Atypical Features in a Large Turkish Family Affected with Friedreich Ataxia

Here, we describe the clinical features of several members of the same family diagnosed with Friedreich ataxia (FRDA) and cerebral lesions, demyelinating neuropathy, and late-age onset without a significant cardiac involvement and presenting with similar symptoms, although genetic testing was negative for the GAA repeat expansion in one patient of the family. The GAA repeat expansion in the frataxin gene was shown in all of the family members except in a young female patient. MRI revealed arachnoid cysts in two patients; MRI was consistent with both cavum septum pellucidum-cavum vergae and nodular signal intensity increase in one patient. EMG showed demyelinating sensorimotor polyneuropathy in another patient. The GAA expansion-negative 11-year-old female patient had mental-motor retardation, epilepsy, and ataxia. None of the patients had significant cardiac symptoms. Description of FRDA families with different ethnic backgrounds may assist in identifying possible phenotypic and genetic features of the disease. Furthermore, the genetic heterogeneity observed in this family draws attention to the difficulty of genetic counseling in an inbred population and to the need for genotyping all affected members before delivering comprehensive genetic counseling.

Molecular Diagnosis of Friedreich Ataxia Using Analysis of GAA Repeats and FXN Gene Exons in Population from Western India

The diagnosis of Friedreich ataxia is based on the clinical symptoms and GAA repeats expansions. In our experience, checking FXN gene exons for mutations along with GAA repeat analysis may give better clue for its diagnosis. In the present study, total 49 suspected Friedreich ataxia patients were analyzed for GAA repeat expansion. Eleven patients have normal number of GAA repeats, thereby termed as FRDA negative patients. Thirty-eight patients showed no amplification using GAA repeat analysis. Since no conclusion was possible based on these results, these patients were designated as uninformative. We have analyzed 5 exons of the FXN gene in FRDA negative and uninformative patients to check for possible mutations. It was observed that there were no mutations found in any of FRDA negative and most uninformative patients. We further used long range PCR to check for deletion of exon 5a. It was found that 18 patients showed expression for exon 5a PCR but none in long range PCR. Five patients showed no expression for exon 5a PCR as well as long range PCR indicating that these 5 patients may be positive FRDA patients. These findings need to be correlated with clinical history of these patients for confirmation.

Childhood Ataxia

Childhood ataxia is characterized by impaired balance and coordination primarily because of cerebellar dysfunction. Friedreich ataxia, a form of childhood ataxia, is the most common multisystem autosomal recessive disease. Most of these patients are homozygous for the GAA repeat expansion located on the first intron of the frataxin gene on chromosome 9. Mutations in the frataxin gene impair mitochondrial function, increase reactive oxygen species, and trigger redistribution of iron in the mitochondria and cytosol. Targeted therapies for Friedreich ataxia are undergoing testing. In addition, a centralized database, patient registry, and natural history study have been launched to support clinical trials in Friedreich ataxia. The 2011 Neurobiology of Disease in Children symposium, held in conjunction with the 40th annual Child Neurology Society meeting, aimed to (1) describe clinical features surrounding Friedreich ataxia, including cardiomyopathy and genetics; (2) discuss recent advances in the understanding of the pathogenesis of Friedreich ataxia and developments of clinical trials; (3) review new investigations of characteristic symptoms; and (4) establish clinical and biochemical overlaps in neurodegenerative diseases and possible directions for future basic, translational, and clinical studies.