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Medical genetics

Tormented bodies

The mutation that stiffens muscles and changes posture has been identified

Museu Lasar Segall museum collection – IPHAN/MINC“Poor people’s interior II”, Lasar Segall, oil on canvas, 1921Museu Lasar Segall museum collection – IPHAN/MINC

At the age of 11, after having had a normal childhood, a boy from Dores de Guanhães, a town of 5 thousand inhabitants located 200 kilometers northeast of the capital city of the State of Minas Gerais, began to feel his legs shake without any apparent reason. Little by little, the shaking began to spread throughout his body and within 2 years had led him to lose control of movements and he was only able to get around in a wheelchair. Medication did not help him or a girl from the same town who, at the age of 7, had difficulty writing; 5 years later, this girl walked around dragging a leg and was barely able to control her arms; her face had been transformed because the muscles were in constant tension, and her voice disappeared.

Another 11-year old boy, from Bom Despacho, a town near the source of the São Francisco river, 156 kilometers west of Belo Horizonte, began to notice that his left hand would snap shut and he could only open it again with the help of his right hand. At the age of 13, his right shoulder was out of line and at the age of 14 his neck would move backwards involuntarily, as if he were looking up at the sky. At the age of 29, he had lost a lot of weight, was unable to walk and his voice was barely audible.

These people knew they had dystonia, a neurological condition whose causes are generally unknown. Dystonia produces involuntary muscle contractions and leads to abnormal posture. But it was only a few months ago that they were told they had a form of dystonia caused by a genetic mutation, discovered by a team from the Federal University of Minas Gerais (UFMG). This form of dystonia had not been diagnosed previously; there is still no treatment available and no cure for it.

In May, a German team coordinated by Christine Klein, from the University of Lübeck, and which three months before had written the editorial introducing the new mutation in Lancet Neurology, described the same mutation, found in a dystonia patient who lives in Germany. “This work brings a new dimension to this illness, which is no longer an idiosyncrasy from Brazil or from the State of Minas Gerais”, says Francisco Cardoso, a neurologist from the Federal University of Minas Gerais (UFMG) who coordinated the work of the Brazilian team. “Perhaps this condition is more frequent than we had imagined”.

The discovery of the gene that causes a new form of dystonia is connected to a project that began in 1993, when Cardoso began to treat patients with motion disorders at the Hospital das Clínicas hospital of the UFMG. The team progressed little by little, but nobody was able to explain why the drugs that helped control the permanently twitching muscles in situations such as those had been a disappointment in the three aforementioned cases, which had appeared in families with apparently no family ties.

Three years ago, neurologist Sarah Camargos joined the group and examined another 120 patients with dystonia at the early stage. She drew the blood of the inhabitants of the towns of Dores de Guanhães and Bom Despacho and then raised the hypothesis that an alteration which de-activates 11 genes of the chromosome 2 (the human being has 23 pairs of chromosomes with approximately 35 thousand genes in each cell) might explain the worsening of the symptoms and the resistance to the drugs.

This genetic form of dystonia – the sixteenth such case already described and possibly the first case of its kind identified in Brazil – appears in adolescence when a person carries this same alteration in each one of the two copies of the gene known as PRKRA, found in the chromosome 2. Each child of normal parents, who have only one copy of the altered gene, has a 25% chance of being the non-symptomatic bearer of the gene.

Neither the physicians nor the geneticists have discovered yet why this defective gene leads to dystonia. What they do know so far is that when two copies of the PRKRA gene contain this mutation, named DYT16, the gene no longer performs its tasks. One of the tasks is to trigger the production of an enzyme called kinesis, which is essential for the neurons – and for all the other body cells – to burn glucose molecules and produce the energy that keeps them alive. Without this enzyme, the neurons will fail to transmit the messages for the muscles to work – and in response, the muscles move as if they were sailing in a stormy and windy sea. The normal version of this gene also helps regulate cell death, called apoptosis – and cells that die before or after the time they are supposed to die can also cause problems to the body.

The team from the UFMG worked with researchers from the US’s National Health Institute/ NIH) and from the University of Coimbra, in Portugal, to characterize this mutation, already found in seven inhabitants from the State of Minas Gerais. One of the families from Bom Despacho and the other family from Dores de Guanhães have three family members with this form of dystonia (the oldest one is 64 years old); the symptoms include contractions in most of the body, difficulty in swallowing food, a curved neck and bent backbone. “Some of them need help to take a bath”, says Sarah, “but not all of them are in wheelchairs”. According to her, this problem has appeared in one of the families from Guanhães for four generations, even though only two generations have been studied so far. The researchers suspect that the families, although living many miles apart, have a common ancestor. “The possibility that the same mutation will appear in people with no kinship would be extremely remote”, says Cardoso.

Next tasks
Cardoso recognizes the limits of this study: “We took a significant leap forward when we found the source of the illness, but we still have a serious problem, which is to discover how to treat it efficiently”. So far, the standard drugs – which re-establish the communication between the nerve cells – have been almost useless in terms of dealing with this form of dystonia. The incidence of the more common forms of this condition ranges globally from 30 to 50 cases in every 1 million people.

These statistics, however, are still not enough for researchers to estimate the incidence of this form of dystonia and to have an idea of the number of people with this condition in Brazil. According to Cardoso, the next step is to evaluate the frequency of the illness in the population and the gene’s ability to express itself. “We have many problems up ahead”, he says. “If a brother of a carrier of this form of dystonia were to ask us about his chance of becoming sick as well, we would not have an exact answer.”