Juvenile Dystonia‐Parkinsonism Due to <scp><i>DNAJC6</i></scp> Mutation

Juvenile parkinsonism is a genetically heterogeneous clinical syndrome that typically presents with other movement disorders, neurological, and imaging abnormalities.1 Most cases are caused by recessively inherited mutations. In this paper, we present a case of juvenile onset dystonia-parkinsonism caused by DNAJC6 mutation. An 11-year-old female was referred to our service because of gait and balance problems. She was currently enrolled in a special education elementary school. Parents report that pregnancy was uneventful, with no exposure to toxins, drugs, head trauma, or parental consanguinity. Since her first steps at 16 months of age, she walked “as if wearing high heels” with some balance problems. During her childhood, she developed problems with her writing, drawing, bicycling, and skating because of developmental delay. When she was 8 years old, she developed progressive rest tremor in her upper limbs, slowness, and balance problems. At age 10, she received a trial treatment with levodopa/benserazide with considerable improvement. However, she did not continue therapy because family opted for alternative medicine. Parents reported patient's maternal grandfather had an undiagnosed parkinsonian syndrome. A Montreal Cognitive Assessment (MoCA) test score of 8/30 suggested cognitive impairment in different domains including orientation, attention, language, memory, calculation, and abstraction, which was later confirmed in a complete neuropsychological examination. The patient's physical examination (see Video 1 showed normal eye movements, hypokinetic dysarthria, and a “sardonic smile” alternated with hypomimia. Cervical dystonic posture with left torticollis and retrocollis was observed. Parkinsonian features were also noted; more predominant in the right side of her body, with a dystonic flexed posture of her left hand. We found hyperreflexia in both lower extremities. Her gait was observed as “high-heel gait,” with marked heel elevation and shifting standing pressure unto the forefoot. While walking, she kept elbows flexed, an erect posture, and presented a diminished arm stride. We described it as a “cock-walk gait.” Pull test was not performed because she was spontaneously falling. Laboratory tests including complete blood count, comprehensive metabolic panel, thyroid panel, serum ceruloplasmin, urinary copper excretion, and brain magnetic resonance imaging were unremarkable. A targeted gene panel sequencing related with recessive hereditary causes of juvenile parkinsonism was performed and a variant was identified previously reported as a probable pathogen in DNAJC6 gene in homozygous state in exon 17 (NM_001256864.2c.2589delG). Based on clinical features and genetic findings, a juvenile Parkinson's disease (PD) because of DNAJC6 gene mutation was diagnosed. She was started on pramipexol 0.25 mg 3 times daily in addition to physical therapy. After 1 month, she showed a 70% improvement of her Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III examination. This is a case report of juvenile dystonia-parkinsonism. The “cock-walk” gait is characterized by a high-stepping gait walking on the metatarsophalangeal joints, flexed elbows, and an erect spine.2 Although classically seen in inherited or acquired manganism,2-4 other causes are spinocerebellar ataxia type 35 and psychostimulants.6 Juvenile parkinsonism commonly has a genetic basis.1 The clinical spectrum of these forms is broad and complex because of the variable combinations of parkinsonism with other clinical manifestations.1 Table 1 describes characteristics of juvenile parkinsonism. Clinicians need to rule out primary inborn errors of neurotransmitter biosynthesis because these may result in movement disorders with a variety of other neurological symptoms presenting at any age.7 DNAJC6 encodes the brain-specific isoform of auxilin.8, 9 Auxilins have a role in clathrin-mediated endocytosis through the formation of vesicles in presynaptic terminals, their recycling, and the uptake of material. DNAJC6 is a recessive juvenile parkinsonism gene. Some core clinical features of DNAJC6 mutation include parkinsonism, neurological regression, and loss of ambulation. Patients commonly develop other symptoms including dystonia, learning difficulties, epilepsy, and neuropsychiatric features. Most patients show limited response to Levodopa. Dopaminergic-induced complications are common.10, 11 (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique. D.G.B.: 1A, 1B, 1C, 2A, 2B C.N.E.H.: 1A, 1B, 1C, 2A, 2B J.R.Z.: 1A, 1B, 1C, 2A, 2B D.M.R.: 1A, 1B, 1C, 2A, 2B The authors confirm that the approval of an institutional review board was not required for this work. The authors confirm that informed consent from the patient has been obtained. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. There are no funding sources or conflicts of interest related to this case. In the past year from the date of submission, D.M.R. received support linked to consultancies from UCB Mexico and speaker honoraria from Abbott Mexico unrelated to this research.

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