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

Kovacevic, Gordana; Todorovic, Slobodanka; Novakovic, Ivana; Dobricic, Valerija; Savic-Pavicevic, Dusanka; Milic Rasic, Vedrana; Svetel, Marina; Brkusanin, Milos; Vukomanovic, Vladislav; Vucinic, Dragana; Ostojic, Slavica; Putnik, Jovana; Kosac, Ana

doi:10.3390/biomedicines13112646

This is an early access version, the complete PDF, HTML, and XML versions will be available soon.

Open AccessArticle

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

by

Gordana Kovacevic

^1,2,*,

Slobodanka Todorovic

^2,3,

Ivana Novakovic

²,

Valerija Dobricic

^4,5,

Dusanka Savic-Pavicevic

⁶

,

Vedrana Milic Rasic

^2,3,

Marina Svetel

^2,4,

Milos Brkusanin

⁶,

Vladislav Vukomanovic

^2,7,

Dragana Vucinic

³,

Slavica Ostojic

^1,2

,

Jovana Putnik

^2,8 and

Ana Kosac

^2,3

¹

Neurology Department, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, 11070 Belgrade, Serbia

²

Faculty of Medicine, University of Belgrade, 11158 Belgrade, Serbia

³

Clinic of Neurology and Psychiatry for Children and Youth, University of Belgrade, 11158 Belgrade, Serbia

⁴

Neurology Clinic, University Clinical Center of Serbia, 11158 Belgrade, Serbia

⁵

Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, 23562 Lübeck, Germany

⁶

Center for Human Molecular Genetics, Faculty of Biology, University of Belgrade, 11158 Belgrade, Serbia

⁷

Cardiology Department, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, 11070 Belgrade, Serbia

⁸

Nephrology Department, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, 11070 Belgrade, Serbia

^*

Author to whom correspondence should be addressed.

Biomedicines 2025, 13(11), 2646; https://doi.org/10.3390/biomedicines13112646

Submission received: 9 September 2025 / Revised: 24 October 2025 / Accepted: 25 October 2025 / Published: 28 October 2025

(This article belongs to the Section Molecular Genetics and Genetic Diseases)

Download Review Reports Versions Notes

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–prospective 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.

Keywords: Friedreich’s ataxia; GAA repeat; genotype–phenotype correlation; cardiomyopathy; nephrotic syndrome

Share and Cite

MDPI and ACS Style

Kovacevic, G.; Todorovic, S.; Novakovic, I.; Dobricic, V.; Savic-Pavicevic, D.; Milic Rasic, V.; Svetel, M.; Brkusanin, M.; Vukomanovic, V.; Vucinic, D.; et al. Multi-Center National Study of Genotype–Phenotype Correlation and Clinical Characteristics in Children and Young Adults with Friedreich’s Ataxia from Serbia. Biomedicines 2025, 13, 2646. https://doi.org/10.3390/biomedicines13112646

AMA Style

Kovacevic G, Todorovic S, Novakovic I, Dobricic V, Savic-Pavicevic D, Milic Rasic V, Svetel M, Brkusanin M, Vukomanovic V, Vucinic D, et al. Multi-Center National Study of Genotype–Phenotype Correlation and Clinical Characteristics in Children and Young Adults with Friedreich’s Ataxia from Serbia. Biomedicines. 2025; 13(11):2646. https://doi.org/10.3390/biomedicines13112646

Chicago/Turabian Style

Kovacevic, Gordana, Slobodanka Todorovic, Ivana Novakovic, Valerija Dobricic, Dusanka Savic-Pavicevic, Vedrana Milic Rasic, Marina Svetel, Milos Brkusanin, Vladislav Vukomanovic, Dragana Vucinic, and et al. 2025. "Multi-Center National Study of Genotype–Phenotype Correlation and Clinical Characteristics in Children and Young Adults with Friedreich’s Ataxia from Serbia" Biomedicines 13, no. 11: 2646. https://doi.org/10.3390/biomedicines13112646

APA Style

Kovacevic, G., Todorovic, S., Novakovic, I., Dobricic, V., Savic-Pavicevic, D., Milic Rasic, V., Svetel, M., Brkusanin, M., Vukomanovic, V., Vucinic, D., Ostojic, S., Putnik, J., & Kosac, A. (2025). Multi-Center National Study of Genotype–Phenotype Correlation and Clinical Characteristics in Children and Young Adults with Friedreich’s Ataxia from Serbia. Biomedicines, 13(11), 2646. https://doi.org/10.3390/biomedicines13112646

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

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

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI