Very rare metabolic disease

Tay-Sachs disease (TSD) is a very rare inherited metabolic disease. Tay-Sachs disease has a deficiency of the enzyme ß-hexosaminidase A. This causes an accumulation of certain fats, the GM2 gangliosides, in the brain and other body cells. This accumulation reaches a level where it becomes toxic. The disease is very rare and affects 1 in 320,000 children.

 

The disease was first described by the ophthalmologist Warren Tay who discovered a remarkable red spot in the center of the retina (the macula) in 1881 and the neurologist Bernard Sachs who described body cell changes in 1887 that mainly affect Jews of Eastern European descent, the Ashkenazi Jewish community.

 

Lysosomal storage disease with enzyme deficiency Hexosaminidase A

Tay-Sachs disease is one of the lysosomal storage diseases. A lysosome is a small part of a cell that ensures that substances can be broken down and reused. Enzymes are needed in this process. In lysosomal storage diseases, the action of an enzyme in the lysosome is insufficient or the enzyme is absent. As a result, waste accumulates and the cell does not function properly, resulting in damage to tissues and organs.

ß-(beta) Hexosaminidase A is the enzyme that breaks down the fatty substance GM2 ganglioside (GM2 ganglion molecule) in healthy people and which is deficient or no longer effective in people with Tay-Sachs disease.

 

If GM2 ganglioside cannot be broken down, it accumulates in the body cells, so that these cells can no longer function properly.
It is known that in people suffering from Tay-Sachs disease there were 100 to 1000 times more GM2 gangliosides in the brain than in healthy people.

 

Error in the genetic material

In Tay-Sachs disease, there is a change (mutation) in the HEXA gene on chromosome 15 (15q23). HEXA is short for the enzyme Hexosaminidase A.

The disease inherits autosomal recessive. Autosomal recessive means that both parents are carriers of the disease and both have passed on an error or mutation to the gene (a sick gene). As a result, the child who inherits a sick gene from both parents has two diseased genes and becomes ill.

 

Autosomal: Both boys and girls can inherit the disease to the same extent.
Recessive: the father or mother has a healthy gene and a sick gene. Because they have a healthy gene, they are not ill themselves, but are only carriers of the disease.
More than a hundred errors in the gene are known that can cause Tay-Sachs disease.

Shapes in which Tay-Sachs emerges

The different forms of Tay-Sachs disease are related to the age at which the disease manifests itself.

• Type 1. The infantile form begins three to six months after birth with a noticeable symptom that the child reacts with shock to sound.
• Type 2. The subacute or juvenile form begins at early childhood between the second and sixth years of life.
• Type 3. The chronic form starts from the age of ten but can also manifest itself in adulthood.

 

Possible complaints Type 1 (the infantile form)

• Fright for sound
• The child does not develop
• Neurodegeneration:
  • motor decline. For example, the child forgets to roll over and sit. (motor retardation)
  • Increasing muscle weakness (hypotonia) that leads to paralysis
  • Twitching (fasciculations)
  • Spasticity
  • Ataxia, a coordination disorder that manifests itself in movement
  • Disability
  • Poorly seeing that results in retinal blindness or cataracts (amaurosis)
  • Epileptic attacks
  • Mental decline (for example loss of attention can make less contact with the environment until no more contact is possible).

Most children die before they are five years old.

 

Possible complaints Type 2 and 3

The complaints of Type 2, the subacute form, and of Type 3, the chronic form, start later and have a slower decline in the complaints mentioned under Type 1. In addition, there are variable neurological findings such as:

• Severely increasing muscle tension disorder (dystonia). The muscle tension is often too high, but normal again at other times,
• Less muscle control, muscle weakness,
• Spinocerebellar degeneration; the nerves in the back and cerebellum become ill, resulting in coordination problems (ataxia) and disorders in position and posture (proprioception) (spinocerebellar ataxia),
• Motor neuron disease (MND); neurological disease in which progressive weakening of the muscles occurs.
• Problems with speech,
• Loss of intellectual skills; with Type 2 and possibly with Type 3,
• Behavioral problems; with Type 2 and possibly with Type 3,
• In some, with the adult variant, a bipolar form of psychosis,
• Cessation of the functioning of the brain (decebration).

Cherry-red spot on the retina

In the eyes a clear bright cherry red spot can be seen (the "cherry-red spot"). Vision of patients with Tay Sachs disease often deteriorates over time.

 

Other names for Tay-Sachs disease

GM2 gangliosidosis (AB variant)
TSD
Hexosaminidase A deficiency
HEX A Deficiency

B variant GM2 gangliosidosis

Sphingolipidosis, Tay-Sachs