Excess iron and Friedreich’s ataxia

Friedreich’s ataxia is a crippling neurological disorder that affects about 1 in 30,000 individuals, making it the most common of the inherited gait disorders, or ataxias.

While there would be fewer than 130 patients in the greater metropolitan Melbourne area, population 3.85 million, by the peculiar calculus applying to autosomal recessive disorders, there would be around a dozen carriers on every crowded commuter train entering Melbourne’s City Loop during the morning rush. The mutant allele’s frequency in Western populations is around 1 in 90.

Associate Professor Martin Delatycki has seen more than 100 Friedreich’s patients during his monthly clinics at Monash Medical Centre – at his most recent clinic, only one patient was from Victoria; the rest from interstate and overseas.

Delatycki is a clinical geneticist director of the Bruce Lefroy Centre for Genetic Health at Melbourne’s Murdoch Childrens Research Institute, and specialises in diagnosing and treating the disorder.

The first symptoms of Friedreich’s ataxia typically manifest in childhood, between the ages of five and 15. Patients develop progressive weakening of the muscles of the arms and legs, lose coordination and develop an unsteady gait. Curvature of the spine, and deformed feet, eventually force them into a wheelchair. Hearing and vision may deteriorate, speech becomes slurred, and they develop cardiomyopathy and an irregular heartbeat.

Diagnosis is straightforward enough, but until recently there was no effective treatment for patients with the progressive, invariably fatal disorder.

Today, however, there is light on the therapeutic horizon – actually, three lights. Delatycki says three drugs are in clinical trials overseas which approach the underlying metabolic defect in Friedreich’s ataxia from different and potentially complementary directions.

Delatycki described his research at the annual scientific meeting of the Human Genetics Society of Australia in Adelaide recently.

---PB--- Genetics of Freidreich’s

The Murdoch Institute is one of the world’s leading centres for Friedreich’s ataxia research, thanks to former director Professor Bob Williamson’s central role in tracking down and identifying the mutant gene.

Williamson pinpointed the location of the gene via linkage disequilibrium – the tendency of chromosome segments to carry highly conserved combinations of alleles of adjacent genes to be transmitted intact between generations, along with unique DNA markers that distinguish between mutant and normal haplotypes.

In 1988, Williamson and his colleagues tracked the defect to the 9q13-q21 region, on the long arm of chromosome 9. The mutation involved a gene called FXN, coding for a novel protein frataxin.

In all but a few patients, the mutation involves the expansion of a repeated GAA trinucleotide in the gene’s first intron, so the protein itself is unaltered.

Most trinucleotide repeat expansion disorders, including Fragile X syndrome, Huntington’s disease and spinobulbar muscular atrophy, introduce a variable-length sequence of a particular amino acid within the protein itself, turning it toxic.

Although encoded by a nuclear gene, the protein is exported to mitochondria. Insufficiency in Friedrich’s patients appears to result in progressive buildup of unbound iron.

The highly reactive iron atoms spawn oxidising free radicals that eventually destroy frataxin-deficient mitochondria in the patient’s neurons. As affected neurons and peripheral nerves die off, patients progressively lose coordination and develop sensory impairments.

Delatycki says it’s still not clear how frataxin helps maintain iron concentrations within safe bounds in mitochondria, but once the fundamental problem was traced to a toxic excess of iron, multiple therapeutic avenues opened up.

Researchers reasoned that antioxidants could reduce the damage to mitochondria. Drugs to ramp up frataxin synthesis, or chelating agents to remove excess iron from mitochondria, might also be effective.

---PB--- Clinical trials

Overseas, Idebenone, a powerful antioxidant that penetrates the blood-brain barrier, is in Phase 3 trials. Researchers including Delatycki and his team are also trialling an iron chelator, Defereprone.

Cell studies and an open label study in 11 individuals with Friedreich’s ataxia indicated that erythropoietin, which boosts production of red blood cells, also had potential. Delatycki is working with a US group to conduct a Phase II/III placebo-controlled study.

Extra red blood cells require increased synthesis of iron-rich haemoglobin, and excess iron may be excreted during their rapid turnover.

Delatycki’s research group at the Murdoch Institute is conducting laboratory studies of compounds that could remedy the problem at source, by increasing fretaxin synthesis.

The laboratory team, led by Dr Joe Sarsero, is developing a knock-in transgenic mouse model of the disorder, by introducing the human form of the gene with the trinucleotide expansion repeat mutation – they have already confirmed that the normal human gene is a perfectly adequate substitute for the murine frataxin gene.

“We’re also trying to establish clinically useful measures of changes in human patients as the disorder progresses – how it affects walking, hand movement, vision and eye movement, hearing, and general quality of life,” Delatycki says.

“This is a very slow, progressive disorder. Motor neuron disease typically takes two years to develop, but Friedreich’s takes 30 to 40 years, and the individual rate of progression is highly variable.”

These clinical measures are essential for assessing how individuals are responding to experimental drugs. “We’d love any drug that could reverse the symptoms, but if it could just slow its progression by 10, 20 or 30 per cent … Given the long course of the disease, any increase in the lifespan, and the quality of life, would be very significant.”

As a recessive disorder, Friedrich’s ataxia occurs only when both parents carry the mutation, and then only in one in four of their offspring, on average.

Delatycki says an unusual aspect of this pattern of inheritance is that the age of onset, and the severity of the disease, is determined by the allele with the fewest trinucleotide repeats – the mechanism involved is unclear, but one hypothesis is that the expansion creates a defect in chromatin structure that limits the access of the cell’s transcription machinery to the frataxin gene’s promoter.

In Huntington’s and several other trinucleotide repeat expansion disorders, the longer allele usually determines the age of onset and severity, so the disorders exhibit a dominant pattern of inheritance.

The recessive pattern of inheritance, and the early age of onset, also means the disorder rarely affect more than one generation of a family. Despite the disease’s rarity, Delatycki says its nature has attracted a diverse range of specialists from other fields, including mitochondria and iron-metabolism experts.

“There has been a huge increase in interest in Friedreich’s ataxia since the gene was identified, and we discovered why nerve cells die. We think the frataxin protein’s main role in mitochondria is in the production of iron-sulfur clusters that are essential for energy production.

“When frataxin levels are insufficient, there is a buildup of free iron in the mitochondria, creating oxygen free radicals that damage multiple mitochondrial respiratory chain enzymes.”

He says the Friedreich’s Ataxia Research Association (Australasia) is “incredibly active” in raising funds for research.

“They’ve funded our program for many years now, and they also play a support role for people newly diagnosed with the disorder.”