Marked variation in clinical presentation and age of onset in a family with a heterozygous parkin mutation.

Parkin gene mutations have been detected in families with early-onset autosomal recessive parkinsonism. We report a novel heterozygous 40 base pair deletion in exon 3 of the parkin gene that increases the susceptibility of carriers to develop parkinsonism/dystonia and manifests remarkable variability in regard to age of onset and phenotype in a single family. After identifying the new mutation in the proband of this kindred, family members were contacted and evaluated by a movement disorders specialist using standardized protocols and prospectively set diagnostic criteria. Importantly, examining physicians and family members were blinded to the genetic testing. Five affected members in two generations carried the parkin mutation. The proband and one of his brothers had disease onset at 24 years of age while another brother had disease at age 44. One exhibited multi-focal dystonia and parkinsonism of 17 years duration, another suffered a unilateral slowly progressive parkinsonism over 13 years while the third suffered dystonia-parkinsonism of recent onset. A sibling pair in the preceding generation had mild previously undiagnosed parkinsonism. Clinicians should be aware that patients carrying a parkin gene mutation may present with dystonia-parkinsonism or very subtle parkinsonism with a markedly varied age of onset.     

Screening PARK genes for mutations in early-onset Parkinson's disease patients from Queensland, Australia

A family history of Parkinson's disease (PD) is the most commonly reported risk factor after age, suggesting a genetic component to the disease in a sub-group of patients. Mutations in at least six genes have been identified that can lead to monogenic forms of PD. We screened a sample of 74 early-onset PD cases out of a cohort of 950 patients (onset <50 years) for genetic abnormalities in known familial Parkinsonism genes. A self-reported family history of PD existed for 30 patients (40.5%). Of these, 13 each had a first- or a second-degree relative with PD and four reported a more distant relative with PD. The entire coding region of the PRKN (MIM 602544), DJ-1 (MIM 602533) and PINK1 (MIM 698309) genes, and exon 41 of the LRRK2 gene (MIM 609007) were screened by direct sequencing. All exons of PRKN were examined for gene-dosage abnormalities. Screening identified five patients with putative genetic disease: two patients carried PRKN mutations (p.G12R heterozygous and p.G430D homozygous), one patient carried a p.G411S heterozygous amino acid change in the PINK1 gene and two individuals were heterozygous for the common p.G2019S mutation in LRRK2. No alpha-synuclein or DJ-1 variants were observed. Our data suggest that approximately 7% of early-onset PD cases seen in Queensland movement disorders clinics have mutations involving known PARK genes.     

How much phenotypic variation can be attributed to parkin genotype?

To establish phenotype-genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations.     

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.     

常染色体隐性遗传早发性帕金森病1个家系临床特征及parkin基因突变分析

目的探讨1个常染色体隐性遗传早发性帕金森病（autosomal recessive early-onset parkinson-ism，AREP）家系的临床特征及parkin基因突变情况。方法对1个AREP家系2例患者的临床资料进行回顾性分析，同时应用DNA直接测序、限制性内切酶酶切、荧光半定量PCR等技术方法进行parkin基因的突变分析。结果该家系共2例患者，发病年龄轻，分别为22岁和23岁；病情进展相对缓慢，症状有波动，呈晨轻暮重，腱反射活跃；对小剂量多巴制剂反应良好。基因突变发现该家系存在parkin基因的复合杂合突变（第7号外显子杂合的G859T和第4外显子杂合缺失突变），其中G859T为新报道的点突变。结论我国的AREP家系有帕金森病的一般临床表现，又有其独特的临床特征，存在parkin基因的突变。     

PINK1 mutations are associated with sporadic early-onset parkinsonism

We have recently reported homozygous mutations in the PINK1 gene in three consanguineous families with early-onset parkinsonism (EOP) linked to the PARK6 locus. To further evaluate the pathogenic role of PINK1 in EOP and to draw genotype-phenotype correlates, we performed PINK1 mutation analysis in a cohort of Italian EOP patients, mostly sporadic, with onset younger than 50 years of age. Seven of 100 patients carried missense mutations in PINK1. Two patients had two PINK1 mutations, whereas in five patients only one mutation was identified. Age at onset was in the fourth-fifth decade (range, 37-47 years). The clinical picture was characterized by a typical parkinsonian phenotype with asymmetric onset and rare occurrence of atypical features. Slow progression and excellent response to levodopa were observed in all subject. Two of 200 healthy control individuals also carried one heterozygous missense mutation. The identification of a higher number of patients (5%) than controls (1%) carrying a single heterozygous mutation, along with previous positron emission tomography studies demonstrating a preclinical nigrostriatal dysfunction in PARK6 carriers, supports the hypothesis that haploinsufficiency of PINK1, as well as of other EOP genes, may represent a susceptibility factor toward parkinsonism. However, the pathogenetic significance of heterozygous PINK1 mutations still remains to be clarified.     

Familial parkinsonism and ophthalmoplegia from a mutation in the mitochondrial DNA helicase twinkle

OBJECTIVE: To describe the clinical phenotype and genetic basis of a family with autosomal dominant progressive external ophthalmoplegia and parkinsonism from a Twinkle mutation. DESIGN: All coding exons of POLG1, Twinkle (aka C10ORF2, PEO1), and ANT1 (SLC25A4) were sequenced in the proband with targeted sequencing of the Twinkle gene in all additional subjects. SUBJECTS: Members of a 3-generation family followed up in a neuromuscular disease center for dominantly inherited progressive external ophthalmoplegia. RESULTS: We identified a heterozygous G1121A mutation (R374Q) in exon 1 of Twinkle that segregated with the disease phenotype in all affected family members. No pathogenic mutations were present in POLG1 or ANT1. CONCLUSION: This finding broadens the clinical spectrum of Twinkle gene mutations and further implicates loss of mitochondrial DNA integrity in the pathogenesis of Parkinson disease.     

Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations

A Dutch family with autosomal recessive early-onset parkinsonism showed a heterozygous missense mutation in combination with a heterozygous exon deletion in the parkin gene. Although the main clinical syndrome consisted of parkinsonism, the proband clinically had additional mild gait ataxia and pathologically showed neuronal loss in parts of the spinocerebellar system, in addition to selective loss of dopaminergic neurons in the substantia nigra pars compacta. Lewy bodies and neurofibrillary tangles were absent, but tau pathology was found.     

Mutation analysis of ATP13A2 in early-onset parkinsonism patients☆○

BACKGROUND： A recent study has found that ATP13A2 is the causative gene for PARK9-linked autosomal recessive early-onset parkinsonism, described previously in Jordanian and Chilean families （Kufor-Rakeb syndrome）. OBJECTIVE： To screen eastern Asian patients with early-onset parkinsonism for mutations in ATP13A2 and to describe positron emission tomography （PET） findings of PARK9-linked parkinsonism. DESIGN, TIME AND SETTING： In total, 117 patients were selected from the Department of Neurology, Juntendo University, from February 2003 to October 2006, for this molecular genetics and case-control study. PARTICIPANTS： The patients with parkinsonism consist of two cohorts. Ninety four patients with onset age of less than 30 years were selected for the first cohort. They included 49 males and 44 females, comprising 73 Japanese, 9 Korean, 8 Taiwanese, and 4 Mainland Chinese. Eleven patients had parkinsonism complicated with dementia, 15 patients had family histories of parkinsonism （including 2 families）, and 5 patients were from consanguineous parents （including one family）. The second cohort of 23 patients was composed of patients with consanguineous parents （n = 15） or who had affected siblings （n = 6） or both （n = 2）, but the age at onset ranged from 30 to 50 years. METHODS： In 117 patients with parkinsonism, direct sequencing of ATP13A2 exons 13, 16, and 26, in which mutations had been reported previously, were performed. Sequencing was also performed in all 29 exons, including splice sites, in 28 probands who showed homozygosity at the PARK9 locus by haplotype analysis. Mutation analysis was also performed in 150 normal people. Linkage analysis was performed on all 3 parkinsonism families using short tandem repeat markers flanking the PARK9 locus. For patients who had ATP13A2 mutation, we performed brain MRI and ^18F-dopa PET scans. MAIN OUTCOME MEASURES： ATP13A2 DNA sequence, ^18F-dopa PET scan and brain MRI findings. RESULTS： A novel F182L mutation in a consanguineous J     

Parkin analysis in early onset Parkinson's disease

We analysed the parkin gene in a large consecutive series (146) of unrelated early onset Parkinson's disease (onset ⩽40 years of age) patients. Twelve cases (8.2%) had homozygous or compound heterozygous point mutations and/or exon rearrangements, while a single mutation was found in four subjects (2.7%). We identified eight exon rearrangements and nine point mutations, two of which were novel: c.735delT (p.C212/X224) and c.815C>G (p.C238W). Genotype–phenotype correlation revealed that parkin carriers had features similar to those of non-carrier early onset Parkinson disease patients.     

Genetic bases and phenotypes of autosomal recessive Parkinson disease in a Turkish population

Background and purpose: To evaluate the phenotype and the frequencies of mutations in PRKN, DJ1 and PINK1 genes in patients with Parkinson disease (PD) in Turkey. Methods: Eighty‐six patients from 77 PD families participated in the study. Seventy‐four families were originating from Turkey, two families from Greece and one family from Bulgaria. All patients underwent detailed neurological examination. PRKN, PINK1 and DJ1 genes were sequenced, and dosage analysis was performed by multiplex ligation‐dependent probe amplification. Results: Sixteen patients with PD were found to carry homozygous (n = 14) or compound heterozygous (n = 2) PRKN mutations. We identified exon rearrangements, three point mutations and one new point mutation in exon 2 (p.K27del). In two families, two new PINK1 point mutations (L31X and P416L) were identified. No pathogenic mutations were found in DJ1 gene. Clinical phenotypes of PRKN patients were comparable to previously described features, but only in four of 13 families, the pedigree structure was clearly consistent with an autosomal recessive (AR) mode of inheritance in comparison with nine families where also different pattern of transmission could have been possible. Conclusions: Our data suggest that the PRKN gene mutation is the most frequent form of ARPD in Turkey. The proportion of mutations with regard to the age of onset in our population is in the range of those previously described, but our pedigrees are characterized by high rate of consanguinity, which might explain the high proportion of families with homozygous mutations and of patients in more than one generation. Pathogenic DJ1 mutations do not seem to play a major role in Turkey.     

Relative high frequency of the c.255delA parkin gene mutation in Spanish patients with autosomal recessive parkinsonism

BACKGROUND: Autosomal recessive juvenile parkinsonism is a neurodegenerative disorder associated with mutations in the parkin gene. OBJECTIVES: To search for the presence of parkin gene mutations in Spanish patients with Parkinson's disease (PD) and characterise the phenotype associated with these mutations. METHODS: Thirty seven PD patients with either early onset or autosomal recessive pattern of inheritance were selected for genetic study. RESULTS: Mutations were identified in seven index patients (19%). Homozygous mutations were detected in six patients and a heterozygous mutation in one. The age at onset was lower in patients with mutations than in patients without mutations. Dystonia at onset was present in two patients with parkin gene mutations. The disease began in two patients with postural tremor in the upper limbs mimicking essential tremor. Four patients exhibited a long term response to dopamine agonists. The c.255delA mutation was identified in four unrelated families. This is a frameshift mutation leading to protein truncation. CONCLUSIONS: Parkin gene mutations are present in Spanish patients with early onset and/or an autosomal recessive parkinsonism. The c.255delA is the most frequent mutation found, suggesting a relative high prevalence in the Spanish population.     

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.     

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.     

DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis complex

DJ-1 gene mutations have been found to cause early-onset Parkinson's disease. We report a family from southern Italy with three brothers affected by early-onset parkinsonism, dementia, and amyotrophic lateral sclerosis. Molecular analysis of the DJ-1 gene in two living patients showed a novel homozygous mutation in exon 7 (E163K) and a new homozygous mutation (g.168_185dup) in the promoter region of the gene. Both mutations cosegregated with the disease and were detected in a heterozygous state in the patients' mother and their healthy siblings. Our findings expand the spectrum of clinical presentations associated with mutations in DJ-1 gene.     

Pseudo-dominant inheritance and exon 2 triplication in a family with parkin gene mutations

The authors report an Italian family with pseudo-dominant inheritance of parkinsonism attributable to parkin gene mutations. The father (disease onset at age 57 years) was homozygous for a triplication of exon 2 that is so far unique. The unaffected mother was heterozygous for deletions of exons 3 and 4, and the son (onset at age 31 years) was a compound heterozygote carrying both mutations. Thus, pseudo-dominant inheritance of parkin gene mutations has to be considered in early-onset parkinsonism, and sensitive screening techniques, such as semiquantitative multiplex PCR, should be applied.     

Parkinson's disease in Ireland: clinical presentation and genetic heterogeneity in patients with parkin mutations.

Early-onset autosomal recessive parkinsonism is associated with parkin gene mutations. Different parkin mutations occur in many ethnic backgrounds; however, the phenotype may vary. We studied 102 young-onset (age at onset <60 years) Parkinson's disease (PD) patients. From 102 patients, 40 with early-onset PD (<45 years at symptomatic onset) were selected for clinical assessment and parkin gene molecular analysis for duplications/deletions and point mutations. We identified parkin mutations in 7 of 40 early-onset patients; including novel compound heterozygotes and potential splice site changes. The mean age at onset in the 7 parkin mutation-positive patients was 33 +/- 9 years (age range, 18-42 years), marginally lower than that of the 33 parkin-negative early-onset patients, 38 +/- 7 years (age range, 17-45 years). A family history of PD was present in 4 of 7 patients with parkin mutations, compared with 6 of 33 early-onset parkin-negative patients. Overall, parkin mutations were found in 4 of 10 patients with a positive family history and 3 of 30 patients without a family history of PD. Patients with parkin mutations had more dystonia, dyskinesia, and sleep benefit compared with parkin-negative patients. We subsequently identified a single point mutation among the 62 young-onset (age at onset 45 to <60 years). Mutations in the parkin gene may account for approximately 17% of early-onset (age at onset <45 years) parkinsonism in Ireland, in agreement with previous European studies.