A novel FBXO7-R345P mutation in a Chinese family with autosomal recessive parkinsonian-pyramidal syndrome

BackgroundMutations in the F-box protein 7 (FBXO7) gene is one of the genetic causes of early-onset Parkinson's disease, which usually presents as autosomal recessive early-onset parkinsonian-pyramidal syndrome (PPS). Herein, we report a Chinese PPS family with a novel FBXO7 homozygous mutation.MethodsClinical data of the proband and his affected sister manifesting as early-onset parkinsonism combined with pyramidal signs were collected. DNAs of the two affected siblings, an unaffected sibling and their unaffected mother were isolated. Whole-exome sequencing (WES) was performed for the proband. After bioinformatic analysis, targeted variants were validated by Sanger sequencing in the family members available for DNAs.ResultsThe proband began to walk unsteadily at 30-year-old and developed mild parkinsonism and stiffness in both lower extremities 4 years later. His older sister also manifested as early-onset parkinsonism with stiffness in both lower limbs and postural instability. Both the proband and his older sister carried a novel homozygous FBXO7 mutation in exon 7 (c.1034G > C, p. R345P). The homozygous mutation co-segregated with disease in this pedigree. The mutation located at a highly conserved amino acid residue in the F-box domain, which was predicted to be damaging in silico.ConclusionsOur study expands the mutational spectrum of autosomal recessive early-onset Parkinson's disease (PARK15) caused by FBXO7 mutations.     

FBXO7–R498X mutation: Phenotypic variability from chorea to early onset parkinsonism within a family

ObjectiveFBXO7 mutations (PARK 15), first reported in 2008, are among the monogenic causes of early-onset parkinsonism. Classically, PARK 15 was suggested to correspond to previously described pallido-pyramidal syndrome. Here, we report clinical and genetic findings in a unique family of Kurdish origin with an FBXO7 mutation and presenting with diverse clinical phenotypes.MethodsThe family consisted of 14 members (12 offspring) of whom three were affected. Two of these three siblings were examined in our clinic. DNA samples from the index case and his elder sister were subjected to homozygosity mapping and exomic sequencing.ResultsThe index case had progressive speech problems, severe apathy, chorea, and tics at presentation and developed very mild parkinsonism and postural instability after 3 years. His sister had young-onset asymmetric tremor-dominant parkinsonism with some atypical features, such as early development of postural instability, tics, and tachyphemic speech. She died of an akinetic-rigid condition and had not developed chorea. A homozygous R498X mutation was found in both patients (NM_012179; chr22:31,224,440). This result was further confirmed by Sanger sequencing in both patients, their consanguineous parents, and their maternal grandfather; the latter three were found to be heterozygous for the mutation (c.C1492T; p.R498X).ConclusionsThe family presented here broadens the clinical spectrum of parkinsonism to include tics and chorea, in addition to the parkinsonian-pyramidal phenotype, in connection with FBXO7 mutations and points to an intrafamilial phenotypic variation.     

A new Turkish family with homozygous FBXO7 truncating mutation and juvenile atypical parkinsonism

Juvenile parkinsonism can be caused by recessive mutations in several genes. Among these, homozygous or compound heterozygous mutations in the F-box only protein 7 gene (FBXO7) cause juvenile parkinsonism with variable degrees of pyramidal disturbances (PARK15). So far, only five families (from Iran, Italy, The Netherlands, Pakistan, and Turkey) have been reported with this form. Here, we describe a new Turkish family with homozygous FBXO7 mutation (c.1492C > T, p.Arg498*). Three out of nine siblings born from consanguineous parents suffered from juvenile-onset progressive parkinsonism. Mental retardation was also documented in two of them. Of note, pyramidal signs were absent. The response to dopaminergic medications was present, but limited by dyskinesias and psychiatric side effects. Further genetic analysis of this Turkish family and the Italian PARK15 family reported previously revealed that the c.1492C > T mutation is present on two different haplotypes in the Italian family, and one of these haplotypes is shared in homozygous state in the Turkish patients. These findings contribute to the ongoing delineation of the genetic and clinical spectrum of PARK15.     

Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability

Mutations in the ATP13A2 (PARK9) and FBXO7 (PARK15) genes are linked to different forms of autosomal recessive juvenile-onset neurodegenerative diseases with overlapping phenotypes, including levodopa-responsive parkinsonism, pyramidal disturbances, cognitive decline, and supranuclear gaze disturbance. However, the associated genotypes and phenotypes are poorly characterized due to the small number of patients described. Here, we report clinical, instrumental, and genetic findings in an Italian family with novel PARK9 and PARK15 mutations. The proband developed a severe progressive phenotype including juvenile-onset parkinsonism, pyramidal disturbances, cognitive decline, and oculomotor abnormalities. On the contrary, his brother only shows mild abnormalities (pyramidal, cognitive, and oculomotor) on the neurological examination at the age of 31?years. These two brothers both carry a novel homozygous PARK9 missense (p.G877R) and a novel heterozygous PARK15 mutation (p.R481C). The PARK9 mutation replaces a crucial residue for the ATPase activity, and is therefore most likely a loss-of-function mutation and disease-causing in homozygous state. The pathogenic significance of the PARK15 single heterozygous mutation remains unclear. In both sibs, DaTSCAN single photon emission computed tomography showed marked nigrostriatal dopaminergic defects, and transcranial magnetic stimulation detected prolonged central motor conduction time. MRI, including T2*-weighted imaging, detected no evidence of brain iron accumulation. This family, the third reported with homozygous PARK9 mutations and the first with mutations in two genes for atypical juvenile parkinsonism, illustrates that PARK9-linked disease might display wide intra-familial clinical variability and milder phenotypes, suggesting the existence of strong, still unknown, modifiers.     

Parkin mutations and early-onset parkinsonism in a Taiwanese cohort

BACKGROUND: Loss of function of the parkin gene (PRKN) is the predominant genetic cause of juvenile and early-onset parkinsonism in Japan, Europe, and the United States. OBJECTIVES: To evaluate the frequency of PRKN mutations in Taiwanese (ethnic Chinese) patients with early-onset parkinsonism and to explore genotype-phenotype correlations. DESIGN: Clinical assessment included medical, neurologic, and psychiatric evaluation. Genomic DNA sequencing and quantitative polymerase chain reaction were performed to identify PRKN mutations. Gene expression was examined in patient lymphoblastoid cell lines, in which PRKN mutations were identified. PATIENTS: Forty-one Taiwanese patients with early-onset parkinsonism (aged <50 years at onset). RESULTS: Four of 41 probands had PRKN mutations. One proband had compound heterozygous mutations, with a PRKN exon 2 deletion and an exon 7 G284R substitution. The phenotype resembled typical Parkinson disease. Three patients were mutation carriers. One proband had PRKN exon 2 and exon 3 deletions in the same allele. However, this patient's phenotype was that of classic "parkin-proven" autosomal recessive juvenile parkinsonism, characterized by symmetrical foot dystonia at onset, gait disturbance, diurnal change, and very slow progression. The 2 remaining carriers had novel heterozygous exon 11 R396G substitutions. Patients with PRKN mutations were younger at onset than those without mutations, and they required a lower dose of levodopa despite longer disease duration. CONCLUSIONS: Mutations in PRKN are a rare cause of early-onset parkinsonism in Taiwanese individuals. The overall mutation frequency, adjusted for age at onset, was comparable with that reported for white cohorts; however, the point mutations identified seem to be population specific.     

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.     

Monogenic Parkinson's disease and parkinsonism: Clinical phenotypes and frequencies of known mutations

Mutations in seven genes are robustly associated with autosomal dominant (SNCA, LRRK2, EIF4G1, VPS35) or recessive (parkin/PARK2, PINK1, DJ1/PARK7) Parkinson's disease (PD) or parkinsonism. Changes in a long list of additional genes have been suggested as causes for parkinsonism or PD, including genes for hereditary ataxias (ATXN2, ATXN3, FMR1), frontotemporal dementia (C9ORF72, GRN, MAPT, TARDBP), DYT5 (GCH1, TH, SPR), and others (ATP13A2, CSF1R, DNAJC6, FBXO, GIGYF2, HTRA2, PLA2G6, POLG, SPG11, UCHL1). This review summarizes the clinical features of diseases caused by mutations in these genes, and their frequencies. Point mutations and multiplications in SNCA cause cognitive or psychiatric symptoms, parkinsonism, dysautonomia and myoclonus with widespread alpha-synuclein pathology in the central and peripheral nervous system. LRRK2 mutations may lead to a clinical phenotype closely resembling idiopathic PD with a puzzling variety in neuropathology. Mutations in parkin/PARK2, PINK1 or DJ1/PARK7 may cause early-onset parkinsonism with a low risk for cognitive decline and a pathological process usually restricted to the brainstem. Carriers of mutations in the other genes may develop parkinsonism with or without additional symptoms, but rarely a disease resembling PD. The pathogenicity of several mutations remains unconfirmed. Although some mutations occur with high frequency in specific populations, worldwide all are very rare. The genetic cause of the majority of patients with sporadic or hereditary PD remains unknown in most populations. Clinical genetic testing is useful for selected patients. Testing strategies need to be adapted individually based on clinical phenotype and estimated frequency of the mutation in the patient's population.     

Analysis of Dosage Mutation in PARK2 among Korean Patients with Early-Onset or Familial Parkinson's Disease

MethodsWe performed a gene-dosage analysis of PARK2 using real-time polymerase chain reaction for 189 patients with early-onset PD or familial PD, and 191 control individuals. In the case of PD patients with heterozygous gene-dosage mutation, we performed a sequencing analysis to exclude compound heterozygous mutations. The association between heterozygous mutation of PARK2 and PD was tested.ResultsWe identified 22 PD patients with PARK2 mutations (11.6%). Five patients (2.6%) had compound heterozygous mutations, and 13 patients (6.9%) had a heterozygous mutation. The phase could not be determined in one patient. Three small sequence variations were found in 30 mutated alleles (10.0%). Gene-dosage mutation accounted for 90% of all of the mutations found. The frequency of a heterozygous PARK2 gene-dosage mutation was higher in PD patients than in the controls.ConclusionsHeterozygous gene-dosage mutation of PARK2 is a genetic risk factor for patients with early-onset or familial PD in Koreans.     

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.     

A novel homozygous DJ1 mutation causes parkinsonism and ALS in a Turkish family

ObjectiveDJ1 mutations (PARK7) are among the monogenic causes of early-onset autosomal recessive parkinsonism. Here, we report clinical and genetic findings in a family with Turkish origin carrying a new DJ1 mutation and presenting with early-onset levodopa responsive parkinsonism and signs of amyotrophic lateral sclerosis (ALS).MethodsThe family consisted of 12 members including 10 offsprings of whom three were affected. All family members underwent detailed clinical examination. DNA samples from the index case, his unaffected sister, and his parents were subjected to whole genome sequencing analysis.ResultsThe index case 38-year-old man developed left hand tremor at the age of 24 years. He had progressive asymmetrical parkinsonism, depression and developed signs of ALS within 4 years. His two affected sisters had young-onset asymmetrical tremor-dominant parkinsonism with signs of ALS. A new homozygous p.Q45X mutation in exon 3 in DJ1 was found in all three patients. Their unaffected parents and one clinically healthy sibling were found to be heterozygous for this mutation.ConclusionsThis is the second report of DJ1 mutations associated with parkinsonism and ALS. This is relevant for genetic counseling as well as for understanding the pathogenesis of the broad spectrum of parkinsonism-ALS disease complex.     

应用SYBR GreenⅠ实时荧光定量聚合酶链反应检测常染色体隐性遗传早发性帕金森综合征的parkin基因外显子重排突变

目的 建立应用SYBR GreenⅠ实时荧光定量聚合酶链反应(Real-time PCR,RT-PCR)检测parkin基因外显子重排突变的技术平台,应用该技术对常染色体隐性遗传早发型帕金森综合征(autosomal recessive early-onset parkinsonism,AREP) 家系进行parkin基因外显子重排突变分析.方法 应用SYBR GreenⅠRT-PCR技术对32个中国AREP家系进行parkin基因外显子重排突变分析.结果 14个家系先证者存在parkin基因外显子重排突变,其中3个为纯合缺失突变、3个为复杂杂合缺失突变和8个杂合缺失突变,未发现外显子重复突变,突变主要累及第2～4号外显子.结论 建立了应用SYBR GreenⅠRT-PCR技术检测parkin基因外显子重排突变的基因检测平台;中国AREP 家系的parkin基因外显子重排突变频率为43.8%,与国外报道相似.     

Familial parkinsonism: study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes

BackgroundSince the causative gene linked to PARK8 parkinsonism was identified as LRRK2, LRRK2 gene mutations have been found to occur in about 4% of patients with hereditary Parkinson disease (PD); this percentage is even higher in certain populations. Moreover, no clear clinical differences between PARK8-linked parkinsonism and sporadic PD have been identified. Neuropathologic findings have been diverse in PARK8 parkinsonism, but few of the clinicopathologic examinations have been performed in the same family tree. We aimed to describe PET and neuropathologic findings in members of the same family tree with PARK8 parkinsonism.MethodsWe conducted PET of 2 subjects and neuropathologically examined 8 subjects in the same family from the Sagamihara district, the original source of PARK8-linked parkinsonism (I2020T mutation).ResultsThe results of the PET scans were virtually identical to those seen in sporadic PD. The neuropathologic study results showed pure nigral degeneration with no Lewy bodies in 6 cases. One case, however, showed the presence of Lewy bodies and was similar neuropathologically to conventional PD with Lewy bodies. Another case had multiple system atrophy pathology.ConclusionsOur study of PARK8-linked parkinsonism affecting several members of the same pedigree shows that the same gene mutation can induce diverse neuropathologies, even if the clinical picture and PET findings are virtually identical.     

Early-onset Parkinson's disease caused by a compound heterozygous DJ-1 mutation

Mutations in DJ-1 have been linked to an autosomal recessive form of early-onset parkinsonism. To identify mutations causing Parkinson's disease (PD), we sequenced exons 1 through 7 of DJ-1 in 107 early-onset (age at diagnosis up to 50 years) PD subjects. One subject had a frameshift mutation in the first coding exon and an exon 7 splice mutation both predicted to result in a loss of functional protein. This subject was diagnosed with probable PD at age 24 years with asymmetric onset and an excellent response to levodopa therapy. Our observations suggest that sequence alterations in DJ-1 are a rare cause of early-onset PD.     

Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism

Two homozygous mutations in the PINK1 gene, encoding a mitochondrial putative protein kinase, recently have been identified in families with PARK6-linked, autosomal recessive early-onset parkinsonism (AREP). Here, we describe a novel homozygous mutation (1573_1574 insTTAG) identified in an AREP patient, which causes a frameshift and truncation at the C-terminus of the PINK1 protein, outside the kinase catalytic domain. The clinical phenotype includes early-onset (28 years) parkinsonism, foot dystonia at onset, good levodopa response, slow progression, early levodopa-induced dyskinesias, and sleep benefit, thereby resembling closely parkin-related disease. These findings confirm that recessive mutations in PINK1 cause early-onset parkinsonism and expand the associated clinical phenotype.     

Neuropathological findings in PINK1-associated Parkinson's disease

IntroductionBiallelic mutations in PTEN-induced putative kinase 1 (PINK1) is a relatively common cause of autosomal recessive early-onset Parkinson's disease (PD). However, only three PINK1 patients with brain autopsy have been reported in the literature.MethodsWe describe the clinical and pathological characteristics of a patient with early-onset PD. We screened for copy number variants SNCA, PRKN, PINK1, DJ-1, ATP13A2, LPA and TNFRSF9 by multiplex ligation-dependent probe amplification (MLPA), and subsequently we performed whole-exome sequencing.ResultsClinically the patient presented with typical parkinsonism that responded well to levodopa. After 23 years of disease she had a bilateral GPi deep brain stimulation (DBS) surgery. Genetic analyses revealed a heterozygous exon 4–5 deletion and a homozygous exon 1 [c. 230T > C (p.Leu77Pro)] mutation in PINK1. Post-mortem neuropathological examination after more than 30 years of disease revealed gliosis and a large loss of melanin-containing neurons in the substantia nigra. Lewy body pathology was evident in substantia nigra, temporal cortex, locus coeruleus and the parahippocampal region.ConclusionWe describe the first clinical and pathological characterization of a PINK1 patient with a typical disease presentation and long disease duration. Previous reports describe two patients with Lewy-related pathologies, albeit with differential distribution, and one patient with no Lewy-related pathology. Hence, it seems that only two patients with parkinsonism due to mutations in PINK1 are consistent with α-synucleinopathy distribution like that seen in the majority of cases with sporadic PD. Our data further extend the clinicopathological characterization of PINK1-associated PD.     

Low frequency of Parkin, Tyrosine Hydroxylase, and GTP Cyclohydrolase I gene mutations in a Danish population of early-onset Parkinson''s Disease

Autosomal recessive Parkinson's disease (PD) with early-onset may be caused by mutations in the parkin gene (PARK2). We have ascertained 87 Danish patients with an early-onset form of PD (age at onset < or =40 years, or < or =50 years if family history is positive) in a multicenter study in order to determine the frequency of PARK2 mutations. Analysis of the GTP cyclohydrolase I gene (GCH1) and the tyrosine hydroxylase gene (TH), mutated in dopa-responsive dystonia and juvenile PD, have also been included. Ten different PARK2 mutations were identified in 10 patients. Two of the patients (2.3%) were found to have homozygous or compound heterozygous mutations, and eight of the patients (9.2%) were found to be heterozygous. A mutation has been identified in 10.4% of the sporadic cases and in 15.0% of cases with a positive family history of PD. One patient was found to be heterozygous for both a PARK2 mutation and a missense mutation (A6T) in TH of unknown significance. It cannot be excluded that both mutations contribute to the phenotype. No other putative disease causing TH or GCH1 mutations were found. In conclusion, homozygous, or compound heterozygous PARK2 mutations, and mutations in GCH1 and TH, are rare even in a population of PD patients with early-onset of the disease.     

Low frequency of the PARK2 gene mutations in Polish patients with the early-onset form of Parkinson disease

ObjectiveMutations in the PARK2 (Parkin) gene result in an early-onset autosomal recessive form of Parkinson Disease (EO-PD). Although the frequency of the PARK2 mutations in EO-PD patients according to several studies is high and has been reported in up to 50% in familial and 19% in sporadic cases, these data remain controversial.MethodsWe performed PARK2 gene analysis for a group of 79 Polish EO-PD patients with onset of disease below the age of 40. All exons were directly sequenced and the exons' copy number variations were analyzed.ResultsMutations in PARK2 gene were found in 3 patients (3.8%), in two sporadic cases in both alleles (2.5%) and in a familial case in only one allele (1.3%). We identified point mutations as well as exon rearrangements (duplication, deletion).ConclusionsThe frequency of the PARK2 mutations our Polish group with EO-PD seems to be lower than in other previously described groups.     

PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations

The authors performed linkage analysis in 39 families with autosomal recessive early-onset PD (AR-EOPD) negative for parkin and DJ-1 mutations. Eight families including three Japanese, two Taiwanese, one Turkish, one Israeli, and one Philippine showed evidence of linkage with PARK6 with multipoint log of the odds (lod) score of 9.88 at D1S2732. The results indicate worldwide distribution of PARK6-linked parkinsonism.