From the Guidelines
Friedreich's ataxia is a rare genetic neurodegenerative disorder characterized by progressive damage to the nervous system resulting in movement problems, caused by mutations in the FXN gene, leading to reduced production of frataxin protein essential for proper mitochondrial function. The disorder arises from a triplet repeat expansion mutation in the first intron of the gene encoding frataxin (FXN), and its prevalence is approximately 1 in 50,000, with a carrier rate of 1 in 60 to 1 in 100 1. Symptoms typically begin between ages 5-15 and include progressive gait and limb ataxia, loss of coordination, muscle weakness, speech problems, scoliosis, foot deformities, and heart complications including cardiomyopathy.
Key Characteristics
- Inherited in an autosomal recessive manner
- Caused by a triplet repeat expansion mutation in the FXN gene
- Prevalence of approximately 1 in 50,000
- Carrier rate of 1 in 60 to 1 in 100
- Symptoms begin between ages 5-15
- Includes progressive gait and limb ataxia, loss of coordination, muscle weakness, speech problems, scoliosis, foot deformities, and heart complications
Pathophysiology
The normal size for the GAA repeat is ≤30 copies, and affected individuals typically have >70 triplets on each copy of this gene, leading to mitochondrial dysfunction and severe oxidative stress despite normal levels of iron in blood 1. Frataxin plays an essential role in the synthesis of Fe-S (iron-sulfur) cluster proteins involved in the regulation of mitochondrial iron content.
Clinical Features
Cardiac disease is the most life-threatening manifestation of Friedreich's ataxia, with additional systemic features including progressive cerebellar dysfunction, ataxia, scoliosis, diabetes mellitus, impaired speech, and loss of vision and hearing 1. The severity of most phenotypic features of Friedreich's ataxia is variable, and the spectrum of phenotypic features fits best with a mitochondrial disorder.
Management
Currently, there is no cure for Friedreich's ataxia, but treatment focuses on managing symptoms and complications, including physical therapy to maintain mobility and function, occupational therapy to assist with daily activities, cardiac medications for heart issues, and scoliosis treatment which might require bracing or surgery 1.
From the Research
Definition and Characteristics of Friedreich's Ataxia
- Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia worldwide 2
- It is characterized by a combination of neurological involvement (ataxia and neuropathy), cardiomyopathy, skeletal abnormalities, and glucose metabolism disturbances 2
- The disease is caused by expanded guanine-adenine-adenine (GAA) triplet repeats in the first intron of the frataxin gene (FXN), resulting in reduction of messenger RNA and protein levels of frataxin in different tissues 2, 3
Clinical Features and Diagnosis
- FRDA patients develop cardiomyopathy, scoliosis, diabetes, and other manifestations 4
- The phenotype of FRDA is unique, giving rise to specific loss of neuronal pathways, a unique form of cardiomyopathy with early hypertrophy and later fibrosis, and diabetes incorporating components of both type I and type II disease 4
- DNA analysis is the hallmark for the diagnosis of FRDA 2
Treatment and Management
- There is no specific treatment to stop the disease progression in FRDA patients 2
- Therapeutic approaches intend to improve mitochondrial functioning and to increase FXN expression 2
- Idebenone, a synthetic analogue of coenzyme Q, is a powerful antioxidant that has been administered to FRDA patients, demonstrating a positive effect on cardiac hypertrophy 5
- Occupational therapy (OT) and neuromotor rehabilitation may contribute to recover common abilities of FA patients, representing the correct approach to the management of the disease 6