Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease

Mutations in five PARK genes (SNCA, PARKIN, DJ-1, PINK1, and LRRK2) are well-established genetic causes of Parkinson disease (PD). Recently, G2385R substitution in LRRK2 has been determined as a susceptibility allele in Asian PD. The objective of this study is to determine the frequency of mutations in these PARK genes in a Korean early-onset Parkinson disease (EOPD) cohort. The authors sequenced 35 exons in SNCA, PARKIN, DJ-1, PINK1, and LRRK2 in 72 unrelated EOPD (age-at-onset ≤50) recruited from ten movement disorders clinics in South Korea. Gene dosage change of the aforementioned genes was studied using multiple ligation-dependent probe amplification. We found four patients with PARKIN mutations, which were homozygous deletion of exon 4, compound heterozygous deletion of exon 2 and exon 4, heterozygous deletion of exon 4, and heterozygous nonsense mutation (Q40X). Four patients had PINK1 mutations; a compound heterozygous mutation (N367S and K520RfsX522) and three heterozygous mutations (G32R, R279H, and F385L). A missense mutation of SNCA (A53T) was found in a familial PD with autosomal dominant inheritance. Nine patients (12.5%) had heterozygous G2385R polymorphism of LRRK2, whereas none had G2019S mutation. However, no mutations were detected in DJ-1 and UCHL1 in our series. We identified genetic variants in PARKIN, PINK1, LRRK2, and SNCA as a cause or genetic risk factors for PD in 25% of Korean EOPD, and mutation of PARKIN was the most common genetic cause. Jung Mi Choi and Myoung Soo Woo equally contributed to this work.     

Common variants in PARK loci and related genes and Parkinson's disease

Rare mutations in PARK loci genes cause Parkinson's disease (PD) in some families and isolated populations. We investigated the association of common variants in PARK loci and related genes with PD susceptibility and age at onset in an outbred population. A total of 1,103 PD cases from the upper Midwest, USA, were individually matched to unaffected siblings (n = 654) or unrelated controls (n = 449) from the same region. Using a sequencing approach in 25 cases and 25 controls, single nucleotide polymorphisms (SNPs) in species‐conserved regions of PARK loci and related genes were detected. We selected additional tag SNPs from the HapMap. We genotyped a total of 235 SNPs and two variable number tandem repeats in the ATP13A2, DJ1, LRRK1, LRRK2, MAPT, Omi/HtrA2, PARK2, PINK1, SNCA, SNCB, SNCG, SPR, and UCHL1 genes in all 2,206 subjects. Case‐control analyses were performed to study association with PD susceptibility, while cases‐only analyses were used to study association with age at onset. Only MAPT SNP rs2435200 was associated with PD susceptibility after correction for multiple testing (OR = 0.74, 95% CI = 0.64–0.86, uncorrected P < 0.0001, log additive model); however, 16 additional MAPT variants, seven SNCA variants, and one LRRK2, PARK2, and UCHL1 variants each had significant uncorrected P‐values. There were no significant associations for age at onset after correction for multiple testing. Our results confirm the association of MAPT and SNCA genes with PD susceptibility but show limited association of other PARK loci and related genes with PD. © 2010 Movement Disorder Society     

The genetics and neuropathology of Parkinson’s disease

There has been tremendous progress toward understanding the genetic basis of Parkinson’s disease and related movement disorders. We summarize the genetic, clinical and pathological findings of autosomal dominant disease linked to mutations in SNCA, LRRK2, ATXN2, ATXN3, MAPT, GCH1, DCTN1 and VPS35. We then discuss the identification of mutations in PARK2, PARK7, PINK1, ATP13A2, FBXO7, PANK2 and PLA2G6 genes. In particular we discuss the clinical and pathological characterization of these forms of disease, where neuropathology has been important in the likely coalescence of pathways highly relevant to typical PD. In addition to the identification of the causes of monogenic forms of PD, significant progress has been made in defining genetic risk loci for PD; we discuss these here, including both risk variants at LRRK2 and GBA, in addition to discussing the results of recent genome-wide association studies and their implications for PD. Finally, we discuss the likely path of genetic discovery in PD over the coming period and the implications of these findings from a clinical and etiological perspective.     

Systematic Review and UK‐Based Study of PARK2 (parkin), PINK1, PARK7 (DJ‐1) and LRRK2 in early‐onset Parkinson's disease

Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early‐onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late‐onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high‐ascertainment regional and community‐based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ‐1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) < 40 (9.5%), an affected first‐degree relative (6.9%), an affected sibling (28.6%), or parental consanguinity (50%). In our study EOPD mutation carriers were more likely to present with rigidity and dystonia, and 6 of 7 mutation carriers had lower limb symptoms at onset. Our systematic review included information from >5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ‐1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity. © 2012 Movement Disorder Society.     

Cognitive and psychiatric symptoms in genetically determined Parkinson’s disease: a systematic review

The aim was to review the existing reports on cognitive and behavioural symptoms in monogenic forms of Parkinson’s disease (PD) and to identify recurring patterns of clinical manifestations in those with specific mutations. A systematic literature search was conducted to retrieve observational studies of monogenic PD. Data pertaining to cognitive and psychiatric manifestations were extracted using standardized templates. The PRISMA guidelines were followed. Of the 1889 citations retrieved, 95 studies on PD‐related gene mutations were included: 35 in SNCA, 35 in LRRK2, four in VPS35, 10 in Parkin, three in DJ1 and eight in PINK1. Nineteen studies (20%) provided adequate data from comprehensive cognitive assessment and 31 studies (32.6%) outlined psychiatric manifestations through the use of neuropsychiatric scales. Cognitive impairment was reported in all monogenic PD forms with variable rates (58.8% PINK1, 53.9% SNCA, 50% DJ1, 29.2% VPS35, 15.7% LRRK2 and 7.4% Parkin). In this regard, executive functions and attention were the domains most affected. With respect to psychiatric symptoms, depression was the most frequent symptom, occurring in 37.5% of PINK1 cases and 41.7% of VPS35 and LRRK2 cases. Co‐occurrence of cognitive decline with visual hallucinations was evidenced. Widespread accumulation of Lewy bodies, distinctive of SNCA, PINK1 and DJ1 mutations, results in higher rates of cognitive impairment. Similarly, a higher degree of visual hallucinations is observed in SNCA mutations, probably owing to the more widespread accumulation. The lower rates of α‐synuclein pathology in LRRK2 and Parkin may underpin the more benign disease course in these patients.     

Genotypic and phenotypic characteristics of Dutch patients with early onset Parkinson's disease

Early onset Parkinson's disease (EOPD) has been associated with mutations in the Parkin, DJ‐1, PINK1, LRRK2, and SNCA genes. The aim of this study is to assess the contribution of these genes in a Dutch EOPD cohort and the phenotypic characteristics of the mutation carriers. A total of 187 unrelated Dutch EOPD patients (age at onset ≤ 50 years) were phenotyped and screened for mutations in all exons of Parkin, DJ‐1, and PINK1 by direct sequencing and gene dosage analysis. Additionally, analysis of the A30P mutation and exon dosage of SNCA and sequencing of exons 19,31,35,38,41, and 48 of LRRK2 was performed. Pathogenic variations could explain disease in 4% (7 of 187) of the patients including five patients carrying homozygous or compound heterozygous mutations in Parkin, one with a novel homozygous deletion in DJ‐1 (P158Del) and one with a heterozygous mutation in LRRK2 (T2356I). We found seven novel mutations. The phenotypic characteristics of mutation carriers varied widely, comparable to the variability seen in sporadic EOPD. Parkin is the most frequently mutated gene in this EOPD cohort, followed by DJ‐1, PINK1 and LRRK2. The low overall mutation frequency indicates that the extrapolation of mutation frequencies from other populations should be applied with caution. © 2008 Movement Disorder Society     

The genetic landscape of Parkinson's disease

The cause of Parkinson's disease (PD) remains unknown in most patients. Since 1997, with the first genetic mutation known to cause PD described in SNCA gene, many other genes with Mendelian inheritance have been identified. We summarize genetic, clinical and neuropathological findings related to the 27 genes reported in the literature since 1997, associated either with autosomal dominant (AD): LRRK2, SNCA, VPS35, GCH1, ATXN2, DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, CHCHD2, and GBA; or autosomal recessive (AR) inheritance: PRKN, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, SPG11, VPS13C, PODXL, and PTRHD1; or an X-linked transmission: RAB39B. Clinical and neuropathological variability among genes is great. LRRK2 mutation carriers present a phenotype similar to those with idiopathic PD whereas, depending on the SNCA mutations, the phenotype ranges from early onset typical PD to dementia with Lewy bodies, including many other atypical forms. DNAJC6 nonsense mutations lead to a very severe phenotype whereas DNAJC6 missense mutations cause a more typical form. PRKN, PINK1 and DJ1 cases present with typical early onset PD with slow progression, whereas other AR genes present severe atypical Parkinsonism. RAB39B is responsible for a typical phenotype in women and a variable phenotype in men. GBA is a major PD risk factor often associated with dementia. A growing number of reported genes described as causal genes (DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, and CHCHD2) are still awaiting replication or indeed have not been replicated, thus raising questions as to their pathogenicity. Phenotypic data collection and next generation sequencing of large numbers of cases and controls are needed to differentiate pathogenic dominant mutations with incomplete penetrance from rare, non-pathogenic variants. Although known genes cause a minority of PD cases, their identification will lead to a better understanding their pathological mechanisms, and may contribute to patient care, genetic counselling, prognosis determination and finding new therapeutic targets.     

Deciphering the role of heterozygous mutations in genes associated with parkinsonism

The association of six genes with monogenic forms of parkinsonism has unambiguously established that the disease has a genetic component. Of these six genes, LRRK2 (leucine-rich repeat kinase 2, or PARK8), parkin (PARK2), and PINK1 (PTEN-induced putative kinase 1, or PARK6) are the most clinically relevant because of their mutation frequency. Insights from initial familial studies suggest that LRRK2-associated parkinsonism is dominantly inherited, whereas parkinsonism linked to parkin or PINK1 is recessive. However, screening of patient cohorts has revealed that up to 70% of people heterozygous for LRRK2 mutations are unaffected, and that more than 50% of patients with mutations in parkin or PINK1 have only a single heterozygous mutation. Deciphering the role of heterozygosity in parkinsonism is important for the development of guidelines for genetic testing, for the counselling of mutation carriers, and for the understanding of late-onset Parkinson's disease. We discuss the roles of heterozygous LRRK2 mutations and heterozygous parkin and PINK1 mutations in the development of parkinsonism, and propose an integrated aetiological model for this complex disease.     

Incidence of mutations in the PARK2, PINK1, PARK7 genes in Polish early-onset Parkinson disease patients

Background and purposeParkinson disease (PD) is a complex disease, comprising genetic and environmental factors. Despite the vast majority of sporadic cases, three genes, i.e. PARK2, PINK1 and PARK7 (DJ-1), have been identified as responsible for the autosomal recessive form of early-onset Parkinson disease (EO-PD). Identified changes of these genes are homozygous or compound heterozygous mutations. The frequency of PARK2, PINK1 and PARK7 mutations is still under debate, as is the significance and pathogenicity of the single heterozygous mutations/variants, which are also detected among PD patients. The aim of the study was to analyze the incidence of autosomal recessive genes PARK2, PINK1, PARK7 mutations in Polish EO-PD patients.Material and methodsThe analysis of the PARK2, PINK1 and PARK7 genes was performed in a group of 150 Polish EO-PD patients (age of onset < 45 years). Mutation analysis was based on sequencing and gene dosage abnormality identification.ResultsMutations were identified only in the PARK2 and PINK1 genes with the frequency of 4.7% and 2.7% of subjects, respectively. In PARK2, point mutations and exons' rearrangements, and in PINK1 only missense mutations were detected. In both genes mutations were found as compound heterozygous/homozygous and single heterozygous. EO-PD patients’ genotype-phenotype correlation revealed similarities of clinical features in mutation carriers and non-carriers.ConclusionsThe frequency of the PARK2, PINK1, PARK7 mutations among Polish EO-PD patients seems to be low. The role of single heterozygous mutations remains a matter of debate and needs further investigations.     

Parkinson's disease: SNCA-, PARK2-, and LRRK2- targeting microRNAs elevated in cingulate gyrus

IntroductionIn order to better understand the role of epigenetic influences in the etiology of Parkinson's disease (PD), we studied the expression of microRNAs in gyri cinguli of patients and controls.MethodsExpression profiling of 744 well-characterized microRNAs in gyri cinguli from patients and controls using TaqMan array microRNA cards. Verification of significantly dysregulated microRNAs by SYBR Green qRT-PCR.ResultsFirst screen by TaqMan array identified 43 microRNAs that were upregulated in gyri cinguli from patients. Of those microRNAs, 13 are predicted to regulate at least one of six genes mutated in monogenic forms of PD (DJ-1, PARK2, PINK1, LRRK2, SNCA, and HTRA2). Five of these 13 microRNAs (-144, -199b, -221, -488, -544) were also found upregulated by SYBR Green qRT-PCR and are predicted to regulate either SNCA, PARK2, LRRK2 or combinations thereof. Consistently, expression of SNCA, PARK2, and LRRK2 was reduced in patients. An additional 5 out of ten potential target genes tested were downregulated. These are DRAM (DNA damage regulated autophagy modulator 1), predicted to be regulated by miR-144, EVC (Ellis Van Creveld Protein) by miR-221, ZNF440 (Zinc Finger Protein 440) by miR-199b, MTFMT (Mitochondrial Methionyl-tRNA Formyltransferase) by miR-488 and XIRP2 (Xin Actin Binding Repeat Containing) possibly controlled by miR-544a.ConclusionThe study identified five microRNAs that play a role in the etiology of Parkinson's disease likely by modifying expression of SNCA, PARK2, LRRK2 and additional genes required for normal cellular function.     

Clinical genetics of Parkinson's disease and related disorders

Our knowledge regarding the genetics of Parkinson's disease (PD) and parkinsonism has evolved dramatically during the past decade, with the discovery of numerous loci and genes. The LRRK2 gene has emerged as the most commonly involved in both familial and sporadic PD. Several variants in LRRK2 and SNCA have been associated with an increased risk of sporadic PD. PRKN, PINK1 and DJ1 mutations cause early-onset recessively inherited PD. Autosomal dominant dementia and parkinsonism is caused by mutations in the MAPT gene, and in the most recently discovered PGRN gene.     

Oxidative stress factors in Parkinson’s disease

Parkinson’s disease (PD) is the second most common cause of neurodegeneration. Over the last two decades, various hypotheses have been proposed to explain the etiology of PD. Among these is the oxidant-antioxidant theory, which asserts that local and systemic oxidative damage triggered by reactive oxygen species and other free radicals may promote dopaminergic neuron degeneration. Excessive reactive oxygen species formation, one of the underlying causes of pathology in the course of PD has been evidenced by various studies showing that oxidized macromolecules including lipids, proteins, and nucleic acids accumulate in brain tissues of PD patients. DNA oxidation may produce various lesions in the course of PD. Mutations incurred as a result of DNA oxidation may further enhance reactive oxygen species production in the brains of PD patients, exacerbating neuronal loss due to defects in the mitochondrial electron transport chain, antioxidant depletion, and exposure to toxic oxidized dopamine. The protein products of SNCA, PRKN, PINK1, DJ1, and LRRK2 genes are associated with disrupted oxidoreductive homeostasis in PD. SNCA is the first gene linked with familial PD and is currently known to be affected by six mutations correlated with the disorder: A53T, A30P, E46K, G51D, H50Q and A53E. PRKN encodes Parkin, an E3 ubiquitin ligase which mediates the proteasome degradation of redundant and disordered proteins such as glycosylated α-synuclein. Over 100 mutations have been found among the 12 exons of PRKN. PINK1, a mitochondrial kinase highly expressed in the brain, may undergo loss of function mutations which constitute approximately 1–8% of early onset PD cases. More than 50 PD-promoting mutations have been found in PINK1. Mutations in DJ-1, a neuroprotective protein, are a rare cause of early onset PD and constitute only 1% of cases. Around 20 mutations have been found in DJ1 among PD patients thus far. Mutations in the LRRK2 gene are the most common known cause of familial autosomal dominant PD and sporadic PD. Treatment of PD patients, especially in the advanced stages of the disease, is very difficult. The first step in managing progressive PD is to optimize dopaminergic therapy by increasing the doses of dopamine agonists and L-dopa. The next step is the introduction of advanced therapies, such as deep brain stimulation. Genetic factors may influence the response to L-dopa and deep brain stimulation therapy and the regulation of oxidative stress. Consequently, research into minimally invasive surgical interventions, as well as therapies that target the underlying etiology of PD is warranted.     

The genetics of Parkinson disease

Parkinson disease (PD) is the second most common neurodegenerative disorder. In most instances, PD is thought to result from a complex interaction between multiple genetic and environmental factors, though rare monogenic forms of the disease do exist. Mutations in 6 genes (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2) have conclusively been shown to cause familial parkinsonism. In addition, common variation in 3 genes (MAPT, LRRK2, and SNCA) and loss-of-function mutations in GBA have been well-validated as susceptibility factors for PD. The function of these genes and their contribution to PD pathogenesis remain to be fully elucidated. The prevalence, incidence, clinical manifestations, and genetic components of PD are discussed in this review.     

Analysis of exon dosage using MLPA in South African Parkinson's disease patients

Genomic rearrangements (exon dosage) are common mutations reported in Parkinson's disease (PD) patients. In the present study, we aimed to investigate the prevalence of genomic rearrangements in 88 South African patients with predominantly early-onset PD (age-at-onset ≤50 years). The multiplex ligation-dependent probe amplification method was used to detect exon dosage changes. Two commercially available probe kits, SALSA P051 and P052, were used and together the kits consisted of probes for exons of α-synuclein, parkin, PINK1, DJ-1, LRRK2, UCH-L1, ATP13A2, LPA, TNFRSF9, CAV2, CAV1, GCH1, and two-point mutations. We identified exonic rearrangements in parkin and α-synuclein in 8% of South African patients from different ethnic groups. One patient had a whole-gene triplication of α-synuclein; representing only the fourth family with this mutation reported to date. We found six patients with parkin mutations who had either heterozygous duplications and deletions, or homozygous deletions. A false positive result of an exonic deletion detected in one patient turned out to be homozygous point mutation (Y258X) in PINK1. No exonic rearrangements were found in four of the PD genes; LRRK2, PINK1, DJ-1, and ATP13A2. Mutations in parkin were the predominant genetic cause; however, the frequency of exon dosage in our study group is low compared with previous studies. This indicates the possible involvement of other as yet unidentified PD genes in the development of the disease in the South African population.     

Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature

Clinical–pathological studies remain the gold‐standard for the diagnosis of Parkinson's disease (PD). However, mounting data from genetic PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. We review the literature of genetic PD autopsies from cases with molecularly confirmed PD or parkinsonism and summarize main findings on SNCA (n = 25), Parkin (n = 20, 17 bi‐allelic and 3 heterozygotes), PINK1 (n = 5, 1 bi‐allelic and 4 heterozygotes), DJ‐1 (n = 1), LRRK2 (n = 55), GBA (n = 10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n = 8 patients, 2 with PD), MPAN (n = 2), FBXO7, RAB39B, and ATXN2 (SCA2), as well as on 22q deletion syndrome (n = 3). Findings from autopsies of heterozygous mutation carriers of genes that are traditionally considered recessively inherited are also discussed. Lewy bodies may be present in syndromes clinically distinctive from PD (eg, MPAN‐related neurodegeneration) and absent in patients with clinical PD syndrome (eg, LRRK2‐PD or Parkin‐PD). Therefore, the authors can conclude that the presence of Lewy bodies are not specific to the diagnosis of PD and that PD can be diagnosed even in the absence of Lewy body pathology. Interventions that reduce alpha‐synuclein load may be more justified in SNCA‐PD or GBA‐PD than in other genetic forms of PD. The number of reported genetic PD autopsies remains small, and there are limited genotype‐clinical‐pathological‐phenotype studies. Therefore, larger series of autopsies from genetic PD patients are required. © 2017 International Parkinson and Movement Disorder Society     

Mutation analyses in amyotrophic lateral sclerosis/parkinsonism–dementia complex of the Kii peninsula,Japan

To clarify the genetic background of amyotrophic lateral sclerosis (ALS)/parkinsonism–dementia complex (PDC) of the Kii peninsula, Japan (Kii ALS/PDC), we performed extended mutation analyses of three patients with pathologically diagnosed Kii ALS/PDC. Direct sequencing analyses were performed in 19 genes, including ALS/frontotemporal lobar degeneration (FTLD)‐related genes (SOD2, SOD3, ALS2/alsin, SMN1, PGRN, ANG, VEGF, VCP, VAPB, DCTN1, CHMP2B, and TARDBP or TDP‐43), tauopathy‐related gene (GSK3β), and parkinsonism‐related genes (alpha‐synuclein, LRRK2, parkin, DJ‐1, PINK1, and ATP13A2). Gene dosage analyses were conducted in screening of MAPT, alpha‐synuclein, TDP‐43 (or TARDBP), GSK3β, and parkin. We found no mutation in the 19 genes. We found a homozygous nonsynonymous SNP (ALS2/alsin V368M) shared by all the three patients. Gene dosage was normal in MAPT, alpha‐synuclein, TDP‐43, GSK3β, and parkin. The present findings, together with a previous negative study on MAPT and SOD1 mutation, further elucidated the lack of causative mutations in all exons, exon–intron boundaries, or some rearrangements of the reported major causative or susceptible genes related to ALS, FTLD, parkinsonism, synucleinopathy, TDP‐43 proteinopathy, and tauopathy. However, the familial aggregation and lack of any environment factors suggest that Kii ALS/PDC is caused by other yet unidentified genetic factors. © 2008 Movement Disorder Society     

Myocardial 123metaiodobenzylguanidine uptake in genetic Parkinson's disease

Myocardial ¹²³Metaiodobenzylguanidine (MIBG) enables the assessment of postganglionic sympathetic cardiac innervation. MIBG uptake is decreased in nearly all patients with Parkinson's disease (PD). Our objective was to evaluate MIBG uptake in patients with genetic PD. We investigated MIBG uptake in 14 patients with PD associated with mutations in different genes (Parkin, DJ‐1, PINK1, and leucine‐rich repeat kinase 2 ‐LRRK2), in 15 patients with idiopathic PD, and 10 control subjects. The myocardial MIGB uptake was preserved in 3 of the 4 Parkin‐associated Parkinsonisms, in 1 of the 2 patients with DJ‐1 mutations, in 1 of the 2 brothers with PINK1 mutations, in 3 of the 6 unrelated patients with Gly2019Ser mutation in the LRRK2 gene, whereas it was impaired in all patients with idiopathic PD. MIBG was preserved in all control subjects. Our study shows that myocardial MIGB uptake was normal in 8 of 14 patients with genetic PD, suggesting that cardiac sympathetic denervation occurs less frequently in genetic PD than in idiopathic PD. Our findings also demonstrate that MIGB uptake has a heterogeneous pattern in genetic PD, because it was differently impaired in patients with different mutations in the same gene or with the same gene mutation. © 2007 Movement Disorder Society     

Novel compound heterozygous FBXO7 mutations in a family with early onset Parkinson's disease

BackgroundMutations in the F-box protein 7 (FBXO7) gene result in autosomal recessive parkinsonism. This usually manifests as early-onset parkinsonian-pyramidal syndrome but patients exhibit high phenotypic variability. Here we describe the findings of a Yemeni family with two novel FBXO7 mutations.MethodsClinical data and DNA were available for three siblings with early-onset parkinsonism together with their parents and three unaffected siblings. A targeted next generation sequencing panel was used to screen the proband for mutations in 14 genes known to cause a parkinsonian disorder. In addition, SNCA, PARK2, PINK1, and PARK7 were screened for copy number variants.ResultsThe proband carried two novel compound heterozygous FBXO7 mutations: a missense mutation in exon 1 (p.G39R; c.115G > A) and a frameshift mutation in exon 5 (p.L280fs; c.838del). The mutations segregated with disease in the family with the exception of a potentially pre-symptomatic individual whose age was below the age of onset in two of their three affected siblings. P.G39R occurred at a highly conserved amino acid residue and both mutations were predicted to be deleterious in silico. In contrast to most reported families, the phenotype in this pedigree was consistent with clinically typical Parkinson's disease (PD) with a lack of pyramidal signs and good response to dopaminergic therapy.ConclusionsOur study expands the phenotype associated with FBXO7 to include early-onset PD and broadens the list of causative mutations. These data suggest that FBXO7 should be included in clinical genetic testing panels for PD, particularly in patients with early onset or a recessive inheritance pattern.     

Early diagnosis and therapy of Parkinson’s disease: can disease progression be curbed?

Parkinson’s disease (PD), the second most common neurodegenerative disorder, is characterized by the loss of dopamine (DA) neurons in the substantia nigra (SN). Currently, there are numerous therapeutic drugs for the treatment of PD; however, they are limited in efficacy and primarily target motor symptoms. Furthermore, these drugs have various adverse effects after long-term use. Usually, PD patients begin to take anti-parkinsonian drugs when they have developed obvious motor symptoms. At that time, a significant portion of the DA neurons in SN has been lost and the biology of the disease may have already been present for over a decade. This stage of PD diagnosis underscores the need for biomarkers that accurately indicate the onset of PD in order to apply disease-modifying therapies at an earlier stage of disease. However, development of disease modifying drugs has faced many setbacks, mostly due to the ways in which clinical trials are planned and executed. In this review paper, we summarize the recent findings of genetic biomarkers such as SNCA, LRRK2, parkin, PINK1, DJ1, etc., as well as evaluate the imaging techniques such as single proton emission computed tomography and positron emission tomography for their potential in diagnosing PD at earlier stages. Clinical trial designs, along with a comprehensive analysis of neuroprotective drugs for future treatment of PD, are also reviewed.     

Autosomal recessive parkinsonism

Several forms of autosomal recessive parkinsonism are known. In three forms, caused by mutations in parkin (PARK2), PINK1 (PARK6), or DJ-1 (PARK7), the phenotype is usually characterized by levodopa-responsive parkinsonism without atypical features. Parkin mutations are most frequent, explaining -50% of the cases with a clinical diagnosis of familial Parkinson's disease compatible with recessive inheritance and onset <45 years, and -15% of the sporadic cases with onset <45. Mutations in PINK1 and DJ-1 are less common, accounting for -1-8%, and -1-2% of the sporadic cases with early-onset. Since point mutations and genomic rearrangements can be present, sequencing and exon dosage are both required for accurate mutational screening of these genes. The phenotype of parkin mutations is characterized by early-onset parkinsonism, good response to levodopa, and benign course. The average onset age is in the 30s, but late-onset cases have been described. The phenotype associated with PINK1 and DJ-1 mutations has been studied in a smaller number of patients but it is overall indistinguishable from that of parkin. Mutations in other genes, including ATP13A2 (PARK9), PLA2G6 (PARK14), and FBX07 (PARK15), cause more rare forms of recessive parkinsonism with very early-onset (<30 years) and usually additional, atypical features (pyramidal, dystonic, ocular movement, and cognitive disturbances). Yet, it is expected that other monogenic forms of parkinsonism will be identified in the future, as mutations in the above-mentioned genes are not found in other patients with similar phenotypes.