DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia.

BACKGROUND: Juvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin-mediated endocytosis (CME), as in DNAJC6-related juvenile parkinsonism. OBJECTIVE: To report on a new patient cohort with juvenile-onset DNAJC6 parkinsonism-dystonia and determine the functional consequences on auxilin and dopamine homeostasis. METHODS: Twenty-five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole-exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G-associated kinase and synaptic proteins. RESULTS: We identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. 123 I-FP-CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G-associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced. CONCLUSIONS: DNAJC6 is an emerging cause of recessive juvenile parkinsonism-dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G-associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G-associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism-dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Why do work patterns differ between men and women GPs?

PURPOSE: The purpose of this study was to explore gender differences in contractual commitments, job satisfaction and spouses' occupation among GP principals in NHS Scotland. DESIGN/METHODOLOGY/APPROACH: This paper is based on data provided by a self-completion, postal questionnaire survey. The response rate was 50 per cent. FINDINGS: Males worked more hours than females and were more likely to work out-of-hours. Females reported greater job satisfaction but only when they worked fewer hours. Females earned less than males but there were no gender differences in total household income. Both genders planned to retire at 59 years. More males would delay retirement if they could work part-time. More females than males were in dual-doctor households. Male respondents in dual-doctor households were more likely to have modified their working hours or career aspirations than males in other households. PRACTICAL IMPLICATIONS: The number of hours worked by GPs is in part determined by the occupation/earning power of their spouse. The number of women GPs is increasing and they are likely to continue to choose to work fewer hours than their male counterparts have done in the past. ORIGINALITY/VALUE: This study has attempted to incorporate spouse's occupation/income as a factor in the career choices of GPs in Scotland.

General practitioner non-principals benefit from flexible working.

PURPOSE: The purpose of this study is to explore non-principals' working patterns and attitudes to work. DESIGN/METHODOLOGY/APPROACH: The article is based on data provided by a questionnaire survey. Findings - Gender division was apparent among the non-principals. Males were more likely to work full-time, because their spouses modified their working hours. RESEARCH LIMITATIONS/IMPLICATIONS: It was impossible to identify all non-principals in Scotland or to compare responders and non-responders, due to the lack of official data. Hence, the results might not be representative. PRACTICAL IMPLICATIONS: More flexible posts would enable GPs to more easily combine paid work with family commitments. It is anticipated that the new GP contract should deliver this. ORIGINALITY/VALUE: This was the first time a study of all non-principals in Scotland had been attempted. The findings provide a more comprehensive picture of GPs in Scotland and provide valuable information for policymakers.