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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\u2010mediated endocytosis (CME), as in DNAJC6\u2010related juvenile parkinsonism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To report on a new patient cohort with juvenile\u2010onset <jats:italic>DNAJC6<\/jats:italic> parkinsonism\u2010dystonia and determine the functional consequences on auxilin and dopamine homeostasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty\u2010five 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\u2010exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G\u2013associated kinase and synaptic proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 6 patients harboring previously unreported, homozygous nonsense <jats:italic>DNAJC6<\/jats:italic> mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. <jats:sup>123<\/jats:sup>I\u2010FP\u2010CIT 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\u2013associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>DNAJC6<\/jats:italic> is an emerging cause of recessive juvenile parkinsonism\u2010dystonia. <jats:italic>DNAJC6<\/jats:italic> 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\u2013associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G\u2013associated kinase, as observed in the auxilin knockout mouse. <jats:italic>DNAJC6<\/jats:italic> parkinsonism\u2010dystonia 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. \u00a9 2020 The Authors. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.28063","type":"journal-article","created":{"date-parts":[[2020,5,30]],"date-time":"2020-05-30T04:16:49Z","timestamp":1590812209000},"page":"1357-1368","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["<scp><i>DNAJC6<\/i><\/scp> Mutations Disrupt Dopamine Homeostasis in Juvenile <scp>Parkinsonism\u2010Dystonia<\/scp>"],"prefix":"10.1002","volume":"35","author":[{"given":"Joanne","family":"Ng","sequence":"first","affiliation":[{"name":"Molecular Neurosciences, Developmental Neurosciences Programme UCL Great Ormond Street Institute of Child Health  London United 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