Vocal cord paralysis as a presenting sign of autosomal recessive spinocerebellar atrophy type 10

Acquired vocal cord paralysis (VCP) is caused by dysfunction or injury of one or both recurrent laryngeal nerves. Here we report a 41-year-old man with spinocerebellar atrophy, autosomal recessive type 10 (SCAR10) due to an autosomal recessive mutation in the ANO10 gene, with VCP as the presenting symptom. He later developed ataxia and speech disturbance.

Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex

BackgroundFetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We aimed to further define the set of genes involved.MethodsWe performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature.ResultsWe identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in the kinesin family member 21A gene (KIF21A) was found.ConclusionOur study underlines the broad locus heterogeneity of FA with well-established and atypical genotype–phenotype associations. We describe KIF21A as a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets.

Somatic Hypermutation Defects in Two Adult Hyper Immunoglobulin M Patients

Hyper immunoglobulin M (HIGM) syndrome is a rare disorder of the immune system with impaired antibody functions. The clinical picture of the patients varies according to the underlying genetic variation. In this study, we identified two novel variants in AID and UNG genes, which are associated with autosomal recessive type HIGM, by targeted next generation sequencing (NGS) panel. A biallelic 11 base pair deletion (c.278_288delATGTGGCCGAC) in the coding sequence of activation-induced cytidine deaminase (AID) gene was identified in a 36-years-old patient. Biallelic two base pair insertion in exon 7 of Uracil nucleoside glycosylase (UNG) gene (c.924_925insGG) was identified in 40-years-old patient. Both variants were confirmed by Sanger sequencing. HIGM, like many of the other primary immunodeficiencies, is a rare and difficult-to-diagnose entity with heterogeneous clinical phenotypes. It should be suspected in patients with a history of early-onset recurrent respiratory infections, enlarged lymph nodes and autoimmune disorders. There might be a delay in diagnosis until adulthood especially in subtle cases or if HIGM is not included in the differential diagnosis due lacking of awareness. In this regard, genetic testing with NGS-based diagnostic panels provide a rapid and reasonable tool for the molecular diagnosis of patients with immunodeficiencies and hence, decrease the time to diagnose and prevent infection-related complications associated with increased morbidity and mortality.

Bilateral Severe Genu Varum in Dyggve-Melchior-Clausen Syndrome – A Case Report

Introduction: Dyggve-Melchior-Clausen (DMC) syndrome was described in 1962 as an autosomal recessive type of spondyloepimetaphyseal dysplasia associated with mental retardation. Dymeclin (DYM) gene on chromosome 18q12.1 that encodes for DYM protein which is expressed in cartilage, bone, and brain is mutated in DMC. Case Report: A 6 year -old male child presented with bilateral gradually progressive genu varum deformity of 4 years’ duration. There was no significant past medical and family history. A plain radiograph of his knee, pelvis, and spine shows some classical signs of skeletal dysplasia. A plain radiograph of the pelvis with both hips shows a classical semilunar, irregular lacy appearance around the iliac crest which is a pathognomonic radiological sign of this syndrome. Conclusion: The radiographic lacy appearance of iliac crests and generalized platyspondyly with double-humped end plates are pathognomonic of DMC. Keywords: Genu varum, Dyggve-Melchior-Clausen syndrome, spondyloepimetaphyseal dysplasia.

Hereditary tubulopathies accompanying polyuia

Tubulopathies are a group of heterogeneous diseases that are manifested in the malfunction of the renal tubules. This review addresses tubulopathies associated with polyuria syndrome, namely renal glucosuria syndrome, nephrogenic diabetes insipidus and pseudohyperaldosteronism. Types of renal glucosuria are described, namely: type A, type B and the most severe type 0. Type A is characterized by a low filtration threshold and low glucose reabsorption. The type of inheritance is autosomal recessive. Type B, autosomal dominant, is characterized by uneven activity of glucose transport, in which its reabsorption is reduced only in some nephrons. That is, normal reabsorption of glucose is maintained, but the filtration threshold of the latter is reduced. Type 0 with a severe course is characterized by complete inability of epithelial cells of the proximal tubules to reabsorb glucose. Nephrogenic diabetes insipidus is a rare inherited disease caused by impaired response of the renal tubules to antidiuretic hormone (ADH). Depending on the degree of inability to concentrate urine, there are complete and partial forms. It is divided into nephrogenic diabetes insipidus type I (X-linked recessive); nephrogenic diabetes insipidus type II (autosomal recessive and autosomal dominant) and nephrogenic diabetes insipidus syndrome with dementia and intracerebral calcifications (type of inheritance remains unknown). Children with autosomal recessive type of inheritance suffer from the more severe disease course. Pseudohypoaldosteronism is characterized by a special condition of the renal tubules which is due to insufficient sensitivity of the tubular epithelium to aldosterone, which in turn leads to hyperaldosteronism, the development of hyponatremia, metabolic acidosis with hyperkalemia, polydipsia and polyuria, decreased sodium reabsorption and retardation of the child's physical development. The classification includes three syndromes of pseudohypoaldosteronism, namely: type I (PHA1), which is divided into PHA1A (autosomal dominant, renal), PHA1B (autosomal recessive, systemic); type II (PHA2; Gordon’s syndrome), type III (secondary), which develops as a result of renal pathology.

Orpha disease – FRASER syndrome (ORPHA:2052) in children: phenotype and genotype characteristics

Fraser syndrome (OMIM # 219000; ORPHA: 2052; ICD-10: Q87.0) is a rare, disease with an autosomal recessive type of inheritance is characterized by abnormalities in the development of the eyes, kidneys, larynx, ears, and bone systems (cryptophthalmos, syndactyly, abnormalities of the kidneys, urogenital tract, and respiratory system). The article presents current literature data on the phenotypic and genotypic features of Fraser syndrome, the management of patients with new opportunities for genetic diagnosis and treatment. The syndrome, described by D. Fraser in 1962, is caused by mutations in the FRAS1, FREM2, GRIP genes. The diagnosis of the Fraser syndrome phenotype is established in the presence of the main criteria (cryptophthalmos, syndactyly, abnormalities of the urinary and respiratory system, genitals, family history indicating a closely related marriage) and secondary (congenital malformations of the nose and ears, skull ossification defects, anorectal abnormalities, umbilical hernia, etc.). Molecular genetic testing proves a rare disease, requires genetic counseling. The management of patients is carried out jointly by an ophthalmologist, an otolaryngologist, an audiologist, a nephrologist, a urologist, a maxillofacial surgeon and other specialists.

BIOCHEMICAL AND PATHOPHYSIOLOGICAL ASPECTS OF DYSFERLIN- ASSOCIATED MUSCULAR DYSTROPHY

Dysferlin is a transmembrane calcium-binding protein of the ferlin-1-like protein family, which includes myoferlin Fer1L3, otoferlin Fer1L2 and other ferlins Fer1L4, Fer1L5, and Fer1L6 along with dysferlin itself. Dysferlin is synthesized in all cells of the body, but most actively – in the symplasts of striated muscle tissue. The full range of functions performed by this protein is not fully clarified, but the following have been clearly shown: participation in the post-injury repair of sarcolemma and intracellular vesicular systems, generation and maintenance of the correct functioning of the sarcolemmal T-tubule system, regulation of endo- and exocytosis and inflammation, participation in phagocytosis. Mutations in the dysferlin gene lead to the development of a number of neuromuscular diseases of the autosomal recessive type of inheritance called dysferlinopathies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy. These diseases are characterized by the impaired expression of mRNA and/or the function of the protein dysferlin in skeletal muscles, which is caused by mutations in the DYSF (dystrophy-associated fer-1-like) gene. Although rare, dysferlinopathy is characterized by continuous progression causing severe disability, which explains the importance of research and development of appropriate treatments, including gene therapy. The article presents information on the structure of dysferlin, the mechanisms of its normal functions, as well as the biochemical basis of the pathogenesis of dysferlinopathies.

Expanding the β-III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration

(1) Background: A non-progressive congenital ataxia (NPCA) phenotype caused by β-III spectrin (SPTBN2) mutations has emerged, mimicking spinocerebellar ataxia, autosomal recessive type 14 (SCAR14). The pattern of inheritance, however, resembles that of autosomal dominant classical spinocerebellar ataxia type 5 (SCA5). (2) Methods: In-depth phenotyping of two boys studied by a customized gene panel. Candidate variants were sought by structural modeling and protein expression. An extensive review of the literature was conducted in order to better characterize the SPTBN2-associated NPCA. (3) Results: Patients exhibited an NPCA with hypotonia, developmental delay, cerebellar syndrome, and cognitive deficits. Both probands presented with progressive global cerebellar volume loss in consecutive cerebral magnetic resonance imaging studies, characterized by decreasing midsagittal vermis relative diameter measurements. Cortical hyperintensities were observed on fluid-attenuated inversion recovery (FLAIR) images, suggesting a neurodegenerative process. Each patient carried a novel de novo SPTBN2 substitution: c.193A > G (p.K65E) or c.764A > G (p.D255G). Modeling and protein expression revealed that both mutations might be deleterious. (4) Conclusions: The reported findings contribute to a better understanding of the SPTBN2-associated phenotype. The mutations may preclude proper structural organization of the actin spectrin-based membrane skeleton, which, in turn, is responsible for the underlying disease mechanism.

INTERETHNIC ASSOCIATIONS OF INCREASED HEART RATE AS A FACTOR OF CARDIOVASCULAR RISK. PART 2: GENETIC MARKERS

Purpose. To study the genetic aspects of increased heart rate (HR) in representatives of various ethnic groups living in Mountain Shoria. Material and Methods. The study involved residents of the villages of Mountain Shoria aged 18 years and older. Included are 901 people – representatives of indigenous nationality (Shors), 408 people – of nonindigenous nationality. The groups did not differ by gender and age. The analysis was carried out depending on the increased level of heart rate (over 80 beats/min). Typing of polymorphic sites of the ACE (I/D, rs4340), ADRB1 (p.145A> G, Ser49Gly, rs1801252), ADRA2B (I/D, rs28365031), MTHFR (c.677C> T, Ala222Val, rs1801133) and NOS3 (VNTR, 4b/4a) was carried out using polymerase chain reaction. The association of different genotypes with heart rates above 80 beats/min was judged by the odds ratio in five inheritance models (codominant, dominant, recessive, overdominant and log-additive), and its 95% confidence interval was calculated. Results. Ethnic features of the prevalence of increased heart rate have been established depending on the polymorphism of candidate genes involved in the pathogenesis of arterial hypertension. The respondents of the indigenous ethnic group had a high probability of developing tachycardia determined by the carriage of the C/T genotype of the MTHFR gene according to an overdominant type of inheritance [OR = 2.46]. Allele D of the ACE gene determined the tendency to the development of this pathology according to the recessive type of inheritance [OR = 1.91]. However, among young people and men, carriage of a prognostically unfavorable D/D genotype of this gene was associated with a high risk of increased heart rate [OR = 3.34] and [OR = 4.62], respectively. In a cohort of non-indigenous nationality, the heterozygous genotype I/D of the ACE gene determined the likelihood of tachycardia by an overdominant type of inheritance [OR = 2.08]. Conclusions. Most epidemiological studies show a significant difference in the contribution of the studied polymorphisms to the appearance of increased heart rate for various ethnic groups. For a small population of Mountain Shoria, genetic features of the development of tachycardia have been established. In this regard, it is advisable to take into account national characteristics when determining individual risk, and apply personalization to correction programs.