A Rare Cause of Myoclonus: A Cupric Conundrum.

A woman aged 22 years presented with a 3-year history of jerks when brushing her teeth and a tremor when carrying drinks. Examination revealed a bilateral jerky tremor, stimulus-sensitive myoclonus, and difficulty with tandem gait. Thyroid and liver function test results were normal, but she had rapidly progressive renal failure. Serum copper, ceruloplasmin, and manganese levels were normal, but her urinary copper level was elevated on 2 occasions. Pathological findings on organ biopsy prompted genetic testing to confirm the diagnosis. The differential diagnosis, tissue biopsy findings, and final genetic diagnosis are discussed.

Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data.

BACKGROUND: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. METHODS: We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. FINDINGS: We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005). INTERPRETATION: Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both. FUNDING: UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health.

Bone health in Parkinson's disease: a systematic review and meta-analysis.

OBJECTIVE: Parkinson's disease (PD) and osteoporosis are chronic diseases associated with increasing age. Single studies have reported associations between them and the major consequence, namely, increased risk of fractures. The aim of this systematic review and meta-analysis was to evaluate the relationship of PD with osteoporosis, bone mineral density (BMD) and fracture risk. METHODS: A literature search was undertaken on 4 September 2012 using multiple indexing databases and relevant search terms. Articles were screened for suitability and data extracted where studies met inclusion criteria and were of sufficient quality. Data were combined using standard meta-analysis methods. RESULTS: 23 studies were used in the final analysis. PD patients were at higher risk of osteoporosis (OR 2.61; 95% CI 1.69 to 4.03) compared with healthy controls. Male patients had a lower risk for osteoporosis and osteopenia than female patients (OR 0.45; 95% CI 0.29 to 0.68). PD patients had lower hip, lumbar spine and femoral neck BMD levels compared with healthy controls; mean difference, -0.08, 95% CI -0.13 to -0.02 for femoral neck; -0.09, 95% CI -0.15 to -0.03 for lumbar spine; and -0.05, 95% CI -0.07 to -0.03 for total hip. PD patients were also at increased risk of fractures (OR 2.28; 95% CI 1.83 to 2.83). CONCLUSIONS: This systematic review and meta-analysis demonstrate that PD patients are at higher risk for both osteoporosis and osteopenia compared with healthy controls, and that female patients are at greater risk than male patients. Patients with PD also have lower BMD and are at increased risk of fractures.

Parkin disease: a clinicopathologic entity?

IMPORTANCE: Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss. OBJECTIVE: To investigate whether parkin-linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD). DESIGN, SETTING, AND PARTICIPANTS: We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison. RESULTS: Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex). CONCLUSIONS AND RELEVANCE: These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies.

Pisa syndrome in Parkinson's disease: a mobile or fixed deformity?

BACKGROUND: Although Pisa syndrome and scoliosis are sometimes used interchangeably to describe a laterally flexed postural deviation in Parkinson's disease (PD), the imaging findings of Pisa syndrome in PD have not been previously studied in detail. METHODS: Patients with PD and Pisa syndrome (lateral flexion >10° in the standing position) were examined clinically and underwent radiological assessment using standing radiograph and supine CT scan of the whole spine. RESULTS: Fifteen patients were included in this observational study. All patients had scoliosis on standing radiographs, and 12 had scoliosis persisting in the supine position. Scoliotic curves improved by a mean of 44% when patients moved from standing to supine. Only a quarter of patients with structural scoliosis had evidence of bony fusion on the side of their lateral deviation rendering their deformity fixed. CONCLUSIONS: Pisa syndrome describes a patient who lists to the side whereas scoliosis is defined by spinal curvature and rotation and may not be associated with lateral flexion. The finding of 'structural scoliosis' in Pisa syndrome should not preclude intervening to improve posture as most patients had little or no evidence of structural bony changes even when the deformity had been present for a number of years.

Primary progressive aphasia with parkinsonism.

A 65-year-old man presented with word-finding difficulty and gait disturbance. His speech was nonfluent with word retrieval impairment and difficulties with sentence repetition. Other cognitive domains were intact initially. He developed asymmetrical bradykinesia, rigidity and a rest tremor. Over the following 8 years, his speech production impairment slowly deteriorated with the development of a motor speech disorder, anomia, impaired repetition of single words as well as sentences, and impaired comprehension of initially sentences then single words. His parkinsonian syndrome also deteriorated with limited response to levodopa. Serial brain MRI revealed progressive asymmetric perisylvian atrophy. He died after a disease duration of 12 years. The clinical syndrome is discussed by an expert, the pathology is described, and important clinical points from the case are highlighted.

Decision making, impulsivity, and addictions: do Parkinson's disease patients jump to conclusions?

Links between impulsive-compulsive behaviors (ICBs) in treated Parkinson's disease (PD), behavioral addictions, and substance abuse have been postulated, but no direct comparisons have been carried out so far. We directly compared patients with PD with and without ICBs with illicit drug abusers, pathological gamblers, and age-matched healthy controls using the beads task, a test of reflection impulsivity, and a working memory task. We found that all patients with PD made more impulsive and irrational choices than the control group. PD patients who had an ICB showed similar behavior to illicit substance abusers, whereas patients without ICBs more closely resembled pathological gamblers. In contrast, we found no difference in working memory performance within the PD groups. However, PD patients without ICBs remembered distractors significantly less than all other patients during working memory tests. We were able to correctly classify 96% of the PD patients with respect to whether or not they had an ICB by analyzing three trials of the 80/20 loss condition of the beads task with a negative prediction value of 92.3%, and we propose that this task may prove to be a powerful screening tool to detect an ICB in PD. Our results also suggest that intact cortical processing and less distractibility in PD patients without ICBs may protect them from developing behavioral addictions.

Globular glial tauopathies (GGT) presenting with motor neuron disease or frontotemporal dementia: an emerging group of 4-repeat tauopathies.

A number of recent studies have described cases with tau-positive globular oligodendroglial inclusions (GOIs) and such cases have overlapping pathological features with progressive supranuclear palsy (PSP), but present with clinical features of motor neuron disease (MND) and/or frontotemporal dementia (FTD). These two clinical phenotypes have been published independently and as a result, have come to be considered as distinct disease entities. We describe the clinicopathological and biochemical features of two cases with GOIs: one with clinical symptoms suggestive of MND and the other with FTD. Histological changes in our two cases were consistent with their clinical symptoms; the MND case had severe neurodegeneration in the primary motor cortex and corticospinal tract, whereas the FTD case had severe involvement of the frontotemporal cortices and associated white matter. Immunohistochemistry in both cases revealed significant 4-repeat (4R) tau pathology primarily in the form of GOIs, but also in astrocytes and neurons. Astrocytic tau pathology was morphologically similar to that seen in PSP, but in contrast was consistently negative for Gallyas silver staining. Tau-specific western blotting revealed 68, 64 and 35 kDa bands, showing further overlap with PSP. The underlying neuropathological features of these two cases were similar, with the major difference relating to the regional distribution of pathology and resulting clinical symptoms and signs. The globular nature of glial inclusions and the non-fibrillar properties of tau in astrocytes are characteristic features that allow them to be distinguished from PSP and other tauopathies. We, therefore, propose the term globular glial tauopathy as an encompassing term to classify this emerging class of 4R tauopathy.

Postural deformities in Parkinson's disease.

Postural deformities are frequent and disabling complications of Parkinson's disease (PD) and atypical parkinsonism. These deformities include camptocormia, antecollis, Pisa syndrome, and scoliosis. Recognition of specific postural syndromes might have differential diagnostic value in patients presenting with parkinsonism. The evidence to date suggests that postural deformities have a multifactorial pathophysiology. Contributing factors include muscular rigidity; axial dystonia; weakness caused by myopathy; body scheme defects due to centrally impaired proprioception; and structural changes in the spine. The relative contribution of these different factors varies between patients and across specific syndromes. Improved understanding of the mechanisms underlying postural deformities in PD might ultimately lead us to more effective management strategies for these disabling and drug-refractory complications.