Article by former Ataxia Clinic Registrar, Dr Christine Albertyn, which appeared in the Irish Medical Times

Friedreich’s ataxia: A review

Dr Christine Albertyn

Introduction

This rare degenerative condition is named after Nicholaus Friedreich, a German professor of medicine, who first described it in 1863 as “degenerative atrophy of the posterior columns of the spinal cord”. Many decades later, in 1996, the causative mutation was identified as the GAA triple repeat expansion on chromosome 9. Since then, remarkable strides have been made in our understanding of the pathogenesis of this, so far, incurable disease.

Epidemiology

Freidreich’s ataxia (FRDA) is an autosomal recessive disease and the most common cause of an inherited ataxia in Europe. Ireland, together with Spain, have the highest prevalence of 1 case per 30 000 individuals (1/30 000). It is seen in people from Europe, the Middle-East, India and North Africa. The reason for the restricted prevalence is speculated to be due to small populations surviving the ice-age, thereby creating a genetic bottleneck. It is estimated that 1 in 90 people are carriers of the gene.

Clinical picture

Symptom-onset is typically during puberty, although it may be as early as 2 years or as late as 25yrs in late-onset FRDA. Life expectancy is typically 40 to 50 years, although exceptions include patients surviving into their 70’s.

Typically, patients present with an unsteady gait. However, non-neurological symptoms like scoliosis, pes cavus and rarely cardiomyopathy can precede the ataxic symptoms.

The cause of the ataxia is two-fold: a cumulative insult on both the sensory system and cerebellum. The loss of vibration and joint position sense is due to atrophy of the dorsal root ganglia affecting the posterior columns of the spinal cord and axonal sensory neurons. The main source of cerebellar output pathways is the dentate nucleus, which is the source of central ataxia in these patients.

Progressive gait instability with a broad-based gait leads to falls with patients requiring escalating degrees of support. Patients usually require a wheelchair 10-15 years after onset of symptoms. Although some muscle weakness can occur late in the disease with pyramidal involvement, the loss of mobility is mainly due to imbalance.

Dysarthria is characterised by a slurring, explosive speech with sudden utterances. With time, speech may become unintelligible. Eye movements are abnormal with the hallmark being square-wave jerks, which are a reflection of fixation instability. A third of patients have gaze-evoked nystagmus. Dysphagia can occur later in the disease. Poor vision can occur with involvement of the optic nerves leading to optic atrophy.

Hearing loss can occur, and the pathophysiology is interesting. The patients usually show hearing within normal limits (three-frequency average hearing levels of ≤20dBHL) when tested with routine audiometry. However, despite detecting sound at low levels as shown by recordable responses from the cochlear hair cells, the patients have an abnormal auditory brainstem response. This has been termed auditory neuropathy/dyssynchrony. Therefore the problem with hearing is a central one, rather than peripheral. Typically, patients with this processing impairment have difficulty understanding speech when there is competing background noise and indeed many of our patients would report being unable to hear in a busy shop or pub.

Limb examination reveals normal tone, although patients may develop spasticity later. Reflexes are typically absent, but may be present in patients with late onset disease. Sensory testing reveals loss of vibration and proprioception, with loss of pinprick and temperature only occuring later. Plantar responses are extensor (Babinski’s sign).
Non-neurological findings include a hypertrophic cardiomyopathy. Patients may develop arrhythmias, which is often a cause of mortality. Diabetes mellitus occurs more frequently than in the general population and is a combination of insulin resistance and inadequate insulin response. Kyphoscoliosis and pes cavus are common skeletal abnormalities and may require surgical correction.

Diagnosis

The diagnosis is confirmed by demonstrating the homozygous abnormal GAA triple repeats on chromosome 9. Two to 5% of patients are compound heterozygous, therefore the abnormal expansion is only demonstrated on one chromosome. In these cases, a different point mutation is sought on the other chromosome which can lead to frataxin loss of function. MRI scans can show mild atrophy of the cervical cord, but cerebellar atrophy is not usually prominent. If severe cerebellar atrophy is present on a MRI scan, it may point to an alternative diagnosis.

Differential diagnosis

The differential diagnosis for an ataxic syndrome is broad, and includes toxic, metabolic, immune (i.e. paraneoplastic), vascular, tumour and demyelination. A good history, clinical exam and appropriate tests can often reveal the cause. Other rare recessively inherited, progressive ataxias include Ataxia with Vitamin E deficiency, Ataxia with Ocular Apraxia type 1 & 2, ataxia telangiectasia and spastic ataxia of Charlevoix-Saguenay.

Pathogenesis

Great progress has been made in understanding the mechanisms underlying disability in FRDA. The genetic mutation that causes FRDA is the GAA repeat expansion on chromosome 9. Repeats in normal chromosomes contain up to 38 triplets, with pathologic repeats ranging from 70 to more than 1000 triplets. It is this GAA expansion that partially silences the frataxin gene and results in low levels of frataxin. Although the exact physiological function of frataxin protein is unknown, it plays a major role in the regulation of mitochondrial iron transport. Frataxin is needed to form iron-sulphur clusters (ISC’s), which are prosthetic groups for a diverse group of proteins involved in electron transport, energy metabolism, DNA repair and iron handling. These reduced activities all contribute to mitochondrial dysfunction and oxidative stress.

Future therapeutic options

Idebenone is an anti-oxidant related to coenzyme Q10. It works by counteracting the toxicity caused by iron compounds. It has been tested in clinical trials and, while it has been shown in some studies to reduce cardiac hypertrophy, it has not consistently showed improvement in neurological function. It has therefore not been licensed for use in America and Europe. However, phase 3 trials are currently underway in Europe (MICONOS trial) and America (IONIA trial). In these two studies, high dose idebenone will be used and the investigators will look for a change in ICARS score. The ICARS is a rating scale used to measure physical disability in ataxias.

Histone deacetylase(HDAC) inhibitors offer a promising therapeutic approach by overcoming the gene silencing imposed by the GAA repeat. This is achieved by interrupting chromatin condensation. The end result would be increased frataxin expression. There is a concern that this drug may modify the expression of many genes unrelated to frataxin and therefore have toxic side-effects. It is currently being tested for cancer therapy. There are no clinical trials underway yet in patients with FRDA.

Diferiprone is an iron chelator, and may limit cell damage by binding mitochondrial iron. It has been shown to reduce iron content in the dentate nucleus of patients with FRDA. This drug has shown some efficacy in pilot trials and animal models and further Phase 2 clinical trials are planned.

Erythropoietin is neuroprotective and has been shown to increase Frataxin levels. It has been tested in pilot studies and further studies are underway. There is concern about ongoing hematopoietic stimulation with possible side-effects including thrombotic events and the need for frequent venesections.

Pioglitazone is a drug already used in diabetes. It stimulates mitochondrial function by acting on the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. It has shown promise in cell models, but the concern is that it can lead to cardiac toxicity. A phase 2 trial is being planned.

The amount of research being done is remarkable, especially when taking into account that this is a rare disease. This is due to the fruitful collaboration across the world between investigators sharing their successes and failures and the generous assistance of patient support groups.

FASI

This patient support group is very active and incorporates all genetic ataxias. By raising funds, they have been able to support individual patients with varying needs. The annual holiday in Roscommon is a highlight of the calendar year and provides respite for patients and their carers. Funding research projects across the world has also been a priority for FASI, giving hope that a treatment will be found soon for this progressive neurodegenerative disorder.