Characterization of the Interruptions of the GAA Expansion and Study of Their Influence on the Severity of Friedreich's Ataxia (INTREP-AF)

Characterization of the Interruptions of the GAA Expansion and Study of Their Influence on the Severity of Friedreich's Ataxia : INTREP-AF

Friedreich's ataxia (FA) is the most frequent recessive genetic ataxia with an estimated prevalence of 1/50 000. The first symptoms appear around the age of 10 years with a progressive course and the need for an armchair 10- 15 years after the first symptoms. More rarely the disease can present with a late onset (after the age of 25) with a picture characterized by spastic paraparesis and slower progression ("LOFA" for "Late Onset Friedreich Ataxia" or VLOFA for "Very Late Appearance of Friedreich's ataxia ").

AF is caused in 96% of cases by an expansion of GAAN triplets (N> 100 repeats) located in intron 1 of the FXN gene, present on the two alleles, and, in the rest of the cases, by an associated expansion a point mutation or a deletion in trans. During molecular diagnostics, it is not uncommon to find the presence of interruptions within the GAA expansion. This results in the absence and / or the shift of peak (s) within the chromatogram.

To date, only the partial correlation between the size of the expansion and the age of onset of Friedreich's ataxia has been established. In particular, very atypical forms of AF with a late onset (after the age of 25) are in particular explained by the low number of repetitions in the expansion, typically between 100 and 500 repetitions. However, the presence of an interruption could stabilize the size of the expansion and, therefore, be mainly associated with expansions of small sizes and therefore with a late onset of the disease.

The objective of this study is therefore to analyse and caracterize the presence and the type of interruptions of the GAA expansions in a group of patients with FA ; this data will be correlated with the age at onset of FA.

Study Overview

• Status: Completed
• Conditions: Friedreich Ataxia
• Intervention / Treatment: Other: Reuse of existing data from patients' medical records

• Study Type: Observational
• Enrollment (Actual): 120

Contacts and Locations

Study Locations

• France
  • Montpellier
    • Montpellier, Montpellier, France, 34295
      • UH Montpellier

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with Friedriech Ataxia genetically confirmed. .

Description

Inclusion criteria:

• Subjects with diagnosis of genetically confirmed Friedreich's Ataxia (AF) and :
• two expansions of GAAN triplets (> 100 repetitions or "premutation", corresponding to> 32 but <100 repetitions) located in intron 1 of the FXN gene present on the two alleles;
• symptomatic (SARA scale> 4);
• having signed a consent for the performance of genetic analyzes which also includes the authorization for the conduct of further studies for research purposes and the authorization for the collection, entry and computer processing of medical data, in all confidentiality. A newsletter on the principle of non-opposition will be sent.

Exclusion criteria:

• Patients with Friedreich's ataxia due to an expansion associated with a point mutation or a deletion in trans;
• Patients who, at the time of signing the genetic consent, objected to the use of their data for research purposes.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with Friedriech Ataxia genetically confirmed	Other: Reuse of existing data from patients' medical records; Reuse of existing data from patients' medical records

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interruptions and date at onset	Study the correlation between the presence and type of interruptions (location within the expansion, nucleotide sequence: "GAAA", "GAG", etc.) and the age of onset of Friedreich's ataxia.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical correlation	Estimate the interaction between the presence and type of interruption and the age of onset of the various functional impacts (walking, cardiac involvement).	18 months

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier
• Collaborators: Neurogenetic department, CHU Bordeaux; Genetic Department , CHU Montpellier-France; Neurology department, CHU La réunion
• Investigators: Principal Investigator: Cecilia Marelli, MD, University Hospitals of Montpellier

Publications and helpful links

General Publications

• Benkirane M, Marelli C, Choumert A, Goizet C, Patat O, Ewenczyk C, Anheim M, Megarbane A, Larrieu L, Charlin C, Ory-Magne F, Chaussenot A, Fradin M, Guissart C, Pointaux M, Cossee M, Vincent MC, Bergougnoux A, Hersent C, Bareil C, Roubertie A, Fluchere F, Renaud M, Kremer L, Tranchant C, Attarian S, Odent S, Laugel V, Walther-Louvier U, Desnous B, Bieth E, Husson I, Azulay JP; INTREP-AF consortium; Rivier F, Doray B, Durr A, Aouinti S, Molinari N, Koenig M. Type and position of repeat interruptions as determinants of disease severity and expansion size in Friedreich ataxia. Genet Med. 2025 Dec;27(12):101588. doi: 10.1016/j.gim.2025.101588. Epub 2025 Sep 23.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2020
• Primary Completion (Actual): March 30, 2024
• Study Completion (Actual): December 1, 2024

Study Registration Dates

• First Submitted: April 10, 2020
• First Submitted That Met QC Criteria: April 10, 2020
• First Posted (Actual): April 15, 2020

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Genetic; Neurology; Friedreich ataxia
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolic Diseases; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Spinal Cord Diseases; Mitochondrial Diseases; Cerebellar Diseases; Spinocerebellar Degenerations; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Friedreich Ataxia
• Other Study ID Numbers: RECHMPL20_0029

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: NC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No