Friedreich's ataxia: clinical and molecular study of 25 Brazilian cases

Abstract

Introduction: Friedreich's ataxia is a neurodegenerative disorder whose clinical diagnostic criteria for typical cases basically include: a) early age of onset (< 20 or 25 years), b) autosomal recessive inheritance, c) progressive ataxia of limbs and gait, and d) absence of lower limb tendon reflexes.Methods: We studied the frequency and the size of expanded GAA and their influence on neurologic findings, age at onset, and disease progression in 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia -19 typical and 6 atypical -using a long-range PCR test.Results: Abnormalities in cerebellar signs, in electrocardiography, and pes cavus occurred more frequently in typical cases; however, plantar response and speech were more frequently normal in this group when the both typical and atypical cases were compared. Homozygous GAA expansion repeats were detected in 17 cases (68%) -all typical cases. In 8 patients (32%) (6 atypical and 2 typical), no expansion was observed, ruling out the diagnosis of Friedreich's ataxia. In cases with GAA expansions, foot deformity, cardiac abnormalities, and some neurologic findings occurred more frequently; however, abnormalities in cranial nerves and in tomographic findings were detected less frequently than in patients without GAA expansions.Discussion: Molecular analysis was imperative for the diagnosis of Friedreich's ataxia, not only for typical cases but also for atypical ones. There was no genotype-phenotype correlation. Diagnosis based only on clinical findings is limited; however, it aids in better screening for suspected cases that should be tested. Evaluation for vitamin E deficiency is recommended, especially in cases without GAA expansion. DESCRIPTORS: Friedreich's ataxia. Trinucleotide expansion repeats. GAA expansion.Friedreich's ataxia (FA) (OMIM 277460) 23 , a neurodegenerative disorder, is the most frequent form of hereditary ataxia, with a prevalence of 1:50,000. Clinical diagnostic criteria for typical cases basically include: a) early age of onset < 20 16 or 25 years 17 , b) autosomal recessive inheritance, c) progressive ataxia of limbs and gait, and d) absence of lower limb tendon reflexes. Chamberlain et al. (1988) 8 mapped the Friedreich's ataxia gene to chromosome 9, which was subsequently confirmed 15 . Later, recombinant events 3 allowed the successive narrowing of the candidate region 7,10,22,26 . Campuzano et al. (1996) 6 detected in about 96% of Friedreich's ataxia patients an expanded GAA (guanine, adenine, and adenine) trinucleotide repeat in intron 1 of the gene X25 (with 7 exons-1 to 5a, 5b, and 6-spanning 95 kb of genomic DNA) that encodes a 210-amino acid protein, frataxin, whose function is unknown. Absence of deep tendon reflexes in lower limbs has been included in the diagnostic criteria both by the Geoffroy et al. (1976) and Harding (1981) 16,17 ; however, clinical variability has been reported 11,14 , especially related to the 144 REV. HOSP. CLÍN. FAC. MED. S. PAULO 56(5): [143][144][145][146][147][148] 2001 SEPTEMBER-OCT...

Clinical heterogeneity of recessive ataxia in the Mexican population

“…This also contrasts with another Brazilian study in which 17 of 19 patients with typical FRDA were homozygotic for GAA expansions. 19 In our cohort, Harding's diagnostic criteria for FRDA showed poor sensitivity (0.714 (95% confidence interval (CI) 0.454 to 0.883)) and positive predictive value (0.385 (95% CI 0.224 to 0.575)), but good specificity (0.867 (95% CI 0.794 to 0.916)) and negative predictive value (0.963 (95% CI 0.909 to 0.986)). This indicates that the use of clinical diagnostic criteria in Mexican Mestizo patients is useful for ruling out FRDA rather than for detecting true cases.…”

Otoneurological Abnormalities in Patients with Friedreich's Ataxia

“…[5][6][7] Other main problems associated to the condition are: nystagmus, optic atrophy, hearing loss (which may be present), atrophy in hands and distal lower limbs, scoliosis, pes cavus, and claw toes. [2][3][4][5][6][7] Diabetes is present in 10% of cases and cardiomyopathy occurs in approximately two-thirds of patients, making the latter the leading cause of death. [7][8][9] There are significant variations in the average duration of the disease, from the onset of symptoms until death, which tends to occur around the fourth decade of life.…”

“…[7][8][9] There are significant variations in the average duration of the disease, from the onset of symptoms until death, which tends to occur around the fourth decade of life. 5,6,8,10 The diagnosis of FA is performed by means of clinical and genetic data.…”

Otoneurological findings prevalent in hereditary ataxias

“…oxidative stress 6,9,10 . The first symptoms are usually observed in childhood or the early teen years; however, in some cases the diagnosis can be made before two or after 20 years of age.…”

“…The main features of the disease are: ataxia (impaired coordination) that initially affects the lower limbs and then the upper, absence of tendon reflexes and weakness in the lower limbs, dysarthria, loss of distal deep sensation, and bilateral Babinski sign. Nerve conduction studies show sensory axonal neuropathy 9,11 . Other features associated with this medical condition are: nystagmus, optic atrophy, hearing loss, atrophy in the hands and distal lower limbs, scoliosis, pes cavus, and hammer toes 6,11 .…”