We present a case of NBIA with mosaic WDR45 mutation and levodopa responsiveness with putaminal signal loss on DaTscan.

This is a 34 year-old non-verbal autistic gentleman with delayed speech development. He lost all spoken language in childhood, although motor milestones remained on target. Around age 30, he developed a shuffling gait, imbalance, and weakness of the lower limbs. He also developed tremor of the upper extremities and eventually required support with assistive device.

 On neurologic examination, there was parkinsonism characterized by hypomimia, bilateral arm rigidity, a mixed tremor of the upper extremities, and shuffling gait. MRI of the brain revealed prominent GRE susceptibility within globus pallidi and substantia nigra, and prominent volume loss involving the cerebrum and cerebellum. DAT scan demonstrated absent tracer activity within the right putamen and decreased tracer activity within the left putamen. Whole genome sequencing revealed a WDR45 IVS 10, c830+1G>A mosaic pathogenic variant and a denovo, novel variant of uncertain significance, c.1019G>A (p.G340D) missense variant in the GNAL gene. Dopaminergic supplementation with carbidopa/levodopa led to moderate improvement in motor function as measured by UPDRS.

The WDR45 IVS 10, c830+1G>A mosaic pathogenic variant causes NBIA type 5 'Beta-propeller protein-associated neurodegeneration (BPAN). More than 50 WDR45 mutations have been identified in people with BPAN, leading to delayed development, movement disorders, and a gradual loss of intellectual functioning in adulthood.  A p.G340S in the GNAL gene has been reported in a female with hypokinesis and a family history of parkinsonism. It is unclear whether the unique parkinsonism that is DaT positive and dopa responsive in this individual is due to the combination of the two genetic changes and deserves further investigation.