Levodopa-responsive Parkinsonism Research Articles

SNP rs11931074 of the SNCA gene may not be associated with multiple system atrophy in Chinese population

Background: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by poorly levodopa-responsive parkinsonism, cerebellar ataxia, and autonomic dysfunction. Pathogenic mechanisms remain obscure, but the neuropathological hallmark is the presence of α-synuclein-positive glial cytoplasmic inclusions. Previous studies suggested that a single nucleotide polymorphism (SNP), rs11931074, in the α-synuclein gene, SNCA, had highly significant association with an increased risk of the development of MSA in the Caucasian subjects. In contrast, a Korean study failed to identify an association with disease risk. Methods: To study the effect of rs11931074 on MSA risk in a Chinese population, we conducted a case–control study and genotyped SNP rs11931074 by Sanger sequencing in 96 Chinese patients with MSA and 120 healthy controls. Moreover, we performed a meta-analysis on the topic. Results: There was no statistical difference in genotypes or allele frequencies of SNP rs11931074 between MSA and control groups in our cohort. The results of meta-analysis showed that the risk allele T of rs11931074 was associated with MSA (pooled odds ratio = 1.26, 95% confidence interval = 1.07–1.49, P = 0.006). Conclusions: Despite a positive result of the meta-analysis, the significant difference in frequency of allele T of rs11931074 between Asian and Caucasian subjects indicates that population heterogeneity at rs11931074 may exist.

Parkinsonism in spinocerebellar ataxia.

Spinocerebellar ataxia (SCA) presents heterogeneous clinical phenotypes, and parkinsonism is reported in diverse SCA subtypes. Both levodopa responsive Parkinson disease (PD) like phenotype and atypical parkinsonism have been described especially in SCA2, SCA3, and SCA17 with geographic differences in prevalence. SCA2 is the most frequently reported subtype of SCA related to parkinsonism worldwide. Parkinsonism in SCA2 has unique genetic characteristics, such as low number of expansions and interrupted structures, which may explain the sporadic cases with low penetrance. Parkinsonism in SCA17 is more remarkable in Asian populations especially in Korea. In addition, an unclear cutoff of the pathologic range is the key issue in SCA17 related parkinsonism. SCA3 is more common in western cohorts. SCA6 and SCA8 have also been reported with a PD-like phenotype. Herein, we reviewed the epidemiologic, clinical, genetic, and pathologic features of parkinsonism in SCAs.

72.: Loss of ATP13A2 (PARK9) leads to mitochondrial dysfunction

Kufor-Rakeb syndrome (KRS, Mendelian Inheritance in Man [MIM] #606693) is a form of autosomal recessive, juvenile or early-onset, levodopa-responsive parkinsonism that has been associated with mutations in ATP13A2 (PARK9, MIM#610513). We identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088), in two siblings of Asian descent with KRS and reported the pathogenic effects of the mutations at protein/mRNA levels including mislocalisation of the mutant protein to endoplasmic reticulum, abnormal proteasome-mediated degradation of the mutant protein and nonsense-mediated mRNA decay. Our aim was to examine the effect of mutations in ATP13A2 on mitochondrial function. We assessed mitochondrial function by measuring mitochondrial membrane potential, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) production, mitochondrial branching and degradation of dysfunctional mitochondria using KRS patient-derived human olfactory neurosphere (hONS) cultured cells. The patient hONS showed lower labelling indexes for JC-1 and TMRM staining, indicating lower mitochondrial membrane potential (Δψm) while no changes were detected in ROS production. Interestingly, H2O2 treatment induced a higher level of ROS production and caused increased cell death in the patient cells compared to the negative control. Also, the patient cells showed a significant reduction in ATP production. There was no difference observed between the patient and control cells in mitochondrial mass and mitochondrial branching under normal growing conditions and Δψm-dissipated conditions. Our findings suggest mutations in ATP13A2 cause mitochondrial dysfunction in KRS. Further investigation to identify the pathogenic mechanism(s) by which mutant ATP13A2 impairs mitochondrial function is warranted.

POLG1-related levodopa-responsive parkinsonism

Parkinsonian features have been described in patients with POLG1 mutations. Notwithstanding, the clinical expression has been revealed heterogeneous and the response to dopaminergic treatment has been document in few cases. We aim to describe the longitudinal clinical features and the treatment response of three unrelated patients with neurodegenerative parkinsonism, preceded by PEO and SANDO syndromes, who harbor POLG1 mutations, including two novel mutations. It was documented a sustained response to levodopa, at 3 and 8 years of follow-up of parkinsonian syndrome, and reduced striatal dopamine uptake. We review the genotypic and phenotypic spectrum of POLG1-related parkinsonism. Our observations stimulate the debate around the role of mitochondrial DNA defects in the pathogenesis of neurodegenerative parkinsonism.

A computational model for bipolar deep brain stimulation of the subthalamic nucleus.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to reduce some of the symptoms of advanced, levodopa-responsive Parkinson's disease that are not adequately controlled with medication. However, the precise mechanism of the therapeutic action of DBS is still unclear. Stimulation-induced side effects are not uncommon and require electrical "dose" adjustments. Quantitative methods are needed to fully characterize the electric field in the deep brain region that surrounds the electrodes in order to help with adjustments and maximize the efficacy of the device. Herein we report a magnetic resonance imaging (MRI)-based head model proposed for analysis of fields generated by deep brain stimulation (DBS). The model was derived from multimodal image data at 0.5mm isotropic spatial resolution and distinguishes 142 anatomical structures, including the basal ganglia and 38 nuclei of the thalamus. Six bipolar electrode configurations (1-2, 1-3, 1-4, 2-3, 2-4, 3-4) were modeled in order to assess the effects of the inter-electrode distance of the electric field. Increasing the distance between the electrodes results in an attenuated stimulation, with up to 25% reduction in electric field amplitude delivered (2-3 vs. 1-4). The map of the deep brain structures provided a highly precise anatomical detail which is useful for the quantitative assessment of current spread around the electrode and a better evaluation of the stimulation setting for the treatment optimization.

Small fiber dysfunction in patients with Wilson's disease

Patients with Wilson's disease (WD) may develop a wide variety of neuropsychiatric symptoms, but there are few reports of autonomic dysfunction. Here, we described evidence of small fiber and/or autonomic dysfunction in 4 patients with WD and levodopa-responsive parkinsonism. We reviewed the charts of 4 patients with WD who underwent evaluation for the presence of neuromuscular dysfunction and water-induced skin wrinkling test (SWT). Two men and 2 women (33±3.5 years) with WD were evaluated. They all had parkinsonism at some point during their disease course. Parkinsonism on patient 4 almost completely subsided with treatment of WD. Two patients had significant sensory and 2 significant autonomic complaints, including syncopal spells. NCS/EMG was normal in all but SWT was abnormal in half of them (mean 4-digit wrinkling of 0.25 and 1). A subset of patients with WD exhibit evidence of abnormal skin wrinkling test (small fiber neuropathy).

Multiple system atrophy.

Multiple system atrophy (MSA) is a rare adult-onset synucleinopathy associated with dysautonomia and the variable presence of poorly levodopa-responsive parkinsonism and/or cerebellar ataxia. Other clinical symptoms that can be associated with MSA include hyperreflexia, stridor, sleep apnea, and rapid eye movement sleep behavior disorder (RBD). Mean survival from time of diagnosis ranges between 6 to 10 years, and definitive diagnosis is made on autopsy with demonstration of oligodendroglial cytoplasmic inclusions consisting of fibrillar α-synuclein. Magnetic resonance imaging (MRI) may be positive for cruciform T2 hyperintensity within the pons (the "hot cross bun sign"), volume loss in the pons and cerebellum, and T2 signal loss in the dorsolateral putamen with hyperintense rim on fluid attenuated inversion recovery (FLAIR) sequencing. Although most cases are sporadic, genetic polymorphisms have been identified both in familial and sporadic cases of MSA, and influence observed phenotypes. Treatment is symptomatic, with both pharmacological and nonpharmacological strategies. There are currently no consensus guidelines on management. Current and future research is aimed at identifying biomarkers and developing disease-modifying therapies.

Identification of a Japanese family with LRRK2 p.R1441G-related Parkinson's disease

Leucine-rich repeat kinase 2 (LRRK2) is a causative gene of autosomal dominant familial Parkinson's disease (PD). We screened for LRRK2 mutations in 3 frequently reported exons (31, 41, and 48) in our cohort of 871 Japanese patients with PD (430 with sporadic PD and 441 probands with familial PD). Direct sequencing analysis of LRRK2 revealed 1 proband (0.11%) with a p.R1441G mutation, identified for the first time in Asian countries, besides frequently reported substitutions including, the p.G2019S mutation (0.11%) and p.G2385R variant (11.37%). Several studies have suggested that the LRRK2 p.R1441G mutation, which is highly prevalent in the Basque country, is extremely rare outside of northern Spain. Further analysis of family members of the proband with the p.R1441G mutation revealed that her mother and first cousin shared the same mutation and parkinsonism. Haplotype analysis revealed a different haplotype from that of the original Spanish families. Our patients demonstrated levodopa-responsive parkinsonism with intrafamilial clinical heterogeneity. This is the first report of familial PD because of the LRRK2 p.R1441G mutation in Asia.

Antecollis and levodopa-responsive parkinsonism are late features of Dravet syndrome.

Dravet syndrome (DS) is a severe genetic epileptic encephalopathy mainly caused by SCN1A mutations.1 Children usually develop frequent and pharmacoresistant seizures of several types. Besides cognitive delay, some patients later develop gait ataxia. “Crouch gait” has also been described in older patients.2,3

Multiple system atrophy of the cerebellar type: Clinical state of the art

Multiple system atrophy (MSA) is a late-onset, sporadic neurodegenerative disorder clinically characterized by autonomic failure and either poorly levodopa-responsive parkinsonism or cerebellar ataxia. It is neuropathologically defined by widespread and abundant central nervous system α-synuclein-positive glial cytoplasmic inclusions and striatonigral and/or olivopontocerebellar neurodegeneration. There are two clinical subtypes of MSA distinguished by the predominant motor features: the parkinsonian variant (MSA-P) and the cerebellar variant (MSA-C). Despite recent progress in understanding the pathobiology of MSA, investigations into the symptomatology and natural history of the cerebellar variant of the disease have been limited. MSA-C presents a unique challenge to both clinicians and researchers alike. A key question is how to distinguish early in the disease course between MSA-C and other causes of adult-onset cerebellar ataxia. This is a particularly difficult question, because the clinical framework for conceptualizing and studying sporadic adult-onset ataxias continues to undergo flux. To date, several investigations have attempted to identify clinical features, imaging, and other biomarkers that may be predictive of MSA-C. This review presents a clinically oriented overview of our current understanding of MSA-C with a focus on evidence for distinguishing MSA-C from other sporadic, adult-onset ataxias.

An 85-Year Old Male with Levodopa-Responsive Parkinsonism Followed by Dementia and Supranuclear Ophthalmoplegia Caused by Alzheimer-Type Pathology without Lewy Bodies

An 85-year-old man developed l-dopa responsive parkinsonism indistinguishable from Parkinson's disease and subsequent dementia, followed by supranuclear ophthalmoplegia and neck dorsiflexion at the terminal stage. Midbrain tegmentum and medial temporal lobe were atrophic on magnetic resonance imaging, while decreased blood flow was predominant in frontotemporal lobes, detected by 3D-SSP of 123I- IMP SPECT. Alzheimer-type pathology without Lewy body pathology was confirmed at autopsy. Substantia nigra showed mild degeneration and several neurofibrillary tangles without Lewy body pathology or progressive supranuclear palsy cytopathology. L-dopa responsive parkinsonism could be an initial manifestation of Alzheimer's disease, which should be included in the differential diagnosis.

パーキンソン症候群と多発ニューロパチーを呈し，<i>POLG1</i>遺伝子変異をみとめた家族性進行性外眼筋麻痺の1家系

Multiple mitochondrial DNA (mtDNA) deletions usually occur secondarily to a mutation in one of the enzymes involved in mtDNA maintenance, such as polymerase γ, which is encoded by the nuclear polymerase γ1 gene (POLG1) and POLG2. Patients with multiple mtDNA deletion disorders show clinical heterogeneity of symptoms, in addition to usually seen progressive external ophthalmoplegia (PEO). We conducted clinical, histological and genetic analyses of two affected sisters in a family with the autosomal dominant inheritance pattern of PEO. A 73-year-old woman (patient 1) with congenital hypogonadism and PEO developed L-dopa responsive parkinsonism about the age of 60. Neurological examination revealed mild proximal muscle weakness and polyneuropathy too. Her 69-year-old sister (patient 2) also showed PEO, parkinsonism and polyneuropathy. Histopathological studies of biopsied muscle specimens from patient 1 revealed numerous ragged red fibers as well as fibers with increased succinate dehydrogenase activity and decreased cytochrome c oxidase activity. Multiple mtDNA deletions were detected, both by Southern blot and long-range PCR assays of total DNA from the biopsied muscle specimens. A systemic mutational analysis in both sisters revealed a heterozygous p.Y955C (c.2864A>G) mutation in POLG1. This is the first Japanese family identified with this mutation. We reviewed cases with this mutation highlighting a wide phenotypic spectrum of this disorder.

SPG15: a cause of juvenile atypical levodopa responsive parkinsonism

Autosomal recessive hereditary spastic paraplegias with thin corpus callosum (AR HSP-TCC) are rare and complex neurodegenerative disorders characterized by a genetic heterogeneity of which several genes (SPG11 and SPG15, SPG21, SPG47) or loci (SPG32, SPG46) have been identified. In SPG15, additional features have been described [1]: mental retardation, motor neuropathy, dysarthria and pigmentary maculopathy and recently, in a single family with a new homozygous mutation, parkinsonism [2]. In order to further confirm that SPG15 should be considered in the diagnosis of juvenile atypical parkinsonism, we describe another patient affected with SPG15, including juvenileonset levodopa-responsive parkinsonism. A female of Portuguese origin with consanguinity was 17 years old when referred to our center following 12 months of gait difficulties. The patient’s history included mild dysarthria and scholarly delay. Clinical examination demonstrated spastic paraplegia with bilateral extensor plantar reflexes and mild proximal motor deficit in the lower limbs. Vertical saccades were slightly hypometric. By age 19, a left upper limb rest tremor had developed as well as moderate bilateral akinesia, hypertonia, and hypomimia (video). An acute levodopa challenge (250 mg) led to a 60 % improvement of United Parkinson disease rating scale motor score (UPDRSIII) devoted to upper limbs (items 20–25, from 8/24 to 3/24). Rest tremor disappearance was sustained with a levodopa daily dose of M. Anheim and C. Tranchant contributed equally to the work and should be considered as co-last authors.

Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease

The glucocerebrosidase gene (GBA) is a known risk factor of Parkinson's disease (PD). We sequenced entire coding exons and exon/intron boundaries of GBA in 147 Japanese familial PD (FPD) patients from 144 families and 100 unrelated control subjects. Twenty-seven of 144 (18.8%) of index patients were heterozygous for known Gaucher disease mutations, suggesting that GBA heterozygous mutations are strongly associated with FPD (odds ratio = 22.9, 95% confidence interval = 3.1–171.2). The frequency was significantly higher in autosomal dominant PD (ADPD) compared with autosomal recessive PD. According to clinical assessments, PD patients with GBA mutations exhibited typical manifestations of PD or dementia with Lewy bodies (DLB), such as L-dopa responsive parkinsonism with psychiatric problems and/or cognitive decline. Interestingly, they also presented with reduced myocardial 123I-metaiodobenzylguanidine uptake. Our findings suggest that heterozygous GBA mutations are strong risk factors in FPD, especially for autosomal dominant PD. Some patients with GBA heterozygous mutations develop clinical features of DLB. We speculate that GBA dysfunction may promote Lewy body formation, resulting in more severe PD or DLB phenotypes that are inherited in families.

POLG-1 related SANDO and levodopa-responsive parkinsonism

Background: Mitochondrial dysfunction has recently emerged as one of the relevant mechanisms associated with the etiology and pathogenesis of neurodegenerative parkinsonism. Mutations in POLG1, the nuclear gene encoding the catalytic subunit of mitochondrial DNA polymerase gamma, have been associated with a wide phenotypic spectrum, including inherited parkinsonism usually in combination with progressive external ophthalmoplegia/INS;.

Levodopa-responsive parkinsonism and autonomic (small fiber) dysfunction in patients with Wilson'/INS;s disease (WD)

Levodopa-responsive parkinsonism and autonomic (small fiber) dysfunction in patients with Wilson'/INS;s disease (WD)

Tremor in Multiple System Atrophy – a review

<strong>Background:</strong> Multiple system atrophy (MSA) is a rare neurodegenerative movement disorder characterized by a rapidly progressive course. The clinical presentation can include autonomic failure, parkinsonism, and cerebellar signs. Differentiation from Parkinson’s disease (PD) is difficult if there is levodoparesponsive parkinsonism, rest tremor, lack of cerebellar ataxia, or mild/delayed autonomic failure. Little is known about tremor prevalence and features in MSA. <strong>Methods:</strong> We performed a PubMed search to collect the literature on tremor in MSA and considered reports published between 1900 and 2013. <strong>Results:</strong> Tremor is a common feature among MSA patients. Up to 80% of MSA patients show tremor, and patients with the parkinsonian variant of MSA are more commonly affected. Postural tremor has been documented in about half of the MSA population and is frequently referred to as jerky postural tremor with evidence of minipolymyoclonus on neurophysiological examination. Resting tremor has been reported in about one-third of patients but, in contrast to PD, only 10% show typical parkinsonian ‘‘pill-rolling’’ rest tremor. Some patients exhibit intention tremor associated with cerebellar dysmetria. In general, MSA patients can have more than one tremor type owing to a complex neuropathology that includes both the basal ganglia and pontocerebellar circuits. <strong>Discussion:</strong> Tremor is not rare in MSA and might be underrecognized. Rest, postural, action and intention tremor can all be present, with jerky tremulous movements of the outstretched hands being the most characteristic. However, reviewing the data on tremor in MSA suggests that not every shaky movement satisfies tremor criteria; therefore, further studies are needed.

Tremor in Multiple System Atrophy - a review.

Multiple system atrophy (MSA) is a rare neurodegenerative movement disorder characterized by a rapidly progressive course. The clinical presentation can include autonomic failure, parkinsonism, and cerebellar signs. Differentiation from Parkinson's disease (PD) is difficult if there is levodopa-responsive parkinsonism, rest tremor, lack of cerebellar ataxia, or mild/delayed autonomic failure. Little is known about tremor prevalence and features in MSA. We performed a PubMed search to collect the literature on tremor in MSA and considered reports published between 1900 and 2013. Tremor is a common feature among MSA patients. Up to 80% of MSA patients show tremor, and patients with the parkinsonian variant of MSA are more commonly affected. Postural tremor has been documented in about half of the MSA population and is frequently referred to as jerky postural tremor with evidence of minipolymyoclonus on neurophysiological examination. Resting tremor has been reported in about one-third of patients but, in contrast to PD, only 10% show typical parkinsonian "pill-rolling" rest tremor. Some patients exhibit intention tremor associated with cerebellar dysmetria. In general, MSA patients can have more than one tremor type owing to a complex neuropathology that includes both the basal ganglia and pontocerebellar circuits. Tremor is not rare in MSA and might be underrecognized. Rest, postural, action and intention tremor can all be present, with jerky tremulous movements of the outstretched hands being the most characteristic. However, reviewing the data on tremor in MSA suggests that not every shaky movement satisfies tremor criteria; therefore, further studies are needed.

Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms

Acquired alterations in mitochondrial DNA are believed to play a pathogenic role in Parkinson's disease. In particular, accumulation of mitochondrial DNA deletions has been observed in substantia nigra pars compacta dopaminergic neurons from patients with Parkinson's disease and aged individuals. Also, mutations in mitochondrial DNA polymerase gamma result in multiple mitochondrial DNA deletions that can be associated with levodopa-responsive parkinsonism and severe substantia nigra pars compacta dopaminergic neurodegeneration. However, whether mitochondrial DNA deletions play a causative role in the demise of dopaminergic neurons remains unknown. Here we assessed the potential pathogenic effects of mitochondrial DNA deletions on the dopaminergic nigrostriatal system by using mutant mice possessing a proofreading-deficient form of mitochondrial DNA polymerase gamma (POLGD257A), which results in a time-dependent accumulation of mitochondrial DNA deletions in several tissues, including the brain. In these animals, we assessed the occurrence of mitochondrial DNA deletions within individual substantia nigra pars compacta dopaminergic neurons, by laser capture microdissection and quantitative real-time polymerase chain reaction, and determined the potential deleterious effects of such mitochondrial DNA alterations on mitochondrial function and dopaminergic neuronal integrity, by cytochrome c oxidase histochemistry and quantitative morphology. Nigral dopaminergic neurons from POLGD257A mice accumulate mitochondrial DNA deletions to a similar extent (∼40-60%) as patients with Parkinson's disease and aged individuals. Despite such high levels of mitochondrial DNA deletions, the majority of substantia nigra pars compacta dopaminergic neurons from these animals did not exhibit mitochondrial dysfunction or degeneration. Only a few individual substantia nigra pars compacta neurons appeared as cytochrome c oxidase-negative, which exhibited higher levels of mitochondrial DNA deletions than cytochrome c oxidase-positive cells (60.38±3.92% versus 45.18±2.83%). Survival of dopaminergic neurons in POLGD257A mice was associated with increased mitochondrial DNA copy number, enhanced mitochondrial cristae network, improved mitochondrial respiration, decreased exacerbation of mitochondria-derived reactive oxygen species, greater striatal dopamine levels and resistance to parkinsonian mitochondrial neurotoxins. These results indicate that primary accumulation of mitochondrial DNA deletions within substantia nigra pars compacta dopaminergic neurons, at an extent similar to that observed in patients with Parkinson's disease, do not kill dopaminergic neurons but trigger neuroprotective compensatory mechanisms at a mitochondrial level that may account for the high pathogenic threshold of mitochondrial DNA deletions in these cells.

One complex world of mitochondrial parkinsonism

Rare neurological diseases are back in the spotlight (Rohn, 2013). Technological advances linked to massively parallel ‘second generation’ sequencing have catalysed an upsurge of interest in monogenic disorders (Singleton, 2011), leading to an unexpected and unprecedented explosion in disease gene discovery (over 20/month in the early part of 2013, of which Brain has published its fair share). These advances are clearly important for the families and patients concerned, providing a clear diagnosis culminating years, and sometimes decades of investigation. This new knowledge enables reliable prognostic and genetic counselling, and disease prevention through prenatal diagnosis. However, there is now additional excitement based on the realization that, in many instances, discovering a new gene responsible for an esoteric familial disorder can have much greater significance, casting light on a disease mechanism relevant for the common diseases seen in general neurological practice. These observations have not escaped the attention of the pharmaceutical industry and Governments (Rohn, 2013). Both now recognize the importance of the common phenotypes seen as part of a rare disease. The precision offered by a molecular diagnosis allows the assembly of near homogenous patient cohorts. When deeply phenotyped over time, these cohorts provide an ideal test bed for novel treatments targeting the known mechanism. If successful, this provides the rationale for much more expensive randomized controlled trials manipulating the same biochemical pathway in patients with a more common disorder sharing some of the clinical characteristics of the rare disease. Although discovered in the ‘pre-exome’ era, mutations in POLG raise just this possibility. POLG mutations are a rare cause of neurological disease, but the tantalizing observation of l-DOPA responsive parkinsonism in some patients (Luoma et al. , 2004) rekindled interest in the role of the mitochondria in idiopathic Parkinson’s disease, and raised the possibility of testing new mitochondria-enhancing antiparkinsonian drugs …