Clinical and genetic analyses of a Swedish patient series diagnosed with ataxia.

Hereditary ataxia is a heterogeneous group of complex neurological disorders. Next-generation sequencing methods have become a great help in clinical diagnostics, but it may remain challenging to determine if a genetic variant is the cause of the patient's disease. We compiled a consecutive single-center series of 87 patients from 76 families with progressive ataxia of known or unknown etiology. We investigated them clinically and genetically using whole exome or whole genome sequencing. Test methods were selected depending on family history, clinical phenotype, and availability. Genetic results were interpreted based on the American College of Medical Genetics criteria. For high-suspicion variants of uncertain significance, renewed bioinformatical and clinical evaluation was performed to assess the level of pathogenicity. Thirty (39.5%) of the 76 families had received a genetic diagnosis at the end of our study. We present the predominant etiologies of hereditary ataxia in a Swedish patient series. In two families, we established a clinical diagnosis, although the genetic variant was classified as "of uncertain significance" only, and in an additional three families, results are pending. We found a pathogenic variant in one family, but we suspect that it does not explain the complete clinical picture. We conclude that correctly interpreting genetic variants in complex neurogenetic diseases requires genetics and clinical expertise. The neurologist's careful phenotyping remains essential to confirm or reject a diagnosis, also by reassessing clinical findings after a candidate genetic variant is suggested. Collaboration between neurology and clinical genetics and combining clinical and research approaches optimizes diagnostic yield.

Nationwide prevalence of primary dystonia, progressive ataxia and hereditary spastic paraplegia.

OBJECTIVE: To determine the nationwide prevalence of primary dystonia, ataxia and hereditary spastic paraplegia (HSP) in Sweden. METHODS: We extracted data on all patients who were registered in The National Patient Register (NPR) in Sweden (population 9.64 million) at least twice during five consecutive years with a diagnosis of primary dystonia, ataxia or HSP. We excluded patients with an additional diagnosis possibly indicating secondary causes, and determined the proportion of wrongly diagnosed patients at our own tertiary center by patient examination or chart review. We analyzed patients' age and disorder subtypes, geographical distribution of patients within Sweden and the country of birth of all patients. RESULTS: Nationwide, we identified 4239 patients (31.6% male) with a diagnosis of primary dystonia. Of 347 patients with dystonia at our center, 20.2% may have had a different final diagnosis. Extrapolation of this uncertainty rate to the national population resulted in a prevalence for primary dystonia of 35.1/100,000. There were 672 patients (49.6% male) with ataxia in NPR, and the diagnostic uncertainty rate among 81 patients in our center was 13.6% (prevalence 6.0/100,000). HSP was diagnosed in 235 patients nationwide (52.3% male, prevalence 2.4/100,000). Patients were distributed relatively evenly throughout the country. The proportions of patients with these diagnoses who were born outside of Sweden were lower (8.0-12.7%) than the proportion of all Swedish residents born abroad (15.9%). CONCLUSIONS: In this large, nationwide study, the prevalence of dystonia was high compared to previous studies, which partly may be explained by the high coverage of NPR.