|
What occurs in less than one-tenth of one percent of the
population, yet
is found in one form or another in almost every family in the world?
A
rare genetic disease.
According to the Orphan Drug Act of 1983, a rare disease is defined
as a disorder that occurs in less than 200,000 people in the United
States, but many rare genetic diseases are substantially less common
than this. For instance, National Human Genome Research Institute (NHGRI)
Clinical Director William A. Gahl, M.D., Ph.D., has seen only five
people with Chediak-Higashi disease over the course of his entire
career. That's still more Chediak-Higashi patients than anyone else
in the United States is currently treating.
Why
does Dr. Gahl work with these patients? Couldn't his time be better
spent on disorders that affect far more people or have a chance of
being cured?
"The study of rare genetic diseases is very important," Dr. Gahl
said. "Rare diseases usually occur when two people who don't know
they carry mutations in the same gene have children. There's no
practical way to find out who has such mutations beforehand. People
with rare genetic diseases are often overlooked or forgotten, but we
gain a great deal from studying their disorders. Their contributions
to medical science are pure gold."
Dr.
Gahl explained that, even though the human genome sequence was
completed a few years ago, the function of most of our genes is
still unknown.
"One way to find out what a gene does is to create an animal, such
as a mouse, that doesn't have the gene and look at what the mouse
can and can't do. These animals are called 'knockouts,'" said Dr.
Gahl, who is also a senior investigator in the Medical Genetics
Branch of NHGRI's Division of Intramural Research. "Many people who
have rare genetic diseases are, in essence, complete or partial
human knockouts. They have missing genes or mutated genes that don't
function or function incorrectly. By studying them, we can discover
the role our genes play in normal cellular metabolism."
For
instance, Chediak-Higashi disease is helping Dr. Gahl and his
colleagues in their efforts to better understand how the body fights
infection and to determine which cellular triggers launch bone
marrow disorders, such as leukemia, multiple myeloma and aplastic
anemia.
The
genetic mutation responsible for Chediak-Higashi disease leads to
the alteration of tiny organelles, called lysosomes, that are
responsible for destroying foreign bacteria inside white blood
cells. Lysosomes are supposed to be lean and mean, but Chediak-Higashi
disease turns them into bloated 'couch potatoes' - huge, flabby and
incapable of killing anything.
Most children born with Chediak-Higashi disease die of infections
soon after birth. Those who survive the infections can go into the
disease's accelerated phase, which resembles a bone marrow disorder.
Blood cells are designed to live only so long. They originate in the
bone marrow, are released into the bloodstream, go through their
natural lifecycle, and then die. During the accelerated phase of
Chediak-Higashi disease, a type of white blood cell called a
lymphocyte somehow disables its normal death mechanism (called
'apoptosis') and ends up living far longer than it should, building
up in tissues and destroying them.
Bone marrow transplants can relieve the problems these lymphocyte
build-ups cause, and people with Chediak-Higashi disease who receive
successful transplants often live into their 20s and 30s, but then
other difficulties develop. Older people with Chediak-Higashi
disease may end up in wheelchairs because of poor balance, lack of
muscle strength and numbness in their hands and feet. They also lose
some of their ability to think. Research is just beginning on
treatments for this stage of the disorder.
Another lysosomal disorder that Dr. Gahl studies is called
cystinosis. One of the things lysosomes do in addition to fighting
infection is to break down unneeded proteins so their constituent
amino acids can be salvaged for future use. In cystinosis, the
transporter protein that carries one of these salvaged amino acids,
called cystine, out of the lysosome and into the cell cytoplasm is
either defective or missing. This causes cystine to build up in the
lysosome and form crystals, which end up destroying both the
lysosome and the cell around it.
One
structure that is ruined early in Cystinosis is the proximal tubule
of the kidney, which salvages nutrients the body needs from fluid
before it is turned into urine and eliminated. The damaged proximal
tubules of people with cystinosis cannot do this, so small
molecules, such as glucose, amino acids and phosphates spill out of
the body and are lost.
Children with the disorder do not grow and have weak, painful bones.
If they don't receive treatment, they go into kidney failure and die
before age 10. A kidney transplant can prolong life, but the disease
can continue to damage other organs, including the eyes, muscles,
pancreas and brain.
Dr.
Gahl was instrumental in establishing a drug called cysteamine as
the treatment of choice for cystinosis. Cysteamine breaks down
cystine and keeps it from building up in the tissues, thereby
delaying or averting kidney failure, improving growth of children
with cystinosis and possibly helping to prevent late complications
of the disease. Since coming to the NIH in 1981, Dr. Gahl and his
colleagues have seen more than 200 people with cystinosis, and some
of his patients who are taking cysteamine are now 40 to 50 years
old.
"Cysteamine
treatment has changed the course of the disease so dramatically that
cystinosis no longer demands the bulk of our efforts," said Dr. Gahl.
"It's a very good feeling."
Studying cystinosis has helped the scientific community understand
more about kidney function. Other diseases that Dr. Gahl's group
explores include: autosomal recessive polycystic kidney disease,
which is teaching researchers how kidney and liver cysts form;
alkaptonuria, which provides insights about how connective tissue
can be destroyed by amino acid breakdowns; hereditary inclusion body
myopathy, an enzyme defect that interferes with the maintenance of
good muscle tissue; and Hermansky-Pudlak syndrome (HPS), another
disorder of the organelles inside cells.
There are eight different types of HPS, each caused by a different
genetic defect. People with HPS have albinism because they lack
organelles called melanosomes that produce pigment in the hair, eyes
and skin. Since melanosome-containing cells nourish the rods and
cones in the eyes, people with HPS also have poor vision. A lack of
dense bodies in their platelets interferes with blood clotting so
they develop bleeding problems, and they have episodes of
inflammation in their lungs that cause a build-up of scar tissue
called pulmonary fibrosis. For two of the eight types of HPS, the
lung disease is fatal. HPS therapy focuses on controlling the
bleeding problems and lung damage, and the solutions that are found
might be able to help people whose lungs have been scarred by other
diseases.
Dr.
Gahl emphasizes that researchers, patients and society as a whole
are partners in the ongoing challenge of developing new and improved
therapies for rare disorders, noting that the impact of such
diseases should not be measured by numbers alone. "The test of a
society is how it treats its most helpless and disadvantaged
members," he said. "People with rare genetic diseases give humanity
so much, scientifically and spiritually, that we owe them a huge
debt of gratitude. In fact, they make us more human."
Courtesy: National Human Genome Research
Institute |
