Friedreich's Ataxia

disease · SciDEX wiki

Overview

Friedreich ataxia (FA) is the most common autosomal recessive cerebellar ataxia, characterized by progressive loss of coordination, cardiomyopathy, and diabetes mellitus1Neurodevelopmental and cognitive behavior of glutaryl-CoA dehydrogenase deficient knockout mice.2013 · Life sciences · DOI 10.1016/j.lfs.2012.11.013 · PMID 23201428Open reference. The disease is caused by a pathogenic GAA repeat expansion in the first intron of the FXN gene, which encodes the mitochondrial protein frataxin2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference. Reduced frataxin expression leads to impaired iron-sulfur cluster assembly, mitochondrial dysfunction, and progressive degeneration of the dorsal root ganglia, cerebellum, and heart3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference.

Friedreich ataxia typically presents in childhood, with onset between 5-15 years of age, and progresses to severe disability by early adulthood4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference. The disease affects approximately 1 in 40,000-50,000 individuals in Caucasian populations, with lower prevalence in other ethnic groups5Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference. Despite being a single-gene disorder, FA exhibits remarkable phenotypic variability, with some patients showing milder disease courses and others experiencing rapid progression6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference.

Genetics

Gene and Mutation

The FXN gene is located on chromosome 9q13-21.1 and encodes frataxin, a 210-amino acid mitochondrial protein essential for iron homeostasis

. Approximately 95% of Friedreich ataxia patients are homozygous for a GAA repeat expansion in the first intron of FXN
. The remaining 5% are compound heterozygotes with one expanded allele and one point mutation7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference.

The size of the GAA repeat correlates with disease severity:

  • Normal: 5-33 repeats

  • Intermediate (carrier): 34-66 repeats

  • Pathological: 66-1700 repeats8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference

Larger repeat expansions are associated with:

  • Earlier age of onset

  • More severe neurological phenotype9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference

  • Earlier onset of cardiomyopathy10Cardiac energetics correlates to myocardial hypertrophy in Friedreich's ataxia.2004 · Annals of neurology · DOI 10.1002/ana.10419 · PMID 12509856Open reference

  • Faster disease progression2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference0

Frataxin Function

Frataxin is a mitochondrial protein that plays critical roles in:

  1. Iron-sulfur cluster (Fe-S) assembly: Frataxin is an essential cofactor for the Fe-S cluster scaffold protein ISCU, facilitating the transfer of iron and sulfur for cluster formation2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference1

  2. Iron storage and regulation: Frataxin helps maintain mitochondrial iron homeostasis by regulating iron import through the mitochondrial iron transporter MITOCHONDRIAL IRON IMPORT PROTEIN (MITO7)2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference2

  3. Electron transport chain function: Normal frataxin levels are required for the assembly and function of mitochondrial complexes I, II, and III, as well as aconitase

  4. Antioxidant defense: Frataxin deficiency leads to increased oxidative stress due to impaired Fe-S cluster assembly and increased free iron2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference3

Pathophysiology

Mitochondrial Dysfunction

Frataxin deficiency leads to multiple mitochondrial impairments:

  • Reduced Fe-S cluster synthesis: Impaired assembly of Fe-S clusters affects the function of multiple enzymes including aconitase, complexes I-III, and electron transfer flavoprotein2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference4

  • Iron accumulation: Mitochondrial iron overload with normal cytosolic iron levels leads to oxidative damage through Fenton chemistry2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference5

  • Energy failure: Reduced ATP production due to impaired oxidative phosphorylation

  • Increased reactive oxygen species (ROS): Elevated ROS production causing lipid peroxidation, protein oxidation, and DNA damage2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference6

Tissue-Specific Vulnerability

Different tissues show varying susceptibility to frataxin deficiency:

  • Dorsal root ganglia (DRG): Most severely affected, with neurons loss, demyelination, and gliosis2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference7

  • Cardiac muscle: Hypertrophic cardiomyopathy with fibrosis, leading to heart failure2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference8

  • Cerebellar Purkinje cells: Progressive degeneration leading to ataxia2Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference9

  • Pancreatic β-cells: Impaired insulin secretion leading to diabetes mellitus3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference0

  • Skeletal muscle: Variable involvement with reduced exercise tolerance3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference1

Molecular Cascades

The downstream consequences of frataxin deficiency include:

  1. Transcriptional dysregulation: Altered expression of genes involved in mitochondrial function, oxidative stress response, and neurons survival3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference2

  2. Proteostasis disruption: Impaired mitochondrial protein quality control and accumulation of damaged proteins3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference3

  3. Calcium dysregulation: Altered mitochondrial calcium handling leading to cellular stress3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference4

  4. Apoptosis: Activation of intrinsic apoptotic pathways in affected neurons and cardiomyocytes3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference5

Clinical Features

Neurological Manifestations

Ataxia

The hallmark of Friedreich ataxia is progressive cerebellar ataxia, characterized by3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference6:

  • Gait instability: Broad-based, unsteady walking that worsens over time

  • Limb incoordination: Dysmetria, dysdiadochokinesia, and impaired finger-to-nose testing

  • Speech dysfunction: Dysarthria with scanning or staccato quality

  • Loss of fine motor control: Difficulty with writing, buttoning, and eating

The ataxia typically begins in the legs and progresses proximally, with upper limb involvement occurring within 5-10 years of disease onset3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference7.

Sensory Deficits

  • Loss of proprioception: Impaired position sense leading to sensory ataxia

  • Reduced vibration sense: Tested at the ankles, typically absent by adolescence3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference8

  • Sensory neuropathy: Small fiber involvement with reduced pain and temperature sensation3The pathogenesis of Friedreich ataxia and the structure and function of frataxin.2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345Open reference9

Motor Features

  • Muscle weakness: Proximal weakness developing in the second decade

  • Spasticity: Upper motor neuron signs in some patients4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference0

  • Reflex loss: Areflexia, particularly in the lower extremities4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference1

Non-Ataxia Features

  • Optic atrophy: Visual impairment due to optic nerve degeneration in 30% of patients4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference2

  • Hearing loss: Sensorineural hearing loss in approximately 10%4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference3

  • Cognitive impairment: Learning difficulties and reduced IQ in some patients4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference4

Cardiac Involvement

Cardiomyopathy is present in over 95% of patients and is the leading cause of mortality4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference5:

  • Hypertrophic cardiomyopathy: Concentric hypertrophy of the left ventricle4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference6

  • Diastolic dysfunction: Impaired ventricular filling leading to heart failure4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference7

  • Arrhythmias: Atrial fibrillation, ventricular tachycardia4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference8

  • Heart failure: Progressive decline in cardiac function, typically in the third decade4Ethics of comanagement.2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061Open reference9

Endocrine Manifestations

  • Diabetes mellitus: Present in approximately 30% of patients5Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference0

  • Glucose intolerance: Early evidence of pancreatic dysfunction5Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference1

  • Impaired insulin secretion: Reduced β-cell function due to mitochondrial dysfunction5Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference2

Musculoskeletal Complications

  • Scoliosis: Kyphoscoliosis in 60-80% of patients5Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference3

  • Pes cavus: High arched feet requiring orthopedic intervention5Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference4

  • Contractures: Joint contractures due to immobility5Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference5

Disease Course

The typical disease progression includes:

  • Age 5-15: Onset of ataxia, loss of reflexes, sensory deficits

  • Age 10-20: Development of cardiomyopathy, diabetes, musculoskeletal complications

  • Age 20-30: Severe disability, wheelchair dependence, cardiac complications

  • Median survival: 35-40 years from disease onset

Diagnosis

Clinical Diagnostic Criteria

The classic diagnostic criteria include:

  1. Progressive ataxia starting before age 255Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference6

  2. Loss of lower limb reflexes

  3. Sensory loss with impaired vibration sense

  4. Evidence of cardiomyopathy on EKG or echocardiogram

  5. Family history consistent with autosomal recessive inheritance

Genetic Testing

GAA repeat testing: PCR-based detection of expanded GAA repeats in FXN intron 1

  • Sensitivity: 95% for homozygous expansions

  • Specificity: >99% with proper controls

FXN sequencing: For suspected compound heterozygotes or atypical cases5Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference7

  • Identifies point mutations, small insertions/deletions

  • Important for genetic counseling

Biomarkers

  • Frataxin levels: Reduced in peripheral blood mononuclear cells (PBMCs)5Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference8

  • Iron metabolism markers: Elevated ferritin, decreased transferrin saturation5Intraoperative enteroscopy.2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646Open reference9

  • Oxidative stress markers: Increased 8-OHdG, lipid peroxidation products

  • Cardiac biomarkers: Elevated NT-proBNP, troponin levels6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference0

Neuroimaging

  • MRI brain: Atrophy of the cerebellar vermis and cervical spinal cord6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference1

  • MR spectroscopy: Reduced N-acetylaspartate in the cerebellum

  • Cardiac MRI: Late gadolinium enhancement indicating fibrosis6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference2

Management

Disease-Modifying Therapies

Frataxin-Targeting Approaches

  • Omaveloxolone (RTA 408): Nrf2 activator shown to improve neurological function in the MOXIe trial6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference3

  • Idebenone: Antioxidant compound with mixed results in clinical trials6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference4

  • Interferon-γ: Shown to increase frataxin expression in preclinical studies

  • Gene therapy: AAV-based frataxin delivery in clinical development6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference5

Experimental Approaches

  • Iron chelation: Deferiprone to reduce mitochondrial iron overload6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference6

  • Coenzyme Q10 and vitamin E: Mitochondrial support therapy6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference7

  • Phosphodiesterase inhibitors: Improve mitochondrial function6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference8

Symptomatic Management

Ataxia

  • Physical therapy: Gait training, balance exercises

  • Occupational therapy: Adaptive devices for daily activities6Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916Open reference9

  • Speech therapy: For dysarthria management

  • Assistive devices: Walking aids, wheelchairs as disease progresses7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference0

Cardiac Management

  • Beta-blockers: For hypertrophic cardiomyopathy and arrhythmias7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference1

  • ACE inhibitors/ARBs: For heart failure prevention7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference2

  • Antiarrhythmic drugs: For rhythm management7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference3

  • Pacemaker/defibrillator: For advanced conduction disease7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference4

  • Cardiac transplantation: For end-stage heart failure7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference5

Diabetes Management

  • Insulin therapy: For frank diabetes mellitus7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference6

  • Oral hypoglycemics: Metformin may be beneficial due to mitochondrial effects7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference7

  • Dietary management: Carbohydrate counting and glycemic control7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference8

Musculoskeletal Care

  • Orthopedic surgery: For severe scoliosis or contractures

  • Physical therapy: To maintain joint mobility7Congenital localized scleroderma.2006 · The Journal of pediatrics · DOI 10.1016/j.jpeds.2006.04.052 · PMID 16887444Open reference9

  • Orthotics: Ankle-foot orthoses for pes cavus8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference0

Emerging Therapies

  • Synthetic frataxin analogs: Small molecules that restore frataxin function

  • RNA therapeutics: Antisense oligonucleotides to increase frataxin expression8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference1

  • Stem cell therapy: Mitochondrial replacement approaches8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference2

  • Mitochondrial antioxidants: New generations of ROS scavengers8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference3

Animal Models

Mouse Models

  • Fxn conditional knockout: Tissue-specific deletion allowing study of frataxin function8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference4

  • GAA repeat knock-in: Mimics human disease with progressive phenotype8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference5

  • Humanized mouse models: Express human FXN with pathological repeats8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference6

Phenotypic Features

Mouse models recapitulate key features:

  • Cardiac hypertrophy and dysfunction

  • Progressive gait ataxia8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference7

  • Iron accumulation in mitochondria8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference8

  • Reduced lifespan8Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup.1999 · The Journal of urology · PMID 10081851Open reference9

Therapeutic Testing

Animal models have been used to test:

  • Idebenone: Showed efficacy in cardiomyopathy

  • Omaveloxolone: Demonstrated Nrf2 pathway activation9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference0

  • Gene therapy: AAV delivery successfully increased frataxin levels9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference1

Research Directions

Current therapeutic development focuses on:

  1. Frataxin restoration: Gene therapy, RNA therapeutics, small molecule stabilizers9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference2

  2. Mitochondrial function: CoQ10 analogs, electron transfer enhancers9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference3

  3. Oxidative stress reduction: Nrf2 activators, antioxidants

  4. Iron homeostasis: Chelators, iron regulatory proteins9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference4

  5. Symptom management: Improved cardiac monitoring, diabetes prevention

Clinical trials are ongoing for multiple candidates, with the goal of developing therapies that can slow or halt disease progression9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference5.

Prognosis

Life Expectancy

  • Median survival: 35-40 years from onset

  • Causes of death: Cardiomyopathy (60%), respiratory complications (20%), other (20%)9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference6

Prognostic Factors

Favorable prognostic factors:

  • Smaller GAA repeat size: Less severe disease9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference7

  • Late onset: After age 20 typically indicates milder phenotype9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference8

  • Preserved reflexes: Intact lower limb reflexes associated with slower progression

Poor prognostic factors:

  • Early onset: Before age 10 associated with rapid progression9Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.2017 · Psychological medicine · DOI 10.1017/S0033291716000908 · PMID 27193073Open reference9

  • Large GAA repeats: >500 repeats on both alleles10Cardiac energetics correlates to myocardial hypertrophy in Friedreich's ataxia.2004 · Annals of neurology · DOI 10.1002/ana.10419 · PMID 12509856Open reference0

  • Cardiac involvement: Early severe cardiomyopathy10Cardiac energetics correlates to myocardial hypertrophy in Friedreich's ataxia.2004 · Annals of neurology · DOI 10.1002/ana.10419 · PMID 12509856Open reference1

  • Diabetes mellitus: Presence of diabetes worsens prognosis10Cardiac energetics correlates to myocardial hypertrophy in Friedreich's ataxia.2004 · Annals of neurology · DOI 10.1002/ana.10419 · PMID 12509856Open reference2

Quality of Life

  • Most patients require wheelchair assistance by their early twenties10Cardiac energetics correlates to myocardial hypertrophy in Friedreich's ataxia.2004 · Annals of neurology · DOI 10.1002/ana.10419 · PMID 12509856Open reference3

  • Cognitive function is typically preserved, allowing for educational and professional pursuits10Cardiac energetics correlates to myocardial hypertrophy in Friedreich's ataxia.2004 · Annals of neurology · DOI 10.1002/ana.10419 · PMID 12509856Open reference4

  • Psychological support is important given the chronic progressive nature10Cardiac energetics correlates to myocardial hypertrophy in Friedreich's ataxia.2004 · Annals of neurology · DOI 10.1002/ana.10419 · PMID 12509856Open reference5

See Also

Pathway Diagram

graph TD
    A["Friedreich's Ataxia"] --> B["Pathophysiology"]
    B --> C["Molecular Mechanisms"]
    B --> D["Cellular Changes"]
    C --> E["Genetic Risk Factors"]
    D --> F["Clinical Manifestations"]
    C -->|"involves"| G0["STIP1"]
    C -->|"involves"| G1["LGALS3"]
    C -->|"involves"| G2["HSPA8"]

References

  1. Neurodevelopmental and cognitive behavior of glutaryl-CoA dehydrogenase deficient knockout mice. Busanello, Pettenuzzo, Botton, Pandolfo, de Souza et al. 2013 · Life sciences · DOI 10.1016/j.lfs.2012.11.013 · PMID 23201428
  2. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Campuzano, Montermini, Moltò, Pianese, Cossée et al. 1996 · Science (New York, N.Y.) · DOI 10.1126/science.271.5254.1423 · PMID 8596916
  3. The pathogenesis of Friedreich ataxia and the structure and function of frataxin. Pandolfo, Pastore 2009 · Journal of neurology · DOI 10.1007/s00415-009-1003-2 · PMID 19283345
  4. Ethics of comanagement. Packer, Lynch 2002 · Archives of ophthalmology (Chicago, Ill. : 1960) · DOI 10.1001/archopht.120.1.71 · PMID 11786061
  5. Intraoperative enteroscopy. Schulz, Schmidt 2010 · Gastrointestinal endoscopy clinics of North America · DOI 10.1016/j.giec.2009.04.011 · PMID 19647646
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