ABSTRACT
BACKGROUND: Ataxia with oculomotor apraxia (AOA) is characterized by early-onset cerebellar ataxia associated with oculomotor apraxia. AOA1, AOA2, AOA3, and AOA4 subtypes may present pathogenic variants in APTX, SETX, PIK3R5, and PNKP genes, respectively. Mutations in XRCC1 have been found to cause autosomal recessive spinocerebellar ataxia-26 (SCAR26) now considered AOA5. OBJECTIVES: To examine a cohort of Brazilians with autosomal recessive cerebellar ataxia plus oculomotor apraxia and determine the frequencies of AOA subtypes through genetic investigation. METHODS: We evaluated clinical, biomarkers, electrophysiological, and radiological findings of 52 patients with AOA phenotype and performed a genetic panel including APTX, SETX, PIK3R5, PNKP, and XRCC1. RESULTS: We found pathogenic variants in SETX (15 patients), PNKP (12), and APTX (5). No mutations in PIK3R5 or XRCC1 were identified. CONCLUSIONS: AOA2 and AOA4 were the most common forms of AOA in Brazil. Mutations in PIK3R5 and XRCC1 were not part of this genetic spectrum. © 2022 International Parkinson and Movement Disorder Society.
Subject(s)
Apraxias , Cerebellar Ataxia , Apraxias/congenital , Apraxias/genetics , Ataxia/genetics , Brazil , Cerebellar Ataxia/complications , Cerebellar Ataxia/genetics , Cogan Syndrome , DNA Helicases/genetics , DNA Repair Enzymes/genetics , Humans , Multifunctional Enzymes/genetics , Mutation/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics , RNA Helicases/genetics , X-ray Repair Cross Complementing Protein 1/geneticsABSTRACT
We present the case of a 68-year-old woman who developed progressive visuospatial deficits in a period of 18 months, leading to the loss of her independence for activities of daily living. After examination, she showed signs of Balint syndrome with optic ataxia, oculomotor apraxia, and simultanagnosia without visual acuity impairment. After brain imaging showing severe bilateral parieto-occipital association cortex atrophy, a diagnosis of posterior cortical atrophy was made according to the 2017 International Consortium's criteria.
Subject(s)
Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Aged , Apraxias/congenital , Apraxias/diagnostic imaging , Apraxias/etiology , Apraxias/pathology , Ataxia/etiology , Atrophy , Brain/diagnostic imaging , Brain/pathology , Cogan Syndrome/diagnostic imaging , Cogan Syndrome/pathology , Female , Humans , Occipital Lobe/pathology , Parietal Lobe/pathology , Vision Disorders/diagnostic imaging , Vision Disorders/etiologyABSTRACT
Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive cerebellar ataxia associated with mutations in SETX, which encodes the senataxin protein, a DNA/RNA helicase. We describe the clinical phenotype and molecular characterization of a Colombian AOA2 patient who is compound heterozygous for a c.994 C>T (p.R332W) missense mutation in exon 7 and a c.6848_6851delCAGA (p.T2283KfsX32) frameshift deletion in SETX exon 21. Immunocytochemistry of patient-derived fibroblasts revealed a normal cellular distribution of the senataxin protein, suggesting that these mutations do not lead to loss or mis-localization of the protein, but rather that aberrant function of senataxin underlies the disease pathogenesis. Furthermore, we used the alkaline comet assay to demonstrate that patient-derived fibroblast cells exhibit an increased susceptibility to oxidative DNA damage. This assay provides a novel and additional means to establish pathogenicity of SETX mutations.