SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia.

Idiopathic basal ganglia calcification (IBGC) is characterized by bilateral calcification of the basal ganglia associated with a spectrum of neuropsychiatric and motor syndromes. In this study, we set out to determine the frequency of the recently identified IBGC gene SLC20A2 in 27 IBGC cases from the Mayo Clinic Florida Brain Bank using both Sanger sequencing and TaqMan copy number analysis to cover the complete spectrum of possible mutations. We identified SLC20A2 pathogenic mutations in two of the 27 cases of IBGC (7 %). Sequencing analysis identified a p.S113* nonsense mutation in SLC20A2 in one case. TaqMan copy number analysis of SLC20A2 further revealed a genomic deletion in a second case, which was part of a large previously reported Canadian IBGC family with dystonia. Subsequent whole-genome sequencing in this family revealed a 563,256-bp genomic deletion with precise breakpoints on chromosome 8 affecting multiple genes including SLC20A2 and the known dystonia-related gene THAP1. The deletion co-segregated with disease in all family members. The deletion of THAP1 in addition to SLC20A2 in the Canadian IBGC family may contribute to the severe and early onset dystonia in this family. The identification of an SLC20A2 genomic deletion in a familial form of IBGC demonstrates that reduced SLC20A2 in the absence of mutant protein is sufficient to cause neurodegeneration and that previously reported SLC20A2 mutation frequencies may be underestimated.

Young onset Parkinson's disease. Practical management of medical issues.

Young Onset Parkinson's disease (YOPD) is defined as Parkinson's disease diagnosed between the ages of 21 and 40 years. Problems faced by this group are different from those faced by older subjects because they face decades with the illness. This article reviews current literature and offers suggestions for intervention when appropriate and practical suggestions in the areas of drug treatment, rehabilitation, nutrition, sexuality, pregnancy, menstruation and menopause. The suggestions are not exclusively restricted to the management of YOPD, but emphasis is placed on items where people with YOPD have either had particular difficulties or where they can proactively self-manage their illness.

Psychosocial issues in young-onset Parkinson's disease: current research and challenges.

Young-onset Parkinson's disease (YOPD) patients have psychosocial issues that create more challenges than for older patients. They are diagnosed during the most productive years of their lives, live longer with the disease, and are at increased risk for non-motor symptoms of PD. This article describes issues that health care professionals may need to address, including anxiety, depression, cognitive disturbances, breakdown of relationships, and employment. These psychosocial problems require as much attention as the medical problems; they negatively impact the emotional stability of both the patient and family, interfering with all relationships. YOPD patients can benefit from a team approach to their treatment.

Understanding the role of the Parkinson's disease nurse specialist in the delivery of apomorphine therpy.

Optimal care of Parkinson's disease (PD) patients should involve a multidisciplinary team (MDT) of which a PD nurse specialist (PDNS) is a key member. The role of a PDNS is particularly prominent in the care of advanced PD patients suitable for apomorphine because, in addition to nursing skills, apomorphine treatment requires liaison, training, interaction and coordination with patients, caregivers and other members of the MDT as well as the interface with primary care physicians. The therapeutic success of apomorphine therapy depends not only upon the pharmacologic drug response, but also on how well the patient understands his/her disease and how to handle the therapy. In this respect, a PDNS is a vital member of the MDT who provides education and training, support, and is available for consultation when problems arise. In this article, we review the literature on the contribution of PDNSs in both continuous subcutaneous apomorphine infusion and intermittent subcutaneous apomorphine injection and highlight the various beneficial aspects of PDNS care, supported by scientific evidence when available. Despite a low level of published evidence, there is strong clinical evidence that the impact of PDNSs on the management of apomorphine therapy is vital and indispensable for the success of this treatment.

What is the evidence to support home environmental adaptation in Parkinson's disease? A call for multidisciplinary interventions.

"Home" is where one has a sense of belonging and feels secure, but it can also be a risky place for people with Parkinson's disease (PD). PD patients need assistance making adjustments to their physical environment to maintain appropriate care and provide a safe environment. This relationship is called the "person-environmental fit" (P-E fit). While most PD patients remain in their own homes, little is known about the specific challenges that PD patients and their caregivers encounter in the routine activities of daily living. The aim of our study was to identify the existing evidence on the issue of housing environmental adaptation in PD by performing a systematic review with a proposal of development strategies to integrate a multidisciplinary team into a home environmental research. MEDLINE, and life science journals were searched by querying appropriate key words, but revealed very few publications in this area. However, early evidence suggested that PD patients do not enjoy an adequate P-E fit in their own homes and face more functional limitations compared to matched controls. We concluded that we need to develop research-based evaluation strategies that can provide us with a theoretical and conceptual basis as well as tools for analysis of the P-E fit for PD patients and caregivers. We recommend that individual members of the multidisciplinary team including patients, caregivers, physicians, rehabilitation specialists, and social workers use a team approach to identify the key indicators and solutions for the development of PD-specific solutions for improving the P-E fit.

Clustering of Parkinson disease: shared cause or coincidence?

BACKGROUND: The spatial and temporal pattern of excessive disease occurrence, termed clustering, may provide clues about the underlying etiology. OBJECTIVE: To report the occurrence of 3 clusters of Parkinson disease (PD) in Canada. DESIGN AND PATIENTS: We determined the population groups containing the clusters, geographical limits, and duration of exposure to the specific environments. We tested whether there was an excessive presence of Parkinson disease by calculating the probability of the observed cases occurring under the null hypothesis that the disease developed independently and at random in cluster subjects. Results of genetic testing for mutations in the alpha-synuclein, parkin, tau genes, and spinocerebellar ataxia genes (SCA2 and SCA3) were negative. RESULTS: The probabilities of random occurrence (P values) in the 3 clusters were P = 7.9 x 10 (-7)for cluster 1, P = 2.6 x 10 (-7)for cluster 2, and P = 1.5 x 10 (-7)for cluster 3. CONCLUSIONS: Our findings indicate an important role for environmental causation in Parkinson disease. A possible role exists for environmental factors such as viral infection and toxins in the light of current evidence.

The psychometric properties of the Parkinson's Impact Scale (PIMS) as a measure of quality of life in Parkinson's disease.

We have previously designed and validated a 10-item bilingual questionnaire, the Parkinson's Impact Scale (PIMS), as a disease-specific instrument to measure the impact of Parkinson's disease (PD) on the quality of life of patients with PD. In this paper we extend the psychometric assessment of PIMS to a new set of patients, in the context of a cross-over trial by Hoffman-La Roche Ltd, comparing two doses of tolcapone in 116 PD patients who had developed wearing off effect on levodopa. Using data from this trial, we evaluate PIMS' test-retest reliability, construct validity, sensitivity and responsiveness to change. Validation is carried out by correlating the PIMS scores with corresponding UPDRS subscales and with the Schwab and England scale. We show that PIMS has excellent psychometric properties, and can therefore be used not only in clinical trials but also to identify quickly potential problems in major subjective areas of PD patients' lives, in order to refer them effectively to appropriate providers of assistance.

Parkinson's disease: implications for nutritional care.

Parkinson's Disease (PD) is a chronic, progressive, neurodegenerative disease. People with PD are particularly susceptible to weight loss and malnutrition. Involuntary movements associated with PD result in increased energy expenditure, while both disease symptoms and medication side-effects can limit food intake. In addition, patients with the disease may choose to follow unconventional nutritional therapies that exacerbate malnutrition. Dietitians play a key role in helping patients with PD to optimize their nutritional status and manage various nutrition-related symptoms and medication side-effects. To assume this role, dietitians need to have current knowledge about PD and its nutritional consequences, as well as strategies for managing a variety of nutrition-related symptoms.

The psychosocial impact of late-stage Parkinson's disease.

The late stage of Parkinson's disease (PD) can be protracted with inexorable changes in physical and mental health, loss of autonomy and self-esteem, altered relationships, and social isolation. Severely affected patients (Hoehn & Yahr stage 4-5) present a challenge to nurses who care for them; addressing their needs takes time and patience. Changes in mental status have profound implications for the welfare of the late-stage PD patient as well as of the caregiver(s). Depression and dementia in patients with PD are two factors that interfere with the ability to deliver effective care in late-stage PD as they lead to loss of initiative and cooperation. Primary caregivers often have their own medical problems, with limited stamina and support; relationships may change, leading to sadness or conflict. Nurses can be powerful advocates for the physical and mental health of both the patient with late-stage Parkinson's disease and the primary caregiver.

Nursing care of patients with late-stage Parkinson's disease.

Patients in the late stages of Parkinson's disease may be significantly disabled for many years, often because of their increasing inability to tolerate therapeutic doses of antiparkinson drugs. Their status and management have been overlooked in the literature. Few current healthcare professionals have cared for patients with Parkinson's disease in the prelevodopa era and do not understand how severe and protracted the illness can be without effective treatment. This article describes a practical approach to the nursing management of severely affected patients (i.e., Hoehn and Yahr Stage 4-5) who no longer derive consistent, therapeutic benefit from their drugs. Specific problems these patients face are adverse drug reactions such as postural hypotension, psychosis, and confusion, as well as difficulties with nutrition, elimination, mobility and falling, communication, sexuality, memory, and mood. Nursing interventions can help minimize the effect of these problems on the patient.

Pallidonigral TDP-43 pathology in Perry syndrome.

OBJECTIVE: Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome. METHODS: Clinical data and autopsy brain tissue samples were collected from eight patients from four genealogically unrelated kindreds with Perry syndrome. Brain tissue was studied with immunohistochemistry and biochemistry for TDP-43. Patients were screened for mutations in the progranulin (GRN) and TDP-43 (TARDBP) genes. RESULTS: The mean age at onset was 47 years (range 40-56), and the mean age at death was 52 years (range 44-64). In all patients, we identified TDP-43-positive neuronal inclusions, dystrophic neurites and axonal spheroids in a predominantly pallidonigral distribution, and we demonstrated changes in solubility and electrophoretic mobility of TDP-43 in brain tissue. The inclusions were highly pleomorphic and predominated in the extrapyramidal system, sparing the cortex, hippocampus and motor neurons. There were no mutations in GRN or TARDBP. INTERPRETATION: Perry syndrome displays unique TDP-43 pathology that is selective for the extrapyramidal system and spares the neocortex and motor neurons.

DCTN1 mutations in Perry syndrome.

Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.