87
CHAPTER THREE
Cells
nine groups of three microtubules with two additional
microtubules in the center, forming a distinct cylindrical
pattern.
Cilia fringe the free surfaces of some epithelial cells.
Each cilium is a hairlike structure about 10 µm long,
which attaches just beneath the cell membrane to a
modiF ed centriole called a
basal body.
Cilia dot cells in
precise patterns. They move in a coordinated “to-and-
fro”manner so that rows of cilia beat one after the other,
generating a wave that sweeps across the ciliated surface.
During cell division, the centrioles migrate to either side
of the nucleus, where they form spindle F bers that pull on
and distribute
chromosomes
(kro
mo-so
ˉmz), which carry
DNA information to the newly forming cells
(f g. 3.14)
.
Centrioles also form parts of hairlike cellular projections
called cilia and fl
agella.
9.
Cilia
(sing.,
cilium
)and
agella
(sing.,
agellum
).
Cilia and fl
agella are motile extensions of certain cells.
They are structurally similar and differ mainly in their
length and abundance. Both cilia and fl
agella consist of
G
erman physiologist Rudolph Virchow
hypothesized cellular pathology—disease
at the cellular level—in the 1850s. Today,
treatments for many disorders are a direct result
of understanding a disease process at the cel-
lular level. Here, we examine how three abnor-
malities—in mitochondria, in lysosomes, and in
peroxisomes—cause whole-body symptoms.
MELAS and Mitochondria
Sharon had always been small for her age, easily
fatigued, slightly developmentally delayed, and
had difficulty with schoolwork. She also had
seizures. At age eleven, she suffered a stroke.
An astute physician who observed Sharon’s
mother, Lillian, suspected that the girl’s symp-
toms were all related, and the result of abnor-
mal mitochondria, the organelles that house
the biochemical reactions that extract energy
from nutrients.
The doctor noticed that Lillian was uncoor-
dinated and had numb hands. When she asked
if Lillian ever had migraine headaches, she said
that she suffered from them nearly daily, as did
her two sisters and one brother. Lillian and her
siblings also had diabetes mellitus and muscle
weakness. The doctor ordered several blood tests
for mother and daughter, which revealed that
both had elevated levels of biochemicals (pyru-
vic acid and lactic acid) that indicated they were
unable to extract maximal energy from nutrients.
Their muscle cells had abnormal mitochondria.
Accumulation of these mitochondria in smooth
muscle cells in blood vessel walls in the brain
caused Sharon’s stroke, migraines,
and seizures.
The affected family members had MELAS,
which stands for the major symptoms—
m
itochondrial
e
ncephalomyopathy,
l
actic
a
cido-
sis, and
s
trokelike episodes. Their mitochondria
cannot synthesize some of the proteins required
to carry out the energy reactions. The mutant
gene is part of the DNA in mitochondria, and
Lillian’s mother transmitted it to all of her chil-
dren. But because mitochondria are inherited
only from the mother, Lillian’s brother will not
pass MELAS to his children.
Tay-Sachs Disease and Lysosomes
Michael was a pleasant, happy infant who seemed
to be developing normally until about six months
of age. Able to roll over and sit for a few seconds,
he suddenly lost those abilities. Soon, he no
longer turned and smiled at his mother’s voice,
and he was no longer interested in his mobile.
Concerned about Michael’s reversals in develop-
ment, his anxious parents took him to the pedia-
trician. It took exams by several other specialists
to diagnose Tay-Sachs disease.
A neurologist saw telltale “cherry red spots”
in Michael’s eyes. His cells provided further
clues—the lysosomes were swollen yet lacked
one of the forty types of lysosomal enzymes,
resulting in a “lysosomal storage disease” that
built up fatty material on his nerve cells. Tests
for the missing enzyme in the blood and tests
for mutant genes confirmed the diagnosis.
Michael’s nervous system would continue to
fail, and he would be paralyzed and unable to
see or hear by the time he died, before the age
of four years.
The cellular and molecular signs of Tay-Sachs
disease—the swollen lysosomes and missing
enzyme—had been present long before Michael
began to lag developmentally. The next time
his parents expected a child, they had the baby,
a girl, tested before birth for the enzyme defi-
ciency. They learned that she would be a carrier
like themselves, but not ill.
Adrenoleukodystrophy (ALD) and
Peroxisomes
For young Lorenzo Odone, the ±
rst sign of adre-
noleukodystrophy was disruptive behavior in
school. When he became lethargic, weak, and
dizzy, his teachers and parents realized that his
problem was not just temper tantrums. His skin
darkened, blood sugar levels plummeted, heart
rhythm altered, and the levels of electrolytes in
his body ²
uids changed. He lost control over his
limbs as his nervous system continued to deterio-
rate. Lorenzo’s parents took him to many doctors.
Finally, one of them tested the child’s blood for an
enzyme normally manufactured in peroxisomes.
Lorenzo’s peroxisomes lacked the second
most abundant protein in the outer membrane
of this organelle, which normally transports an
enzyme into the peroxisome. The enzyme con-
trols breakdown of a type of very long chain fatty
acid. Without the enzyme, the fatty acid builds
up in cells in the brain and spinal cord, eventually
stripping these cells of their lipid sheaths, made
of a substance called myelin. Without the myelin
sheaths, the nerve cells cannot transmit mes-
sages fast enough. Death comes in a few years.
Boys inherit ALD from carrier mothers.
A 1992 film,
Lorenzo’s Oil,
told the story of
Lorenzo’s parents’ e³
orts to develop a mixture of oils
to slow the buildup of the very long chain fatty acids.
Although the oil is still a questionable treatment
because of adverse e³
ects, it did enable Lorenzo to
live far longer than his doctors expected—he died
at the age of 30 in 2008. At the time of his death, he
could not talk or see and communicated with ±
nger
movements and eye blinks. Some boys with ALD
have been cured with transplants of bone marrow
stem cells, and an experimental gene therapy that
delivers a functional version of the responsible
mutant gene.
3.2
CLINICAL APPLICATION
Disease at the Organelle Level
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