Friedreich ataxia in Norway - an epidemiological, molecular and clinical study

Abstract

Background: Friedreich ataxia is an autosomal recessive hereditary spinocerebellar disorder, characterized by progressive limb and gait ataxia due to proprioceptive loss, often complicated by cardiomyopathy, diabetes and skeletal deformities. Friedreich ataxia is the most common hereditary ataxia, with a reported prevalence of 1:20 000 - 1:50 000 in Central Europe. Previous reports from south Norway have found a prevalence varying from 1:100 000 - 1:1 350 000; no studies are previously done in the rest of the country.

Methods: In this cross-sectional study, Friedreich ataxia patients were identified through colleagues in neurological, pediatric and genetic departments, hospital archives searches, patients' associations, and National Centre for Rare Disorders. All included patients, carriers and controls were investigated clinically and molecularly with genotype characterization including size determination of GAA repeat expansions and frataxin measurements. 1376 healthy blood donors were tested for GAA repeat expansion for carrier frequency analysis.

Results: Twenty-nine Friedreich ataxia patients were identified in Norway, of which 23 were ethnic Norwegian, corresponding to a prevalence of 1:176 000 and 1:191 000, respectively. The highest prevalence was seen in the north. Carrier frequency of 1:196 (95 % CI = [1:752-1:112]) was found. Homozygous GAA repeat expansions in the FXN gene were found in 27/29, while two patients were compound heterozygous with c.467 T < C, L157P and the deletion (g.120032_122808del) including exon 5a. Two additional patients were heterozygous for GAA repeat expansions only. Significant differences in the level of frataxin were found between the included patients (N = 27), carriers (N = 37) and controls (N = 27).

Conclusions: In this first thorough study of a complete national cohort of Friedreich ataxia patients, and first nation-wide study of Friedreich ataxia in Norway, the prevalence of Friedreich ataxia in Norway is lower than in Central Europe, but higher than in the last Norwegian report, and as expected from migration studies. A south-north prevalence gradient is present. Based on Hardy Weinberg's equilibrium, the carrier frequency of 1:196 is consistent with the observed prevalence. All genotypes, and typical and atypical phenotypes were present in the Norwegian population. The patients were phenotypically similar to European cohorts. Frataxin was useful in the diagnostic work-up of heterozygous symptomatic cases.

Fig. 1

Flowchart showing patient ascertainment and the Friedreich ataxia population in Norway

Fig. 2

Total and regional FRDA prevalence in Norway on 30.11.2014

Fig. 3

Frataxin levels in whole blood in FRDA patients, carriers and controls. The frataxin level is significantly different between the three groups and correlates with number of GAA1 repeats in FRDA patients and healthy carriers. The levels of frataxin were measured in blood from FRDA patients (N = 26), healthy carriers (N = 37) and healthy controls (N = 27). a The Tukey box plot shows pg frataxin per μg (mcg) total protein. The whiskers extends to a maximum of 1.5 x interquartile range (IQR) beyond the edge of the box (“Tukey’s inner fence”). Values outside these fences represent outliers and are marked as dots. b Linear regression analyses were performed to analyze the correlation between frataxin levels (pg/mcg) in blood and number of GAA1 repeats in FRDA patients (upper plot), number of GAA2 repeats in healthy carriers (middle plot) and number of GAA2 repeats in healthy controls. R² = coefficient of determination

Fig. 4

Frataxin amounts in percentage of average amounts in healthy controls in subgroups of carriers and patients. The graph displays the mean relative frataxin amounts for the indicated subgroups of carriers and patients; Healthy controls (N = 27), Healthy carriers (N = 37), pFRDA carrier = healthy carrier with heterozygous point mutation in the FXN gene (N = 1), delFRDA carrier = healthy carrier with heterozygous deletion in the FXN gene (N = 1), cFRDA = classic FRDA (N = 22), FARR = Friedreichs ataxia with Retained Reflexes (N = 2), pFRDA = compound heterozygous with point mutation (N = 1), delFRDA = compound heterozygous with deletion (N = 1), Carriers with symptoms (N = 2)