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Sudden immobility

Genetic alteration could bring about paralysis in the limbs of people with hyperthyroidism

MARIANA SAMPAIOA difficult diagnosis made in 1998 disturbed the endocrinologist Magnus Régios Dias da Silva, from the Federal University of São Paulo (Unifesp), and led him to identify one of the factors that predispose people to a rare form of paralysis: hypokalemic thyrotoxic periodic paralysis, due to an abnormal increase in the production of hormones by the thyroid, the gland located at the front of the neck. This condition affects 1 percent of men and 0.1 percent of women with hyperthyroidism. In an investigation that took 10 years and included patients from five other countries, Magnus found at least two genetic defects that, under certain circumstances, help to temporarily block the contraction of muscles and immobilize the arms and legs for minutes or hours.

Presented in a series of scientific articles, the most important published this year in the journal Cell, these findings help scientists to understand the chain of biochemical reactions that from time to time cause muscles to stop responding to either voluntary (conscious) or involuntary (instinctive) orders to execute a movement. The search for connections between alterations in genes, fluctuations in blood hormone and mineral levels, and the appearance of the physical signs of this paralysis has already produced at least two important developments for both doctors and those who suffer from the problem.

The first is that now there is a better understanding of how, when and why those with hyperthyroidism may suffer this sudden loss of strength and sensitivity, which for unknown reasons is more common in the legs. The crises that leave the muscles flabby, sometimes without even enough strength to flex the toes, usually emerge in the early hours of the morning, hours after intense physical activity or following a large meal of pasta and desserts. The second development is of particular interest to those who suffer from this form of complication of hyperthyroidism. Finding out that it results from the simultaneous occurrence of a genetic defect and a hormonal disorder should allow for a more precise diagnosis and more appropriate treatment. Little known among doctors of other specializations, this form of paralysis is only finally eased when the production of thyroid hormones is controlled.

Since 1998, Magnus has identified nearly 40 problem cases in the São Paulo Hospital, which is attached to Unifesp, and noted that many were not receiving the correct medication. Most of these people had already had consultations with doctors from other areas, normally general practitioners and psychiatrists, and had received medication indicated for the treatment of other illnesses. As the signs of hyperthyroidism are often subtle and escape the doctors, the problem is usually confused with another, similar form of paralysis – hypokalemic familial periodic paralysis, which does not involve hormonal changes – or even with psychiatric disorders, such as anxiety or even hysteria, a physical manifestation of emotional problems studied in the late nineteenth century in France by the neurologist Jean-Martin Charcot, Freud’s teacher. “About 70 percent of the people whom we see at the university with this form of paralysis have already been treated with tranquilizers, which don’t solve the problem”, says Magnus.

Magnus’s interest in the subject arose when he was doing his specialization in endocrinology in the late 1990s. One night when he was on duty at the São Paulo Hospital, in the south of the city, he received a motorcycle courier who was a little over 20 years old and who arrived at the emergency department looking for help because he had been unable to get up to go to work that day. He told the doctor that when the alarm went off in the morning he could not get out of bed because his legs would not move. Magnus was suspicious of the story, since the motorcycle courier no longer had any signs of paralysis. He imagined that this was another one of those cases of someone looking for a medical certificate to justify his absence from work, so he carried out a rapid clinical examination and discharged the patient.

Four days later, however, during another spell of night duty, the doctor was surprised to see the motorcycle courier return to the emergency department. This time he was sitting in a wheelchair because of another bout of weakness that prevented him from standing. Closer examination made it clear that something was wrong. The motorcycle courier had the typical signs of hyperthyroidism – his eyes were staring, his heart was beating fast and his thyroid had increased in size. Analysis of his blood confirmed that his thyroid was producing high levels of triiodothyronine (T3) and thyroxine (T4), hormones that control the body’s production and spending of energy. To complete the picture, in attacks of paralysis the blood level of potassium, a chemical element essential for muscle contraction, was lower than normal.

The symptoms corresponded to those of temporary thyrotoxic hypokalemic paralysis, which as the name suggests is marked by a reduction in the level of blood potassium (hypokalemia) and hyperthyroidism, also called thyrotoxicity, except for one detail. Until then this type of paralysis had only been described in Japanese and Chinese people, and the motorcycle courier was Brazilian mulatto, with a probable mixture of European and African genes. “At the time it was hard to believe that it could occur in the western population”, says Magnus.

With data in hand, he sought out the endocrinologist Rui Maciel, who in the 1980s had described a similar case and proposed that they investigate the genetic cause of the problem, which might be more common than was believed. Magnus thought that if this complication had escaped him at first, perhaps it had gone unnoticed by others. He consulted endocrinologists and examined the cases of paralysis dealt with at the São Paulo Hospital in previous years. He found some that were similar to that of the motorcycle courier and invited them to undergo a reassessment.

From 1998 to 2004, Magnus and Maciel assembled a further 24 cases; only 4 of them were of Japanese descent. Most were of Western origin; 10 were white, there were 8 mulattoes, 2 blacks and an Amerindian, the researchers reported in 2004 in the Brazilian Archives of Endocrinology and Metabolism. There was sufficient evidence to overthrow the belief that this was a problem almost exclusive to the Japanese and Chinese.

Brazilians and Asians
“I believe that this form of paralysis is more common in our Brazilian population than among Europeans”, Maciel comments. “Studies by Sergio Pena’s team from Minas Gerais have already shown that some Brazilians have Indian genetic traits, and it is known that American Indians descend from Asian populations, which arrived on the continent thousands of years ago via the Behring Strait”.

While they were identifying new cases, Magnus and Maciel began looking for genetic alterations that might explain why the muscles became flaccid in the crises and they got in touch with the neuro-geneticist Louis Pácek, from the University of California in San Francisco, an expert in the hereditary (non-hormonal) form of paralysis. As the physical signs were similar, it was possible that both had similar genetic alterations.

Anyone who has the hereditary form of the disease usually has a mutation in some of the genes responsible for the formation of the pores that allow the entry or exit of substances from the cells. These pores are the ionic channels that regulate the passage of calcium, sodium or potassium – chemical elements with a positive charge (ions) that form part of the mineral salts of food and are responsible for the change in cell electricity.

At rest, muscle cells accumulate a larger number of negative ions than positive ones. However, when someone picks up a pen from the floor or steps on a shard of glass, the nervous system sends signals that make these cells contract. Upon receiving the order, they open the sodium and calcium channels, which flood the cells with positive ions. Only when they return to their initial state after opening the channels do they release potassium and reduce the excess of positive charges.

From California, Pácek sought the collaboration of colleagues in France, China, Thailand and Singapore, who sent blood samples from people with paralysis associated with hyperthyroidism. Analysis of genes, however, did not identify the same changes in the DNA of those who had the hormonal problem as found in those who were free of hyperthyroidism. The answer would come from Brazil. Among the patients here, Magnus detected seven alterations in a gene that codes a protein of the potassium channels. Analyzing the regulation of these channels by the thyroid hormone, he noticed that two of them made the cells produce defective channels, which eliminate potassium more slowly.

The findings, described in Cell, enabled the group to propose the biochemical mechanism that explains the paralysis of muscle cells. “But just the mutations are not enough to produce paralysis”, Magnus explains. “There has to be an event that triggers the crisis”.

One of the triggers is the level of T3, a hormone that regulates the activity of the gene responsible for the production of the potassium channel. If the gene is altered and the level of T3 is high, more defective channels are produced and the cells do not eliminate the potassium efficiently. The consumption of large amounts of carbohydrates, on the other hand, causes the retention of potassium for another reason. In the cells, carbohydrate is converted into the ATP cell fuel, which facilitates the closing of the potassium channels. “Only now”, says Magnus, “can we complete this picture”.

Tireoide or tiroide
Some people call it tireoide [which would translate as thyreoid], others, tiroide [i.e., thyroid]. The attempt to define the correct word is ancient – and controversial. The cartilage, which has the same name as the gland, has been known for two thousand years , whereas the gland was only described in 1656. The idea that the cartilage looks like a shield – thyreós in Greek, hence the spelling tireoide – has prevailed for a long time. However, in recent decades, the root thyra, meaning door in Greek, has been adopted for the cartilage, the gland and the hormones. The preferred international name is tiroide, but the Orthographic Vocabulary of the Portuguese Language records both forms.

Scientific article
RYAN, D. P.; DIAS DA SILVA; M. R. et al. “Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis”. Cell. v. 140(1), p. 88-98. Jan. 2010.

The projects
1. Detection of mutations in the genes of the calcium channels (CACNL1A3) in patients with hypokalemic thyrotoxic periodic paralysis (nº 2000/03442-4); Type Grant in the country – Doctorate; Coordinator Rui Monteiro de Barros Maciel (grant holder: Magnus Régios Dias da Silva) – EPM/Unifesp; Investment R$ 75,728.97.
2. Sequencing laboratory in the Human Cancer Genome program (nº 1999/03688-4); Type Regular Research Awards’ Genome program; Coordinator Rui Monteiro de Barros Maciel – EPM/Unifesp; Investment R$282,950.70.