Levodopa-responsive parkinsonism with dystonia in RAB39B-related Waisman syndrome: a case report

Abstract

Pathogenic variants in RAB39B, located on chromosome Xq28, cause a rare X-linked neurodevelopmental disorder characterized by intellectual disability and early-onset parkinsonism, commonly referred to as Waisman syndrome. RAB39B encodes a neuron-specific small GTPase involved in vesicular trafficking and synaptic regulation. Increasing evidence suggests that RAB39B deficiency produces a clinical continuum spanning neurodevelopmental impairment and later neurodegeneration. While parkinsonism is the most consistently reported motor manifestation, the spectrum of associated movement disorders remains incompletely defined, and cranial dystonia has been rarely characterized. We report a case of genetically confirmed RAB39B-related disease presenting with levodopa-responsive parkinsonism associated with multifocal dystonia, including upper-limb dystonia and mixed oromandibular dystonia. A 48-year-old right-handed man with longstanding intellectual disability presented with an eight-year history of progressive extrapyramidal symptoms beginning with a resting tremor of the right upper limb. Over time he developed bradykinesia, rigidity, freezing of gait, and oromandibular dystonia. Childhood history was notable for developmental delay and longstanding dystonic posturing of the digits. Family history revealed similar neurological features in a younger brother and dystonic toe posturing in the mother, suggesting X-linked inheritance. Neurological examination demonstrated hypomimia, slow saccades, tongue bradykinesia, mixed oromandibular dystonia, generalized rigidity with right-predominant resting tremor, and dystonic digital posturing. Brain magnetic resonance imaging showed susceptibility changes involving the bilateral globus pallidi, substantia nigra, and posterior thalami. Whole-exome sequencing identified a hemizygous frameshift variant in RAB39B (c.137del; p.Phe46SerfsTer38), classified as pathogenic according to American College of Medical Genetics criteria. The same variant was identified in the affected brother and heterozygous mother. Treatment with levodopa–carbidopa resulted in marked improvement in parkinsonian symptoms, although motor fluctuations and dyskinesias later developed. The patient died three years after treatment initiation due to aspiration pneumonia. This case suggests that dystonia, including cranial dystonia, may occur in selected RAB39B-related cases and reinforces the concept that RAB39B deficiency represents a disorder spanning neurodevelopment and neurodegeneration. Recognition of dystonia, familial patterns of inheritance, and suggestive imaging findings may facilitate earlier genetic diagnosis and improve clinical management of affected individuals.