Nick McNallen P8 Tay-Sachs disease

Tay-Sachs Disease:

Tay -Sachs Disease Nick McNallen , AP Bio P8

An Overview of TSD:

An Overview of TSD Tay -Sachs disease is a recessively inherited autosomal neurodegenerative disorder caused by mutations in the α -subunit of hexosaminidase A, the enzyme that normally degrades GM2 ganglioside .

An Overview of TSD:

An Overview of TSD With a defective enzyme, the lysosomes of the nerve cells are unable to break down the gangliosides , and begin to accumulate with them. This accumulation results in the progressive collapse of the central nervous system.

History of Tay-Sachs Disease:

History of Tay -Sachs Disease Two men are credited with the discovery of TSD; British Warren Tay and American Bernard Sachs. The two men were not collaborators; in fact, they never actually came in contact. They both performed related research and presented their findings in the late 19 th century.

History of Tay-Sachs Disease:

History of Tay -Sachs Disease Tay presented a case of a twelve-month old male that exhibeted general weakness and “symmetrical changes in the region of the yellow spot in each eye.” It later died at twenty months. A second and third male child of the same family showed the same defects, as well as atrophy of the optic nerves. The second developed seizures before its death at 18 months, and third was lost to follow-up. Cherry red spot on the retina of the eye

History of Tay-Sachs Disease:

History of Tay -Sachs Disease Six years later, Bernard Sachs wrote an article describing the same disease Tay was studying. His paper, “On Arrested Cerebral Development,” was published in the Journal of Nervous and Mental Disease . The paper describes the relentless clinical progression of the disorder, opthalmologic finding, and a postmortem examination of patient “S.”

History of Tay-Sachs Disease:

History of Tay -Sachs Disease Sachs described the patient as feeble, unable to sit upright or attempt voluntary movement at all. Blindness set in accompanied by atrophy of the optic nerves. In the autopsy, he noted neurons with a normal histological appearance were scarce, but instead most were rounded and swollen.

History of Tay-Sachs Disease:

History of Tay -Sachs Disease Continuing research on the disease that he first described in his first years of clinical practice, Sachs stressed both the familial nature of the disease, and its occurrence in Jewish children. He proposed the term amaurotic family idiocy for the disorder, but as other scientists were presented with similar cases, they consulted Tay and Sach’s previous reports. The eponym Tay -Sachs became linked to the disease

Symptoms of TSD:

Symptoms of TSD With the knowledge Sachs accumulated, he summarized the symptoms as follows: Cessation of mental development and idiocy at the age of a few months. Paresis of the greater part of the body Deficient or increased reflexes Diminution of vision terminating in blindness Marasmus and fatal termination at about two The occurrence of the affection in several members of the same family.

Symptoms of TSD:

Symptoms of TSD Today, more is known about TSD and its diversity of clinical phenotypes. Many of the early effects revolve around the infant’s sense, particularly sight. These symptoms include decreased eye contact, myoclonic jerks, difficulty focusing on objects, and excessive startling by sharp noises.

Symptoms of TSD:

Symptoms of TSD Between six and ten months, other symptoms become dominantly apparent. These symptoms include noticeable behavior changes such as decreased alertness and playfulness, difficulty sitting up or rolling over, and a loss of motor and intellectual skills.

Symptoms of TSD:

Symptoms of TSD Other eventual symptoms include decreased hearing and eventual deafness, gradual loss of vision, feeding difficulties, and macrocephaly . An affected child may have hypotonia , a state of low muscle tone resulting in an infant’s muscles inability to resist movement. This can result in difficulty swallowing and breathing. Beyond ten months, a child may become blind, mentally retarded, paralyzed, and completely unresponsive. Seizures are not uncommon as the condition progressively worsens.

Diagnosis of Tay-Sachs Disease:

Diagnosis of Tay -Sachs Disease Tay -Sachs is relatively easy to diagnose. Any evaluation begins with a complete physical examination. There will also be a review of a detailed history of symptoms and family hereditary disorders.

Diagnosis of Tay-Sachs Disease:

Diagnosis of Tay -Sachs Disease However, what makes TSD easiest to diagnosis is the characteristic “cherry-red spot,” originally identified by Warren Tay in his original case. He identified “in the region of the yellow spot in each eye there was a conspicuous tolerably defined, large white patch, more or less circular in outline, and showing at its centre a brownish-red fairly circular spot”

Diagnosis of Tay-Sachs Disease:

Diagnosis of Tay -Sachs Disease The retina, because it has eight to ten layers of ganglion cells, appears white as a result of the accumulation of sphingolipids . Conversely, the macular region, particularly the foveola , is almost devoid of ganglion cells and remains transparent. These histological features result in the appearance of the central red area, surrounded by a dull halo.

Other Methods of Diagnosis:

Other Methods of Diagnosis A blood test can also be administered to diagnose Tay -Sachs disease. Using the blood test, doctors can determine the level of hexosamindase A activity of the affective infant. The biological parents may too have their blood tested in order to determine whether they are carriers.

Pathology of Tay-Sachs:

Pathology of Tay -Sachs Tay -Sachs is particularly tragic in its pathology. Children at first are born without incident and appear absolutely normal for the first couple months. In reality, GM2 gangliosides are already building up.

Pathology of Tay-Sachs:

Pathology of Tay -Sachs As the nerve cells distend, symptoms begin to become apparent, approximately around six months. The senses deteriorate and behavior changes, often described as the child becoming less attentive. Muscles weaken, and seizures may set in. Beyond a year of age, any mental function is clearly debilitated, the senses and ability to move is lost, and they are completely unable to interact with the environment. An affected child will unavoidably die before age five even with all available treatments.

TSD Treatments:

TSD Treatments There is currently no successful treatment for Tay -Sachs disease. The only truly effective way to treat it is to prevent the conception of an affected fetus from the start. Because it is a genetic disease, it is only passed on by individuals carrying the defective gene.

TSD Treatments:

TSD Treatments Population-based carrier screenings have proven effective in dramatically reducing the amount of cases, especially in particular ethnic groups like the Ashkenazi Jews. The results of the test help individuals who have tested as carriers become aware and consider consequences when choosing a partner.

TSD Treatments and Recent Discoveries:

TSD Treatments and Recent Discoveries As the deficiency of the enzyme Hexosaminidase A is the cause, a possible treatment is replacing it. If doctors were able to inject the enzyme into the body and make it available in the lysosomes , any degeneration of the nervous system should stop. Experiments have demonstrated intracellular correction of storage following the addition of exogenous enzymes to fibroblast cultures. It has shown promise in treating Gaucher’s disease. However, HEXA is a larger enzyme, and is unable to pass through the blood-brain barrier.

TSD Treatments and Recent Discoveries:

TSD Treatments and Recent Discoveries Substrate reduction therapy is a more novel approach to treating lysosomal storage disorders. Preventing the buildup of ganglioside is done with drugs that decrease their production rather than attempting to replace the enzyme. Then, the residual amount of enzyme may not be overwhelmed. Recent discoveries in preclinical studies of animals were successful, implying that the drugs are successful in passing through the blood-brain barrier.

TSD Treatments and Recent Discoveries:

TSD Treatments and Recent Discoveries A final prospective treatment is chaperone therapy. Rather than focusing on the enzyme or substrate, chaperone therapy attempts to treat the enzyme-producing proteins that may have become misfolded as a result of the mutation. They are usually destroyed, but introducing “chaperones” that correct misshapen proteins may be successful in treating TSD and other lysosomal storage disorders.

Works Cited:

Works Cited Fernandes Filho JA, BE Shapiro. “ Tay - Sachs Disease.” Archives of Neurology. 61.9 (2004): 1466-8 Kaback MM, and RJ Desnick . “ Tay -Sachs Disease: from Clinical Description to Molecular Defect” Advances in Genetics. 44 (2001): 11-14 Perl DP. “Barney Sachs and the History of the Neuropathologic Description of Tay -Sachs Disease” Advances in Genetics. 44 (2001): 11-23