Objective: To describe genotype-phenotype correlation in Indian FRDA patients.

Background: Friedreich’s Ataxia(FRDA), an early onset  rare autosomal recessive ataxia is caused by bi-allelic loss of function of  FXN(chr9q21.11) due to intronic (GAA)n tandem nucleotide repeat hyper-expansion (98% homozygous).

Method: A total of 160 genetically proven FRDA patients were clinically evaluated for neurological features, electrophysiological abnormalities and echocardiography based cardiac defects. The genotype confirmation for GAA repeats expansion and length estimation was done throught triplet repeat primed-PCR, and long-range PCR. The statistical analysis (Pearson correlation at p-value 0.05 significance) was done using SPSS(22.0).

Results: The observed mean(SD) age of the 160 patients(100Males:60Females) was 20.65(7.84) years, and mean(SD) age of onset;AO was 14.09±5.74 with disease duration of (DD) 6.45±4.57. The mean(SD) of GAA repeats lengths was 742.02(184.67) (range 120-1204) for the smaller allele (GAA1) and 964.05(186.66) (range 467-1800) for the larger allele (GAA2). Among neurological features, FRDA patients showed gait-ataxia(91.9%), tremor(28.75%), dysarthria(70.0%), extensor planter responses(79.40%), lower limb areflexia(79.40%), nystagmus(56.90%), slow saccades(27.50%), broken pursuit(35.60%), extrapyramidal sign (45.60%), decrease vibration sense(31.90%), pes cavus (48.10%), scoliosis(68.80%), dysphagia(5.60%), vision problem(2.50%), muscles cramp(8.80%), muscles twitching(1.90%) and hearing loss(1.3%). We observed blood glucose levels in diabetic range in 8.80% and cardiomyopathy in 31.90% patients and abnormal nerve conduction studies in 71.90% and cerebellar atrophy in MRI in 16.30% patients.
An inverse correlations of AO was observed more significantly with GAA1, r²=0.252 (p-<0.0003) than GAA2, r²=0.068  (p<0.02). Furthermore, GAA1 was shown to determine the presence of cerebellar atrophy (p<0.042), and extensor planter response (p<0.026), and GAA2 was shown to determine the occurrence of scoliosis (p<0.008).

Conclusion: This is the largest genotype and phenotype series on FRDA in Indian population. This study showed that GAA1 may affect the cerebellar atrophy and planter responses whereas GAA2, scoliosis apart from age and age at onset which is affected by both.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-correlation-with-the-genotype-of-friedreichs-ataxia-frda-patients-in-indian-population/