Information

Tay-Sachs disease

Synonyms:Beta-hexosaminidase A deficiency; GM2 gangliosidosis type I 

Basic information

Tay-Sachs disease is a rare but very serious neurometabolic disease. The cause of the disease is a reduced activity (deficiency) of the enzyme beta-hexosaminidase A, which is caused by the presence of pathogenic variants (mutations) in the HEXA gene. Depending on the severity of the enzyme deficiency, the disease manifests itself at different ages, from early infancy to adulthood. There is currently no known effective treatment that would be able to stop or reverse the course of the disease.

Causes of the disease

The disease is caused by reduced activity of the lysosomal enzyme beta-hexosaminidase A, which is necessary for the degradation (breakdown) of a complex lipid (fatty substance), GM2-ganglioside. GM2-ganglioside and other similar substances (glycosphingolipids) are an essential part of the cell membrane and other membrane structures in cells, they are continuously renewed and decomposed, which occurs in the part of the cell called the lysosome. Lysosomes in addition to beta-hexosaminidase A contain a variety of other enzymes that specifically break down other complex molecules. If the relevant enzyme (in this case beta-hexosaminidase A) does not work sufficiently, the undegraded substances accumulate in the lysosomes, their products may also be missing in the cell, which will gradually manifest itself in a malfunction and subsequently in the death of the entire cell. The most serious impaired function of this enzyme is manifested in neurons, which are the basic cells of the nervous system. Insufficient beta-hexosaminidase A function is caused by erroneous genetic information in a small section of deoxyribonucleic acid (DNA) strands, this section is called the HEXA gene. Each cell of the body contains two strands of DNA, one comes from the father, the other from the mother, only in the germ cells (sperm and egg) there is only one strand of DNA. If the erroneous information (pathogenic variant, mutation) is present in the HEXA gene only on one strand (one allele), the individual is completely healthy and usually does not know that it is transmitting the pathogenic variant for the relevant disease (it is a healthy carrier or heterozygous for the disease). The disease will only manifest itself if the erroneous information is present on both DNA strands in the HEXA gene (on both alleles) in the individual concerned, which can occur with a 25% probability in the pregnancy of two healthy carriers of the disease. The described type of inheritance is called autosomal recessive and there are a large number of serious diseases with this type of inheritance. Since there are relatively few carriers of this disease in the general population, and the likelihood of meeting and pregnancy of these partners is even lower, the occurrence of Tay-Sachs disease in the general population is rare. In the past, the disease occurred significantly more often in Ashkenazi Jews due to the relative isolation of the community, but in recent decades the incidence in this population has declined significantly thanks to the possibilities of genetic counseling. The presence of some pathogenic variants in the HEXA gene can lead to an almost complete loss of beta-hexosaminidase A function, then the disease manifests itself in early infancy in the so-called infantile form of Tay-Sachs disease. A combination of other pathogenic variants on both strands of the HEXA gene can lead to only a partial reduction in enzyme function, then the disease begins to manifest itself later in childhood, adolescence or even in adulthood (patients with the first manifestations are known after the age of 40). Almost all patients with the manifestation (first manifestations) of the disease in adulthood carry the pathogenic variant c.805G>A on at least one strand of the HEXA gene, leading to the substitution of the amino acid glycine for serine at position 269 in the relevant protein, which causes a relatively slight decrease in the stability of the enzyme and late development of the disease manifestations.

Clinical manifestations of Tay-Sachs disease

 The acute infantile form of Tay-Sachs disease caused by virtually zero beta-hexosaminidase A activity begins to manifest itself in an originally healthy newborn between 3-6 months of age with minor twitching and persistent startle reactions to even minor stimuli. At the same time, there is a noticeable lack of interest in watching objects and faces, atypical eye movements are present, ophthalmological examination usually reveals the presence of the so-called "cherry spot" on the eye fundus. Already at this time, the development of affected children lags behind peers, in the second half of the first year of life, the infant loses the previously achieved abilities, spasticity increases (increased muscle tension with impaired coordination), epileptic seizures occur and the head circumference gradually increases (macrocephaly), both as a result of secondary gliosis and as a result of internal hydrocephalus (most pronounced around 18 months of age). Between the 2nd and 3rd year of life, most affected children are in the so-called vegetative state, unresponsive to environmental stimuli, with increased muscle tension with head tilt and epileptic seizures. Nutrition is necessary through gastrostomy due to the inability to swallow and the high risk of inhalation of food. Children usually die as a result of inflammation of the respiratory tract.

The subacute juvenile form of Tay-Sachs disease begins to manifest itself between 2-5 years of age, and by the age of 2 the child usually develops normally. The first manifestations may be stagnation or slowing down of speech development and common skills compared to peers. Spasticity (increased muscle tension with typical coordination disorder), swallowing problems, epileptic seizures gradually appear. Deterioration of vision and atypical eye movements appear later in the course of the disease. A "cherry spot" on the fundus is rare, optic atrophy or retinal pigmentation is more common on eye examination. The course of the disease is significantly slower than in the infantile form of the disease, but in adolescence most sick children also reach a vegetative state.

Late-onset Tay-Sachs disease (LOTS) manifests itself with the first symptoms from adolescence to middle adulthood. Most patients gradually develop weakness in the lower limbs in adolescence or young adulthood, especially the quadriceps (muscles on the front of the thighs) and hip flexors (flexors). Sometimes small muscle twitches (fasciculations) may be present. Weakening leads to typical problems when standing up from a low chair or toilet (it is necessary to help yourself with your hands), problems when walking up the stairs, getting on and off public transport. If a patient with LOTS falls, it is extremely difficult to stand up again without help. The condition deteriorates very slowly but steadily. Gradually, there is also a weakening of the brace on the stretched upper limbs. At the same time, there is a deterioration of articulation with normal speech content, speech is fast and as if "pushed", which leads to a significant reduction in intelligibility, especially in emotions. Swallowing disorders are not common. The condition is complicated by tremors and impaired limb coordination. About 30% of patients may develop acute psychiatric symptoms of an atypical psychosis (usually a transient disorder of perception, thinking and behaviour significantly disrupting the patient's social behaviour). The condition requires acute psychiatric care and in the vast majority of cases it can be managed with adequate treatment. Another problem is anxiety and situational depression, understandable given the nature of the illness. Cognitive functions are preserved in patients, many patients with manifestation of the disease in middle adulthood (in the 4th decade of life) retain the ability to work in a job requiring mainly intellectual knowledge and skills until retirement age. In some patients with the first symptoms of the disease in adolescence, a certain deterioration of executive functions may occur with a longer course of the disease. Some patients already at school age report a certain clumsiness compared to peers.

Diagnosis

 If the attending physicians have experience with patients with infantile or late form of Tay-Sachs disease, they usually suspect this disease soon. Subsequently, enzymatic testing of beta-hexosaminidase A activity in serum and leukocytes and molecular genetic testing of the HEXA gene is usually performed. However, this situation is exceptional, as most doctors have not encountered patients with this rare disease.

The infantile form of the disease has been rare in the Czech population since the end of World War II, but developmental stagnation and regression (loss of previously achieved abilities) together with visual impairment, finding of a "cherry spot" on the ocular fundus, startle reactions and the development of macrocephaly usually lead pediatric neurologists to the correct diagnosis. The electrical activity of the brain in the electroencephalogram (EEG) does not correspond to age, epileptic graphoelements may be present. When examining the brain using magnetic resonance imaging (MRI of the brain), it is possible to detect gliosis with concomitant cortical atrophy in an advanced pediatric form of the disease, there are no signs of so-called leukodystrophy, which can distinguish the disorder from other neurodegenerative diseases of this age. If the child is not in a very advanced stage of the disease with organ complications, there are no signs of heart, liver, spleen, kidney disease. Because the symptoms of the disease are mainly neurological, children are usually soon taken care of by a paediatric neurologist, who usually recommends an examination at one of the inpatient departments of paediatric neurology. In the case of clinical suspicion of an infantile form of Tay-Sachs disease, the attending physicians will then contact the staff of the Metabolic Center of the KPDPM of the General University Hospital in Prague, who will provide enzymatic testing of beta-hexosaminidase A, first usually in serum or plasma, and then in leukocytes if reduced activity is demonstrated in the above materials. Usually, the activity of the enzyme is also tested in healthy parents (carriers of Tay-Sachs disease), where it should be about half the average of other healthy people. The diagnosis is definitively determined by DNA analysis of the HEXA gene if pathogenic variants (mutations) are found on both alleles. To verify the fact that the variants found are each located on a different DNA strand (on a different allele), DNA analysis of the variants found in the parents of the affected patient is used.

 Establishing the correct diagnosis in patients withthe uvenile, and often late, form of the disease can be difficult, sometimes it takes many years. The reason is the rare occurrence of the disorder, with which most doctors have no experience, and the fact that the disease resembles a number of other neurodegenerative diseases. The late form of the disease occurs in all populations. In recent years, the diagnosis has been increasingly determined by means of molecular genetic testing of the next generation, the so-called next generation sequencing (NGS), where the coding regions of a large group of genes (gene panels) or coding regions of all clinically important genes (clinical exom), or all genes (celoexom, WES) or even coding and non-coding regions of all genes (genome, WGS). Huge amounts of data in whole-exome or whole-genome sequencing require their computer processing and filtering, which is time-consuming, labor-intensive and costly, and sometimes the relevant data may not be captured with the set type of filtering. In adolescent and adult patients, a relatively specific clinical picture described above (weakness of the quadriceps, impaired articulation, sometimes atypical psychiatric illness) together with typical cerebellar atrophy during magnetic resonance imaging (MRI of the brain) may lead to suspicion of the disorder. Fundus findings are normal in adult patients. In the case of weakness of the lower limbs, an electromyographic (EMG) examination is performed in most patients, but it should not be limited to an examination of the speed of conduction through peripheral nerves (conduction study), because the finding is normal during this examination. Needle (insertion) EMG is necessary, where in adult patients with Tay-Sachs disease we find typical manifestations of axonal polyneuropathy or signs of involvement of the anterior horns of the spinal cord. Evaluation of electromyogram requires experience, the finding is sometimes incorrectly interpreted as a "myogenic lesion". A slight increase in creatine kinase (CK) activity and a slight increase in serum myoglobin concentration, which is common in these patients, may also contribute to the erroneous suspicion of primary muscle disease. If a muscle biopsy is performed in patients with late Tay-Sachs disease and the sample is evaluated by an experienced neuropathologist, the finding corresponds to a neurogenic lesion with selective atrophy of some muscle fibers. This finding, even if another genetic disease is suspected, should always lead to a supplementation of enzymatic testing of beta-hexosaminidase A activity at least in serum or plasma.

Treatment of Tay-Sachs disease

 Currently, only symptomatic and supportive treatment aimed at alleviating the symptoms of the disease and compensating for them by various means is available for both pediatric and adult patients with Tay-Sachs disease. In the rapidly progressing childhood form of the disease, physiotherapy is aimed at reducing pain, spasticity and other related problems as much as possible, and it is important to equip patients and their families with appropriate compensatory aids. To ensure adequate nutrition and to prevent aspiration (inhalation) of food, it is usually necessary to perform a percutaneous endoscopic gastrostomy (PEG) as the symptoms of the disease progress. Very important is the all-round psychological and social support of families caring for child patients with this disease. In recent years, there have been several attempts at gene therapy of the childhood form of the disease using different viral vectors and with different forms of application. A clear effect of this therapy has not yet been reported in patients with infantile forms of the disease.

In patients with a slowly progressing form of the disease with manifestation of symptoms in adolescence or adulthood, an international multicenter study with venglustat (a substrate reducing therapy) was conducted between 2020 and 2024, which was terminated due to the absence of a sufficient effect of the product. 9 of our patients also participated in the study. A phase 2 clinical trial of N-acetyl-L-leucine (IB-1001) has now been completed, the results indicate a positive effect on some clinical manifestations of Tay-Sachs disease and some other lysosomal disorders with progressive neurological impairment. The FDA has approved an orally administered product under the brand name Aqneursa as a modifying treatment for late Tay-Sachs disease in the US. The approval process of this product is currently underway in Europe through the European Medicines Agency (EMA). The EMA's approval of this drug for the treatment of late Tay-Sachs disease is a prerequisite for its subsequent registration in the Czech Republic.