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

Abstract

BackgroundFriedreich 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.MethodsIn 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.ResultsTwenty-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).ConclusionsIn 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0328-4) contains supplementary material, which is available to authorized users.

Essential tremor: the most common form of cerebellar degeneration?

“…For example, the prevalence of the autosomal dominant SCAs has been estimated to be 1 -9 cases per 100 000 people [8][9][10][11][12][13][14][15]. Autosomal recessive ataxias are similarly characterized by low prevalence; Friedreich's ataxia, the most common, has a prevalence of 0.5 -5/100,000 [13,16,17]. Acquired degenerative ataxias are similarly rare: multiple system atrophy (3.4 -4.3/100,000) [18,19], paraneoplastic cerebellar degeneration (1.2/100,000) [20], and ataxia with vitamin E deficiency (0.06/100,000) [21].…”

“…Among these, SCA2 and SCA3 are the most common subtypes worldwide; SCA1, SCA6, SCA7 and SCA8 often make up a relatively larger proportion of SCAs and the remainder tends to be rarer, although there is variation in prevalence from country to country [ 8 , 10 , 11 , 13 , 15 ]. Autosomal recessive ataxias are similarly characterized by a low prevalence, with Friedreich’s ataxia being the most common (prevalence = 0.5 – 5/100,000) [ 13 , 16 , 17 ]. Acquired degenerative ataxias are similarly rare – multiple system atrophy (3.4 – 4.3/100,000) [ 18 , 19 ], paraneoplastic cerebellar degeneration (1.2/100,000) [ 20 ], and ataxia with vitamin E deficiency (0.06/100,000) [ 21 ].…”

Progressive Ataxia with Elevated Alpha-Fetoprotein: Diagnostic Issues and Review of the Literature

“…32 In the context of ataxia with or without strabismus, polyneuropathy, and mild to moderate elevated AFP, it is reasonable to perform a targeted test for AOA2 as in the case we have described. Increasing accessibility, faster turnaround, and lower costs make either whole exome or genome sequencing reasonable options when AOA2 is hard to discern from its differential diagnosis.…”

Secondary Amenorrhea With Hypogonadotropic Hypogonadism Associated to a Cerebellar Ataxia: Diagnosis Contingencies.

“…Even though, estrogenic substitutive therapy will be proposed to our patient after the management of the mammary nodule, in order to substitute the gonadal axis, prevent her from osteoporosis, and eventually for its benefits on the ataxia. Specially as we ruled out the ataxia with Fridereich ataxia ,the most common hereditary ataxia .It is an autosomic recessive syndrome due in more than 96% of cases to an expansion of the repetition of GAA triplets inintron 1 of the FXN gene, causing the loss of function of a protein called frataxin [8,9,10,11,12]. In nearly 4% of cases, there is, in addition to expansion, a punctuel mutation [12,12].…”

“…Electromyogram (EMG) showing pure sensory neuropathy of the 4 limb. Serum Vitamin E was low 4, 7 mg/l (6,(8)(9)(10)(11)(12)(13)(14)(15) . Apo lipoproteins were normal.…”