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The Results of 2021, the Launch of New Diagnostic Programmes and New Methods of Diagnostics of Rare Diseases Were Announced in the RCMG

A press conference was held in the press-centre of IIC «News» dedicated to the International Day of Rare (Orphan) Diseases on February 24, 2022. 

The conference was attended by: 

Sergey Kutsev – Holder of an Advanced Doctorate in Medical Sciences, Professor, Corresponding Member of the RAS, Director of the Research Centre for Medical Genetics, Chief External Expert in Medical Genetics of the Ministry of Healthcare of the Russian Federation; 

Ekaterina Zakharova – Holder of an Advanced Doctorate in Medical Sciences, Professor, Head of the Laboratory of Metabolic Hereditary Diseases at the Research Centre for Medical Genetics; 

Yelena Kondratieva – Holder of an Advanced Doctorate in Medical Sciences, Professor, Head of the Scientific Clinical Department of Cystic Fibrosis at the Research Centre for Medical Genetics, Deputy Director for Science at the Scientific Research Clinical Centre for Childhood of the Ministry of Healthcare of Moscow Region; 

Vladimir Strelnikov – Holder of an Advanced Doctorate in Biological Scineces, Professor, Head of the Epigenetics Laboratory at the Research Centre for Medical Genetics; 

Olga Shchagina - PhD, Leading Researcher of the DNA Diagnostics Laboratory at the Research Centre for Medical Genetics. 

The problem of availability of expensive orphan medications for children is solved today due to the Charity Fund «The Circle of Well». In today’s world, questions of accurate diagnostics of rare diseases are coming to the fore. The development of new methods of diagnostics of hereditary diseases is one of the key goals of the Research Centre for Medical Genetics, a subordinate institution of the Ministry of Science and Higher Education of the Russian Federation. Leading experts of RCMG summarised the results of 2021 at a press-conference in IIC “News”, announced the launch of new diagnostic programmes and told about new methods of rare diseases´ diagnostics. 

“The Research Centre for Medical Genetics is today the key link in providing assistance to patients with orphan diseases. The RCMG has the unique diagnostic capabilities. These are complex DNA diagnostic methods, biochemical methods, many of which are performed only in the RCMG. Today, more than ninety percent of hereditary diseases diagnoses in Russia are established in the Research Centre for Medical Genetics”, - said Sergey Kutsev, Director of the Research Centre for Medical Genetics, Chief External Expert in Medical Genetics of the Ministry of Healthcare of the Russian Federation.  
“The Circle of Well” Charity Fund, established in 2021 by the President of the Russian Federation, has the possibility to help patients due to the work of our highly qualified specialists. It is the RCMG where the diagnosis is made for the majority of relevant patients. More than sixty seven thousand researches were carried out in the Research Centre for Medical Genetics, specialists treated more than eleven thousand patients in 2021. 

2021 in Figures 

The main step in the application of pathogenetic therapy for hereditary diseases is the diagnostics at the clinical, biochemical and molecular-genetic levels. The precise identification of the molecular cause of a disease allows for targeted correction of the effects of genetic defects. Selective screening programmes for several nosological forms of hereditary diseases are conducted in the DNA Diagnostics Laboratory of RCMG. These programmes identify patients who have already shown the first symptoms of diseases and for whom modern therapy is possible. The Leading Researcher of the Laboratory, PhD Olga Shchagina, provided specific figures. 

- Within the framework of selective screening programmes, to date, more than five thousand patients suspected of spinal muscular atrophy (CMA), Duchenne/Becker´s muscular dystrophy, achondroplasia, hereditary forms of retinal pathology, hereditary angioneurotic oedema, phenylketonuria have been examined with molecular genetic methods. Selective screening for spinal muscular atrophy has been under way since February 2020. The diagnosis in 662 out of 3,600 patients suspected of CMA have been confirmed since the start of the programme, and by the end of February 2022. All patients were also analysed concerning the number of copies of the SMN2 gene to determine whether pathogenic therapy could be used. The selective screening programme for Duchenne/Becker’s dystrophy started in 2018, and so far 1,044 patients have been examined, with a confirmed diagnosis in 758 cases. Thirty five percent cases among them have mutations for which target medications exist. Other forms of hereditary muscle dystrophy have been identified in 86 patients. The selective achondroplasia screening programme was launched in November 2021, and thanks to the high activity of the patient community, 204 patients have already been given free genetic testing. The diagnosis of achondroplasia has been confirmed in 141 patients, and mutations responsible for hypochondroplasia have been found in 17 patients.

The HMD laboratory has developed new diagnostic techniques for mucopolysaccharides and deficits of decarboxylase aromatic amino acids 

RCMG has developed multiplexed analysis of mucopolysaccharides in the laboratory of hereditary metabolic diseases (HMD). It is based on the definition of four glucosaminoglycans in the biomaterial. Unlike spectrophotometric, the new method allows both qualitative and quantitative evaluation of the substances of interest in a small amount of biomaterial, which is important for monitoring the effectiveness of the therapy. The preparation for the treatment of children with mucopolysaccharidosis type IV A is purchased with the funds of «The Circle of Well». The laboratory specialists are also working on the creation of a new method for diagnosing deficiency of decarboxylase of aromatic amino acids (AADCD). It is based on a determination in the blood stain of a certain metabolite. 

Ekaterina Zakharova, the Head of the laboratory of HMD at the RCMG, stressed that the laboratory is preparing a whole range of methods that will allow to make the screening for hereditary metabolic diseases more advanced, and analyse as many diseases as possible for one test in one blood stain. 

“New approaches allow to make diagnosis of mucopolysaccharides and deficiency of decarboxylase of aromatic amino acids (AADCD) available to patients throughout Russia, as the biomaterial can be provided to the HMD laboratory in the form of a dry stain on the filter”,- said Ekaterina Zakharova.  
“In the future, we expect that these methods will be included in the programme of mass neonatal screening. I would like to emphasize a disease like Pompe’s disease. It is included in the mass screening programme in some countries , and we also have all the facilities to diagnose the disease in our country, including through mass neonatal screening. We are starting to develop a new technology to identify additional metabolites in our HMD laboratory this year that will help to diagnose complicated cases. It’s a very promising technique for mass screening of newborns”. 

Sergey Kutsev noted: «As a result of the long work of RCMG staff, technological and methodological aspects have been worked out that will allow the whole country to carry out extended neonatal screening effectively in 2023». He also stated that the RCMG will conduct several training sessions for doctors who will conduct extended neonatal screening in 2022. 

Reasons for poor target therapy in cystic fibrosis patients 

Сhildren with cystic fibrosis gained access to targeted preparations due to the charity fund “The Circle of Well” in 2021. However, early experience with their application has shown that results do not always match expectations. Experts of scientific and clinical department for cystic fibrosis at RCMG have determined the reason for the low effectiveness of targeted therapy in some cases. 

“The first experience in the use of targeted therapy in the form of the preparation ivakaftor -lumakaftor has shown that not all patients have the expected effect. Sequencing of the CFTR gene has made it possible to find a reason for the absence of the ivakaftor-lumakaftor target medication effect in patients with a certain mutation. That is F508del mutation in homozygous condition,” – explained Elena Kondratyeva, the Head of the scientific and clinical department for cystic fibrosis at RCMG, at a press-conference. The reason is the presence of a complex allele on one of the chromosomes, that is another mutation L467F which is coupled with the mutation F508del. As for now, more than seven hundred patients with this genotype of cystic fibrosis have been examined. The results showed a high prevalence of complex allele in the Russian Federation - about 8%. We have determined which medications will be effective in patients with complex allele, with the help of a unique method (forescaline test on intestinal organoids). The personalised approach made it possible to avoid prescribing medications as a targeted therapy for this category of patients and to recommend a comprehensive triple-action target medication. 

RCMG opens a new neurofibromatosis diagnostic programme 

Neurofibromatosis is a hereditary disease in which patients develop multiple benign tumors on their skin, nervous system, and internal organs. The cause of the disease is a mutation of the NF1 gene, which is a tumor growth suppressor. An auction was announced for the purchase of a newly registered medication for neurofibromatosis patients supported by the charity fund “The Circle of Well” at the beginning of the year. The new RCMG diagnostic programme will identify patients who need the appropriate treatment. 

The RCMG laboratory of epigenetics has developed a methodology for the diagnostics of neurofibromatosis. It is based on two methods: New Generation Sequencing (NGS) and MLPA. The combination of methods makes it possible to establish a diagnosis even in complicated cases where a single examination will not reveal the genetic cause of the disease. Diagnostics is free of charge for patients. 

“Doctors from thirty regions of the country joined the programme in the first weeks of its launch. The most active regions referring patients are St. Petersburg, Chechen Republic, Orenburg Oblast, Sverdlovsk Oblast, Novosibirsk oblast, North Ossetia Republic, Chelyabinsk Oblast, Altai Krai,” – said Vladimir Strelnikov, the Head of the epigenetics laboratory, holder of an advanced doctorate in biological sciences.
“Neurofibromatosis has already been confirmed in sixty two patients”. 

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