotherapy. The most common motor features are limb tremor and bradykinesia, but there are also reported such as poor balance or freezing episodes. Patients with PRKN mutations have autonomic symptoms like urinary urgency (45%), impotence (28%), and orthostatic faintness (13%) [82]. They also have a lower frequency of excessive daytime sleepiness than general PD population, and insomnia is considered as a most common sleep problem [83]. The results of Mini-Mental State Examination score (MMSE) in PRKN patients are ranged 30–25; thus, cognitive functions are normal [82]. The study of Kim et al. [83] showed that the patients with two mutations have significantly younger AOO and longer duration of the disease in comparison to patients without PRKN mutations. Moreover, they can have a positive family history with PD and use a lower dose of L-dopa. Patients can also present psychiatric dysfunction like depression, psychosis, obsessive–compulsive disorder, or anxiety [84]. Some literature data indicate that PRKN mutation carriers and non-mutation carriers are clinically indistinguishable [85].

Most of EOPD patients with mutations in PINK1 gene show typical symptoms of the disease resting tremor, rigidity, and bradykinesia. They have very good and sustained response to L-dopa treatment [46]. The Ibáñez et al. [86] study showed that even after 45 years of disease duration, the patient has a good response to L-dopa therapy. Moreover, there is a very slow progression of the disease and patients have no worsening for several decades. Siuda et al. [43] demonstrated two homozygous Q456X mutation carriers in a Polish family, who developed their first symptom, foot dystonia, in 16 and 27 years. Subsequently, patients suffered from progressive gait difficulties and had sensory symptoms in the lower limbs. It seems that disease onset in the lower limbs and early gait impairment can be characteristic for PD with PINK1 mutations [86, 87]. Besides having classical motor symptoms, patients with PINK1 mutations present L-dopa–responsiveness dystonia or restless leg syndrome (RLS) [81]. Cognitive impairment is rare and appears only in cases with a long duration of PD [86].

The phenotype of DJ1-related EOPD varies among mutations. Patients with the M26I mutation are characterized similar phenotype as PRKN mutation carriers. They have early leg dystonia before starting treatment and psychological disturbance, mainly anxiety [59]. The study of Hering et al. [62] showed that EOPD starts with slowing of movements and stiffness in the left leg and arm among patient with identified novel E64D mutation. Moreover, the first features were sleep disturbances, depression, and speech difficulties. In the patient with bradykinesia, rigidity and postural tremor occurred only on the left side of the body, but there was no problem with cognition. The observation of Abbas et al. [88] indicate that the patient with missense mutation I105F found in exon 5 presented asymmetric onset, moderate L-dopa response, but no pyramidal features or dystonia. It seems that special feature in this patient was extreme motor restlessness to L-dopa. However, in the same study, it is demonstrated that homozygous R98Q variant is responsible for good L-dopa response and the treatment induces dyskinesia.

GBA mutation carriers have significantly younger AOO in comparison to non-carriers [89, 90]. Patients characterize of good or excellent response to L-dopa therapy and present a typical PD phenotype. Furthermore, some of them present impressive to subthalamic nucleus deep-brain stimulation. There are also cases of GBA patients that affect depression [90]. The study of Sato et al. [89] indicates that GBA mutation carriers have a positive history of PD in families. They present poorer motor progression, more often postural instability, persistent asymmetry, and responsive for L-dopa for more than 5 years [91]. According to the literature data, GBA mutations are associated with cognitive impairment, which is revealed by a lower MMSE score [92]. It is considered that patients with both GD and PD present mild Gaucher’s symptoms [65].

The phenotype of SNCA-related EOPD consists of typical features for this type of the disease—asymmetric onset, good responsiveness for L-dopa in initial time, and early motor complications. The literature indicates that SNCA A53T mutation carriers with long-term PD present cognitive defects like dementia and average or inconsiderable in shorter term one. Besides, it was noted psychiatric syndromes, for example, depression, anxiety, dysautonomia, or olfaction impairments [93]. There can be observed numbness in the first of the disease, insomnia and occasional hypotensive attacks [94]. Whereas G51D carrier has phenotype differing from those with A53T. Patient characterizes the rapid progression of the disease, which consequently leads to loss of autonomy and death in few years. There were also noted manifested cognitive deterioration, visual hallucinations, and seizures [95]. The study of Somme et al. [96] shows that E46T mutation in early stages is also associated with a visual hallucination, sleep disorder, rigidity, and dementia.


5. Neuroimaging of early-onset Parkinson’s disease

A lot of neuroimaging techniques are used to diagnose PD properly, follow the progress, and also get to know the neurobiology mechanism involved in revealing the disease. The most commonly used methods are magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance spectroscopy (MRS), and transcranial sonography (TCS). There are also multimodal neuroimaging techniques that combine imaging with complementary modalities to increase the benefits of examination.

PET imaging is a technique using radiolabeled agents like 11C, 18F, and 15O. It is more sensitive and presents a better special resolution in comparison to SPECT, which employs radioisotopes 123I or 99mTc. It is thought that SPECT is cheaper, more widely available, and a valuable imaging modality for many PD applications [97]. It seems that Technetium99m-labeled tropane derivative (99mTc-TRODAT-1) can be used to reveal dysfunction of dopaminergic system by binding DAT [98]. It was also showed that striatal DAT-binding potential was 34% lower among EOPD than LOPD patients [99]. The study of Shyu et al. [100] identified lower uptake of 99mTc-TRODAT-1 in the putamen, but normal in the caudal nucleus among patients with PRKN mutations in early stages of EOPD. There is more symmetrical loss demonstrated in both structures in the latter stages of the disease. However, the PET results of Nagasawa et al. [101] show that the function of presynaptic dopamine terminals does not correlate with PD severity and degrees of main symptoms.

MRS is a kind of magnetic resonance for identifying many endogenous compounds involved in the pathomechanism of PD like DA, γ-aminobutyric acid (GABA), and glutamate, so it gives an opportunity for probing biochemical systems [102, 103]. It allows research neurochemicals directly, without invasion and radiation exposure.

There is also another kind of resonance MRI in patients with EOPD. MRI creates images of the human body by detecting spin properties of nuclei [97]. MRI is not able to directly image dopaminergic neuronal loss, but it can provide complementary data to those obtained with nuclear tracer imaging [104]. The study of Wang et al. [105] shows that pathological asymmetry between both hemispheres in NG pathways in the early stage of EOPS using an MRI method.

TCS is another technique used in PD. It is a noninvasive, validated ultrasound method for demonstrating characteristic alterations of deep brain regions especially SN, but also lenticular nucleus (NL) or ventricles [106]. It is less expensive than the previously described tools, that is why it can be an important advantage of its application [97]. The literature indicates that TCS-MRI fusion allows analyzing SN and NL echogenicity as highly sensitive and specific markers for EOPD [107].

There are also multimodal imaging for imaging structure and metabolism like PET/CT. Using this method, the study of Shi et al. [108] shows the unequal radioactive distribution of 18F-2-deoxy-D-glucose among patients with compound mutations in the PRKN gene. Moreover, the authors observed the reduction of 11C-2 β-carbomethoxy-3 β-(4-fluorophenyl) tropane uptake in the caudal putamen.


6. Summary

The occurrence of EOPD is associated with molecular factors both genetic and biochemical ones. The presence of various genetic variants such as PRKN gene is associated with Parkin protein, the PINK1 gene affecting the efficiency of the ubiquitin-proteasome system, the DJ-1 gene linked with mitochondria, GBA gene connected with lysosomes and SNCA gene encoding ASN may accelerate revealing of PD. It seems that discovering the relationship between genetic bases and protein parameters may lead to explain the causes of appearance PD depended of age. Furthermore, in the future, it could entail with bases for earlier diagnosis of EOPD and in consequence introduction of more effective pharmacotherapy.


  1. 1. Gazewood JD, Richards DR, Clebak K. Parkinson disease: An update. American Family Physician. 2013;87(4):267-273
  2. 2. Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, et al. Incidence of Parkinson’s disease: Variation by age, gender, and race/ethnicity. American Journal of Epidemiology. 2003;157(11):1015-1022
  3. 3. Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet (London, England). 2004;363(9423):1783-1793. DOI: 10.1016/S0140-6736(04)16305-8
  4. 4. de Lau LML, Breteler MMB. Epidemiology of Parkinson’s disease. Lancet Neurology. 2006;5(6):525-535. DOI: 10.1016/S1474-4422(06)70471-9
  5. 5. Smith KM, Dahodwala N. Sex differences in Parkinson’s disease and other movement disorders. Experimental Neurology. 2014;259:44-56. DOI: 10.1016/j.expneurol.2014.03.010
  6. 6. Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurology. 2006;5(4):355-363. DOI: 10.1016/S1474-4422(06)70411-2
  7. 7. Wickremaratchi MM, Knipe MDW, Sastry BSD, Morgan E, Jones A, Salmon R, et al. The motor phenotype of Parkinson’s disease in relation to age at onset. Movement Disorders: Official Journal of The Movement Disorder Society. 2011;26(3):457-463. DOI: 10.1002/mds.23469
  8. 8. Ferguson LW, Rajput AH, Rajput A. Early-onset vs. Late-onset Parkinson’s disease: A clinical-pathological study. The Canadian Journal of Neurological Sciences. 2016;43(1):113-119. DOI: 10.1017/cjn.2015.244
  9. 9. Lesage S, Brice A. Parkinson’s disease: From monogenic forms to genetic susceptibility factors. Human Molecular Genetics. 2009;18(R1):R48-R59. DOI: 10.1093/hmg/ddp012
  10. 10. Poewe W. Non-motor symptoms in Parkinson’s disease. European Journal of Neurology. 2008;15(Suppl 1):14-20. DOI: 10.1111/j.1468-1331.2008.02056.x
  11. 11. Politis M. Neuroimaging in Parkinson disease: From research setting to clinical practice. Nature Reviews. Neurology. 2014;10(12):708-722. DOI: 10.1038/nrneurol.2014.205
  12. 12. Pagano G, Niccolini F, Politis M. Imaging in Parkinson’s disease. Clinical Medicine (London, England). 2016;16(4):371-375. DOI: 10.7861/clinmedicine.16-4-371
  13. 13. McHugh PC, Buckley DA. The structure and function of the dopamine transporter and its role in CNS diseases. Vitamins and Hormones. 2015;98:339-369. DOI: 10.1016/bs.vh.2014.12.009
  14. 14. Bisaglia M, Filograna R, Beltramini M, Bubacco L. Are dopamine derivatives implicated in the pathogenesis of Parkinson’s disease? Ageing Research Reviews. 2014;13:107-114. DOI: 10.1016/j.arr.2013.12.009
  15. 15. Mhyre TR, Boyd JT, Hamill RW, Maguire-Zeiss KA. Parkinson’s disease. Sub-Cellular Biochemistry. 2012;65:389-455. DOI: 10.1007/978-94-007-5416-4_16
  16. 16. Shen J, Cookson MR. Mitochondria and dopamine: New insights into recessive parkinsonism. Neuron. 2004;43(3):301-304. DOI: 10.1016/j.neuron.2004.07.012
  17. 17. Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: A target for neuroprotection? Lancet Neurology. 2009;8(4):382-397. DOI: 10.1016/S1474-4422(09)70062-6
  18. 18. Cookson MR. Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways. Cold Spring Harbor Perspectives in Medicine. 2012;2(9):a009415. DOI: 10.1101/cshperspect.a009415
  19. 19. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839-840. DOI: 10.1038/42166
  20. 20. Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature. 2006;443(7113):780-786. DOI: 10.1038/nature05291
  21. 21. Dorszewska J, Prendecki M, Oczkowska A, Rozycka A, Lianeri M, Kozubski W. Polymorphism of the COMT, MAO, DAT, NET and 5-HTT genes, and biogenic amines in Parkinson’s disease. Current Genomics. 2013;14(8):518-533. DOI: 10.2174/1389202914666131210210241
  22. 22. Butler B, Saha K, Rana T, Becker JP, Sambo D, Davari P, et al. Dopamine transporter activity is modulated by α-synuclein. The Journal of Biological Chemistry. 2015;290(49):29542-29554. DOI: 10.1074/jbc.M115.691592
  23. 23. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011;146(1):37-52. DOI: 10.1016/j.cell.2011.06.001
  24. 24. Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options. Current Neuropharmacology. 2009;7(1):65-74. DOI: 10.2174/157015909787602823
  25. 25. Murphy MP. How mitochondria produce reactive oxygen species. The Biochemical Journal. 2009;417(1):1-13. DOI: 10.1042/BJ20081386
  26. 26. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. Journal of Neurochemistry. 1990;54(3):823-827
  27. 27. Bisaglia M, Tosatto L, Munari F, Tessari I, de Laureto PP, Mammi S, et al. Dopamine quinones interact with alpha-synuclein to form unstructured adducts. Biochemical and Biophysical Research Communications. 2010;394(2):424-428. DOI: 10.1016/j.bbrc.2010.03.044
  28. 28. Girotto S, Sturlese M, Bellanda M, Tessari I, Cappellini R, Bisaglia M, et al. Dopamine-derived quinones affect the structure of the redox sensor DJ-1 through modifications at Cys-106 and Cys-53. The Journal of Biological Chemistry. 2012;287(22):18738-18749. DOI: 10.1074/jbc.M111.311589
  29. 29. Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, et al. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(27):11441-11446. DOI: 10.1073/pnas.0702717104
  30. 30. Schulte C, Gasser T. Genetic basis of Parkinson’s disease: Inheritance, penetrance, and expression. The Application of Clinical Genetics. 2011;4:67-80. DOI: 10.2147/TACG.S11639
  31. 31. Seirafi M, Kozlov G, Gehring K. Parkin structure and function. The FEBS Journal. 2015;282(11):2076-2088. DOI: 10.1111/febs.13249
  32. 32. Büeler H. Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Experimental Neurology. 2009;218(2):235-246. DOI: 10.1016/j.expneurol.2009.03.006
  33. 33. Brüggemann N, Klein C. Parkin type of early-onset Parkinson disease. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, et al., editors. Gene Reviews. Seattle (WA): University of Washington, Seattle; 2001
  34. 34. Jiang H, Ren Y, Yuen EY, Zhong P, Ghaedi M, Hu Z, et al. Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nature Communications. 2012;3:668. DOI: 10.1038/ncomms1669
  35. 35. Li H, Yusufujiang A, Naser S, Zhu Y, Maimaiti M, He X, et al. Mutation analysis of PARK2 in a Uyghur family with early-onset Parkinson’s disease in Xinjiang, China. Journal of the Neurological Sciences. 2014;342(1–2):21-24. DOI: 10.1016/j.jns.2014.03.044
  36. 36. Kilarski LL, Pearson JP, Newsway V, Majounie E, Knipe MDW, Misbahuddin A, et al. Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson’s disease. Movement Disorders: Official Journal of the Movement Disorder Society. 2012;27(12):1522-1529. DOI: 10.1002/mds.20810
  37. 37. Erer S, Egeli U, Zarifoglu M, Tezcan G, Cecener G, Tunca B, et al. Mutation analysis of the PARKIN, PINK1, DJ1, and SNCA genes in Turkish early-onset Parkinson’s patients and genotype-phenotype correlations. Clinical Neurology and Neurosurgery. 2016;148:147-153. DOI: 10.1016/j.clineuro.2016.07.005
  38. 38. Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harbor Perspectives in Medicine. 2012;2(1). DOI: 10.1101/cshperspect.a008888
  39. 39. Brooks J, Ding J, Simon-Sanchez J, Paisan-Ruiz C, Singleton AB, Scholz SW. Parkin and PINK1 mutations in early-onset Parkinson’s disease: Comprehensive screening in publicly available cases and control. Journal of Medical Genetics. 2009;46(6):375-381. DOI: 10.1136/jmg.2008.063917
  40. 40. Hedrich K, Eskelson C, Wilmot B, Marder K, Harris J, Garrels J, et al. Distribution, type, and origin of Parkin mutations: review and case studies. Movement Disorders: Official Journal of the Movement Disorder Society. 2004;19(10):1146-1157. DOI: 10.1002/mds.20234
  41. 41. Ross OA, Braithwaite AT, Farrer MJ. Chapter 2—Genetics of Parkinson’s disease. In: Parkinson’s Disease. San Diego: Academic Press; 2008. pp. 9-33
  42. 42. Narendra DP, Jin SM, Tanaka A, Suen D-F, Gautier CA, Shen J, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biology. 2010;8(1):e1000298. DOI: 10.1371/journal.pbio.1000298
  43. 43. Siuda J, Jasinska-Myga B, Boczarska-Jedynak M, Opala G, Fiesel FC, Moussaud-Lamodière EL, et al. Early-onset Parkinson’s disease due to PINK1 p.Q456X mutation—clinical and functional study. Parkinsonism & Related Disorders. 2014;20(11):1274-1278. DOI: 10.1016/j.parkreldis.2014.08.019
  44. 44. Morais VA, Verstreken P, Roethig A, Smet J, Snellinx A, Vanbrabant M, et al. Parkinson’s disease mutations in PINK1 result in decreased complex I activity and deficient synaptic function. EMBO Molecular Medicine. 2009;1(2):99-111. DOI: 10.1002/emmm.200900006
  45. 45. Gispert S, Auburger G, Kuruvilla KP, LeDoux MS. Chapter 19—Rodent models of autosomal recessive Parkinson disease. In: Movement Disorders. 2nd ed. Boston: Academic Press; 2015. pp. 329-343
  46. 46. Bonifati V, Rohé CF, Breedveld GJ, Fabrizio E, De Mari M, Tassorelli C, et al. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology. 2005;65(1):87-95. DOI: 10.1212/01.wnl.0000167546.39375.82
  47. 47. Tan E-K, Yew K, Chua E, Puvan K, Shen H, Lee E, et al. PINK1 mutations in sporadic early-onset Parkinson’s disease. Movement Disorders: Official Journal of the Movement Disorder Society. 2006;21(6):789-793. DOI: 10.1002/mds.20810
  48. 48. Scornaienchi V, Civitelli D, De Marco EV, Annesi G, Tarantino P, Rocca FE, et al. Mutation analysis of the PINK1 gene in Southern Italian patients with early- and late-onset parkinsonism. Parkinsonism & Related Disorders. 2012;18(5):651-653. DOI: 10.1016/j.parkreldis.2011.08.017
  49. 49. Wilson MA, Collins JL, Hod Y, Ringe D, Petsko GA. The 1.1-A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson’s disease. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(16):9256-9261. DOI: 10.1073/pnas.1133288100
  50. 50. Zhang L, Shimoji M, Thomas B, Moore DJ, Yu S-W, Marupudi NI, et al. Mitochondrial localization of the Parkinson’s disease related protein DJ-1: Implications for pathogenesis. Human Molecular Genetics. 2005;14(14):2063-2073. DOI: 10.1093/hmg/ddi211
  51. 51. Moore DJ, Zhang L, Troncoso J, Lee MK, Hattori N, Mizuno Y, et al. Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Human Molecular Genetics. 2005;14(1):71-84. DOI: 10.1093/hmg/ddi007
  52. 52. Tang B, Xiong H, Sun P, Zhang Y, Wang D, Hu Z, et al. Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson’s disease. Human Molecular Genetics. 2006;15(11):1816-1825. DOI: 10.1093/hmg/ddl104
  53. 53. Björkblom B, Adilbayeva A, Maple-Grødem J, Piston D, Ökvist M, Xu XM, et al. Parkinson disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity. The Journal of Biological Chemistry. 2013;288(31):22809-22820. DOI: 10.1074/jbc.M113.482091
  54. 54. Hayashi T, Ishimori C, Takahashi-Niki K, Taira T, Kim Y, Maita H, et al. DJ-1 binds to mitochondrial complex I and maintains its activity. Biochemical and Biophysical Research Communications. 2009;390(3):667-672. DOI: 10.1016/j.bbrc.2009.10.025
  55. 55. Lev N, Barhum Y, Pilosof NS, Ickowicz D, Cohen HY, Melamed E, et al. DJ-1 protects against dopamine toxicity: Implications for Parkinson’s disease and aging. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2013;68(3):215-225. DOI: 10.1093/gerona/gls147
  56. 56. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299(5604):256-259. DOI: 10.1126/science.1077209
  57. 57. van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Houwing-Duistermaat JJ, Snijders PJ, et al. Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. American Journal of Human Genetics. 2001;69(3):629-634. DOI: 10.1086/322996
  58. 58. Sironi F, Primignani P, Ricca S, Tunesi S, Zini M, Tesei S, et al. DJ1 analysis in a large cohort of Italian early onset Parkinson disease patients. Neuroscience Letters. 2013;557(Pt B):165-170. DOI: 10.1016/j.neulet.2013.10.048
  59. 59. Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW. The role of pathogenic DJ-1 mutations in Parkinson’s disease. Annals of Neurology. 2003;54(3):283-286. DOI: 10.1002/ana.10675
  60. 60. Clark LN, Afridi S, Mejia-Santana H, Harris J, Louis ED, Cote LJ, et al. Analysis of an early-onset Parkinson’s disease cohort for DJ-1 mutations. Movement Disorders: Official Journal of the Movement Disorder Society. 2004;19(7):796-800. DOI: 10.1002/mds.20131
  61. 61. Guo JF, Xiao B, Liao B, Zhang XW, Nie LL, Zhang YH, et al. Mutation analysis of Parkin, PINK1, DJ-1 and ATP13A2 genes in Chinese patients with autosomal recessive early-onset Parkinsonism. Movement Disorders: Official Journal of the Movement Disorder Society. 2008;23(14):2074-2079. DOI: 10.1002/mds.22156
  62. 62. Hering R, Strauss KM, Tao X, Bauer A, Woitalla D, Mietz E-M, et al. Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). Human Mutation. 2004;24(4):321-329. DOI: 10.1002/humu.20089
  63. 63. Beutler E. Gaucher disease: New molecular approaches to diagnosis and treatment. Science. 1992;256(5058):794-799
  64. 64. Gegg ME, Schapira AHV. The role of glucocerebrosidase in Parkinson disease pathogen- esis. The FEBS Journal. 2018. DOI: 10.1111/febs.14393 [Epub ahead of print]
  65. 65. Sidransky E, Lopez G. The link between the GBA gene and parkinsonism. Lancet Neurology. 2012;11(11):986-998. DOI: 10.1016/S1474-4422(12)70190-4
  66. 66. Kalinderi K, Bostantjopoulou S, Paisan-Ruiz C, Katsarou Z, Hardy J, Fidani L. Complete screening for glucocerebrosidase mutations in Parkinson disease patients from Greece. Neuroscience Letters. 2009;452(2):87-89. DOI: 10.1016/j.neulet.2009.01.029
  67. 67. Ortega RA, Torres PA, Swan M, Nichols W, Boschung S, Raymond D, et al. Glucocerebrosidase enzyme activity in GBA mutation Parkinson’s disease. Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia. 2016;28:185-186. DOI: 10.1016/j.jocn.2015.12.004
  68. 68. Brockmann K, Berg D. The significance of GBA for Parkinson’s disease. Journal of Inherited Metabolic Disease. 2014;37(4):643-648. DOI: 10.1007/s10545-014-9714-7
  69. 69. Goker-Alpan O, Schiffmann R, LaMarca ME, Nussbaum RL, McInerney-Leo A, Sidransky E. Parkinsonism among Gaucher disease carriers. Journal of Medical Genetics. 2004;41(12):937-940. DOI: 10.1136/jmg.2004.024455
  70. 70. Jin H, Kanthasamy A, Ghosh A, Yang Y, Anantharam V, Kanthasamy AG. α-Synuclein negatively regulates protein kinase Cδ expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity. Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2011;31(6):2035-2051. DOI: 10.1523/JNEUROSCI.5634-10.2011
  71. 71. Park SM, Jung HY, Kim TD, Park JH, Yang C-H, Kim J. Distinct roles of the N-terminal-binding domain and the C-terminal-solubilizing domain of alpha-synuclein, a molecular chaperone. The Journal of Biological Chemistry. 2002;277(32):28512-28520. DOI: 10.1074/jbc.M111971200
  72. 72. Martinez J, Moeller I, Erdjument-Bromage H, Tempst P, Lauring B. Parkinson’s disease-associated alpha-synuclein is a calmodulin substrate. The Journal of Biological Chemistry. 2003;278(19):17379-17387. DOI: 10.1074/jbc.M209020200
  73. 73. Zhu M, Qin Z-J, Hu D, Munishkina LA, Fink AL. Alpha-synuclein can function as an antioxidant preventing oxidation of unsaturated lipid in vesicles. Biochemistry (Mosc). 2006;45(26):8135-8142. DOI: 10.1021/bi052584t
  74. 74. Rodriguez-Araujo G, Nakagami H, Takami Y, Katsuya T, Akasaka H, Saitoh S, et al. Low alpha-synuclein levels in the blood are associated with insulin resistance. Scientific Reports. 2015;5:12081. DOI: 10.1038/srep12081
  75. 75. Peng X, Peng XM, Tehranian R, Dietrich P, Stefanis L, Perez RG. Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. Journal of Cell Science. 2005;118(Pt 15):3523-3530. DOI: 10.1242/jcs.02481
  76. 76. Emamzadeh FN. Alpha-synuclein structure, functions, and interactions. Journal of Research in Medical Sciences: The Official Journal of Isfahan University of Medical Sciences. 2016;21. DOI: 10.4103/1735-1995.181989
  77. 77. Polymeropoulos MH. Mutation in the -synuclein gene identified in families with Parkinson’s disease. Science. 1997;276(5321):2045-2047
  78. 78. Choi JM, Woo MS, Ma HI, Kang SY, Sung YH, Yong SW, et al. Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. Neurogenetics. 2008;9(4):263-269. DOI: 10.1007/s10048-008-0138-0
  79. 79. Puschmann A, Ross OA, Vilariño-Güell C, Lincoln SJ, Kachergus JM, Cobb SA, et al. A Swedish family with de novo α-synuclein A53T mutation: Evidence for early cortical dysfunction. Parkinsonism & Related Disorders. 2009;15(9):627-632. DOI: 10.1016/j.parkreldis.2009.06.007
  80. 80. Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Annals of Neurology. 2004;55(2):164-173. DOI: 10.1002/ana.10795
  81. 81. Nishioka K, Kefi M, Jasinska-Myga B, Wider C, Vilariño-Güell C, Ross OA, et al. A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psychiatry. 2010;81(4):391-395. DOI: 10.1136/jnnp.2009.185231
  82. 82. Khan NL, Graham E, Critchley P, Schrag AE, Wood NW, Lees AJ, et al. Parkin disease: A phenotypic study of a large case series. Brain: A Journal of Neurology. 2003;126(Pt 6):1279-1292
  83. 83. Kim HJ, Kim HJ, Lee JY, Yun JY, Kim SY, Park SS, et al. Phenotype analysis in patients with early onset Parkinson’s disease with and without parkin mutations. Journal of Neurology. 2011;258(12):2260-2267. DOI: 10.1007/s00415-011-6110-1
  84. 84. Wu RM, Shan DE, Sun CM, Liu RS, Hwu WL, Tai CH, et al. Clinical,18F-dopa PET, and genetic analysis of an ethnic Chinese kindred with early-onset parkinsonism andparkin gene mutations. Movement Disorders. 2002;17(4):670-675. DOI: 10.1002/mds.10184
  85. 85. Fiala O, Pospisilova L, Prochazkova J, Matejckova M, Martasek P, Novakova L, et al. Parkin mutations and phenotypic features in Czech patients with early-onset Parkinson’s disease. Neuro Endocrinology Letters. 2010;31(2):187-192
  86. 86. Ibáñez P, Lesage S, Lohmann E, Thobois S, De Michele G, Borg M, et al. Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain: A Journal of Neurology. 2006;129(Pt 3):686-694. DOI: 10.1093/brain/awl005
  87. 87. Zadikoff C, Rogaeva E, Djarmati A, Sato C, Salehi-Rad S, St George-Hyslop P, et al. Homozygous and heterozygous PINK1 mutations: Considerations for diagnosis and care of Parkinson’s disease patients. Movement Disorders: Official Journal of the Movement Disorder Society. 2006;21(6):875-879. DOI: 10.1002/mds.20854
  88. 88. Abbas MM, Govindappa ST, Sudhaman S, Thelma BK, Juyal RC, Behari M, et al. Early onset Parkinson’s disease due to DJ1 mutations: An Indian study. Parkinsonism & Related Disorders. 2016;32:20-24. DOI: 10.1016/j.parkreldis.2016.04.024
  89. 89. Sato C, Morgan A, Lang AE, Salehi-Rad S, Kawarai T, Meng Y, et al. Analysis of the glucocerebrosidase gene in Parkinson’s disease. Movement Disorders: Official Journal of the Movement Disorder Society. 2005;20(3):367-370. DOI: 10.1002/mds.20319
  90. 90. Wu YR, Chen CM, Chao CY, Ro LS, Lyu RK, Chang KH, et al. Glucocerebrosidase gene mutation is a risk factor for early onset of Parkinson disease among Taiwanese. Journal of Neurology, Neurosurgery, and Psychiatry. 2007;78(9):977-979. DOI: 10.1136/jnnp.2006.105940
  91. 91. Pulkes T, Choubtum L, Chitphuk S, Thakkinstian A, Pongpakdee S, Kulkantrakorn K, et al. Glucocerebrosidase mutations in Thai patients with Parkinson’s disease. Parkinsonism & Related Disorders. 2014;20(9):986-991. DOI: 10.1016/j.parkreldis.2014.06.007
  92. 92. Alcalay RN, Mejia-Santana H, Tang MX, Rakitin B, Rosado L, Ross B, et al. Self-report of cognitive impairment and mini-mental state examination performance in PRKN, LRRK2, and GBA carriers with early onset Parkinson’s disease. Journal of Clinical and Experimental Neuropsychology. 2010;32(7):775-779. DOI: 10.1080/13803390903521018
  93. 93. Ricciardi L, Petrucci S, Di Giuda D, Serra L, Spanò B, Sensi M, et al. The contursi family 20 years later: Intrafamilial phenotypic variability of the SNCA p.A53T mutation. Movement Disorders: Official Journal of the Movement Disorder Society. 2016;31(2):257-258. DOI: 10.1002/mds.26549
  94. 94. Pasanen P, Myllykangas L, Siitonen M, Raunio A, Kaakkola S, Lyytinen J, et al. Novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s disease-type pathology. Neurobiology of Aging. 2014;35(9):2180.e1-2180.e5. DOI: 10.1016/j.neurobiolaging.2014.03.024
  95. 95. Lesage S, Anheim M, Letournel F, Bousset L, Honoré A, Rozas N, et al. G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Annals of Neurology. 2013;73(4):459-471. DOI: 10.1002/ana.23894
  96. 96. Somme JH, Gomez-Esteban JC, Molano A, Tijero B, Lezcano E, Zarranz JJ. Initial neuropsychological impairments in patients with the E46K mutation of the α-synuclein gene (PARK 1). Journal of the Neurological Sciences. 2011;310(1–2):86-89. DOI: 10.1016/j.jns.2011.07.047
  97. 97. Weingarten CP, Sundman MH, Hickey P, Chen N. Neuroimaging of Parkinson’s disease: Expanding views. Neuroscience and Biobehavioral Reviews. 2015;59:16-52. DOI: 10.1016/j.neubiorev.2015.09.007
  98. 98. Sasannezhad P, Juibary AG, Sadri K, Sadeghi R, Sabour M, Kakhki VRD, et al. 99mTc-TRODAT-1 SPECT imaging in early and late onset Parkinson’s disease. Asia Oceania Journal of Nuclear Medicine and Biology. 2017;5(2):114-119. DOI: 10.22038/aojnmb.2017.8844
  99. 99. Shih MC, Franco de Andrade LA, Amaro E, Felicio AC, Ferraz HB, Wagner J, et al. Higher nigrostriatal dopamine neuron loss in early than late onset Parkinson’s disease?—a [99mTc]-TRODAT-1 SPECT study. Movement Disorders: Official Journal of the Movement Disorder Society. 2007;22(6):863-866. DOI: 10.1002/mds.21315
  100. 100. Shyu WC, Lin SZ, Chiang MF, Pang CY, Chen SY, Hsin YL, et al. Early-onset Parkinson’s disease in a Chinese population: 99mTc-TRODAT-1 SPECT, Parkin gene analysis and clinical study. Parkinsonism & Related Disorders. 2005;11(3):173-180. DOI: 10.1016/j.parkreldis.2004.12.004
  101. 101. Nagasawa H, Tanji H, Itoyama Y, Saito H, Kimura I, Fujiwara T, et al. Brain 6-[18F]fluorodopa metabolism in early and late onset of Parkinson’s disease studied by positron emission tomography. Journal of the Neurological Sciences. 1996;144(1–2):70-76
  102. 102. Emir UE, Tuite PJ, Öz G. Elevated pontine and putamenal GABA levels in mild-moderate Parkinson disease detected by 7 tesla proton MRS. PLoS One. 2012;7(1):e30918. DOI: 10.1371/journal.pone.0030918
  103. 103. Gröger A, Kolb R, Schäfer R, Klose U. Dopamine reduction in the substantia nigra of Parkinson’s disease patients confirmed by in vivo magnetic resonance spectroscopic imaging. PLoS One. 2014;9(1):e84081. DOI: 10.1371/journal.pone.0084081
  104. 104. Tuite PJ, Mangia S, Michaeli S. Magnetic resonance imaging (MRI) in Parkinson’s disease. Journal of Alzheimers Disease and Parkinsonism. 2013;(Suppl 1):001. DOI: 10.4172/2161-0460.S1-001
  105. 105. Wang J, Yang QX, Sun X, Vesek J, Mosher Z, Vasavada M, et al. MRI evaluation of asymmetry of nigrostriatal damage in the early stage of early-onset Parkinson’s disease. Parkinsonism & Related Disorders. 2015;21(6):590-596. DOI: 10.1016/j.parkreldis.2015.03.012
  106. 106. Walter U, Dressler D, Wolters A, Wittstock M, Benecke R. Transcranial brain sonography findings in clinical subgroups of idiopathic Parkinson’s disease. Movement Disorders: Official Journal of the Movement Disorder Society. 2007;22(1):48-54. DOI: 10.1002/mds.21197
  107. 107. Mašková J, Školoudík D, Burgetová A, Fiala O, Brůha R, Záhoráková D, et al. Comparison of transcranial sonography-magnetic resonance fusion imaging in Wilson’s and early-onset Parkinson’s diseases. Parkinsonism & Related Disorders. 2016;28:87-93. DOI: 10.1016/j.parkreldis.2016.04.031
  108. 108. Shi Y, Kawakami H, Zang W, Li G, Zhang J, Xu C. Novel compound heterozygous mutations in the PARK2 gene identified in a Chinese pedigree with early-onset Parkinson’s disease. Brain and Behavior: A Cognitive Neuroscience Perspective. 2018;8(1):e00901. DOI: 10.1002/brb3.901

Written By

Katarzyna Wize, Wojciech Kozubski and Jolanta Dorszewska

Submitted: 01 May 2018 Reviewed: 19 July 2018 Published: 31 October 2018