Myopathy GNE: Ways to Resolve Conflict

УДК 615.01

Myopathy GNE: Ways to Resolve Conflict

Kosykh Alexander Vyacheslavovich

Teacher, pharmacist- organizer,

clinical pharmacologist

FSBEI of HE «Stavropol State Medical University» Essentuksky branch

(Russia, Essentuki)

Email: alekskosyx@mail.ru

The article examines the issues of diagnosis, treatment and conflict resolution in patients with myopathy-GNE.Nonaka myopathy is a rare distal myopathy with late onset and autosomal recessive inheritance, first described in 1981, also known as distal myopathy with framed vacuoles and GNE myopathy. The concept of GNE myopathy is broader, including 2 allelic variants, caused by mutations in the GNE gene mapped to chromosome 9p. This gene is also responsible for the development of an inherited form of inclusion myositis.

Key words: Nonaka myopathy, GNE gene, GNE-myopathies

Миопатия GNE-способы разрешения конфликта

Косых Александр Вячеславович

Преподаватель, провизор-организатор,

клинический фармаколог

ФГБОУ ВО «Ставропольский государственный медицинский университет» Ессентукский филиал

(Россия, Ессентуки)

Электронная почта: alekskosyx@mail.ru

В статье изучаются вопросы диагностики, лечения и разрешения конфликта у больных с миопатией-GNE. Миопатия Нонака - редкая дистальная миопатия с поздним дебютом и аутосомно-рецессивным наследованием, впервые описанная в 1981 г., также известная как дистальная миопатия с обрамленными вакуолями и GNE-миопатия. Понятие GNE-миопатии более широкое, включающее 2 аллельных варианта, обусловленных мутациями в гене GNЕ, картированном на хромосоме 9р. Этот ген также ответственен за развитие наследственной формы миозита с включениями.

Ключевые слова: миопатия Нонака, ген GNE, GNE-миопатии

Presented are the clinical and genetic characteristics of 9 patients with Nonaka myopathy (GNE-myopathy) from Russia. As a result of exome sequencing, 11 different mutations in the GNE gene were registered, 8 of which were described earlier, and 3 - Cys203Ser, Met263CysfsTer, and a deletion of an entire gene - were identified for the first time. The features of clinical manifestations in patients of the formed sample are described.

Nonaka myopathy is a rare distal myopathy with late onset and autosomal recessive inheritance, first described in 1981, also known as distal myopathy with framed vacuoles and GNE myopathy. The concept of GNE myopathy is broader, including 2 allelic variants caused by mutations in the GNE gene mapped to chromosome 9p. This gene is also responsible for the development of an inherited form of inclusion myositis.

The gene contains 13 coding exons. Its protein product, the bifunctional enzyme uridyldiphosphate-acetylglucosamine-2-epimerase-acetyl-manosaminase, participates in various biochemical processes, including catalyzing the first 2 stages of sialic acid synthesis in tissues.

The age of debut in Nonaka myopathy has a wide age range from 10 to 61 years (average age 28 years), which is manifested by weakness and malnutrition of the muscles of the anterior leg group with the development of steppage. The disease has a steadily progressive slow course with a gradual spread of motor deficit to the proximal muscle groups of the legs and pelvic girdle. The muscles of the hands are involved in the process after a few years. A feature of this variant of myopathy is the preservation of the quadriceps muscle, which is usually not affected even in the advanced stages of the disease, which can be clearly seen with dynamic visualization of the muscles. Cardiomyopathy, respiratory disorders, and neck muscle weakness have been reported in isolated reports and only in the later stages of the disease. Usually, patients lose the ability to walk on their own after 5-10 years from the moment of manifestation of the disease.

Analysis of the phenotype of patients with point mutations in a homozygous state showed a pronounced intrafamilial variability, which suggests only a partial dependence of clinical manifestations and their severity on the type of mutation. A common problem with rare diseases is the difficulty of conducting representative studies with obtaining reliable clinical and genetic correlations or their absence.

Nonaka myopathy is a rare genetic variant of distal myopathy with an autosomal recessive mode of inheritance. It is believed that the main pathogenetic mechanism of the disease is a violation of the sialation of various substrates in the muscles.

Today, more than 200 mutations in the GNE gene have been described in patients with the discussed form of distal myopathy. Most of the patients are found in Japan (> 400), although the disease occurs around the globe. Major mutations have been identified in some countries. Thus, in 86.2% of patients from Japan, mutations leading to amino acid substitutions Val603Leu and Asp207Val are most often found. In the countries of the Middle East, the Met743Thr mutation was found in Israelis, Arabs, and Karaites, which with a high probability may turn out to be major with an increase in the number of patients examined. When examining patients from China, some authors did not find major mutations in GNE myopathy, while others showed that Asp207Val mutation was recorded in one third of patients.

Treatment with sialic acid in the form of an oral sustained-release drug (SA-ER). Preliminary results showed that serum free sialic acid levels doubled. There was a statistically significant slowdown in the progression of upper limb weakness over a short treatment period.

The results of 48 weeks of treatment with SAER are still being studied. A phase I study with metabolic drugs (ManNAc) was also completed. A phase 2 study is pending at the US National Institutes of Health. Will these metabolic changes bypassing the defect be sufficient to stop the progression of the disease or restore muscle function? At this stage, there is no definite answer to this question, but research is ongoing.

If, in fact, a lack of healthy genes in muscle is critical to the progression of the disease, gene therapy should be considered as a treatment. The laboratory of our institute under the guidance of prof. Mitrani-Rosenbaum is working hard to develop a similar therapy, using viruses to deliver genes to muscles. A model was developed based on wild-type human GNE AAV8 regulated by a muscle creatine kinase stimulator (MCC). This model was injected intravenously into healthy mice and isolated stable intramuscular human GNE mRNA. The study of an experimental model in Japanese transgenic mice in order to find out whether this model is able to prevent or reverse the development of myopathy is currently ongoing.

LITERATURE:

1. Nonaka I., Sunohara N., Ishiura S., Satoyoshi E. Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 1981

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a unique disorder in Iranian Jews.

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of phenotypic variability in GNE myopathy. Neurol Genet 2019;