Multi-Center National Study of Genotype–Phenotype Correlation and Clinical Characteristics in Children and Young Adults with Friedreich’s Ataxia from Serbia

TL;DR

This study examines the genetic and clinical features of Friedreich’s ataxia in Serbian patients, revealing new comorbidities and partial genotype–phenotype correlations.

Contribution

The first genotype–phenotype analysis of Friedreich’s ataxia in Serbia, identifying novel comorbidities and partial correlations with GAA repeat lengths.

Findings

Hypertrophic cardiomyopathy was present in 73.3% of patients.

Larger GAA1 expansions were associated with extensor plantar responses.

Disease duration strongly correlated with neurological signs and loss of ambulation.

Abstract

Background/Objectives: Friedreich’s ataxia (FA) is a rare neurodegenerative disorder caused by GAA repeat expansions in the FXN gene. While well-studied in larger populations, data from Southeastern Europe are limited. This study aimed to characterize the clinical and genetic features of FA in a Serbian cohort and explore genotype–phenotype correlations. Methods: A multi-center, retrospective analysis was conducted on 30 genetically confirmed FA patients. Clinical assessments included neurological, cardiological, and metabolic evaluations. GAA repeat sizes were determined in 26 patients, and correlations with clinical features were analyzed. Results: The mean age at disease onset was 9.0 ± 3.0 years, with ataxia as the initial symptom in 80% of patients. Hypertrophic cardiomyopathy was present in 73.3%, and 43.3% of patients lost ambulation within 1.5 to 15 years after symptom onset. Two patients developed diabetes, and two were diagnosed with nephrotic syndrome. Genetic analysis revealed an average GAA1 repeat length of 805 and GAA2 of 1024 alleles. Larger GAA1 expansions were associated with extensor plantar responses, while longer GAA2 repeats correlated with impaired vibration sense. Disease duration was strongly linked to multiple neurological signs and loss of ambulation. No significant correlation was found between GAA repeat length and age at onset. Conclusions: This study provides the first genotype–phenotype analysis of FA in Serbia, confirming known patterns and revealing new comorbidities, such as nephrotic syndrome. GAA repeat length influences some clinical features but does not fully predict disease onset or progression, indicating the need for broader genetic and environmental studies.

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