Michela Zini

The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor

Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson’s disease. Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson’s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson’s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson’s disease identified so far. It is especially frequent among cases with familial Parkinson’s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson’s disease.

The Gly2019Ser Mutation in LRRK2 is not Fully Penetrant in Familial Parkinson's Disease: The GenePD Study

BackgroundWe report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinsons disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.MethodsA sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.ResultsThirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.ConclusionLifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Survival and dementia in GBA-associated Parkinson's disease: The mutation matters.

The objective of this work was to investigate survival, dementia, and genotype‐phenotype correlations in patients with Parkinsons disease (PD) with and without mutations on the glucocerebrosidase gene (GBA).

Parkin analysis in early onset Parkinson's disease

We analysed the parkin gene in a large consecutive series (146) of unrelated early onset Parkinsons 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.

Dopamine dysregulation syndrome in Parkinson's disease: from clinical and neuropsychological characterisation to management and long-term outcome

Objective Dopamine dysregulation syndrome (DDS) refers to a compulsive pattern of dopaminergic drug misuse complicating Parkinsons disease (PD). To date, few data are available on DDS risk factors, cognitive profile and long-term outcome. Methods In this retrospective case-control study, consecutive PD outpatients fulfilling criteria for DDS were assessed over a 6-year period (2005–2011). They were compared with 70 PD cases matched for age at onset, gender and disease duration, and with 1281 subjects with motor fluctuations and dyskinesias. DDS patients and matched controls underwent extensive neuropsychological assessment. Strategies for DDS patients management and the outcome at the last follow-up visit were recorded. Results Thirty-five patients with DDS were identified, reporting history of depression, family history of PD and drug abuse, greater difference between ‘Off’ versus ‘On’ motor symptoms compared to age-matched controls. They had younger age at onset (but not any gender difference) compared to general PD population. Cognitive profile of DDS did not show major abnormalities, including executive functions. DDS patients have been followed up for 3.2±2.1 years and remission was recorded in 40% of cases. Negative DDS outcome was significantly associated with poor caregiver supervision. Sustained remission occurred more commonly on clozapine and on duodenal levodopa infusion and subthalamic nucleus deep brain stimulation (STN-DBS) than on apomorphine pump treatment. Conclusions Clinicians should be aware of risk factors predisposing to DDS. Duodenal levodopa infusion and, less consistently, STN-DBS were more commonly associated with DDS remission. Effective caregiving plays a key role in long-term behavioural outcome.

α-Synuclein multiplication analysis in Italian familial Parkinson disease

The alpha-synuclein gene (SNCA) multiplication causes autosomal dominant Parkinson Disease (PD): triplication is associated with early-onset rapidly progressing parkinsonism with a strong likelihood of developing dementia, while duplication is associated with a less severe phenotype similar to idiopathic PD. We tested for SNCA multiplication 144 unrelated PD patients with a dominant family history. We identified one patient with SNCA duplication (0.7%). The SNCA-duplicated patient was a woman of 45 years of age with PD onset at 41 years of age. She experienced a rapidly progressive disease with early motor complications (on/off fluctuations and dyskinesias). Medical records confirmed that the probands mother developed PD at 47 years of age and died at 63 with dementia. She experienced rapid progression in both motor and cognitive symptoms: development of dementia at 54 years of age, 7 years after onset. Although SNCA duplication is an unusual cause of familial PD testing for it is worthwhile. The clinical presentation of duplicated cases may be more aggressive than usual.

Striatal dopamine transporter binding in Parkinson's disease associated with the LRRK2 Gly2019Ser mutation

We measured striatal dopamine transporter binding using [123I]ioflupane and SPECT in patients with Parkinsons disease associated with the LRRK2 (PARK8) Gly2019Ser gene mutation (LRRK2‐PD) and in gene‐negative patients with idiopathic Parkinsons disease (IPD) of comparable disease duration and severity. The LRRK2‐PD group consisted of a total of 10 patients (3 sporadic) with mean age 62 ± 14 years, disease duration 9 ± 3 years, and UPDRS III motor score 21.60 ± 6.65. The control IPD group consisted of 15 patients with mean age 59 ± 9 years, disease duration 9 ± 5 years, and UPDRS III motor score 23.80 ± 8.69. [123I]ioflupane–specific uptake ratios were calculated for caudate nucleus and putamen using the occipital cortex as reference region. We found no differences between the LRRK2‐PD group and IPD in all items studied. In particular, putamen and caudate uptake values as well as side asymmetry indexes and putamen/caudate ratios all revealed comparable between‐group values. We conclude that in these patients carrying the LRRK2 Gly2019Ser mutation, the neurodegenerative process results in a pattern of nigrostriatal dopaminergic dysfunction similar to that observed in IPD.

Genetic, clinical, and imaging characterization of one patient with late-onset, slowly progressive, pantothenate kinase-associated neurodegeneration

We report on a patient with late‐onset, pantothenate kinase‐associated neurodegeneration (PKAN) who revealed two new heterozygous mutations at gene testing and showed asymmetric moderately reduced striatal dopamine transporter binding with single photon emission computed tomography, possibly due to prolonged neuroleptic treatment. These findings expand the genetic and imaging spectrum of this rare disorder.

Parkinson's disease beyond 20 years

Background A very limited number of studies report data on the clinical features of Parkinsons disease (PD) 20 years after onset and beyond. Objective To characterise PD 20 years after onset, investigating the impact of age at onset and disease duration on the clinical picture and the predictors of outcomes in patients reaching the 20-year time point. Methods We conducted a retrospective, cross-sectional study and a longitudinal study. All case visits of patients with a disease duration ≥20 years (N=401) were stratified by disease duration (20–22, 23–25, ≥26 years) and by age at onset (cut-off, 50 years). Patients with a disease duration of 20–22 years (N=320) were prospectively followed up for a median of 45 months (IQR 23–89) for the new occurrence of fracture, percutaneous endoscopic gastrostomy, institutionalisation, confinement to a wheelchair or bed and death. Results Older age at onset and longer disease duration were independently associated with a higher prevalence of major motor and non-motor milestones of disease disability (no interaction observed). In the longitudinal study, the most frequent outcomes were death (N=92), confinement to a wheelchair or bed (N=67) and fracture (N=52). Mortality was associated with the gender: male, older age, dysphagia, orthostatic hypotension, postural instability, fractures and institutionalisation. Fracture was associated with postural instability. Predictors of permanent confinement to a wheelchair or bed were older age, postural instability and institutionalisation. Comorbid dementia at the 20-year examination did not predict any of the outcomes. Conclusions Age at onset and disease duration are independent determinants of the clinical features of PD beyond 20 years. Non-motor symptoms depend more on age at onset rather than the disease duration itself. Non-levodopa-responsive axial symptoms are the main predictors of all relevant outcomes.

Levodopa in Parkinson's disease: from the past to the future

Importance of the field: Levodopa is the mainstay of symptomatic treatment for Parkinsons disease (PD). Although other treatments have been developed in the last 30 years, most patients use levodopa in view of its superior efficacy in controlling PD symptoms. Unfortunately, levodopa is associated with long-term motor complications (motor fluctuations and dyskinesias). The main causes of these undesirable effects are the narrowing of the therapeutic window with the natural progression of the disease, pulsatile dopaminergic stimulation due to the short half-life of the drug and erratic absorption. Several studies suggest that PD control could be enhanced by changing the mode of levodopa delivery so as to ensure continuous and stable supply of the drug to the brain. The objective of this text is to review the ascertained strengths and limitations of levodopa in PD, starting from its history, and propose novel modes of usage designed to cover currently unmet medical needs. Areas covered in this review: Medline literature search (from 1973 to date). What the reader will gain: A perspective on the evolution of PD pharmacological treatment. Take home message: Levodopa still is the best treatment for PD. Truly stable and controlled formulations that ensure clinical response should be developed to reduce the undesirable effects that restrict its efficacy.