Genetics knocks on the doors of operating rooms

A guest from the present

Svetlana Belyaeva, "Search" No. 12 (2014)
Photo by Nikolay Stepanenkov

Contrary to popular opinion that genetics is a "guest from the future", in the Russian Scientific Center of Surgery named after Academician B.V.Petrovsky is confident and successfully proves that this science has already become a powerful help for surgeons today.

Elena Zaklyazminskaya, MD, head of the Laboratory of Medical Genetics of the Russian National Research Center, tells the correspondent of "Search" about why operating doctors often focus on the result of genetic counseling and DNA diagnostics when choosing treatment tactics.

– Elena Valeryevna, due to what circumstances is your laboratory organized at the RNC?

– The Laboratory of Medical Genetics was established by order of Director Sergey Dzemeshkevich in the fall of 2009, and this is certainly a happy circumstance. However, the surgeons did not immediately realize that this was a great success for all of us. When the laboratory was just formed, there was a perplexity – why are you here if you don't operate? And this is the traditional attitude of the operating doctor to our non-surgical specialty. Surgeons are lucky that patients are diagnosed with hereditary diseases in a timely manner, DNA diagnostics is carried out, we discuss a possible range of complications, specific risks, and the choice of treatment tactics. It is important for geneticists that we are in a multidisciplinary surgical center, where a patient can be hospitalized, where he can be examined, provide him with diverse assistance, because often hereditary diseases are systemic, they affect more than one organ. After surgery, patients regularly return for observation, we see how the disease develops after surgery, whether there is a response to treatment. This gives a completely unique experience, which there is nowhere to take if the geneticist conducts only a polyclinic appointment.

– It turns out that only the director of the RNC surgeon Sergei Dzemeshkevich showed foresight?

– Yes, it was Sergey Leonidovich's initiative, and our meeting with him is another happy circumstance. I have been engaged in genetic counseling and the development of DNA diagnostics of cardiac diseases since 1997, the topic of my doctoral dissertation is "Genetics of cardiac arrhythmias with the risk of sudden cardiac death". Since few specialists dealt with these problems in our country, I had extensive contacts with cardiologists from different centers. Cardiologists often referred patients with whom "it is not clear what is happening" to me for consultation. So I got an unusual patient with the usual diagnosis of cardiomyopathy (damage to the heart muscle). The end amputations of the phalanges of the fingers and benign tumors – keratoangiomas on the surface of the abdomen were unusual. Due to polyneuropathy and blood microcirculation disorders, such patients often develop frostbite, hypersensitivity to hot and cold, and kidney failure may occur with age. Sometimes hypertrophic cardiomyopathy, pathology of the heart valves occur... Therefore, the diagnosis of Fabry's disease was assumed, which occurs with a frequency of one in a million. This diagnosis was then confirmed at the biochemical and molecular levels. And to the cardiologists, who did not really understand what was happening to the patient, the patient returned with a diagnosis, with recommendations for treatment, with a prognosis about which systems he might suffer in the near future.

Sergey Leonidovich was impressed by all this and decided to hire a geneticist who "understands something about cardiology," to which I gladly agreed. So this story ended with the creation of a genetics laboratory at the RNC. And the patient was successfully operated in our center and now regularly receives treatment – enzyme replacement therapy – a completely new generation of therapy. Once every two weeks, he is given ivs with artificially synthesized genetically engineered protein, which makes up for the hereditary deficiency of this enzyme in his body.

– But it doesn't often happen that surgical patients first of all go to a genetic consultation, not to mention that you won't find genetic diagnostics laboratories in ordinary clinics.

– Indeed, very few surgical centers are sufficiently advanced to open a genetic laboratory, introduce into practice consultations of a geneticist and DNA diagnostics. In this sense, the RNC is unique. I know of only two similar centers in Europe, and in the USA, as far as I know, they are just going to create such a program.

At the same time, geneticists can help patients very significantly. We understand the root causes of diseases, we know how they develop, and in many cases the correct genetic diagnosis really determines the tactics of treating "unusual" patients. Sometimes this is the answer to the question – to be or not to be a heart, liver or kidney transplant, surgical intervention. Sometimes more local recommendations: is it possible, for example, to use classical anesthesia for a specific patient.

Some of our patients suffer from diseases that can be cured thanks to new approaches to the treatment of hereditary diseases. For example, with the help of enzyme replacement therapy, which makes it possible to replenish the protein missing in the body, which is necessary for the breakdown of high-molecular compounds. If there is a deficiency of such a protein due to a defect in a gene, these compounds "clog" the cell. It swells, becomes huge, and then, like any littered system, it cannot work and dies. In patients with Fabry's disease, which is formed according to this principle, hypertrophic cardiomyopathy develops in this way.

But it turns out that all this can be prevented if a genetic diagnosis is made in time and treatment is started. When we start therapy, we sort of "preserve" the patient in the form in which he came to us.

There are hereditary metabolic diseases that can manifest themselves as cardiomyopathies, and sometimes, depending on what the origin of this disease is, a violation of the heart rhythm may occur. If cardiomyopathy is ischemic or toxic, then myocardial remodeling can be performed. And if it has arisen for genetic reasons, then it is worth using more aggressive treatment tactics. Heart transplantation is indicated for patients with primary dilated cardiomyopathies. However, this prospect can be postponed (there are not enough donors for everyone) if surgical remodeling of the heart is performed. Having found out what the root cause of cardiomyopathy is, the geneticist can tell whether the waiting period will be successful or not. In some cases, remodeling makes sense, and in others we understand that we need to immediately look for a donor.

With some hereditary pathologies, patients look the same – for example, boys and girls who are too tall are usually diagnosed with Marfan syndrome right away. In fact, in the group of connective tissue dysplasia, when patients, for example, develop an enlargement of the aorta (veins and arteries are unable to withstand blood pressure), there are 240 nosological forms. And each of them has its own forecast, its own risks. In Marfan syndrome, the disease can be the result of mutations in three different genes – the fibrin gene (the most common) or two minor genes (growth factors). And if the mutation occurred not in the main, but in the minor gene, then there is no correlation between the diameter of the aorta and the risk of rupture. In other words, such patients should be operated on as early as possible, without waiting for the aortic diameter to reach 55 mm (standard indication for surgery). Such patients, by the way, have very low postoperative risks, but the risk of dying suddenly from a rupture of the aorta is very high.

– At the beginning of the conversation, you said that your scientific interests include the diagnosis of sudden death as a result of cardiac arrest.

– Yes, it all started with the genetics of sudden death, which we continue to do now. We have a department of arrhythmology, where patients are selected tactics of surgery and drug therapy, depending on the result of genetic analysis. You can't do without genetics here. Many of the patients we work with came to us for the first time after a sudden death in the family. The survivors need help, and the first person they need is a geneticist. Because if for a cardiologist the story ends when the patient dies, then genetics is interested in another subject of the study – the family, all relatives – both living and deceased. We are talking about sudden death, when a healthy child went to school and did not return home, or when a healthy man walked calmly, but suddenly fell and died. An open genetic service has been organized in the RNC, and two days a week we consult people "from the street". Anyone who thinks he has questions about genetics can contact us.

– In what cases does such a need arise? What events suggest that a geneticist is needed?

– Some of the people who come to us are those who are planning to start a family, but something in the history of their relatives worries them – cases of early deaths, heart disease or several cases in a row of schizophrenia, progressive muscular dystrophy. That is, some recurring early disease is a reason to consult with a geneticist. For many diseases, there is a predictive genetic diagnosis, so pregnant women often apply.

We have three geneticists in our laboratory who advise patients who, due to their disease, will need surgery sooner or later. As a rule, surgeons show us patients who are somewhat unusual: for example, there is an early manifestation of the disease. But in order to correctly formulate the question of genetics, the surgeon must be informed about the range of features of hereditary pathologies. Therefore, we try to conduct educational lectures for the center's employees, we go on rounds in the departments. For three or four years, we have developed a common strategy for working with such patients, and even now surgeons say that at least 40 percent of patients suffer from certain hereditary diseases, although it was previously believed that there were none at all.

– You have been working in your field for a long time, can you assess the effect of genetic counseling today?

– It has been developed and manifested for decades. Now, for example, I am being approached by my former wards, to whom, as a child, 10-15 years ago, I did a DNA diagnosis of the long QT syndrome. This is another disease of hereditary heart rhythm disorder, which is often manifested only by the fact of sudden death and is often confused with hereditary epilepsy. They have grown up and are thinking about their own children or want to examine an already born child...

DNA diagnostics of about 100 hereditary diseases is carried out in our laboratory, including with the help of new generation sequencing. And this opens up completely unique opportunities for confirming the diagnosis and improving treatment.

In medicine, it is often considered that to treat is to prescribe a course of pills or perform a surgical operation. But this is not always the case. What cannot be cured can be controlled in a variety of ways. Sometimes geneticists diagnose hereditary diseases, after which doctors tell the patient: "What do you want? You have a genetic disease!" And he wants to be healthy, have a family and a good quality of life. The fact of the hereditary nature of the disease does not exclude medical care. Often, out of ignorance, doctors "kick off" these patients. But a lot can be prevented if DNA diagnostics are done in time and wisely, on which the strategy of later life often depends. I would say that a geneticist is a switchman of medicine who directs the patient along the right path.

Portal "Eternal youth" http://vechnayamolodost.ru24.03.2014