Frequency and Genetic Profile of Compound Heterozygous Friedreich's Ataxia Patients-the Brazilian Experience.

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia in Caucasian populations. It is caused by a homozygous GAA expansion in the first intron of the frataxin gene (FXN) (OMIM: 606829) in 96% of the affected individuals. The remaining patients have a GAA expansion in one allele and a point mutation in the other. Little is known about compound heterozygous patients outside Europe and North America. We have thus designed a study to determine the frequency and mutational profile of these patients in Brazil. To accomplish that, we recruited all patients with ataxia and at least one expanded GAA allele at FXN from 3 national reference centers. We identified those subjects with a single expansion and proceeded with further genetic testing (Sanger sequencing and CGH arrays) for those. There were 143 unrelated patients (128 families), five of which had a single expanded allele. We identified point mutations in three out of these five (3/128 = 2.34%). Two patients had the c.157delC variant, whereas one individual had the novel variant c.482+1G>T. These results indicate that FXN point mutations are rare, but exist in Brazilian patients with FRDA. This has obvious implications for diagnostic testing and genetic counseling.

Genetic epidemiology of familial ALS in Brazil.

Many genes associated with familial forms of the amyotrophic lateral sclerosis (fALS) have been identified in European and North American cohorts. However, little is known about the genetic bases of fALS in Latin America and Brazil, in particular. To address this question, we recruited 107 patients with fALS from 93 unrelated families from Southeastern, Southern, and Northeastern regions of the country. A 3-step diagnostic approach was used: 1) Triplet repeat primed polymerase chain reaction to search for C9orf72 expansions, then 2) fragment digestion to search for the c.166 C>T VAPB variant, and finally, 3) whole exome sequencing for those who tested negative. We identified the genetic cause for fALS in 70% of the families. VAPB and C9orf72 were the most frequent genes (30% and 22%, respectively), followed by SOD1, TARDBP, ANXA11, and FUS. Five novel variants in known ALS genes were found, including the SOD1 Val120Leu and ANXA11 Asp40Tyr, which were seen in 2 unrelated families each. In conclusion, VAPB and then C9orf72 are the genes most commonly related to fALS in Brazil.