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

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

Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia

<div><p>Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited <i>KIF1A</i> variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in <i>SACS</i> in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.</p></div

Pedigree structures of families with <i>KIF1A</i> variants.

<p>(a) Pedigree structure of family HCT-024 (III-7) with a c.80T>C, p.(Ile27Thr) variant in <i>KIF1A</i>. The filled symbols indicate affected individuals. The striped symbol indicates an individual that was initially classified as a non-affected individual, but after clinical re-examination was also found to be possibly affected. (b) Pedigree structure of family of HCT-026 (IV-6) with a c.22G>A, p.(Val8Met) variant. The symbols with a question mark are not confirmed regarding the phenotype. The diamond shaped symbols indicate masked gender. A line crossing a symbol represents a deceased individual. Probands are labelled with ‘P’.</p

Clinical flowchart.

<p>The figure explains the selection of probands from the clinicogenetic database, and the resulting total number of molecular diagnoses. VUS: variants of uncertain significance. * Indicates selection criteria of 105 probands: 1) Verified family history; 2) Completed thorough investigations; 3) Availability of probands; 4) Sporadic cases considered to be HSP or HA, fulfilling 2) and 3).</p

Clinical characteristics of the 105 probands included in the study.

<p>Clinical characteristics of the 105 probands included in the study.</p

Pedigree structure and MRI scans of a family with <i>SACS</i> variants.

<p>(a) Pedigree structure of family HCT-106 (V-3) with a c.12688G>A, p.(Gly4230Ser) and c.12661C>G, p.(Leu4221Val) variants in <i>SACS</i>. A consanguineous marriage between individuals IV-2 and III-4 is indicated by a double line. Cerebral MRIs of HCT-106 at disease duration of 28 years in (b) FLAIR sequence in midline sagittal plane, (c) FLAIR sequence in coronal plane at the level of dorsal aspect of cerebellum, (d) FLAIR sequence in transversal plane at the level of the middle cerebellar peduncles, and (e) T2 sequence in transversal plane at the level of the superior cerebellar peduncles, showing atrophy of the cerebellar hemispheres and vermis with widening of fissures and folia.</p

List of variants of uncertain significance.

<p>List of variants of uncertain significance.</p

Summary of the clinical features of four SPG 7 patients.

<p>Summary of the clinical features of four SPG 7 patients.</p

Immunohistochemistry in serial sections of the muscle of patient AIV-5.

<p>Immunohistochemistry for complex I (A), complex II (B), complex III (C) and COX/SDH histochemistry (D) in serial sections of the muscle of patient AIV-5. There are complex I, III and IV deficient fibres, but complex I deficiency is most pronounced. Arrows mark serial sections of the same muscle fibers stained for different complexes.</p