Predictive coding and adaptive behavior in patients with genetically determined cerebellar ataxia--A neurophysiology study.

Genetically determined cerebellar ataxias (CA) are a heterogeneous group of disorders with progressive decline of cerebellar functions. The cerebellum influences internal forward models that play a role in cognitive control, but whether these processes are dysfunctional in CA is unclear. Here, we examined sensory predictive coding processes and response adaptation in CA and healthy controls (HC) using behavioral tests with concomitant EEG recordings. N = 23 patients and N = 29 age- and sex-matched HC were studied. Sensory prediction coding was tested with an auditory distraction paradigm and error-related behavioral adaptation with a visual flanker task. As neurophysiological markers we studied different event-related potentials: the P3a for orientation of attention; the N2 and the error-related negativity (ERN) for cognitive adaptation processes/consequences of response errors; error-related positivity (Pe) for error-awareness; the mismatch negativity (MMN) for sensory predictive coding; and reorientation negativity (RON) for reorientation after unexpected events. Overall reaction times were slower in patients compared to HC, but error rates did not differ. Both in patients and HC, P3a amplitudes were larger in distraction trials, but the P3a amplitude was smaller in patients compared to HC. The MMN as well as behavioral and EEG-correlates of response adaptation (ERN/N2) did not differ between groups, while the Pe was attenuated in patients. During sensory predictive coding, RON amplitudes were significantly larger in HC compared to patients. In HC, but not in patients, RON amplitudes were also larger in deviant compared to frequent trials. Processes generating internal forward models are largely intact in genetically determined CA, whereas updating of mental models and error awareness are disturbed in these patients.

Spinocerebellar Ataxia Type 28-Phenotypic and Molecular Characterization of a Family with Heterozygous and Compound-Heterozygous Mutations in AFG3L2.

While heterozygous mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia 28 (SCA28), homozygous mutations in the same gene can cause spastic ataxia 5 (SPAX5). AFG3L2 encodes a mitochondrial ATP-dependent metalloprotease. We here report a SCA28 patient with biallelic AFG3L2 variants and his heterozygous mother. The patient and his mother underwent a detailed neurological examination and fibroblast lines were established. The effect of the two missense variants on mitochondria was assessed by form factor analysis and quantification of mitochondrial proteins (TOMM70, complex V). The 39-year-old index patient presented with a slowly progressive cerebellar gait disorder for 19 years, bilateral ptosis, and dysarthria. A cranial MRI showed mild cerebellar atrophy. He carried two compound-heterozygous, rare, missense variants (c.1847A>G [p.Y616C], c.2167G>A [p.V723M]) in AFG3L2, while his mother was heterozygous for the first change that had previously been described in SPAX5. Altered mitochondrial morphology and interconnectivity, together with reduced protein levels of TOMM70 and complex V (ATPase), suggest mitochondrial structural defects in the patient's fibroblasts. No significant abnormalities were found in his mother's fibroblast cultures albeit all measurements were slightly below the control level. We here present a SCA28 patient with compound-heterozygous AFG3L2 variants and demonstrate mitochondrial abnormalities in skin fibroblast cultures from this patient. Thus, AFG3L2 variants should be considered in both slowly progressive ataxias and phenotypes with clinical features reminiscent of mitochondrial disease. Of note, ptosis was present in both mutation carriers and may serve as a red flag in the diagnosis of SCA28.