Delayed-onset Friedreich's ataxia revisited

Area of Science:

• Neurology
• Genetics
• Rare Diseases

Background:

• Friedreich's ataxia (FA) typically manifests before age 25.
• Late-onset FA (LOFA) and very-late-onset FA (VLOFA) are rare variants occurring after 25 and 40 years, respectively.
• This study compares clinical, functional, and molecular aspects of LOFA and VLOFA with typical-onset FA (TOFA).

Purpose of the Study:

• To compare the clinical, functional, and molecular characteristics of delayed-onset Friedreich's ataxia (DOFA) with typical-onset Friedreich's ataxia (TOFA).
• To investigate the relationship between GAA repeat expansions and age of onset in FA.
• To determine if LOFA and VLOFA represent distinct phenotypes or a continuum.

Main Methods:

• Phenotypic and genotypic comparison of 44 LOFA, 30 VLOFA, and 180 TOFA patients.
• Analysis of clinical symptoms, functional scores (Scale for the Assessment and Rating of Ataxia, Spinocerebellar Degeneration), and GAA repeat expansion sizes.
• Statistical analysis to correlate GAA expansion size with age at disease onset.

Main Results:

• DOFA patients (LOFA and VLOFA) exhibited less frequent dysarthria, absent reflexes, weakness, amyotrophy, scoliosis, and cardiomyopathy compared to TOFA.
• DOFA was associated with less severe functional disability, lower ataxia scores, and longer disease duration before wheelchair confinement.
• Both smaller and larger GAA expansions negatively correlated with age at onset, with the smaller expansion being a stronger predictor (62.9% variation).
• No significant differences were found between LOFA and VLOFA phenotypes.

Conclusions:

• Typical- and delayed-onset Friedreich's ataxia are distinct, highlighting the heterogeneity of FA.
• LOFA and VLOFA share clinical and molecular continuum, supporting their classification as "delayed-onset Friedreich's ataxia" (DOFA).
• FA should be considered in patients with atypical phenotypes, delayed onset (even after 60), or slow progression.