Childhood-onset parkinsonism, dystonia and severe muscle wasting in a Sudanese girl caused by a novel homozygous DnaJ heat shock protein family (heat shock protein 40) member C6 frameshift variant, with an incidental pathogenic breast cancer 1 gene s

Abstract Background DNAJC6 -related juvenile parkinsonism is a rare autosomal recessive disorder of auxilin, a co-chaperone essential for clathrin-mediated synaptic vesicle recycling. Fewer than 50 kindreds have been reported worldwide, and the condition is easily missed when first-line investigations come back normal. We describe a Sudanese adolescent in whom a previously unreported homozygous DNAJC6 frameshift variant was identified only after a prolonged diagnostic journey that included a period during which her illness was mistakenly attributed to a functional neurological disorder. Clinical whole-exome sequencing additionally returned an incidental medically actionable BRCA1 secondary finding. Case presentation A 13-year-old Sudanese girl, the eldest child of first-cousin parents, was born preterm and ventilated neonatally for severe respiratory distress. Her development was normal until age five, when an isolated upper-limb tremor first appeared. Over the next 8 years her condition progressed into severe juvenile parkinsonism: bilateral rest-and-action tremor, rigidity, bradykinesia, generalized dystonia with prominent oromandibular involvement, dysphagia, profound cachexia, cognitive and behavioral decline, sleep and autonomic disturbance, episodic oculogyric crises and three discrete seizures. By approximately 11 she was wheelchair-dependent. Earlier, unrevealing investigations had led to a psychiatric diagnosis of functional neurological disorder, and the dopamine antagonists prescribed on that basis worsened her condition. Whole-exome sequencing later identified a novel homozygous DNAJC6 frameshift deletion (NM_001256864.2:c.1480del; p.Glu494ArgfsTer12), absent from population databases, alongside a heterozygous pathogenic BRCA1 deletion reported as an actionable secondary finding. Levodopa produced partial motor benefit, complicated by on-state dyskinesias, visual hallucinations and excessive daytime somnolence. Subsequent up-titration of carbidopa/levodopa to approximately 5-hourly dosing produced a further, clinically evident improvement in gait and fine-motor function. Conclusions This case adds a previously unreported allele to the DNAJC6 catalog and characterizes the severe end of its phenotype, where corticospinal signs and life-threatening cachexia accompany the more familiar extrapyramidal features. It illustrates the harm that follows premature labeling of a progressive organic movement disorder as functional, especially when dopamine antagonists are then prescribed. The accompanying pathogenic BRCA1 secondary finding shows the dual diagnostic yield that clinical whole-exome sequencing can deliver. Early genetic investigation in childhood-onset movement disorders, particularly with consanguinity, should be the rule, and cascade pathways for actionable secondary findings embedded in routine practice.