Background. Myotonic dystrophy type 1 (DM1) is a hereditary slowly progressive multisystem disease with an autosomal dominant mode of inheritance, caused by the expansion of trinucleotide (CTG)_n repeats in the 3’ untranslated region of the DMPK gene. Among the clinical manifestations of DM1, an important place is occupied by symptoms of damage to the central nervous system, in particular cognitive and emotional disorders.

Aim. To evaluate the type of cognitive and emotional impairments in patients with different forms of DM1 and their impact on quality of life.

Materials and methods. 60 patients with genetically confirmed DM1 were examined (average age 37.0 ± 12.4 years; 36 (60.0 %) of them were men). All patients underwent neuropsychological testing using the Montreal Cognitive Rating

Scale, Mini‑Mental State Examination, Addenbrooke’s III, Wechsler tests, pathfinding, symbolic and numeric modalities, Luria’s 10 Words, Frontal Dysfunction Battery; assessment of emotional disturbances using the Hospital Anxiety and Depression Rating Scale and the Apathy Scale; quality of life assessment –  36‑Item Short‑Form Medical Outcomes Study. Brain magnetic resonance imaging was performed in 53 patients to assess the severity of white matter lesions and gray matter atrophy.

Results. The study included 8 (13.3 %) patients with congenital, 19 (31.7 %) – childhood, 33 (55 %) – adult forms of MD1. The group of patients with the congenital form had the most severe cognitive deficits, especially in tests of executive functions and visuospatial perception. Cognitive impairment was also characteristic of the adult form, but to a lesser extent. Compared to controls, patients with DM1 were significantly more likely to exhibit apathy (p = 0.002) rather than anxiety and depression. In DM1, damage to both the white and gray matter of the brain was established, and a connection between damage to the gray matter and depression (r = 0.296) and apathy (r = –0.291) was revealed. The quality of life is largely influenced by emotional disorders (anxiety, r = –0.577; depression, r = –0.650; apathy, r = –0.545).

Conclusion. In patients with DM1, a typical pattern of cognitive impairment has not been identified; different domains of cognitive functions are affected. The greatest cognitive deficit is typical for the group of patients with the congenital form. A connection between damage to the gray matter of the brain and emotional disorders has been revealed.

The presence of the latter reduces the quality of life of patients with DM1.

Pathogenic heterozygous variants in the PIEZO2 gene cause distal arthrogryposis type 5 – a rare autosomal dominant disease, which is characterized by the development of congenital contractures, ophthalmoparesis, ptosis and restrictive respiratory disorders. We have presented clinical and genetic characteristics of seven Russian patients with distal arthrogryposis type 5  caused by previously described and newly identified nucleotide variants in the PIEZO2 gene. It was shown that the most severe clinical manifestations were found in patients with newly identified nucleotide variants c.8238G>A (p.Trp274Ter) and c.7095G>T (p.Trp2365Cys), while in patients with other previously described variants c.8181_8183delAGA (p.Glu2727del) and c.2134A>G (p.Met712Val) the clinical phenotype is more moderately expressed. The dynamics of phenotype formation were also noted. It has been shown that the disease progression may occur as the child grows and requires monitoring of this group of patients.

Aim. Evaluating pain sensation after C nociceptor activation with transdermal sinusoidal current wave stimulation protocol and skin biopsy.

Materials and methods. Healthy volunteers aged 20–30 years (17 females and 18 males) participated after having given their informed consent. Half‑sine wave pulses of 0.5 sec duration (1 Hz) were generated at intensities of 0.2 to 1 mA by a constant current stimulator. Apart from half‑sine wave stimulation, sine wave pulses of 60 sec duration (4 Hz) were generated at intensity of 0.2 mA also by the constant current stimulator (Digitimer Ltd, Welwyn Garden City, UK) controlled by DAPSYS 8 (www.dapsys.net). Moreover, we performed 3‑mm skin punch biopsies 10 cm above the lateral malleolus of the leg and in the middle of the volar side of the forearm to the volunteer’s group.

Results. Delivering transdermal sinusoidal half‑sine wave when trying to stimulate mechano‑sensitive C fibers, when the amplitude of the delivered wave is increased from 0.2 to 1 mA according to our protocol, pain sensation is also increased following the same scheme. If we observe a different scheme of activation in C fibers, this could be a sign of neuropathic pain. Considering the mechano‑insensitive C fibers of pain, when trying to stimulate them we expect increasing pain sensation and then familiarization, desensitization and reduction of pain sensation. As a result, if this scheme isn’t observed when sine wave is delivered transdermal with 1 min of duration, and we observe a different scheme, a C fiber neuropathy and neuropathic pain could be involved. Regarding the skin biopsies, a correlation between pain sensation of sine wave (delivered transdermal to stimulate mechano‑insensitive C fibers of pain on the forearm), and the nerve fiber density was observed. A correlation between the bifurcated fibers of the biopsy site and the pain sensation was observed when mechanosensitive and mechano‑insensitive fibers are stimulated, which needs further investigation. Also, a correlation between the remnant nerve fibers of subepidermal nerve plexus and mechano‑insensitive nerve fibers of pain is observed that also needs further investigation.

Conclusion. Skin biopsy and transdermal electrical stimulation are very promising available tools of diagnosing C fiber neuropathies and assessing neuropathic pain.

Duchenne muscular dystrophy is one of the most common inherited muscular dystrophies. The cause of this disease with an X‑linked recessive type of inheritance is mutations in the DMD gene, leading to the absence of the dystrophin protein this gene encodes or its impaired function. Loss of dystrophin leads to severe degenerative processes in patients, especially in muscle tissue, with impaired muscle function, loss of ability to move independently, respiratory failure, cardiomyopathies, etc.

The collective efforts of many researchers over the years since the 19^th century, when the diseases was described, not allowed to achieve a cure or significantly influencing the trajectory of the illness. The only notable impact on the disease course has come with the integration of corticosteroid medications into Duchenne muscular dystrophy therapy. While their application can decelerate disease progression and extend the average life expectancy up to 30–40 years, it comes with substantial adversely affects influencing patients’ quality of life.

Certain hopes were associated in recent decades with the development of etiotropic therapy for Duchenne muscular dystrophy, aimed at restoration of the dystrophin’s function. Some of such approaches were based on the overcoming of the effect of premature stop codons in the DMD gene using aminoglycoside antibiotics, ataluren, etc. Several subsequent studies were conducted to explore the applicability of exon‑skipping approaches in the dystrophin gene, aimed at excluding exons carrying pathogenic genetic variants. The rationale for these studies was the available information about a milder course of the disease associated with a truncated but functional dystrophin. The possibility of the pathology correction by means of introduction of the exogenous functional DMD gene copy from the outside (gene replacement therapy) has been under study since the beginning of the 20^th century. One of the most promising directions in recent years was the development of approaches related to genome editing, which, unlike the methods mentioned above, allows for the permanent correction of the underlying cause of genetic diseases. Some of corresponding drugs have already received approval, while others, related to gene therapy, are at the stage of clinical trials.

Single pulse transcranial magnetic stimulation is a non‑invasive method for assessing the integrity of the corticospinal tract in children with diseases of the central nervous system. The use of the method in a number of cases is associated with the development of reversible adverse events, the most dangerous of which is considered to be the provocation of epileptic seizures. An important aspect of the use of transcranial magnetic stimulation is the application of the unified safety questionnaire for children before procedures. Careful interpretation of the results of single pulse trans cranial magnetic stimulation in the pediatric population makes it possible to assess the degree of damage and predict the terms and volume of rehabilitation measures.

Aromatic L‑amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. The disease manifests in early childhood with nonspecific symptoms such as hypotension, movement disorders (oculogyric crisis, dystonia, hypokinesia), developmental delay and vegetative symptoms.

Currently, diagnostic criteria for this disease have been determined, as well as possible options for correcting the patient’s condition. However, often, the no specificity of AADC deficiency symptoms leads to a significant delay in diagnosis or even misdiagnosis in patients with AADC deficiency. Identification of patients with AADC deficiency will improve their quality of life due to possible syndromic treatment, facilitate their care and prolong life. In the absence of a correct diagnosis, children with AADC deficiency may be observed for a long time with diagnoses such as cerebral palsy or epilepsy and receive therapy that has no therapeutic effect or may lead to a worsening of the symptoms of the underlying disease.

Pathogenetic nucleotide variants at many genetic loci can cause conditions like cerebral palsy. Establishing the etiologic diagnosis is clinically important for optimal disease management and treatment.

The presented family case demonstrates a clinical polymorphism associated with variants in the EBF3 gene that impaired transcription regulation. The described variant c.703C>T (p.His235Tyr) in the EBF3 leads to severe motor and intellectual disability mimicking cerebral palsy.

Timely detection of monogenic diseases hiding under the mask of cerebral palsy will help to establish a timely diagnosis and conduct medical and genetic counseling to prevent recurrent cases in the family.

Zhu–Tokita–Takenouchi–Kim syndrome (ZTTK syndrome) is a rare autosomal dominant nuclear speckleopathy characterized by developmental delay, hypotonia, intellectual disability, facial dysmorphism in association with variable brain malformations, musculoskeletal abnormalities and ocular involvement. Currently, 87 cases of ZTTK syndrome have been described worldwide. The syndrome caused by mutations in the SON gene, located on the long arm of chromosome 21 (21q22.11). Nonsense and frameshift mutations have been described in the SON gene. Missense mutations, partial or whole gene deletions are less common.

The aim of the work is to analyze the clinical picture and molecular genetic results of patients with confirmed ZTTK syndrome and compare them with data from foreign literature.

We observed the one boy and two girls with ZTTK syndrome aged 13 months to 59 months, averaging about 38 months. DNA diagnostic was performed by next generation sequencing. All patients and all parents were confirmed by Sanger sequening. Three pathogenic variants were identified: c.5753_5756delTTAG (p.Val1918Glufs*87), c.1531del (p.Thr511Glnfs*9) and c.403delG (p.Glu135Asnfs*14). The first one was is most common, the other two are novel variants. Most patients had growth, motor and speech delay, seizures, hypotonia, congenital heart defects, urinary tract abnormalities and brain malformations. Comparative analysis of facial features in patients with ZTTK syndrome showed downslanting palpebral fissures, epicantal folds, broad or depressed nasal bridge, flared nares, smooth philtrum, thin upper lip and low set, rotated ears. The use of next generation sequencing as a first‑line test for research and diagnostic of ZTTK syndrome is advisable due to the pronounced clinical polymorphism.