DEFINITION
Tay-Sachs disease is a rare, inherited disorder. It causes too much of a fatty substance to build up in tissues and nerve cells of the brain. This buildup destroys the nerve cells, causing mental and physical problems.
Infants with Tay-Sachs disease appear to develop normally for the first few months of life. Then, as nerve cells become distended with fatty material, mental and physical abilities deteriorate. The child becomes blind, deaf, and unable to swallow. Muscles begin to atrophy and paralysis sets in. Even with the best of care, children with Tay-Sachs disease usually die by age 4.
Tay-Sachs is most common in Eastern European Ashkenazi Jews. A blood test can determine if you carry or have the disease. There is no cure. Medicines and good nutrition can help some symptoms. Some children need feeding tubes.
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EPIDEMIOLOGY
age, sex, seasonality, etc
Historically, Eastern European people of Jewish descent (Ashkenazi Jews) have a high incidence of Tay-Sachs and other lipid storage diseases. Documentation of Tay-Sachs in this Jewish population reaches back to 15th century Europe. In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier. French Canadians and the Cajun community of Louisiana have an occurrence similar to the Ashkenazi Jews. Irish Americans have a 1 in 50 chance of a person being a carrier. In the general population, the incidence of carriers (heterozygotes) is about 1 in 300.
A continuing controversy is whether heterozygotes, individuals who are carriers of one copy of the gene but do not actually develop the disease, have some selective advantage. The classic case of heterozygote advantage is sickle cell anemia, and some researchers have argued that there must be some evolutionary benefit to being a heterozygote for Tay-Sachs as well. Four different theories have been proposed to explain the high frequency of Tay-Sachs carriers in the Ashkenazi Jewish population:
- Heterozygote advantage with tuberculosis resistance. Being a Tay-Sachs carrier may serve as a form of protection against tuberculosis. TB's prevalence in the European Jewish population was very high, in part because Jews were forced to live in crowded conditions. However, several statistical studies have demonstrated that grandparents of Tay-Sachs died proportionally from the same causes as non-carriers.
- Heterozygote advantage because of higher intelligence. Another theory (attributed to Gregory Cochran) proposes that Tay-Sachs and the other lipid storage diseases that are prevalent in Ashkenazi Jews may enhance dendrite growth and promote higher intelligence when present in carrier form, thus providing a selective advantage at a time when Ashkenazi Jews were restricted to intellectual occupations.
- Reproductive compensation. Parents who lose a child because of disease tend to "compensate" by having additional children to replace them, and this may increase the incidence of autosomal recessive disease.
- Founder effect. This hypothesis states that the high incidence of the 1278insTATC mutation is the result of genetic drift, which amplified a high frequency that existed by chance in an early founder population.
Because Tay-Sachs disease was one of the first autosomal recessive genetic disorders for which there was an enzyme assay test (prior to polymerase chain reaction testing methods), it was intensely studied as a model for all such diseases. The researchers of the 1970s often favored theories of heterozygote advantage, but failed to find much evidence for them in human populations. They were also unaware of the diversity of the Tay-Sachs mutation base. In the 1970s, complete genomes had not yet been sequenced, and researchers were unaware of the extent of polymorphism. The contribution to evolution of genetic drift (as opposed to natural selection) was not fully appreciated.
Since the 1970s, DNA sequencing techniques using PCR have been applied to many genetic disorders, and in other human populations. Several broad genetic studies of the Ashkenazi population (not related to genetic disease) have demonstrated that the Ashkenazi Jews are the descendants of a small founder population, which may have gone through additional population bottlenecks. These studies also correlate well with historical information about Ashkenazi Jews. Thus, a preponderence of the recent studies have supported the founder effects theory.
SYMPTOMS
At 3 to 6 months:
•Decreased eye contact.
•Twitchy eyes (myoclonic jerks).
•Difficulty focusing on objects.
•Excessive startling by sharp but not necessarily loud noises.
At 6 to 10 months:
•Limp and floppy muscles (hypotonia).
•Decreased alertness and playfulness.
•Difficulty sitting up or rolling over
•Loss of motor skills.
•Decreased hearing and eventual deafness.
•Gradual loss of vision.
•An abnormal increase in head size (macrocephaly).
10 months and older:
As a child with Tay-Sachs grows older, he or she may become blind, mentally retarded, paralyzed, and unresponsive to the environment. The child also may have seizures, difficulty swallowing, and difficulty breathing. Children with Tay-Sachs disease rarely live beyond 4 or 5 years of age.
Affected infants generally appear to be completely normal at birth. Mild motor weakness begins at three to six months of age, along with myoclonic jerks and an exaggerated startle reaction to sharp noise. By six to ten months of age, the infant fails to achieve new motor skills or even loses previously demonstrated skills. Decreasing visual attentiveness and unusual eye movements are associated with pallor of the perifoveal macula of the retina with prominence of the fovea centralis, the so-called cherry-red spot, which is seen in virtually all affected individuals.
After eight to ten months of age, progression of the disease is rapid. Spontaneous or purposeful voluntary movements diminish and the infant becomes progressively less responsive. Vision deteriorates rapidly. Seizures are common by 12 months of age. Subtle partial complex seizures or absence attacks typically become more frequent and more severe.
Progressive enlargement of the head typically begins by 18 months of age; it results from reactive cerebral gliosis, not hydrocephalus.
Further deterioration in the second year of life results in decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death usually occurs between two and four years of age from bronchopneumonia.
DIAGNOSIS
histopathology
An evaluation begins with a complete physical examination, along with a detailed history of symptoms and family hereditary disorders, including Tay-Sachs disease. A physical exam of the eyes in patients with Tay-Sachs may reveal a "cherry-red" spot in the back of the eyes, a telltale symptom of the disease.
All patients with Tay-Sachs disease have a "cherry-red" macula, easily observable by a physician using an ophthalmoscope, in the back of their eyes (the retina). This red spot is the area of the retina which is accentuated because of gangliosides in the surrounding retinal ganglion cells (which are neurons of the central nervous system). The choroidal circulation is showing through "red" in this region of the fovea where all of the retinal ganglion cells are normally pushed aside to increase visual acuity. Thus, the cherry-red spot is the only normal part of the retina seen. Microscopic analysis of neurons shows that they are distended from excess storage of gangliosides. Without molecular diagnostic methods, only the cherry red spot, characteristic of all GM2 gangliosidosis disorders, provides a definitive diagnostic sign.
Unlike some other lysosomal storage diseases (i.e. Gaucher disease, Niemann-Pick disease, Sandhoff disease), hepatosplenomegaly is not a feature of Tay-Sachs disease.
radiology
NMR
laboratory tests
Diagnosis Before Birth
Tay-Sachs and many other defects can be diagnosed before birth by amniocentesis and chorionic villus sampling (CVS).
In amniocentesis, a needle is inserted into the mother's abdomen between weeks 16 and 18 of pregnancy to take a sample of fluid which surrounds the fetus. The fluid contains sloughed-off fetal cells which can be examined for the presence of the gene called hex A which is absent in Tay-Sachs. If the chemical is present, the baby will not have TSD. If it is missing, he or she will be affected.
In CVS, the doctor retrieves a sample of cells through a tube inserted through the vagina and cervix to the placenta. The placenta contains cells of fetal origin. These are examined for the presence of the chemical. CVS is usually done around week 10 of pregnancy. Since this procedure can be done safely earlier in pregnancy, it is preferred.
Blood test
A blood test can measure hexosaminidase A (hex A) activity. The biological parents may also have their blood tested to determine if they are genetic carriers of Tay-Sachs. The blood sample may be used for DNA testing to determine genetic mutations that could cause hex A deficiency.
PATHOGENESIS
The hexosaminidase A is absent from virtually all the tissues, including leukocytes and plasma, and so GM2 ganglioside accumulates in many tissues (e.g., heart, liver, spleen), but the involvement of neurons in the central and autonomic nervous systems and retina dominates the clinical picture.
On histologic examination, the neurons are ballooned with cytoplasmic vacuoles, each of which constitutes a markedly distended lysosome filled with gangliosides.
Stains for fat such as oil red O and Sudan black B are positive. With the electron microscope, several types of cytoplasmic inclusions can be visualized, the most prominent being whorled configurations within lysosomes composed of onion-skin layers of membranes.
In time, there is progressive destruction of neurons, proliferation of microglia, and accumulation of complex lipids in phagocytes within the brain substance. A similar process occurs in the cerebellum as well as in neurons throughout the basal ganglia, brain stem, spinal cord, and dorsal root ganglia and in the neurons of the autonomic nervous system.
PATIENT RISK FACTORS
The list of risk factors mentioned for Tay-Sachs in various sources includes:
•Family history of Tay-Sachs
•Ashkenazi Jews
TSD is transmitted through heredity. It cannot be caught from another child and cannot develop in later life. The carrier state cannot turn into the illness. The Tay-Sachs carrier has one normal gene and one Tay-Sachs gene. The carrier does not have the illness and can lead a normal, healthy life.
TSD affects about one in every 2,500 Ashkenazic Jews (Eastern and Central European origin), and it is estimated that approximately one in every 25 Jews in the United States is a carrier of the TSD gene. Two other populations of French descent also show an increased risk - French Canadians, particularly from Quebec Provence, and those of Cajun ancestry in Louisiana.
Risk factors for Tay Sachs are factors that do not seem to be a direct cause of the disease, but seem to be associated in some way. Having a risk factor for Tay Sachs makes the chances of getting a condition higher but does not always lead to Tay Sachs. Also, the absence of any risk factors or having a protective factor does not necessarily guard you against getting Tay Sachs.
Genetic
Tay-Sachs disease is an autosomal recessive genetic disorder, meaning that when both parents are carriers, there is a 25% risk of giving birth to an affected child. As with all genetic disease, Tay-Sachs disease may arise in any generation from a novel mutation, although such mutations are rare.
Tay-Sachs disease is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of fatty acid derivatives known as gangliosides. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down lipids. When Hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. Gangliosides are made and biodegraded rapidly in early life as the brain develops. Patients and carriers of Tay-Sachs disease can be identified by a simple blood test that measures hexosaminidase A activity.
Hydrolysis of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A, and the third is a small glycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate specific cofactor for the enzyme. Deficiency in any one of these proteins leads to storage of the ganglioside, primarily in the lysosomes of neuronal cells. Tay-Sachs disease (along with GM2-gangliosidosis and Sandhoff disease) occurs because a genetic mutation inherited from both parents deactivates or inhibits this process. Most Tay-Sachs mutations appear not to affect functional elements of the protein. Instead, they cause incorrect folding or assembly of the enzyme, so that intracellular transport is disabled.
As previously said, the disease results from mutations on chromosome 15 in the HEXA gene encoding the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase A. By the year 2000, more than 100 mutations had been identified in the HEXA gene, and new mutations are still being reported. These mutations have included base pair insertions and deletions, splice site mutations, point mutations, and other more complex patterns. Each of these mutations alters the protein product, and thus inhibits the function of the enzyme in some manner.
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* Quaternary structure
Proteins involved
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
TISSUE SPECIFIC RISK FACTORS
anatomical (due its structure)
vascular (due to the local circulation)
physiopathological (due to tissue function and activity)
There are no tissue specific risk factors in Tay-Sachs disease, because its only risk factors concern genetic features and the origins (for example, Ashkenazic Jews).
COMPLICATIONS
Symptoms appear during the first 3 to 10 months of life and progress to spasticity, seizures, and loss of all voluntary movements.
THERAPY
Because there is no cure for Tay-Sachs disease, the goal of treatment is to make the patient comfortable. Treatment options include:
Respiratory care
Patients with Tay-Sachs disease frequently will accumulate mucus in their lungs. To reduce the lung mucus, chest physiotherapy (CPT) is usually used.
Children with Tay-Sachs disease are at high risk of respiratory infections, which affect the lungs and cause breathing problems, and need to be carefully monitored and provided with prompt treatment.
Assistive devices
Respiratory problems may also develop when children with Tay-Sachs disease swallow food or liquid into their lungs while eating (aspiration). Assistive feeding devices may be necessary. Two options:
•Nasogastric (NG) tube
This is a tube inserted through the nose to the stomach.
•Percutaneous Esophago-Gastrostomy (PEG) tube
PEG tubes are placed through the abdomen into the stomach during a surgical procedure that is commonly done by a physician specializing in gastroenterology or radiology. This option is more permanent than the NG tube.
Medication
To reduce the patient's symptoms, a number of prescription medications are available, including seizure medications.
Physical therapy
As Tay-Sachs progresses, the patient may receive physical therapy to stimulate the muscles and joints, such as physically moving the affected body parts.
The purpose of physical therapy is to help keep joints flexible and maintain as much ability to move (range of motion) as possible. This can help to delay joint stiffness, or contractures, and reduce or delay the loss of function or the pain that can result from contractures.
Experimental treatments
Historically, there has been no cure or treatment for TSD. However, a cord-blood transplant system pioneered by Dr. Joanne Kurtzberg of Duke University Medical Center has saved the lives of several infants with TSD. Without this, children with Infantile TSD die by the age of 5, and the progress of Late-Onset TSD can only be slowed, not reversed. However, research is ongoing. Several methods of treatment are being investigated, although significant hurdles remain before any of them pass the experimental stages.
•Enzyme replacement therapy. The goal would be to replace the missing enzyme, a process similar to insulin injections for diabetes. However, the enzyme has proven to be too large to pass through the blood into the brain through the blood-brain barrier. Blood vessels in the brain develop junctions so small that many toxic (or large) molecules cannot enter into nerve cells and cause damage. Researchers have also tried instilling the enzyme into cerebrospinal fluid, which bathes the brain. However, neurons are unable to take up the large enzyme efficiently even when it is placed next to the cell, so the treatment is still ineffective.
•Gene therapy. The most recent option explored by scientists has been gene therapy. If the defective genes were to be replaced throughout the brain, Tay Sachs could theoretically be cured. However, researchers working in this field believe that they are years away from the technology to transport the genes into neurons, which would be as difficult as transporting the enzyme. Currently, most research involving gene therapy involves developing a method of using a viral vector to transfer new DNA into neurons. Another approach to gene therapy, under study at Duke University, uses stem cells from umbilical cord blood in an effort to replace the defective gene. Although the Duke University approach has been effective with Krabbé disease, the researchers have not yet reported any results for Tay-Sachs.
•Metabolic therapy. Other highly experimental methods being researched involve manipulating the brain's metabolism of GM2 gangliosides. One experiment has demonstrated that, by using the enzyme sialidase, the genetic defect can be effectively bypassed and GM2 gangliosides can be metabolized so that they become almost inconsequential. If a safe pharmacological treatment can be developed, one that causes the increased expression of lysosomal sialidase in neurons, a new form of therapy, essentially curing the disease, could be on the horizon. Metabolic therapies under investigation for Late-Onset TSD include treatment with the drug OGT 918 (Zavesca).
Protein Aminoacids Percentage
The Protein Aminoacids Percentage gives useful information on the local environment and the metabolic status of the cell (starvation, lack of essential AA, hypoxia)
Model (Width 600 px)
