Hereditary transthyretin amyloidosis is described in this review, including the TTR gene structure and mutation spectrum, the transthyretin protein structure and functions, the main clinical manifestations of transthyretin amyloidosis. Also the problems of differential diagnosis are discussed, the history of the spread of the disease among various ethnic groups is examined, information is provided on the current possibilities of pathogenetic and etiological treatment of the disease.

Transthyretin amyloidosis (ATTR-amyloidosis) is a systemic progressive fatal disease, for which a modifying therapy has recently been proposed that delays the progression of the disease and improves the patient’s quality of life. The delay in the diagnosis of ATTR-amyloidosis is associated with the heterogeneity of the manifestations of the disease, as well as insufficient awareness of doctors of different specialties about the disease. A review of recent studies on the symptomatology, diagnosis, molecular genetic characteristics of ATTR-amyloidosis and the most common forms of the disease with the predominant involvement of peripheral nerves and the heart, as well as the kidneys, gastrointestinal tract, and eyes is presented. The international consensus recommendations for the diagnosis of suspected ATTR-amyloidosis using modern methods that facilitate early and accurate diagnosis are discussed. The reasons and the most frequent misdiagnoses of ATTR-amyloidosis, which also lead to a delay in the timely appointment of therapy, are considered. Molecular genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy and cardiomyopathy. A diagnostic algorithm based on the initial symptoms and manifestations of the cardiovascular and nervous systems facilitates the identification of a patient with clinical suspicion of ATTR-amyloidosis by the general practitioner. Early diagnosis is critically important for patients with ATTR polyneuropathy, since the early prescription of Vyndaqel (tafamidis), registered in the Russian Federation in 2017, allows a significant clinical effect to be obtained. Timely administration of Vyndaqel significantly slows down the progression of the disease, improves the prognosis and quality of life in patients with ATTR polyneuropathy.

The problem of timely diagnosis and proper management of patients with cystic fibrosis is crucial not only in our country, but throughout the world. Experts of the Union of Pediatricians of Russia have considered various issues of etiology, pathogenesis, epidemiology, diagnosis, and treatment of this genetic disease in a modern light. Particular attention was paid to screening methods for early diagnosis of cystic fibrosis. The principles of complex therapy were justified, including rational use of antibacterial and mucolytic drugs and enzyme replacement therapy that significantly determine the disease prognosis.

The objective is to study the occurrence of common genetic factors of male infertility in men with reproductive problems, their combinations and spermatological characteristics. Materials and methods . 393 men with infertility in marriage were examined. According to the results of the cytogenetic study, the sample is divided into 3 groups: 135 men with numerical sex chromosome abnormalities; 58 male patients with a balanced structural rearrangement; 200 men with normal karyotype. Y chromosome microdeletions, CFTR gene mutations and CAG-repeats polymorphism of AR gene were analyzed. Results . The Y-chromosome microdeletions partially AZFc deletions were detected in 13 % male patients with sex chromosome abnormalities. A combination of chromosomal abnormalities with AZF deletions and/or CFTR gene mutations and long CAG repeats of AR gene was found in 19 % infertile men with balanced chromosome rearrangements. Infertile men with normal male karyotype presented the frequency of common genetic factors of male infertility was almost 2 times higher than the combined frequency of these factors in groups of patients with chromosomes abnormalities. Azoospermia in men with normal karyotype and patients with chromosome abnormalities was diagnosed with the same frequency (58 %). In all men who have identified the presence of two or more genetic factors of male infertility, severe forms of pathozoospermia (azoospermia and severe oligozoospermia) were found. Conclusion . The combination of genetic factors of male infertility is accompanied by severe forms of pathozoospermia that indicates a possible additive effect of negative effect on spermatogenesis and male fertility.

Cystic fibrosis (CF) is a systemic hereditary disease caused by a mutation of the CFTR gene and characterized by damage to the glands of external secretion and severe dysfunctions of the respiratory system. The “severe” genotypes are associated with more pronounced and early clinical manifestations. The “mild” genotypes are associated with a delayed onset of clinical manifestations.Methods. An analysis of the medical history of patients with asymptomatic CF from the Russian CF centers was carried out. Rectal biopsy specimens were used for intestinal current measurement (ICM) and forskolin-induced swelling assay in intestinal organoids. DNA for sequencing was isolated from the venous blood leukocytes.Results. 2 CF patients with genotypes F508del/c.1584+18672A>G (patient 1, 12 years old) and F508del/G509D-E217G (patient 2, 3 years old) were examined. The diagnosis was based on neonatal screening. The ICM assay showed a reduced function of the CFTR channel: ΔISC for forskolin was 12.33 ± 2.35 μA/cm2 in patient 1 and 25 ± 3.37 μA/cm2 in patient 2. The negative response to carbachol and histamine reflects the entry of potassium ions into the cells, which is typical for CF. The assay in intestinal organoids showed that the amount of functional protein on the apical membrane of the intestinal epithelium increases both under the action of the potentiator and the corrector in both patients. The greatest effect is observed when the VX-770 and VX-809 are used together.Conclusion. The ICM functional assay and the forskolin-induced swelling assay in intestinal organoids are sensitive enough to determine the residual functional activity of the CFTR channel and clarify the diagnosis in difficult cases. The studied genetic variants c.1584+18672A>G and G509D-E217G belong to class IV – VI mutations. The clinical picture corresponds to the manifestations of “mild” mutations. The studied patients still attend the Russian cystic fibrosis centers.

The DNA analysis revealed a transthyretin amyloidosis with a rare Phe53Leu mutation in a woman of 62 y.o. with the late onset progressive generalized axonal sensomotor neuropathy, dry eye syndrome, and an episode of severe unintentionally weight loss. The same mutation was found in her healthy 34 y.o. son, but not in a 42 y.o. daughter. The Congo red staining were negative in nerve and salivar gland biopsies samples. The reassessment of the transthyretin amyloidosis “red flags” showed that the patient fulfilled the criteria of the disease and the absence of amyloid deposition was not the ground to reject the hereditary cause of the condition. The reasons of the misdiagnosis are discussed.