Background
A Task Force was convened by the EFNS/MDS‐ES Scientist Panel on Parkinson's disease (PD) and other movement disorders to systemically review relevant publications on the diagnosis of PD.
...Methods
Following the EFNS instruction for the preparation of neurological diagnostic guidelines, recommendation levels have been generated for diagnostic criteria and investigations.
Results
For the clinical diagnosis, we recommend the use of the Queen Square Brain Bank criteria (Level B). Genetic testing for specific mutations is recommended on an individual basis (Level B), taking into account specific features (i.e. family history and age of onset). We recommend olfactory testing to differentiate PD from other parkinsonian disorders including recessive forms (Level A). Screening for pre‐motor PD with olfactory testing requires additional tests due to limited specificity. Drug challenge tests are not recommended for the diagnosis in de novo parkinsonian patients. There is an insufficient evidence to support their role in the differential diagnosis between PD and other parkinsonian syndromes. We recommend an assessment of cognition and a screening for REM sleep behaviour disorder, psychotic manifestations and severe depression in the initial evaluation of suspected PD cases (Level A). Transcranial sonography is recommended for the differentiation of PD from atypical and secondary parkinsonian disorders (Level A), for the early diagnosis of PD and in the detection of subjects at risk for PD (Level A), although the technique is so far not universally used and requires some expertise. Because specificity of TCS for the development of PD is limited, TCS should be used in conjunction with other screening tests. Conventional magnetic resonance imaging and diffusion‐weighted imaging at 1.5 T are recommended as neuroimaging tools that can support a diagnosis of multiple system atrophy (MSA) or progressive supranuclear palsy versus PD on the basis of regional atrophy and signal change as well as diffusivity patterns (Level A). DaTscan SPECT is registered in Europe and the United States for the differential diagnosis between degenerative parkinsonisms and essential tremor (Level A). More specifically, DaTscan is indicated in the presence of significant diagnostic uncertainty such as parkinsonism associated with neuroleptic exposure and atypical tremor manifestations such as isolated unilateral postural tremor. Studies of 123IMIBG/SPECT cardiac uptake may be used to identify patients with PD versus controls and MSA patients (Level A). All other SPECT imaging studies do not fulfil registration standards and cannot be recommended for routine clinical use. At the moment, no conclusion can be drawn as to diagnostic efficacy of autonomic function tests, neurophysiological tests and positron emission tomography imaging in PD.
Conclusions
The diagnosis of PD is still largely based on the correct identification of its clinical features. Selected investigations (genetic, olfactory, and neuroimaging studies) have an ancillary role in confirming the diagnosis, and some of them could be possibly used in the near future to identify subjects in a pre‐symptomatic phase of the disease.
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Abstract Background The LRRK2 G2019S mutation is the most frequent known cause of familial and sporadic Parkinson's disease. Knowledge of its worldwide frequency distribution is essential for ...clinical and molecular research as well as genetic counseling. Objectives To conduct a systematic review of the reported frequency of G2019S in different populations and to assess critically the quality of the clinical studies. Methods We conducted a systematic review of all published papers on G2019S frequency in homogeneous ethnic groups or sub-groups of patients. Selected papers were analyzed for methodological quality. Results 68 studies from 32 countries were included in the analysis. A heterogeneous distribution was observed with high frequencies in North African Arab countries, the Middle East, southern Europe, North American Ashkenazi Jewish populations and in South American countries with known European ethnic influence. Frequencies ranged from the no cases to 35.7% in sporadic and 42% in familial North-African Arab patients. Only one paper from one sub-Saharan country was found. Methodological pitfalls were identified. Conclusions Estimated frequencies were found to be variable, which may reflect ethnic differences and methodological discrepancies. We make recommendations on the methods of selection of participants and on the definition of familial Parkinson's disease to improve the quality of frequency studies on LRRK2 mutations.
The combination of early-onset, progressive parkinsonism with pyramidal tract signs has been known as pallido-pyramidal or parkinsonian-pyramidal syndrome since the first description by Davison in ...1954. Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause.
We performed clinical and genetic studies in two families with early-onset, progressive parkinsonism and pyramidal tract signs.
An FBXO7 homozygous truncating mutation (Arg498Stop) was found in an Italian family, while compound heterozygous mutations (a splice-site IVS7 + 1G/T mutation and a missense Thr22Met mutation) were present in a Dutch family. We also found evidence of expression of novel normal splice-variants of FBXO7. The phenotype associated with FBXO7 mutations consisted of early-onset, progressive parkinsonism and pyramidal tract signs, thereby matching clinically the pallido-pyramidal syndrome of Davison. The parkinsonism exhibits varying degrees of levodopa responsiveness in different patients.
We conclusively show that recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. Understanding how FBXO7 mutations cause disease will shed further light on the molecular mechanisms of neurodegeneration, with potential implications also for more common forms of parkinsonism, such as Parkinson disease and multiple system atrophy.
To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism.
The authors studied 134 patients (116 ...sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases.
Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later.
PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.
We report the results of a family-based study of LRRK2 G2019S penetrance in Parkinson disease. We studied 19 families identified through the analysis of unrelated consecutive patients. The cumulative ...incidence of the disease was 15% at 60 years, 21% at 70 years, and 32% at 80 years. This study provides accurate estimates of G2019S penetrance by minimizing the selection bias.
Four chromosomal loci ( PARK2, PARK6, PARK7, and PARK9) associated with autosomal recessive, early onset parkinsonism are known. We mapped the PARK7 locus to chromosome 1p36 in a large family from a ...genetically isolated population in the Netherlands, and confirmed this linkage in an Italian family. By positional cloning within the refined PARK7 critical region we recently identified mutations in the DJ-1 gene in the two PARK7-linked families. The function of DJ-1 remains largely unknown, but evidence from genetic studies on the yeast DJ-1 homologue, and biochemical studies in murine and human cell lines, suggests a role for DJ-1 as an antioxidant and/or a molecular chaperone. Elucidating the role of DJ-1 will lead to a better understanding of the pathogenesis of DJ-1-related and common forms of Parkinson's disease.
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