What is Friedreich’s ataxia?
Friedreich’s ataxia is a genetic, progressive, neurodegenerative movement disorder.1 Friedreich’s ataxia is considered the most common early-onset hereditary ataxia, with a prevalence of ~1 in 50,000 individuals.1 It is characterized by a debilitating loss of balance and coordination in all 4 limbs.2
The major pathological abnormalities of Friedreich’s ataxia are located outside the cerebellum.1 The degeneration of the large fiber dorsal root ganglion neurons and their axons results in severe sensory ataxia and loss of proprioception. Most patients also have dysarthria and loss of lower limb reflexes, reflected by pyramidal weakness of the legs and loss of vibration and proprioception sensation.1
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What causes Friedreich’s ataxia?
The onset and presentation of Friedreich’s ataxia usually takes place within the first 5–15 years of life, but later onsets are also observed.2,3 Patients usually become wheelchair-bound after a mean disease duration of 10–15 years.2,4
The genetic basis of Friedreich’s ataxia is the loss of function of the frataxin mitochondrial protein, encoded by the frataxin gene (FXN).5
Frataxin loss of function is caused predominantly (in 95% of cases) by an alpha glucosidase GAA trinucleotide repeat expansion in FXN in the positive strand of chromosome 9q21.11.1,2,6 Individuals without Friedreich’s ataxia have up to 43 GAA repeats, while affected individuals have 44–1,700 GAA repeats, most commonly between 600 and 900.6–9
The remaining ~5% are compound heterozygotes, carrying 2 recessive alleles for the same gene, with those 2 alleles differing from one another.2 These individuals carry a point mutation (missense, nonsense, and intronic) in the gene on 1 allele in association with an expanded repeat on the opposite allele.1 This intronic trinucleotide repeat leads to the disruption of transcription and the almost complete absence of frataxin (loss of function mutation);1 GAA repeat expansions decrease, but do not eliminate, frataxin expression.2
Just as the expanded repeat may produce a loss of function phenotype by altering RNA transcription, the point mutations also result in a loss of function phenotype.10 Therefore, in compound heterozygotes the frataxin protein is very low in quantity, with a larger repeat expansion on 1 allele and no protein is expressed with the point mutation on the other allele.11
GAA repeat size and age of onset
The size of the GAA expansion in Friedreich’s ataxia is correlated with disease severity or clinical presentation, as in other trinucleotide-expansion diseases, such as myotonic dystrophy and Huntington’s disease.12 Frataxin levels are correlated with age of onset and inversely correlated with the length of the GAA repeat length.13
The role of frataxin
Frataxin is mitochondrially targeted and may be implicated in the process of iron (Fe) incorporation into protoporphyrin or Fe influx or export, which then results in mitochondrial Fe accumulation.14 Associated with this, it plays a role in mitochondrial energy conservation, activating the iron-sulfur cluster (ISC) protein assembly as part of a multiprotein complex.2 As such, frataxin is required for the biosynthesis of ISCs that are required for mitochondrial electron transport and assembly of functional aconitase, and iron metabolism of the entire cell.15 Indeed, frataxin deficient cells are depleted of ISC proteins in all compartments and lack mitochondrial ISC-containing subunits of respiratory chain complexes I, II, and III and aconitase activities.2 The cell-selective mitochondrial dysfunction that results subsequently leads to clinical manifestations including neurological features.15
Alongside the assembly of ISCs, frataxin is thought to:2
- Interact with complex II subunits, implicating its role in the respiratory chain
- Be involved in the synthesis of heme-containing proteins involved in processes such as oxygen metabolism and electron transfer
Cytosolic iron responsive element binding protein 1 (IRB1), a key regulator of iron metabolism, is an ISC protein. When iron decreases in the cytosol, IRB1 binds to specific sequence motifs, iron-responsive elements (IREs), found in the 3’- and 5’-untranslated regions (UTRs) of mRNAs for proteins involved in iron metabolism.2,14 This consequently prevents the degradation of mRNA encoding iron import proteins and inhibits translation of mRNA for proteins implicated in iron storage or proteins requiring iron for proper function.2,14 Mitochondrial iron uptake via the mitochondrial iron transporter, Fe-binding protein transferrin (Tf), is concomitantly enhanced.2
In the absence of frataxin, however, the assembly of ISC is prevented, resulting in mitochondrial iron overload.2 In frataxin-deficient mitochondria, H2O2 concentration is excessively high due to the defective respiratory chain; this oxidizes ferrous iron (Fe2+) thereby producing further toxic radicals.2 Toxic reactive oxygen species (ROS) disrupt the cells’ redox balance and thereby increase oxidative stress levels.2
The estimated prevalence of Friedreich’s ataxia
The prevalence of Friedreich’s ataxia varies between 1:20,000 and 1:725,000 in Western populations.2 Epidemiological studies show a west to east prevalence gradient in Europe, with the lowest levels in Scandinavia and Russia and higher levels observed in Northern Spain, Southern France, and Ireland.16 Frequencies of carriers vary between 1:55 in Northern Spain and 1:336 in Russia.16
The signs and symptoms of Friedreich’s ataxia
The Friedreich’s ataxia phenotype varies substantially in its classical presentation, however, the following are always detectable:17,18
- Mixed ataxia (ie, gait, limb): resulting from peripheral sensory neuropathy, spinocerebellar tract degeneration and cerebellar pathology17,18
- Dysarthria: consisting of slow, slurred speech which progresses from early in the disease towards unintelligibility in the advanced stages
- Loss of lower limb reflexes: reflecting underlying peripheral neuropathy, and early loss of vibration senses reflects the loss of neurons in the dorsal root ganglion and spinal column17,18
Other neurological and neuromuscular manifestations of Friedreich’s ataxia include:17
- Pyramidal weakness and distal wasting
- Spasticity developed as a result of painful muscles spasms and contractures
- Oculomotor abnormalities; ~2/3rds of patients exhibit clinical or subclinical optic neuropathy, and visual acuity tends to decline slowly with the disease
- Aberrant central auditory processing
- Urinary urgency and frequency
- Bowel symptoms, in the form of constipation or incontinence
- Sleep-related breathing problems
- Pes cavus
- Extensor plantar responses
While the “classical” phenotype, underscored by mixed ataxia, dysarthria, and loss of lower limb function, is by far the most prevalent, several cases are documented as atypical and demonstrate delayed-onset.17 Compared to the classically-presenting phenotype of Friedreich’s ataxia, which commonly develops between the ages of 5 and 15 years, late-onset Friedreich’s ataxia (LOFA) develops after the age of 25 years and very late-onset Friedreich’s ataxia (VLOFA) develops after the age of 40 years.17 These cases are characterized by slower progression of disease, increased variability of signs and symptoms, and a milder phenotype.17 Gait and limb ataxia remain the most common clinical characteristics in delayed-onset cases, however:17
- Dysarthria presents late, and spasticity and retained reflexes are encountered more frequently compared with the “classical” phenotype
- Non-neurological features including cardiomyopathy, scoliosis, pes cavus, and diabetes are less frequent compared with the “classical” phenotype
A small number of patients (~20%) will develop symptoms before the age of 5 years, and such cases are classified as early-onset Friedreich’s ataxia.2,17 These cases are associated with larger GAA repeats, a more severe phenotype, faster disease progression and higher incidence of cardiac complications.17
Determining a diagnosis of Friedreich’s ataxia
Clinical diagnosis of Friedreich’s ataxia may be difficult as the clinical phenotype is similar to Charcot-Marie-Tooth disorder, ataxia with a vitamin E deficiency, ataxia with coenzyme Q10 deﬁciency, and others.1,2
Genetic testing plays a critical role in accurate diagnosis.19 Genetic tests include:19
- Triplet-repeat primed polymerase chain reaction (TP-PCR), which uses a set of 3 primers, amplifies the region containing the repeat
- Long-range PCR, which is used to amplify regions of DNA containing GAA repeats
- Real time quantitative PCR
- Southern blotting
- Lateral flow immunoassay
The gold standard of genetic testing for Friedreich’s ataxia is southern blot analysis.20
Patients with a genetically confirmed diagnosis of Friedreich’s ataxia should undergo a comprehensive clinical and neurological assessment, including:21
- Electrocardiography (ECG), echocardiography and other cardiological evaluations
- Neurological evaluation
- Ophthalmological examination
- Selected hematological tests, including red and white cell blood counts and concentrations of hemoglobin, glucose and electrolytes
- Magnetic resonance imaging (MRI)
What is the prognosis of Friedreich’s ataxia?
Friedreich’s ataxia is a slowly progressive disorder in which clinical symptoms do not progress at the same rate.2 Dysarthria manifests within 10–15 years and diabetes within 16 years, whereas loss of proprioception takes more than 40 years to develop.2 Typical causes of death include cardiac complications, diabetic coma, trauma sequelae, stroke, and aspiration pneumonia.2
Cardiac involvement is seen in most patients, with cardiomyopathy occurring mostly in patients with early disease onset for whom it may be life threatening.4 Both early disease onset and cardiac involvement are associated with faster progression of neurological symptoms.2 Although progressive, the disease progress landscape frequently includes periods of stability at the beginning of the illness.4
The management of Friedreich’s ataxia involves many healthcare professionals, and coordination among them is crucial to maximizing therapeutic benefit.
The complex and variable clinical phenotype of Friedreich’s ataxia requires a broad multidisciplinary approach to management, which focuses on symptoms.17 A comprehensive set of consensus clinical management guidelines outline the importance of early referral to a specialist ataxia center to facilitate access to the multidisciplinary team and ensure an approach that is tailored to the individual needs of each patient.22
Multiple interventions are required to manage Friedreich’s ataxia17
- Physiotherapy provides an important means of ensuring flexibility, balance, strength, and accuracy of limb movements are maintained, which can improve the functional consequences of gait and limb ataxia
- Rehabilitation may help counteract the effects of ataxia, weakness, and spasticity
- Occupational therapy reduces the impediments to daily activities through the provision of equipment to maximize independence, retraining of functional skills, and management of educational and vocational issues
- Behavioral management strategies
- Patients showing dysphasia can benefit from compensatory posture training to facilitate safe swallowing. Dietary modification can also aid weight maintenance, and in severe cases, nasogastric or gastronomy interventions may be required
- Additional screening of the eyes, bladder, sleep-related breathing, heart, and blood glucose are important to determine whether additional imports by way of symptom management are necessary
Since the identification of mutations in FXN as the cause of Friedreich’s ataxia, there has been progress in the understanding of the pathogenesis of this disorder. This has led to identification of potential therapies with multiple clinical trials completed, underway and planned.23
ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; CTCF, CCCTC-binding factor; ECG, electrocardiography; EMG, electromyography; FAST-1, FXN antisense transcript 1; Fe2+, ferrous iron; FRDA, Friedreich’s ataxia; FRDA1, first Friedreich’s ataxia locus; FRDA2; second Friedreich’s ataxia locus; GAA, alpha glucosidase; GTT, glucose tolerance test; HbA1c, glycated hemoglobin; IRB1, iron responsive element binding protein 1; IREs, iron-responsive elements; ISC, iron–sulfur cluster; LOFA, late-onset Friedreich’s ataxia; MRI, magnetic resonance imaging; NCS, nerve conduction studies; PCR, polymerase chain reaction; ROS, reactive oxygen species; Tf, transferrin; TP-PCR, triplet-repeat primed PCR; UTR, untranslated region; VLOFA, very late-onset Friedreich’s ataxia.
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