3 research outputs found
AUTOSOMAL RECESSIVE PERIPHERAL NEUROPATHY WITH NEUROMYOTONIA (ARAN-NM): DESCRIPTION OF A CLINICAL CASE CONFIRMED BY A MUTATION IN THE HINT1 GENE
Autosomal recessive peripheral neuropathy with neuromyotonia (ARAN-NM) is a relatively newly described disease associated with mutations in the HINT1 gene. It accounts for a significant part of the poorly differentiated forms of axonal polyneuropathies. We present the first in Russia description of the genetically confirmed case of ARAN-NM in a boy aged 14 years and 11 months without the hereditary-tainted anamnesis. On presentation, the patient experienced progressive distal muscular weakness, asymmetric foot deformity, gait disorders and minimal manifestations of neuromyotonia (stiffness in the fingers). During examination, we detected an increase in the level of creatine phosphokinase up to 635 U/l, a disturbance of conduction of motor and, to a lesser extent, sensory fibers of the peripheral nerves (according to the stimulation electromyography, EMG), denervation-reinnervation changes, single positive acute waves, fibrillation potentials, complex repeated discharge (according to the data of needle EMG). In the study of exome, a homozygous mutation c.110G>C, p.R37P was determined in exon 01 of the HINT1 gene, which confirmed the presence of ARAN-NM. A molecular-genetic examination of the patient's immediate relatives was carried out. The described case is compared with literature data. An overview of currently available information on ARAN-NM is provided. Diagnostic criteria of the disease are presented
Magnetic resonance imaging for diagnosing a rare disease: incontinentia pigmenti (Bloch–Sulzberger syndrome) on the example of a clinical case
Incontinentia pigmenti, also known as Bloch–Sulzberger syndrome, is a rare hereditary disease characterized by typical skin rashes and involvement of other organs and systems. Magnetic resonance imaging stands as the primary method for visualizing the structural pathology of the brain and predicting neurological manifestations in an affected child.
Diagnosing incontinentia pigmenti predominantly falls within the domain of dermatologists; verification is performed by molecular genetic analysis of the IKBKG gene. This study involved magnetic resonance imaging of the brain in a patient with skin rashes, characteristic of Bloch–Sulzberger syndrome, and deletion in the IKBKG gene, where numerous foci of ischemia, hemorrhages, and lesions of the tracts were detected.
Magnetic resonance imaging of the brain in patients with Bloch–Sulzberger syndrome is used to evaluate the severity of damage to the brain substance, which makes it possible to explain the cause of neurological symptoms and correct habilitation, as well as predict the development of the child
Clinical and Genetic Characteristics of Pediatric Patients with Hypophosphatasia in the Russian Population
(1) Hypophosphatasia (HPP) is a rare inherited disease caused by mutations (pathogenic variants) in the ALPL gene which encodes tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by impaired bone mineral metabolism due to the low enzymatic activity of TNSALP. Knowledge about the structure of the gene and the features and functions of various ALPL gene variants, taking into account population specificity, gives an understanding of the hereditary nature of the disease, and contributes to the diagnosis, prevention, and treatment of the disease. The purpose of the study was to describe the spectrum and analyze the functional features of the ALPL gene variants, considering various HPP subtypes and clinical symptoms in Russian children. (2) From 2014–2021, the study included the blood samples obtained from 1612 patients with reduced alkaline phosphatase activity. The patients underwent an examination with an assessment of their clinical symptoms and biochemical levels of TNSALP. DNA was isolated from dried blood spots (DBSs) or blood from the patients to search for mutations in the exons of the ALPL gene using Sanger sequencing. The PCR products were sequenced using a reagent BigDye Terminator 3.1 kit (Applied Biosystems). Statistical analysis was performed using the GraphPad Prism 8.01 software. (3) The most common clinical symptoms in Russian patients with HPP and two of its variants (n = 22) were bone disorders (75%), hypomyotonia (50%), and respiratory failure (50%). The heterozygous carriage of the causal variants of the ALPL gene was detected in 225 patients. A total of 2 variants were found in 27 patients. In this group (n = 27), we identified 28 unique variants of the ALPL gene, of which 75.0% were missense, 17.9% were frameshift, 3.6% were splicing variants, and 3.6% were duplications. A total of 39.3% (11/28) of the variants were pathogenic, with two variants being probably pathogenic, and 15 variants had unknown clinical significance (VUS). Among the VUS group, 28.6% of the variants (7/28) were discovered by us for the first time. The most common variants were c.571G > A (p.Glu191Lys) and c.1171del (Arg391Valfs*12), with frequencies of 48.2% (13/28) and 11% (3/28), respectively. It was found that the frequency of nonsense variants of the ALPL gene was higher (p < 0.0001) in patients with the perinatal form compared to the infantile and childhood forms of HPP. Additionally, the number of homozygotes in patients with the perinatal form exceeded (p < 0.01) the frequencies of these genotypes in children with infantile and childhood forms of HPP. On the contrary, the frequencies of the compound-heterozygous and heterozygous genotypes were higher (p < 0.01) in patients with infantile childhood HPP than in perinatal HPP. In the perinatal form, residual TNSALP activity was lower (p < 0.0005) in comparison to the infantile and childhood (p < 0.05) forms of HPP. At the same time, patients with the heterozygous and compound-heterozygous genotypes (mainly missense variants) of the ALPL gene had greater residual activity (of the TNSALP protein) regarding those homozygous patients who were carriers of the nonsense variants (deletions and duplications) of the ALPL gene. Residual TNSALP activity was lower (p < 0.0001) in patients with pathogenic variants encoding the amino acids from the active site and the calcium and crown domains in comparison with the nonspecific region of the protein