Gene diagnosis of Strumpel's spastic paraplegia (SPG4) in Moscow

In the language of medical specialists around the world, ankylosing spondylitis has different names: ankylosing spondylitis (AS), Strumpell-Bekhterev-Marie disease. All of these concepts indicate a general pathology: inflammation of the intervertebral joints with a subsequent decrease in their mobility - ankylosis. This complication is caused by fusion of the articular ends due to their increase in size as the inflammatory process progresses. The fusion of the vertebrae locks the spinal column into a rigid bony sheath, making it immobile. The disease causes the patient to assume the classic bowed position (the so-called “begging pose”) and causes pain when trying to change the position of the body.

Statistics and etiology of the disease

The first mentions of cases of ankylosing spondylitis are found in medical records of the European Middle Ages. Doctors of that time were quite surprised to discover skeletons with characteristic ossification of the spine, the individual elements of which formed a strong “bone” column. In the mid-19th century, the disease became the subject of general medical study, as evidenced by surviving records of patient complaints and examinations of deceased people. The works of the Russian doctor Vladimir Bekhterev, the German Adolf Strumpel and the Frenchman Pierre Marie are accepted as the basis of etiology and are currently being studied in medical institutions.

Current statistics on ankylosing spondylitis indicate a gender link. In men it occurs 4-6 times more often and has a more aggressive, accelerated course than in women. The latter note:

• low degree of pain syndrome;
• preservation of full spinal function for a long time;
• arthritis occurs with long-term remission;
• signs of sacroiliitis (inflammation of the sacroiliac joint) are recorded relatively rarely.

The area of ​​development of the pathological process is the spine, large joints of the lower extremities and the sacroiliac joint. With extra-articular localization, the first signs of the disease are damage to the eyeballs in the form of redness of the sclera, inflammation of the iris or cornea. Characteristic signs are observed in 5-10% of patients, which in some cases makes it possible to make an accurate diagnosis at the initial stage of development of ankylosing spondylitis. Less common is an alternative onset of pathology in the form of inflammation of the walls of the aorta or muscle fibers of the heart muscle, developing against the background of an actively occurring pathological process in the joints of the spinal column.

Ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory disease of the spine (spondylitis) and sacroiliac joints (sacroiliitis), as well as peripheral joints (arthritis), entheses (enthesitis), in some cases the eyes (uveitis) and the aortic root (aortitis), which The disease usually occurs before the age of 40, and in more than 90% of cases the genetic marker HLA-B27 is detected [1,7].

Figure 1. Ankylosed spine.
History Anatomical and clinical descriptions of patients with AS date back to the 16th century.
The first description of this disease in the literature dates back to 1559, when the Italian anatomist and surgeon R. Colombo described in his book two skeletons with changes characteristic of AS. It was recently reported that three pharaohs of the 18th and 19th dynasties of Ancient Egypt (Amenhotep II, Ramses II and the latter's son Merenptah) also had radiographically confirmed AS. Probably the oldest documented familial case of the disease belongs to the Medici family (15th–16th centuries AD), who ruled Florence. AS was discovered in two representatives of this genus after opening the family crypt and comparing pathological findings with the description of their disease by contemporaries. The first qualitative descriptions of AS are considered to be the reports of the Russian neurologist V.M. Bekhterev in 1893, the German doctor A. Strumpell in 1897, the French doctor P. Marie in 1898. Therefore, AS is called ankylosing spondylitis and Marie-Strumpell disease. Figure 2. Booklet by the American doctor D. Thacker. He described the clinical case of patient Leonard Trask with spinal deformity, a clinical picture similar to AS. In 1833, Trask fell from his horse, which aggravated his condition and resulted in severe deformity.

Sh.F. Erdes lists the following names that AC bore during its history:

• Bekhterev's disease;
• ankylosing spondylitis;
• ankylosing spondylitis;
• Marie-Strumpel's disease;
• Strumpell-Bekhterev-Marie disease;
• chronic ankylosing inflammation of the vertebral column (Strümpell, 1897);
• pelvospondylitisossificans (Romanus, 1951);
• rheumatoid ossifying pelvispondylitis;
• rheumatoid spondylitis (ARA 1941);
• bamboo spine;
• poker back;
• spondylitis ankylopoetica (Fraenlel, 1904);
• spondylitis deformans (Goldwaite, 1899);
• atrophic spondylitis;
• spondylarthritis ankylopoetica;
• ankylosing spondyloarthritis;
• atrophic ligamentous spondylitis;
• ossifying ligamentous spondylitis (Knaggs, 1924);
• rhizomelic spondylosis (Marie, 1898);
• spondylitis rhizomelique;
• syndesmophite ossificante (Simmonds, 1931);
• ankylosing spondylitis (Tichy, 1961; ARA, 1963).

The current concept of AS is associated with the development of radiography.
In the 1930s, Krebs, a German radiologist, studied a relatively large number of patients with AS and described that radiographic sacroiliitis was present in almost all of these patients and occurred in the early stages of the disease. These data were subsequently confirmed by Forestier in France and Scott in England and formed the basis for the central role of radiographic sacroiliitis in the criteria for AS. In the 70s, Moll and Wright created the concept of a group of interrelated diseases (the so-called seronegative spondyloarthritis), which included: AS, psoriatic arthritis, reactive arthritis, arthritis associated with Crohn's disease, Whipple's disease, Behçet's disease. Negative rheumatoid factor is typical for these diseases. They were considered related due to the presence of a putative genetic background, similar clinical manifestations such as involvement of the sacroiliac joints or spine, peripheral joints, skin and mucous membranes, and the absence of subcutaneous nodules. Later, Behçet's disease and Whipple's disease were excluded from the group of spondyloarthritis. In 1990, the first classification criteria for seronegative spondyloarthritis of Amor appeared, and soon the second, developed by the European Group for the Study of Spondyloarthritis in 1991. In 1995, an international group of experts on AS (ASAS - ASsesment in Ankylosing Spondylitis working group) was formed at the European Anti-Rheumatic League (EULAR), which began to coordinate the development of a new classification, diagnostic methods, monitoring and treatment of spondyloarthritis (Figure 3) [2]. . Figure 3. Criteria for axial spondyloarthritis proposed by ASAS experts.

Epidemiology

The prevalence of AS varies widely: from 0.1% to 1.4% (Norway). In none of the rheumatic diseases is there such a clear linkage to the histocompatibility antigen as in AS: HLA-B27 is detected in 90-95% of patients. The prevalence of AS depends on the frequency of HLA-B27 carriage. HLA-B27 is more common in the population of northern countries. AS is prevalent primarily among young men (15-30 years old), the disease is less common in women, the ratio of men to women is 2:1[3]. In 80% of patients, the first symptoms appear before the age of 30 years, and at the age of over 45 years they are detected for the first time in less than 5% of patients [5]. .

Genetic aspects

Twin studies confirm that susceptibility to AS is almost entirely determined genetically. Thus, two studies claim that AS is inherited in more than 90% of cases. Heritability of clinical manifestations of the disease is also significant and includes age at first onset of symptoms (heritability 40%), disease activity measured using the widely used BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index) questionnaires (heritability 51 % and 76%, respectively), as well as radiological severity (heritability 62%). The association of HLA-B27 with AS is one of the strongest genetic associations with a common disease currently known. However, studies in families suggest that less than 50% of the overall genetic risk is due to isolated HLA-B27 mutations, and it is likely that several other genes are involved. First-degree relatives have a 5- to 16-fold higher risk of AS than HLA-B27-positive individuals in the general population, further confirming the existence of other modifying risk factors for AS other than HLA-B27. The most likely models of the disease suggest that genes modifier the effect of HLA-B27 determine the risk of AS in its carriers. Studies of the risks of recurrence of AS (in relatives of the patient) show that this disease cannot be considered as monogenic. The risk of recurrence of the disease in a family depends on its genetic pattern. The frequency of monogenic diseases decreases by approximately half with each distance from the proband along the family tree. The frequency of polygenic diseases decreases by approximately the square root of the original frequency under the same conditions. AC appears to fall somewhere between these two models; HLA-B27 almost completely determines the inheritance of AS, but its penetrance is largely influenced by other genes. Findings from studies of families with AS suggest that a moderate number of genes with significant effects are involved; the closest models likely suggest a set of five genes, but other fitting models suggest a range of 3 to 9 genes involved. It is likely that in addition to the major HLA-B27, there are a small number of genes with a moderate determining effect and a large number of genes with a small effect. Thus, large families with multiple cases of disease, typical of diseases with a monogenic etiology, are extremely rare in AS [5].

MHC genes

The major histocompatibility complex (MHC) on the short arm of chromosome 6 is closely associated with AS. Although most of the genetic associations of this locus depend on the association of AS with HLA-B27, the interactions are apparently much more complex.

1. HLA-B27 and B27 subtypes. Approximately 8% of Europeans are carriers of HLA-B27, compared with, for example, an incidence of approximately 5% in the Chinese. HLA-B27 carriage is more common in northern Europeans and is rare in Africans and Australian Aborigines. The prevalence of AS generally corresponds to the prevalence of HLA-B27 in the population. In most studies, 80% to 95% of patients with AS are HLA-B27 carriers. Despite this, only a few HLA-B27 carriers develop AS. Thus, screening for HLA-B27 carriage in the population is not valuable, but in patients with back pain it is a useful component of the diagnostic process. There is compelling evidence in specific populations that different HLA-B27 subtypes have varying strengths of association with the occurrence of AS. There are now up to 45 HLA-B27 subtypes. The rapid increase in the number of subtypes over the past 5 years is associated with the increased use of DNA-based HLA typing. In most cases, the described subtypes occurred only in some unaffected individuals, and therefore it is impossible to say whether they are associated with AS. However, some subtypes are common enough to be relatively comparable to their association with AS. AS (not only undifferentiated spondyloarthritis) is reported to occur in the presence of the following subtypes: B * 2701, * 2702, * 2703, * 2704, * 2705, * 2706, * 2707, * 2708, * 2710, * 2714, * 2715, and * 2719.
2. Other histocompatibility complex genes. MHC is localized on chromosome 6 (6p21.3) and contains about 220 genes, many of which perform immunoregulatory functions. There is compelling evidence that the MHC contains several other non-HLA-B27 genes that determine disease susceptibility, including HLA-B60 (the HLA-B allele) as well as non-HLA-B genes. The association of HLA-B60 with AS is much weaker than the association of HLA-B27; the odds ratio for it is 3.6. So it is unknown whether HLA-B60 is a disease-causing gene or a marker for an MHC haplotype that carries other disease-causing genes. The association of the HLA-B60 gene with disease is well established among HLA-B27-positive patients, and there is also evidence demonstrating its role in cases of HLA-B27-negative AS [5] .

Non-MHC genes

Mechanism of disease development

Despite active study and collected statistics, the origin of the disease remains unclear. Most experts are inclined to the version of genetic predisposition: the presence of the HLA-B27 antigen in patients passes to first-degree relatives in 25-30%, and occurs within the family only in 7-8% of cases. In residents of the equatorial regions, the pathology is practically not diagnosed, and as we move towards the poles, its frequency increases to 30-40%.

Describing the causes of ankylosing spondylitis, experts talk about an inadequate immune response to the musculoskeletal system of the spinal column. Its tissues are perceived by the body as foreign, and the effect of their rejection occurs, characteristic of all autoimmune diseases. The subsequent inflammatory process is triggered by a cytokine substance consisting of TNF-α peptide signaling molecules called tumor necrosis factor alpha. Due to its active influence, the spine gradually becomes ossified and immobilized. Confirmation of the negative effect of the TNF-α molecule is the maximum concentration of the cytokine in the sacroiliac joint.

Concomitant pathologies or unfavorable external factors can accelerate the transition of ankylosing spondylitis to new stages. These usually include chronic infectious diseases, hypothermia, pelvic or spinal injuries, the consequences of which could not be completely eliminated. At risk are persons with hormonal disorders, infectious and allergic diseases, chronic inflammatory processes in the pelvic and intestinal organs.

Detailed description of the study

Hereditary spastic paraplegia (HSP), or Strumpel's disease, includes a group of rare hereditary diseases that are characterized by:

1. The development of lower spastic paraparesis - a decrease in strength in the muscles of the lower extremities, up to its complete absence;
2. Progressive deterioration in walking;
3. Hyperflexion is a pathological strengthening of reflexes.

Basically, the disease is inherited in an autosomal dominant manner, i.e. develops in offspring in approximately 50% of cases. Cases of autosomal recessive inheritance (the disease manifests itself only when a “defective” gene is inherited from both parents) and X-linked inheritance, when the “defective” gene is located on the X chromosome, have also been described.

The most important clinical manifestation of Strumpel's disease is lower spastic paraparesis, as a result of which the muscles stop receiving nerve impulses and gradually lose muscle strength. Other neurological symptoms may also develop, for example, oculomotor, cognitive impairment, etc.

To date, 32 chromosomal regions are known, disturbances in which can lead to the development of pathology.

10 loci (regions) have been described for autosomal dominant Strumpel disease, 14 loci for the autosomal recessive form, and 3 for the X-linked form.

The SPG4 gene is localized in the chromosomal region 2p22.3 and encodes the protein spastin. More than 500 mutations have been identified in the SPG4 gene. This gene is involved in the development of approximately 40% of cases of all autosomal dominant spastic paraplegia.

The spastin protein is a member of the AAA family of proteins, a special class of ATPases with multiple types of cellular activities. These proteins are involved in a number of cellular processes, such as the cell cycle, intracellular transport, proteolysis (the process of protein breakdown). Spastin is involved in the processes of formation and destruction of special protein complexes, which are important for maintaining the integrity of neurons and transmission of nerve impulses.

Gene mutations change the structure of the spastin protein, as a result of which neurons are damaged and cannot fully conduct nerve impulses.

The average age of onset of clinical manifestations of the disease is 30-40 years, although the disease can also be diagnosed in a child.

The severity of symptoms and how quickly they progress can vary greatly. The disease may progress slowly from birth and stabilize by adolescence. In this case, it is possible to maintain the ability to move independently. In other patients the course is continuous.

The presence of characteristic clinical manifestations of the pathology, as well as a family history, suggests Strumpel’s spastic paraplegia. Genetic testing is used to confirm a preliminary diagnosis.

Symptoms in men and women

Among the signs of the disease, all patients without exception note pain in the back, legs and buttocks with a simultaneous feeling of stiffness in the spine. Discomfort increases in the second half of the night due to prolonged lying down. Also among the symptoms of ankylosing spondylitis are chest stiffness, pain in the heel bones, and discomfort when trying to change body position.

In most cases, signs of ankylosing spondylitis are detected without visible external causes. But pathology has a number of precursors that cannot be ignored. Among them:

• stiffness of the back, noticeable limitation of movements, which can be overcome with the help of a hot shower;
• weakness in the morning, fatigue;
• mild back pain without clear localization;
• pain in the sacrum, pelvis and ribs, which gets worse when coughing, sneezing or talking;
• discomfort when sitting on a hard surface;
• changes in gait associated with heel pain;
• redness of the eyes, accompanied by itching and burning.
• decreased range of motion of the cervical spine.

Often, ankylosing spondylitis “hides” under the signs of rheumatoid arthritis with pain in the heart and small joints of the extremities. Sometimes a disease at the acute stage can be discovered by chance during a comprehensive diagnosis of the body or when other diseases are suspected. X-rays show ossification and fusion of the intervertebral joints, which allows us to speak with confidence about the development of pathology of the musculoskeletal system.

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What is Strumpel's disease

Strumpell's disease, also known as familial spastic paraplegia, is a pathological process from the group of degenerative myelopathies. This disease is characterized by damage to the anterior and lateral columns of the spinal cord. In this case, the spinal structures are affected mainly in the lumbar spine, in more rare cases in the thoracic region.

This disease affects the pyramidal tracts of the spinal cord. As a result, the central nervous system is damaged, resulting in disorders of the musculoskeletal system. In the vast majority of cases, Strumpel's disease affects the lower extremities; the mechanism of its development is progressive paraparesis of the lower extremities. As the disease progresses, hypertonicity of the muscle structures of the lower extremities increases.

According to statistics, the manifestation of the disease occurs between the ages of 10 and 30 years. However, in a broad sense, the onset of Strumpel's disease is possible at any age from birth to 80 years. As for the causes of this pathology, we are talking about a genetic predisposition caused by gene mutations.

The classification of the pathological process is closely related to the reasons for its development and includes the following types of spastic paraplegia:

• autosomal dominant – the disease is observed in one of the parents, the risk of its development in the child is about 50%;
• autosomal recessive - both parents are carriers of the defective gene (only carriers), the risk of pathology in the child is about 25%;
• X-linked - only women are carriers of the defective gene, however, the disease develops in a male child.

Possible complications

In the absence or voluntary refusal of the patient to treat ankylosing spondylitis, the pathology develops as follows:

• pain in the back and hips becomes constant, intensifying with prolonged rest of the body;
• the spinal column loses flexibility and the patient’s movements become difficult;
• it is more difficult for the patient to breathe;
• the inflammatory process moves from the pelvic area higher to the chest.

With moderate physical activity, the pain becomes less pronounced, while in a prolonged state of rest the discomfort intensifies. In the absence of treatment and ignoring the signs of the disease, the spine takes on a slightly bent shape, the arms are deformed at the elbows, the back is slouched, and the legs are bent at the knees. Over time, these changes become irreversible. The pathology significantly complicates the work of internal organs, as a result of which pneumonia, osteoporosis, eye damage with loss of vision, damage to the vascular system with an increased risk of myocardial infarction, and renal failure develop.

Classification of forms

Based on research data, experts distinguish the following forms of the disease:

• central, localized on the spine;
• kyphosis, in which inflammation affects the vertebrae of the cervical and thoracic spine;
• rigid, leading to smoothing of the natural curves of the back;
• rhizomelic, the area of ​​localization of which is the spine and root joints;
• peripheral, involving the joints of the lower extremities;
• Scandinavian, which is characterized by damage to the joints of the hands;
• visceral, which combines the symptoms of any of the listed forms with simultaneous inflammation of the kidneys, heart or arteries.

Diagnostics

It is possible to obtain a comprehensive picture of the disease and clarify the area of ​​its localization using the following research methods:

• radiography, which will show pathologies of the sacroiliac region, where the development of the disease begins;
• Magnetic resonance imaging;
• gene diagnostics for the presence of HLA-B27 antigen in the body;
• a general clinical blood test, where the inflammatory process is indicated by a sharp increase in the erythrocyte sedimentation rate.

Treatment and prognosis

Treatment of the disease is necessary throughout the patient’s life with adjustment of the set of drugs depending on the results achieved and visible changes in the patient’s condition. The complex includes:

• hormonal drugs to relieve inflammation;
• immunosuppressants to suppress the process of inhibition of “foreign” spinal tissues by the body’s immune system;
• methods of physiotherapy and exercise therapy.

A new page in the history of treatment of ankylosing spondylitis was opened after the creation of TNF inhibitor drugs that block the activity of TNF-α molecules. They do not affect the immune system, but stop the synthesis of substances that activate the inflammatory process in the joints. Thanks to their use, it is possible to stop the spread of inflammation and maintain the mobility of bone joints, while simultaneously eliminating the process of their fusion. Additional recommendations for ankylosing spondylitis include cryotherapy, massage and manual therapy, and sodium chloride baths. Their combination increases the duration of remissions and makes it easier for the patient to go through the exacerbation phase.

Treatment

Strumpel's disease, the treatment of which can only be symptomatic, is a complex disease from a psychological point of view. Patients need to be provided with comprehensive moral support, and courses of symptomatic treatment should be carried out at least twice a year.

Therapy for the disease is aimed primarily at relieving muscle hypertonicity, using muscle relaxants (mydocalm, baclosan, sirdalud and others). Orthopedic methods of influence (wearing orthoses and other devices), neuroprotective drugs (B vitamins) are also used. Patients are prescribed physiotherapeutic procedures, paraffin baths, relaxing massage, and metabolic drugs.

With constant and complete treatment, the progression of the disease is very slow and a person may not significantly lose quality of life for a long time.

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