Tay-Sachs disease S. F. Khatami Neonatologist

Ganglioside is a molecule composed of a glycosphingolipid(ceramide and oligosaccharide) with one or more sialic acids (e.g. n- acetylneuraminic acid, NANA) linked on the sugar chain

GangliosidosesLysosomal storage disease Tay-Sachs disease

Tay-Sachs disease (abbreviated TSD, also known as "GM2 gangliosidosis") is a genetic disorder, fatal in its most common variant known as Infantile Tay-Sachs disease.

Warren Tay

The disease is named after the British ophthalmologist Warren Tay who first described the red spot on the retina of the eye in 1881, and the American neurologist Bernard Sachs who described the cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish (Ashkenazi) population in 1887 Tay-Sachs

TSD is inherited in an utosomal recessive pattern. The disease occurs when harmful quantities of a fatty acid derivative called a ganglioside accumulate in the nerve cells in the brain. Gangliosides are present in lipids, which are components of cellular membranes, and the ganglioside GM2, implicated in Tay-Sachs disease, is especially common in the nervous tissue of the brain. Tay-Sachs disease

INCIDENCE Research in the late 20th century demonstrated that Tay-Sachs disease is caused by mutations on the HEXA gene on chromosome 15. A large number of HEXA mutations have been discovered, and new ones are still being reported. These mutations reach significant frequencies in several populations. French Canadians of southeastern Quebec and Cajuns of southern Louisiana have a carrier frequency similar to Ashkenazi Jews 1/25, but they carry a different mutation. Most HEXA mutations are rare, and do not occur in genetically isolated populations. The disease can potentially occur from the inheritance of two unrelated mutations in the HEXA gene, one from each parent.

Pathogenesis The condition is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of fatty acid derivatives known as gangliosides.

The allele for TSD is recessive, meaning that both parents must be carriers in order to create an affected child; even then, there is only a 25% chance of having a child with TSD.

Tay Sachs Disease High power view of anterior horn cell neurons excess lipid,due to the storage disorder.On electron microscopy, this stored material is made of concentrically laminated bodies.The lipid accumulates in neurons, interfering with the function of organelles and finally leading to the death of the neuron

Tay-sachs disease Healthy neuron and neuron affected by Tay-Sachs

Symptoms All patients with Tay-Sachs have a "cherry-red" spot in the back of their eyes (the retina).

Photograph of undus showing changes in the retina and is associated with GM2 gangliosidosis

Infantile TSD Infants with Tay-Sachs disease appear to develop normally for the first six months of life. Then, as nerve cells become distended with gangliosides, a relentless deterioration of mental and physical abilities occurs. The child becomes blind,deaf, and unable to swallow. Muscles begin to atrophy and paralysis sets in. Death usually occurs before the age of five.

Juvenile TSD Extremely rare, Juvenile Tay-Sachs disease usually presents itself in children between two and ten years. They develop cognitive, motor, speech, and swallowing difficulties; unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile TSD usually die between 5-15 years.

Adult/Late Onset TSD A rare form occurs in patients 20s and early 30syr. LOTS is frequently misdiagnosed, non fatal. Symptoms: unsteadiness of gait and progressive neurological deterioration. speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), spasticity, cognitive decline, and psychiatric illness, and seizures particularly schizophrenic-like psychosis. Patients with LOTS frequently become wheelchair-bound in adulthood.

Genetic counseling The disease results from mutations on chromosome 15 in the HEXA gene encoding the alpha-subunit of the Iysosomal enzyme beta-N-acetylhexosaminidase A. This enzyme is necessary for breaking down N- galactosamine from GM2 gangliosides in brain and nerve cells.

Genetic counseling More than 90 mutations have been identified to date in the HEXA gene, and new mutations are still being reported.

Tay-sachs- Chromosome 15

Screening Carrier testing- this is usually done by couple who are at risk for acquiring this problem. This test aims to detect if an individual is carrying the copy of the genetic mutation. Prenatal testing- this test is done to know if the fetus has inherited the defective genes from each parents.

Testing In populations with a high carrier frequency for TSD, genetic counseling is recommended so genetic testing can be done to detect carriership. Preimplantation genetic diagnosis can be considered in couples where both are carriers. In countries where selective abortion is legal, this method can be contemplated.

Tay-Sachs disease Diagnosis blood tests are taken to measure the HEX a or hexosaminidase A activity. The ophthalmologist will examine the eyes of the patient wherein “cherry-red” spot is seen at the back of the eyes.

Therapy Unfortunately, there are no treatments for Tay-Sachs disease. Anticonvulsants are given to control seizure. Supportive or Palliative treatments are also given especially in nutrition and hydration and ways to keep the airway open. Feeding tubes are attached to children since motor skills are affected.

Therapy There is currently no way to cure or treat TSD. Even with the best care children with Infantile TSD will die by the age of five, and the progress of Late-Onset TSD can only be slowed, not reversed. However, research is ongoing and several methods of treatment are being investigated, although significant hurdles remain before any of them will be past the experimental stages.

Therapy The first treatment method that was investigated by scientists was enzyme replacement therapy, whereby functional Hex A would be injected into the patient to replace the missing enzyme. However, the enzyme was found to be too large to be able to pass from the blood into the brain through the blood-brain barrier, where the blood vessels in the brain develop junctions so small that many toxic (or large) molecules cannot enter into nerve cells and cause damage.

Therapy Researchers also tried instilling Hex A into the cerebrospinal fluid, which bathes the brain. However, neurons are not able to take up the large enzyme efficiently even when it is placed next to the cell, so the treatment is still ineffective.

Therapy The most recent option explored by scientists has been gene therapy. However, scientists still believe that they are years away from the technology to transport the genes into neurons, which they say would be just as hard 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. If the defective genes were to be replaced throughout the brain Tay Sachs could theoretically be cured.

Therapy Other highly experimental methods being researched involve the manipulation of the brain's metabolism of GM2 gangliosides. One experiment has shown that, using the enzyme sialidase, the genetic defect can be effectively bypassed and GM2 gangliosides metabolized to be almost inconsequential. If a safe pharmacological treatment causing the increased expression of lysosomal sialidase in neurons can be developed, a new form of therapy, essentially curing the disease, could be on the horizon.

Therapies being investigated for Late-Onset TSD include treatment with the drug OGT 918 (Zavesca).