DE LA SALLE UNIVERSITY-DASMARIÑAS
MEDICAL BIOLOGY
2-2
IN PARTIAL FULFILLMENT OF THE
REQUIREMENT IN THE COURSE
BIOL327: INTRODUCTORY TO GENETICS
“ TAY-SACHS DISEASE ”
SUBMITTED TO:
MS. JONNAHCAR S. SAN SEBASTIAN
SUBMITTED BY:
ARIDA, GERI LOU Y.
CAMACHO, KATE FRANCES G.
DELFIN, ALYSSA A.
SORIANO, AIRA LAINEY L.
MAY 2020
INTRODUCTION
A fatal genetic metabolic disorder, Tay-Sachs The child will have an afflicted dull response
disease, most commonly found in children to outside stimuli together with exaggerated
that caused by deficiency of the enzyme
startle response to sharp sounds (sudden
hexosaminidase A (hex-A) that results in a
extension of arms and legs). By the 6-10th
failure to process a lipid called GM2
month of the infant, motor and mental skill
ganglioside that accumulates in the brain
and other tissues. will begin to regress. Another progression of
this disease at this age is progressive loss in
It is known to progressively destroy nerve cells, visual attentiveness where in a macular pallor
neurons, in both the brain and the spinal cord. It and presence of “cherry red-spot” in the area
is a fatal inborn error of ganglioside of the fovea centralis of the eye is seen.
metabolism, inherited as an autosomal Around 8-10 months these symptoms begin
recessive trait. Waren Tay and Bernard Sachs to progress rapidly, infants are increasingly
are the two physicians that described the non-responsive to patrental stimulation and
disease's progression and provided differential exaggerated startle response becomes
diagnostic criteria to distinguish it from other pronounced. Also seizure would likely occur,
neurological disorders with similar symptoms. becoming more severe after the first year of
the infant. In the second year, psycho-motor
The severity of expression and the age at onset deteriorates leading to decerebrate
of Tay-Sachs varies from infantile and juvenile posturing (mostly in patients in vegetative
forms. It is mostly seen in infants but could also state), increased seizure activity and difficulty
be in adolescence and adulthood but is more in swallowing. Ultimately, the patient will
rare and milder than it is within an infant. This progress to an unresponsive vegetative state
disease is uncommon in the general population with death resulting from
but frequently seen in Ashkenzani Jews but can bronchopneumonia resulting from aspiration
also be found in the French Canadians of in conjunction with a depressed cough.
Southern Quebec, Cajuns in South Louisiana
and other existent populations, but it is rare.
This disease appears normal until as early as 3-
5 months old infants where mild motor
weakness is manifested.
Its common form is usually in infancy or infantile form which is fatal but with children
on the juvenile form, also called as subacute form, develop symptoms later than those
with the infantile form, and they usually live until later in childhood or adolescence.
The adult form, also called late-onset Tay-Sachs disease, may occur anytime from
adolescence to the mid-30s. The symptoms and severity can vary from one person to
another. Some other symptoms are characterized by apathy, hyperacusis, motor
weakness, and appearance of a macular cherry-red spot in the retina. Seizures and
progressive mental deterioration follow with blindness, deafness, and spasticity,
leading to a state of decerebrate rigidity. These infants usually die by 3 years of age.
Some effects of the disease are shown in Figure 1 below.
FIGURE 1. EFFECTS OF TAY-SACHS DISEASE
Tay-Sachs disease affects the 15th chromosome. Everyone has two of these
chromosomes, when one isn’t working they’re just a carrier, but can pass on the
disease to offspring. When both chromosomes aren’t working the person has Tay-
Sachs disease. If both parents are carriers the percentages will be: 25% Normal child:
50% Carrier child: 25% Child with Tay-Sachs disease.
PATTERN OF
INHERITANCE
Tay-Sachs is an autosomal recessive genetic
disorder. Autosomal means it affects males and
females equally and recessive means both
parents must be a carrier for the children to be at
risk. This means that to have the disease, a
person must have a mutation in both copies of
the responsible gene in each cell. There is
nothing either parent can do, before or during a
pregnancy, to cause a child to have Tay-Sachs
FIGURE 2. PATTERN OF INHERITANCE
disease.
This disease is caused by a mutation in the
People with Tay-Sachs disease inherit one alleles of gene HEXA of chromosome 15. This
mutation from each of their parents. The parents, gene codes for the subunit of an enzyme called
who each have one mutation, are known as β-hexosaminidase A which is found in
carriers. Carriers of an autosomal recessive lysosomes and helps it break down large
disease typically do not have any signs or molecules and in this case, helps in breaking
symptoms (they are "unaffected"). Seen in down ganglioside GM2s.
Figure 3.0 is the illustration of how this disease is
accumulated and inherited from the parents to
the child and to the next generations.
A child can only have Tay-Sachs disease if both
parents are carriers of the gene. When two
carriers have a child together, there's a:
50% chance that their child will be a carrier,
but not have the disease
25% chance that their child will not be a
carrier and not have the disease
FIGURE 3. HEXA
25% chance that their child will have the
disease
Hexosaminidase is a dimer composed of 2 subunits, either the α subunit (encoded by
the HEXA gene) and/or the β subunit (encoded by the HEXB gene). The various
isoforms of β-hexosaminidase result from the combination of α and β subunits. The β-
hexosaminidase S (HexS) enzyme is a homodimer of αα, the β-hexosaminidase A
(HexA) enzyme is a heterodimer of αβ, and the β-hexosaminidase B (HexB) enzyme is a
homodimer of ββ. It is the α-subunit that carries out the catalysis and only the HexA
form of β-hexosaminidase can catalyze the cleavage of GM2 gangliosides
FIGURE 4 & 5. MECHANISM
In normal conditions, β-hexosaminidase A works in the lysosome of nerve cells to
breakdown unwanted ganglioside GM2, a component of the nerve cell membrane.
This requires three components: a ɑ-subunit, a β -subunit and an activator subunit. The
activator will first bind to the ganglioside GM2, this complex will bind to β-
hexosaminidaseA and then digestion occurs. With these components working
together, it gives the ability of making exocytosis happen. In Tay-sachs disease, the
alpha subunit of hexosaminidase malfunctions or mutated, leading to no exocytosis
meaning there will be a toxic build-up of the GM2 ganglioside in the lysosome. To this
toxic build-up, swells the lysosome the will excessively fill the cell eventually choking
off normal cellular functions. The natural hydrolysis reaction of the gangliosides cannot
occur as normal and the accumulation of the lipids in the brain, central nervous system
and the retina of the eyes, disrupts the normal physiological processes of the neurons
which leads to the presentation of symptoms of Tay-Sachs disease.
PROGNOSIS health of the patient may occur leading to
death of the patient.
This disease is a neurodegenerative disorder
Although there is no appropriate cure for this
which shows fatality to be affected as it affects
disease, there was a research conducted in
one's motor, cognitive function etc. Upon
2005 by Sabata Martino’s research group
symptoms shown by a patient, the disease is in
wherein gene therapy helped decrease the
need to be screened and tested if it is positively
build-up of GM2 in the mice’s brain with tay-
the Tay-Sachs Disease. However, if one is
sachs disease. Through injecting their self-
diagnosed with this disease, it has no direct cure,
created virus that coded for a specific gene
only the symptoms are the ones being treated,
missing in the tay-sachs affected mice, the
helping the patient to live comfortably with the
GM2 ganglioside build-up had disappeared in
said disease.
the mice injected with the highest dose of the
viral vector, indicating that the viral vector had
Treatment plans are the only options for Tay-
produced Hexa enzymes in the mice’s brains,
Sachs patients, depending on the specialists
and that those enzymes had functioned in
and also the parents of whether what treatment
normal processes of disintegrating the fat
plans are going to be conducted with the
buildups. The mice injected with the lower
patient, this could also be called “palliative care”.
dose of the viral vector showed improvement
Treatments may include; medicines for seizures
but not a full disappearance of GM2
and stiffness, speech and language therapy for
gangliosides. Furthermore, there is already a
feeding and swallowing problems – sometimes
clinical trial about the use of a viral vector
special bottles or a feeding tube may be needed,
presented in the European Society of Gene &
physiotherapy to help with stiffness and improve
Cell Therapy (ESGCT) and promising results
coughing (to reduce the risk of pneumonia),
were observed and seen wherein it mirrors the
antibiotics to treat infections like pneumonia if
results of the results such that GM2
they occur. These possible treatments relieve
gangliosides build-up disappeared or
the effects of the disease but do not cure it, even
decreased.
with the best care, children with this disease still
usually die at the age of 4 mostly from recurring
Life expectancy of a patient with this disease
or intercurrent infections. There is no other
may vary of the type, the classic infantile tay-
option to treat this certain disease rather proper
sachs disease is fatal by age 2-3. In juvenile
care and medications to help ease the patient’s
form, death usually occurs by age 10-15 years;
state. The disease progresses on its own and as
preceded by several years of vegetative state
the patient’s condition worsens the body can be
with decerebrate rigidity. And on adult form,
more susceptible to infections and degradation
most patients have a normal life expectancy.
in the
DIAGNOSIS
The diagnosis of Tay-Sachs disease requires a consultation to gather information about the
family and medical history of the patient, then by a physical examination and blood tests to
validate the diagnosis. Prenatal screening such as chorionic villus sampling (CVS) and
amniocentesis for the disease is also possible, which authorizes parents the choice to carry
on or terminate the pregnancy before it gets to the completion of a normal length of
pregnancy and other types of screening.
Family and Medical History
Since the genetic disease has an autosomal recessive pattern, both parents must be
carriers for a child to have a chance of being afflicted from the disease. This is the reason
why it is essential to ask about the family history of the disease on the side of both
parents of the child. Signs of Tay-Sachs disease usually present at around the age of six
months. Parents may observe that the infant is a late bloomer in gaining independence
from learning to take a seat and crawl, and they may become overly disturbed by
unwanted sounds or movements. The presence of red spots near the center of the
retina in the eye is also a common indication that may be considered in the early stages
of the condition.
Physical Examination
A physical examination of the patient is conducted in the case early symptoms of the
disease are present to examine it further. Particularly, an eye examination is usually
required to visualize the presence of the distinctive red spot in the center of the macula
of the retina.
Blood Test
Deficiency of Hexosaminidase A (HEXA) protein in the blood may be used as a
diagnostic indicator of the disease. A blood test can be conducted and analyzed for the
presence of HEXA. While patients with different conditions may be likely to have
decreased levels of the protein, a total deficiency of the protein is a substantial
diagnostic factor for Tay-Sachs disease. This is generally due to a genetic mutation that
affects the production of the HEXA protein. Aside from this, blood tests can determine
whether individuals are carriers for Tay-Sachs disease. It is necessary to discuss your
ancestry with the genetics provider so that appropriate carrier screening is ordered.
Molecular Genetic Testing
Aside from a Blood test, Molecular genetic testing can confirm a diagnosis of Tay-Sachs
disease. It studies single genes or short lengths of DNA to identify variations and can
detect mutations in the HEXA gene that can lead to a genetic disorder. However, it is
only accessible as a diagnostic service at specialized laboratories. Prenatal diagnosis is
also possible through molecular genetic testing of tissue samples obtained through
CVS or amniocentesis if the specific disease-causing mutation in the HEXA gene is
known in the family.
Antenatal Screening
Antenatal Screening is the process of identifying those at high risk of a disorder. Parents
that are both carriers of the Tay-Sachs disease gene mutation may benefit from
preimplantation genetic diagnosis. This involves a process of in-vitro fertilization, where
the embryo is only implanted into the mother’s uterus if it does not carry the affected
genes. If both parents carry genetic mutations of the disease, there is a 25% chance that
any children will be affected. A diagnosis can be conducted prenatally with specific
testing methods to determine if a fetus is affected by the disease before it is born such
as:
(a) Chorionic villus sampling (CVS) is a prenatal test that can be performed between 10
and 14 weeks of the pregnancy and uses a cell sample of chorionic villi from the
placenta, taken through the cervix or the abdominal wall.(b) Amniotic fluid testing also
called amniocentesis, may be performed between weeks 15 and 20 of pregnancy in
which a small amount of amniotic fluid is removed from the sac surrounding the fetus
taken with a fine needle inserted into the uterus through the abdomen, under
ultrasound guidance.
These samples used in CVS and Amniotic fluid testing are studied to determine whether
hexosaminidase A is present or, as in people with Tay-Sachs disease, absent or present
in greatly reduced levels. This is called an enzyme assay.
Molecular Genetic Screening
Genetic carrier screening is a test to determine if an individual is a carrier for certain
genetic diseases. In the case of Tay-Sachs disease, it is conducted by reading across
both copies of one’s HEXA genes and detecting if there are any known modifications
(mutations). A negative (normal) result decreases the possibility of being a carrier, but it
does not eradicate the chance. It is possible to carry a mutation that has still not been
discovered or that modern technology is incapable of detecting.
It is also possible to receive an “uncertain” or vague result called a “variant of uncertain
significance” (VUS). It is an allele or variant form of a gene that has been identified
through genetic testing but whose significance to the function of an organism is
unknown. It connotes that a change was identified in the spelling of the HEXA gene, but
it is still unknown if that change is a normal human variation or if it denotes carrier
status. It is necessary to discuss how a VUS result may affect your family’s health with a
genetic professional.
Enzyme Screening
Screening consists of individually testing each sample of a series such as various
enzyme mutants, reaction conditions, for the targeted reaction. Enzyme screening is
presently the gold standard for Tay-Sachs disease carrier screening. It is conducted
using an enzyme assay that detects the level of protein produced in the blood from the
HEXA gene for Tay-Sachs. It is performed using serum or leukocytes isolated from
blood. The serum is most commonly used but leukocyte screening is recommended
when the person screened is pregnant, taking birth control pills, or on any medications
that affect hormones. The enzyme measured in Tay-Sachs disease screening is called
Hexosaminidase A. Individuals with infantile-onset Tay-Sachs are expected to have
absent or nearly absent Hexosaminidase A enzyme activity while those with juvenile or
adult-onset Tay-Sachs disease tend to have 6-15% Hexosaminidase A enzyme activity.
Juvenile Diagnosis
Children with juvenile Tay-Sachs disease are typically diagnosed around the age of two
to ten years old. Initial symptoms such as developmental delay. It means that the child is
slower to develop skills that are expected at a certain age. Some developmental delay is
a delay in reaching language, thinking, and motor skills milestones. Similarly to infantile-
onset, the diagnosis can be confirmed with a blood test.
Late-Onset Diagnosis
Patients with late-onset Tay-Sachs disease are usually diagnosed in adolescence or
early adulthood. Initial symptoms may involve speech disorders, motor coordination,
and muscular control. The diagnosis can be confirmed with a blood test.
TREATMENT
At present, no treatment will terminate or decelerate the progression of Tay-Sachs disease.
Some treatments such as anticonvulsants and antipsychotic medications intend to
alleviate several symptoms, manage infections, prevent complications, and increase life
expectancy. Research into potential treatments for Tay-Sachs disease is ongoing.
REFERENCES
