Lysosomal storage diseases form a category of genetic
disorders resulting from defective enzymes that normally
function to degrade unneeded molecules in cells. These
enzymes do their work in the lysosome, a small
compartment in a cell analogous to a garbage disposal.
The lysosome contains between thirty and forty different
degradative enzymes. When any one of the lysosomal
enzymes is defective, the molecules requiring that specific
enzyme for their degradation will accumulate and cause
that individual’s lysosomes to swell enormously. The
physiological effects of such swelling on the individual
include motor and mental deterioration, often to the point
of premature death. But each disease resulting from one
specific defective lysosomal enzyme has its own
characteristic pathology. The age of onset, rate of
progression, and severity of the clinical symptoms
observed in patients with the same defective lysosomal
enzyme are highly variable. For many years, this variability
in patients with the same defective enzyme puzzled
scientists. Only recently have researchers begun to answer
the riddle, thanks to a genetic analysis of a lysosomal
storage disorder known as Tay-Sachs disease.
As in most lysosomal storage diseases, patients suffering
from Tay-Sachs disease show both mental and motor
deterioration and variability in age of onset, progression,
and severity. Physicians have categorized the patients into
three groups: infantile, juvenile, and adult, based on onset
of the disease. The infantile group begins to show
neurodegeneration as early as six months of age. The
disease advances rapidly and children rarely live beyond
3 years old. The first symptoms of the disease appear in
juvenile cases between 2 and 5 years of age, with death
usually occurring around age 15. Those with the adult
form generally live out a normal lifespan, suffering from
milder symptoms than do those with the infantile and
juvenile forms. Researchers hoped that the categorization
would yield insight into the cause of the variability of
symptoms among Tay-Sachs patients, but this turned out
not to be the case.
In Tay-Sachs disease, undegraded materials accumulate
mainly in the lysosomes in the brains of patients, but the
kinds of molecules left undegraded and the specific identity
of the defective lysosomal enzyme responsible for the
malfunction were not discovered until the 1950s and 60s,
respectively. The main storage molecule was found to be
a lipid-like material known as GM2 ganglioside. The
defective enzyme was later identified as hexosaminidase.
In 1985, the gene coding for the normal hexosaminidase
enzyme was cloned and its DNA sequence determined.
Shortly thereafter, the DNA sequences of genes encoding
hexosaminidase from many Tay-Sachs patients were
studied. It soon became apparent that not one or two but
many different types of mutations in the hexosaminidase
gene could result in Tay-Sachs disease. Some of the
mutations prevented the synthesis of any hexosaminidase,
preventing all such enzyme activity in the cell. Patients
with this type of mutation all had the infantile form of
Tay-Sachs disease. Other mutations were found in certain
regions of the gene coding for areas of the enzyme known
to be critical for its catalytic activity. Such mutations would
allow for only extremely crippled hexosaminidase activity.
Most of the patients with these mutations clustered in the
juvenile category. Adult Tay-Sachs patients presented
mutations in the regions of the hexosaminidase gene that
were less important for the enzyme’s activity than were
those affected in juvenile patients. Scientists quickly
hypothesized that the variation in age of onset and severity
of Tay-Sachs disease correlated with the amount of
residual enzymatic activity allowed by the genetic mutation.
Though more research is needed to demonstrate similarity
with other lysosomal storage diseases, the work done on
Tay-Sachs disease has already offered a promising
glimpse into the underlying mechanisms of these
disorders.1) The passage suggests that which of the following lines of inquiry would be most useful in determining the relevance of the research done on Tay-Sachs disease to lysosomal storage diseases generally?
. Do patients suffering from other lysosomal storage
diseases have the same mortality rate as those
suffering from Tay-Sachs?
. Do other lysosomal storage diseases affect the
· How many different mutations are present in the
defective genes responsible for other lysosomal
· Does the onset of other lysosomal storage diseases
vary with the location of mutations in DNA sequences?
· What purpose does GM2 ganglioside serve in the
human body?2. It can be inferred from the passage that which of the following statements is true of lysosomal storage diseases?
· They are generally caused by mutations to the
· They are undetectable until physical symptoms are
· They can be fatal even when allowing some
· They are most lethal when onset is in a patient’s
· Their causes were unknown before the 1950s.3. The author of the passage is primarily concerned with
· illuminating the physiological consequences of Tay-
· explaining the importance of research on a specific
disease to other diseases of that type
· arguing for a more detailed examination of lysosomal
· challenging a traditional view of a class of diseases
· describing the implications of genetic mutations for
KUDOS is the good manner to help the entire community.