Novel Homozygous Pathogenic Variant in DNAJC6 Causes Rapid Progressive Parkinsonism.
BACKGROUND Biallelic variants in DNAJC6 cause PARK-DNAJC6 (historically referred to as PARK19), a rare autosomal recessive juvenile-onset dystonia-parkinsonism syndrome. Neurodevelopmental delay or regression, epilepsy, movement disorders, and psychiatric symptoms are also present. Progression is fast with frequent bulbar, gastrointestinal involvement and early loss of ambulation. CASES We report two siblings (17 and 14 years) harboring a novel homozygous nonsense variant in DNAJC6, p.Cys325*, not previously described in the medical literature and absent from population databases. The variant is predicted to truncate the protein, supporting a loss-of-function mechanism consistent with the gene's disease biology. Both patients exhibited developmental regression, parkinsonism with dystonia, cognitive decline, dysphagia, and marked sialorrhea, with severe, accelerated functional deterioration. Levodopa produced only mild benefit; in the older sibling, dose escalation provoked an adverse reaction with sustained upgaze/ophthalmoparesis, opisthotonus, and hypertension. LITERATURE REVIEW We found 23 previously reported DNAJC6 patients, most with early-onset parkinsonism with variable levodopa responsiveness, frequent developmental and psychiatric comorbidity, and prominent bulbar features. CONCLUSIONS The novel DNAJC6 p.Cys325* variant is associated with severe, early-onset parkinsonism and developmental regression. DNAJC6 should be considered in children and adolescents presenting with parkinsonism plus neurodevelopmental decline, particularly when levodopa benefit is modest, and dose-related adverse motor crises occur.