Tay-Sachs disease: what is it, symptoms, treatment, prognosis

What is Tay-Sachs disease?

Tay-Sachs disease Is a rare neurodegenerative disease in which a deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerves cells. This excessive accumulation of gangliosides leads to progressive central nervous system dysfunction. The disease belongs to the group lysosomal storage diseases. Lysosomes are the main digestive units in cells. Enzymes in lysosomes break down or "digest" nutrients, including certain complex carbohydrates and fats. When an enzyme such as hexosaminidase A, which is required to break down certain substances such as fats, is absent or ineffective, they accumulate in the lysosomes. This is called abnormal “build-up”. When too much fat accumulates in the lysosome, it becomes toxic, destroying cells and damaging surrounding tissues.

Symptoms associated with Tay-Sachs disease may include excessive startle responses to sudden sounds, lethargy, loss of previously acquired skills (for example, psychomotor regression) and severely reduced muscle tone (hypotension). Hypotensive babies can be described as “flexible”. As the disease progresses, affected infants and children may develop cherry-red patches in the middle layer of the eyes, gradually losing vision and hearing loss, increased muscle stiffness and limited movement (spasticity), paralysis, uncontrolled electrical disturbances in the head brain (

epilepsy) and deterioration of cognitive processes (dementia). The classic form of Tay-Sachs disease occurs in infancy. It is the most common form and is usually fatal in early childhood. There are also juvenile and adult forms of Tay-Sachs disease, but this is rare. Children with the juvenile form, also called the subacute form, develop symptoms later than children with infantile form, and they usually survive into later childhood or adolescence. The adult form, also called late-onset Tay-Sachs disease, can occur at any time from adolescence to the mid-30s. Symptoms and severity can vary from one person to another. Some people can be between the juvenile and adult forms.

Tay-Sachs disease is transmitted in an autosomal recessive manner. The disease occurs as a result of changes (mutations) in a gene known as the gene HEXA, which regulates the production of the enzyme hexosaminidase A. Gene HEXA found on the long arm (q) of chromosome 15 (15q23-q24). There is no cure for Tay-Sachs disease, and treatment is aimed at relieving specific symptoms that arise.

Another name for Tay-Sachs disease is type 1 GM2 gangliosidosis. There are two other related diseases called Sandhoff disease and activator hexosaminidase deficiency, which are indistinguishable from Tay-Sachs disease on the basis of symptoms and can only be differentiated by analyzes of the underlying reasons. These two disorders also cause decreased hexosaminidase activity, but are caused by changes in different genes. Collectively, these three disorders are known as GM2 gangliosidosis.

Signs and symptoms

Tay-Sachs disease is classified into the classic or infantile form, the juvenile form, and the adult or late-onset form. In individuals with infantile Tay-Sachs disease, symptoms usually first appear between three and five months of age. People with late onset can have symptoms at any time from adolescence to their mid-30s.

- Infantile form of the disease.

The childhood form of Tay-Sachs disease is characterized by an almost complete lack of activity of the enzyme hexosaminidase A. The disorder often progresses rapidly, resulting in significant mental and physical deterioration.

Babies may appear completely unaffected at birth. Initial symptoms, which usually develop between 3 and 6 months of age, may include mild muscle weakness, muscle twitching (myoclonic twitching) and excessive startle response, such as when suddenly or unexpectedly sound. The startle response may in part be related to increased sensitivity to sound (acoustic hypersensitivity).

Between 6 and 10 months, affected infants may not acquire new motor skills. They stop looking into their eyes and they may experience unusual eye movements. They can be lethargic and irritable. As babies grow older, they may experience slow growth, progressive muscle weakness, decreased muscle tone (hypotension), and decreased mental performance. Affected infants may also experience gradual loss of vision, involuntary muscle spasms that lead to slow, stiff movements (spasticity) and loss of previously acquired skills (eg, psychomotor regression), such as crawling or sitting.

A characteristic symptom of Tay-Sachs disease is the appearance of cherry-red spots on the eyes. This condition occurs when the macular cells of the eye are destroyed, exposing the underlying choroid. The choroid is the middle layer of the eye, made up of blood vessels that supply blood to the retina. This characteristic is found in about 90% of patients.

As babies get older, more serious complications can develop, including:

• epilepsy;
• dysphagia (violation of the act of swallowing or difficulty swallowing);
• progressive hearing loss;
• confusion, disorientation and / or deterioration in intellectual ability (dementia);
• paralysis;
• and ongoing loss of vision, which can be rapid and lead to blindness.

Ultimately, babies can become immune to their environment and surroundings. Life-threatening complications such as respiratory failure can occur between the ages of three and five.

- Juvenile (subacute) Tay-Sachs disease.

The onset of this form can be between 2 and 10 years of age. Clumsiness and coordination problems are often one of the first signs. This is because affected children have trouble controlling their body movements (ataxia). Behavioral problems, progressive loss of speech, life skills and intellectual ability also develop. Children may or may not have cherry red spots in their eyes. Degeneration of the nerve that transmits impulses from the eye to the brain to form images (optic atrophy) can occur. Some children may have retinitis pigmentosa, a large group of visual impairments that cause progressive degeneration of the retina, the light-sensitive membrane that covers the inside of the eye. Children will become less responsive to their environment.

- Late onset Tay-Sachs disease.

Symptoms associated with late-onset Tay-Sachs disease vary greatly from person to person. Patients will not have all of the symptoms listed below. The disorder progresses much more slowly than the infantile form. Variability in late-onset Tay-Sachs disease can be observed even in members of the same family. One person may have symptoms at age 20 and another at age 60 or 70 with only minor muscle problems.

The initial symptoms associated with late-onset Tay-Sachs disease may include clumsiness, mood changes, progressive muscle weakness, and wasting (amyotrophy). As they age, patients experience tremor, muscle twitching (fasciculations), seizures, slurred speech (dysarthria), inability to coordinate voluntary movements (ataxia), difficulty swallowing (dysphagia) and a condition known as dystonia. Dystonia is a group of conditions characterized by involuntary muscle contractions that can cause certain parts of the body to adopt unusual and sometimes painful movements and positions. Some people have involuntary muscle spasms, resulting in slow, hard movements (spasticity).

As the late-onset Tay-Sachs disease progresses, people have trouble walking, running, and other similar activities. In severe cases, those affected will eventually need assistive devices such as a walker or wheelchair.

In some cases, patients may experience mental deterioration, memory problems, and behavior changes, including short attention span and personality changes. Approximately 40% of patients present with mental episodes, including loss of contact with reality, paranoia, hallucinations, bipolar episodes, and depression.

Causes

Tay-Sachs disease is caused by a change (mutation) in the gene encoding the alpha subunit of hexoaminidase A (HEXA). Genes provide instructions for making proteins that are critical to many bodily functions. When a gene mutation occurs, the protein product may be defective, ineffective, or missing. Depending on the function of the protein, it can affect many organ systems in the body, including the brain.

Gene HEXA regulates the production of the enzyme hexosaminidase A. More than 80 different gene mutations have been identified in people with this disease HEXA. Inheritance of two mutated copies of a gene HEXA (homozygote) causes a deficiency of the enzyme hexosaminidase A, which is required for the breakdown of a fatty substance (lipid) known as GM2-ganglioside in the cells of the body. Failure to break down GM2-ganglioside leads to abnormal accumulation in the brain and nerves cells, which ultimately leads to a progressive deterioration in the state of the central nervous systems.

In childhood Tay-Sachs disease, there is an almost complete absence of hexosaminidase A. In late-onset Tay-Sachs disease, there is a deficiency in the activity of the enzyme hexosaminidase A. Due to some enzyme activity, the disease is less severe and progresses much more slowly than childhood Tay-Sachs disease. The exact magnitude of enzyme activity in late-onset Tay-Sachs disease varies greatly from person to person. Consequently, age of onset, severity, specific symptoms, and rate of progression of late-onset disease also vary greatly from one person to another.

Changes in HEXA the gene that causes Tay-Sachs disease is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of two copies of a gene, one from the father and one from the mother. Recessive genetic disorders occur when a person inherits two copies of an abnormal gene for the same trait, one from each parent. If a person inherits one normal gene and one gene for the disease, they will carry the disease but are usually asymptomatic. The risk for two carrier parents of passing on the altered gene and having a sick child is 25% with each pregnancy. The risk of having a child who will be a carrier, like the parents, is 50% with every pregnancy. The probability that a child will receive normal genes from both parents is 25%. The risk is the same for men and women.

The researchers determined that the Tay-Sachs disease gene is located on the long arm (q) of chromosome 15 (15q23-q24). Chromosomes are located in the nucleus of human cells and carry the genetic information of each person. The cells of the human body usually have 46 chromosomes. Pairs of human chromosomes, numbered 1 through 22, are called autosomes, and the sex chromosomes are designated X and Y. Men have one X and one Y chromosome, while women have two X chromosomes. Each chromosome has a short arm, indicated by the letter "p", and a long arm, indicated by the letter "q". Chromosomes are further subdivided into many numbered bands. For example, "chromosome 11p13" refers to lane 13 on the short arm of chromosome 11. The numbered stripes indicate the location of the thousands of genes present on each chromosome.

Affected populations

Tay-Sachs disease affects men and women equally. The disease is more common among Jews of Ashkenazi origin, that is, immigrants from Eastern or Central Europe. About one in 30 Ashkenazi Jews carry an altered gene for Tai Sachs disease. In addition, every 300 people of non-Tashkentazi Jewish ancestry are a carrier.

In this specific Jewish population, about 1 in 3,600 live births are affected. It also affects some Italian, Irish Catholic, and non-Jewish people. of French-Canadian descent, especially among those living in the Kajun community in Louisiana and Southeast Quebec. In the general population, the rate of transmission of the altered gene is approximately 1 in 250-300 people.

The late form of Tay-Sachs disease is less common than the infantile form. However, rare diseases such as late-onset Tay-Sachs disease often go unrecognized. These disorders are underdiagnosed, making it difficult to determine the true frequency of such disorders in the general population.

Diagnostics

The diagnosis of Tay-Sachs disease can be confirmed by careful clinical evaluation and specialized tests such as blood tests that measure the level of hexosaminidase A in the body. Hexosaminidase A is reduced in patients with Tay-Sachs disease and is absent or almost absent in infants.

Molecular genetic testing can confirm the diagnosis of Tay-Sachs disease. Molecular genetic testing can detect mutations in a gene HEXA, known to cause the disorder, but are only available as a diagnostic service in specialized laboratories.

In some cases, it is possible that a diagnosis may be suspected before birth (prenatally) based on specialized tests such as amniocentesis and chorionic villus sampling (CVS). During amniocentesis, a sample of the fluid surrounding the developing fetus is removed, while CVS involves removing tissue samples from a portion of the placenta. These samples are studied to determine if hexosaminidase A is present or, as in people with Tay-Sachs disease, is absent or present at significantly low levels. This is called an enzyme assay. Prenatal diagnosis is also possible through molecular genetic testing of tissue samples, obtained by CVS or amniocentesis, if a specific mutation is known in the family that causes the disease in gene HEXA.

Blood tests can determine if people are carriers of the disease (i.e. e. whether they have one copy of the disease gene). Relatives of patients with Tay-Sachs disease should be tested to determine if they carry the disease gene. Couples who are planning to have a baby and are of any Jewish origin (not just Ashkenazi) are advised to undergo a carrier test prior to pregnancy.

Standard treatments

There is no specific treatment for Tay-Sachs disease. Treatment is aimed at addressing the specific symptoms that each person experiences. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, speech therapists, specialists who evaluate and treat hearing problems (audiologists), ocular professionals and other healthcare providers may need to systematically and comprehensively plan treatment injured child. Genetic counseling can be beneficial for those affected and their families. Psychosocial support is recommended for the whole family.

Because of potential feeding difficulties, infants should be monitored for nutritional status and adequate hydration. Nutritional support and supplementation may be required, and sometimes a tube feeding may be required. In addition to nutritional support, a feeding tube may be required to prevent food, fluid, or other foreign matter from accidentally entering the lungs (aspiration).

Anticonvulsants can be used to treat seizures associated with Tay-Sachs disease, but not in all people. In addition, the type and frequency of seizures may change in a person, requiring a change in the type or dosage of the medication.

Forecast

Tay-Sachs disease is a progressive neurodegenerative disease.

• The classic infantile form is usually fatal at the age of 2-3 years. Death usually occurs due to intercurrent infection.
• In the juvenile form, death usually occurs at the age of 10-15 years; preceded by several years of vegetative state with rigidity of decerebrates. Death usually occurs due to infection.
• In the adult form, most patients have a normal life span.