Neuropsychological profile of POLR3A-related spastic ataxia.

Background and objectives: POLR3-related disorders are a group of autosomal recessive neurodegenerative diseases that usually cause leukodystrophy and can lead to cognitive dysfunction. Literature reporting comprehensive neuropsychological assessment in POLR3A-related diseases is sparse. Here we describe the neuropsychological profile of a case of childhood-onset POLR3A-related spastic ataxia without leukodystrophy.

Methods: Extensive neuropsychological assessment covering the domains of attention, executive function, memory, language, visuospatial processing and social cognition in a patient with a compound heterozygous POLR3Amutation (c.2000T>A (p.Leu667*) / c.1909+22G>A) and a spastic ataxic phenotype.

Results: Neuropsychological testing showed a marked slowing of basic information processing (reading, colour naming on Stroop test), executive deficits (alternating attention through Letter-Digit Substitution Test and semantic word fluency) and social cognition impairment (facial emotion recognition via Facial Expressive Action Stimulus Test, intention and emotion attribution via Story-based Empathy Task).

Discussion: While originally described as a typical hypomyelination disorder, leukodystrophy nor striatal lesions seem pivotal to cognitive dysfunction in POLR3-related disease, as demonstrated in this patient. Further investigation of a larger cohort of (c.1909 + 22G>A) heterozygous patients is warranted to reveal which neuropsychological features correspond to this less aggressive phenotype.