Infants lose newly acquired abilities such as crawling, walking, smiling, flipping, or it takes them a long time to reach milestones such as learning to crawl or walk — these are just some of the symptoms of Tay-Sachs disease. Tay Sach is a rare autosomal recessive lysosomal accumulation disease that suppresses the normal functioning of the central nervous system (CNS), leading to neurological diseases and eventually death. It was first discovered in 1883 by British ophthalmologist Warren Tay after he noticed a cherry-red spot on the eye of a sick infant. It was then first described in 1887 by American neurologist Benard Sachs in one of his articles. Hence the name Tai-Sax.

A mutation of the chromosome 15 (15q23) gene has been detectedresponsible for the synthesis of the lysosomal enzyme beta-hexosamidase A (HEX A), leads to Tay-Sachs disease. HEX A is responsible for breaking down a lipid called ganglioside GM2, which is normally found in neurons. Due to mutations, HEX A is missing, which leads to the accumulation of ganglioside GN2. 78 mutations in the HEX A gene have been described, including 65 single nucleotide substitutions, 1 large and 10 small deletions and 2 small inserts [1]. All these mutations damage the catalytic activity of beta-hexosamidase to varying degrees, which leads to the accumulation of GM2 gangliosides at different stages of life.

Gangliosides are important glycolipids.The membranes of nerve cells provide normal cellular activity and function. The expression of gangliosides in the brain is highly region-dependent and highly regulated. This is closely related to milestones in the development of the nervous system, including neurogenesis, synaptosis, and myelination. It plays an important role in modulating ion channel function and receptor signaling, ensuring optimal function and adaptation of neural circuits involved in nerve impulse transmission, memory, and learning. But HEX A deficiency causes ganglioside accumulation to toxic levels, especially in neurons. Because of this, it participates in the death of neurons, and when neurons die, degeneration of the central nervous system begins[2].

depending on the age of onset, Tay-Sachs disease is divided into infatal (from 3 to 6 months), juvenile (from 2 to 5 years), as well as Tay-Sachs disease with a late onset (from 20 to 30 years). Tay-Sachs disease is characterized by a decrease in muscle tone, children slowly reach milestones such as walking, crawling, and lose skills they have already learned. Lethargy and weakness are observed, which increase until paralysis is achieved. This leads to the collapse of the lungs and, eventually, pneumonia. Difficulty swallowing, hearing and vision. Seizures are characteristic of Tay-Sachs, and a cherry-red spot is visible on the retina of the affected person.Tay-Sachs disease mainly affects infants and young children.However, it can occur in early adulthood and is then called Tay-Sachs disease with a late onset. In young people, it also contributes to the development of bipolar type.psychological personality. However, this does not always inevitably lead to a reduction in life expectancy.

Studies have shown that this is common among isolated communities such as Ashkenazi Jews, French Canadians, and Amish [1]. 1 out of every 25 Jews carries this mutated gene. Tea-Saha disease is recessive, which means that if heterozygous parents have a child, then there is a 25% chance he will be normal, with a 25% chance he will be sick and with a 50% chance he will be a carrier.Heterozygous people do not show symptoms of this disease, but become known as carriers. Therefore, it is important to know the human genotype in order to prevent the birth of children with this disease.

The diagnosis is made by testing the activity of HEX A in serum, leukocytes, tears, body tissues and other body samples. Genetic testing is performed to detect the HEX A gene mutation and sequencing.Prenatal testing of fetal cells

It can be performed by taking samples of chorionic villi at 10 to 12 weeks of pregnancy or by amniocentesis at 15 to 18 weeks of pregnancy in families when the analysis of the Hex A enzyme shows that the parents are heterozygous, and molecular genetic testing excludes a pseudodeficient allele.in any of the parents [4]. Preimplantation genetic testing is possible in families with identified pathogenic variants.

currently, Tay-Sachs disease is incurable, but there are methods of symptomatic treatment. Basically, this is a supportive therapy aimed at making the sTau-Sachs as comfortable as possible for a living. Specialists provide physical therapy to help with breathing in order to reduce the possibility of pneumonia. Medications for cramps and stiffness are provided. Including antiepileptic drugs. However, the roads become more progressive and the pattern changes. Therefore, the dose should be changed frequently and new medications should be used. In childhood, this disease becomes more invalid and weak, and bowel movement becomes necessary.

Fortunately, scientific therapeutic modalities aimed at correcting the underlying problem, which is the disadvantage of HEX A, have been attempted. These include Bone marrow Transplantation (BMT) and gene therapy, among others [5]. Gene therapy tests have yielded the most interesting and viable results that can help to better understand this disease.

TSD and Sandhoff's disease are inherited recessively and are caused by mutations in the HEX A and HEX B genes, respectively, encoding the heterodimeric enzyme BN-acetylhexosaminidase A (HEX A). Enhanced access to gene therapy for adenoassociated virus (AAV) in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and the absence of secondary gene endpoints that provide the basis for disease reduction [3].

AAV gene therapy is used in the treatment of neurological disorders, including spinal muscular atropia type 1 and decarboxylase of aromatic L-amino acids. The combination of AAV delivery to the thalamus and cerebrospinal fluid is an effective approach to the treatment of Tay-Sachs disease. AAV therapy is described here below.

Medical history

TSD-001 (female) showed developmental delay at the age of 5-6 months, an exaggerated fright reflex at the age of 8 months and macrocephaly, seizures and abnormal myelination at the age of 12 months. Simultaneously with the onset of the attack (14 months) TSD-001 was diagnosed with infantile TSD (hexamutations: insert from 4 pp. c.1274-1278 and c.82C>T p.Gln28X).

TSD-002 (female) was clinically healthy at enrollment (6 months), she had normal milestones, including sitting on a tripod, but showed weakness in her lower extremities and cherry-red spots. TSD-002 was diagnosed shortly after birth with infantile TSD (hexamutations: deletion of exons 11-13 with a length of 1.75 bp; p.Val381X) due to two previous siblings with TSD, who had delays in the development of the nervous system at the age of 7 months, exaggerated flinching and, in one case, death before the age of 3 years.

Dosing

The agent under study consists of an equimolar mixture of AAVrh8-HEXA and AAVrh8-HEXB vectors. The scaling of the dose for patients was based on the ratio of the weight of the primate brain (NHP) and the human brain (additional table).1).

TSD-001 was treated at the age of 30 months only due to severe degeneration of the thalamus. The dose (1 × 1014vg) was divided between a large cistern (75%; 9 ml) and a thoracolumbar junction (25%; 3 ml) using an SL-10 microcatheter in the intrathecal space.23 TSD-002 was treated after 7 months with bilateral injections into the thalamus, followed by delivery, as indicated above, to the total combined dose 4.2 × 1013o.g. The dose was 3.08 × 1012vg divided between thalamuses with a total volume of 180 µl per thalamus and 3.89 × 1013vg in 4.5 ml, it was divided by 75% in a large cistern and by 25% in the lumbar intrathecal space [3].

both patients had immunodeficiency. Injection procedures were well tolerated, and to date, no side effects (NS) associated with carriers have been noted. HexA activity in cerebrospinal fluid (CSF) increased compared to baseline and remained stable in both patients. TSD-002 demonstrated stabilization of the disease 3 months after injection with continued myelination, a temporary deviation from the natural course of childhood TSD, but the progression of the disease was obvious 6 months after treatment. TSD-001 remains seizure-free at the age of 5 years with the same anticonvulsant therapy as before therapy. TSD-002 developed seizures reacting to anticonvulsants at the age of 2. This study provides early evidence on the safety and validation of the concept of treating TSD patients with AAV gene therapy in humans[3].

In conclusion, Tay-Sachs disease is a complex disease in which degeneration of the central nervous system occurs. Appropriate genetic counseling should be offered to those who are carriers and at risk of becoming carriers. Autosomal recessive diseases occur when one copy of an abnormal gene of the same trait is inherited from each parent. Thus, the parents of a sick child with Tea-Saha disease are obligate heterozygous carriers. Parents and guardians should be properly consulted regarding the diagnosis, progression and expected complications of Tea-Saha disease. Families should be informed of the expected outcome, such as progressive neurological deterioration, refractory seizure patterns, and the risk of aspiration and recurrent infections. Patients with Tay-Saha disease with late onset (in adolescence and adulthood) should be informed about the risk of falls due to ataxia, and appropriate measures such as assistive devices should be recommended. In addition, it is also difficult to treat mental symptoms.