Tag Archives: genetic disorders

Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease, named for the two French scientists and the English doctor who separately discovered it in 1886, is a genetic disease that affects about one in 2,500 people, making it the most common genetically based nervous system disorder. It is caused by genetic mutations that affect the myelin sheath that protects the nerves, disrupting the signals from the brain. It leads to muscle weakness, foot problems, pain or loss of sensation in the extremities, poor muscle development and muscle loss, frequent falls, and an odd gait. Symptoms usually start in early childhood, though in some cases initial onset may not strike until after age 30. Charcot-Marie-Tooth is a hereditary condition, afflicting anyone born with the genetic mutations that cause the symptoms.

As the disease progresses, the patient may slowly lose manual dexterity and suffer increasing weakness in the hands and arms. In some people, hearing and eyesight get progressively worse over time. Many patients develop the spinal deformation known as scoliosis, in which the spine starts to curve into an S shape. In some cases, the vocal cords atrophy and the person has difficulty swallowing and speaking. Charcot-Marie-Tooth patients are often shorter than average due to the muscular problems. People with the disease are particularly prone to gastrointestinal problems.

Treatment for Charcot-Marie-Tooth disease is focused on alleviating the symptoms, because there is no cure, though researchers have begun to investigate the possibility of using an analog to a growth factor ordinarily produced by the cells but that Charcot-Marie-Tooth disease interferes with. People with the condition often require orthopedic devices for mobility, but doctors use physical therapy and occupational therapy to avoid or forestall this. Other assistive devices can be helpful in allowing patients to do everyday tasks.

Now, however, a new study may put doctors on the road to a cure. Zebrafish are commonly used in medical research because they are similar to humans in surprisingly many respects, and the zebrafish complete genome is known, making mutations easy to both introduce and recognize. One research team has begun using zebrafish to explore Charcot-Marie-Tooth disorder, and have learned that motor neurones are involved in the condition. This suggests possible treatment approaches along the line of other motor neuron diseases.

Gaucher And Parkinson’s

About one in 20,000 children is born with a form of Gaucher’s disease, a genetic condition in which the body is unable to remove a type of lipid from cells. It affects the bones and organs. It is the most common genetic illness affecting Ashkenazi Jews; one in 450 Ashkenazi infants is born with the disease. Overall, one percent of Americans are carriers of Gaucher’s disease. That means one percent of people have one copy of the flawed gene that causes the condition. If two carriers have children, each of those children has a one in four chance of getting two copies of the gene—one from each parent—and having the disease, and a one in two chance of inheriting one copy and being a carrier.

Gaucher’s disease can be spotted in advance by genetic testing. Testing to look for the genes associated with the condition is about 70 percent accurate in the general population, higher in Ashkenazi Jews. This testing can determine help whether someone with a family history is a carrier of the disease. Carriers have reduced levels of the enzyme affected by the genetic mutation, but show no symptoms. Blood tests can also detect these reduced levels and identify carriers, particularly in conjunction with genetic testing. Couples who are both at risk are advised to get tested so they have some awareness and can know what their options are. Amniocentesis can determine whether a mother who is a carrier is going to have a child with the disease.

Though carriers of Gaucher’s disease do not have symptoms of the disease itself, there is some evidence that carriers and patients alike are at increased risk of Parkinson’s disease. The cellular mechanisms work overtime to both compensate for the damaged enzyme and get rid of the accumulated lipids and to deal wit the actual broken enzyme, which accumulates in cells as well. This extra effort leads to cell death and causes neurological damage of the sort that leads to Parkinson’s disease. There are a number of genetic mutations that can result in Parkinson’s, and very few patients with Gaucher’s disease will go on to develop Parkinson’s, but experts say it noticeably raises the risk.

About Cystic Fibrosis

A single mistake on a single gene can cause serious medical problems. In fact, it is just such a mistake, the omission of a three-letter word from the genetic code, that causes cystic fibrosis, a congenital lung disease that also affects the digestive system, in 90 percent of the about 30,000 cases in the United States. This deletion, or any of the approximately 1,500 other mutations that can cause cystic fibrosis, can be inherited from other parent, but only causes disease when it is inherited from both. All these mutations have similar effects, mucus forms in the lungs, interfering with breathing and leaving the person prone to infection. Cystic fibrosis also causes poor growth, infertility, and a reduced lifespan.

In fact, some researchers are suggesting that the mutation is associated with two or more different illnesses. One is the disease commonly thought of as cystic fibrosis, in which unusually thick mucus is produced, coating the lungs and causing the respiratory symptoms associated with the disease; another, often considered harmless, is now believed to cause problems with the pancreas and digestive system, with the reproductive system, with the sinuses, or elsewhere in the body.

Thickened mucus is not the only reason people with cystic fibrosis are especially prone to lung infections. People with cystic fibrosis also have high rates of an infection called cepacia syndrome, which disrupts the immune response. Cepacia syndrome is also a disease in its own right, causing fever, pneumonia, and, often, death. However, there is new evidence emerging that cystic fibrosis itself causes damage to the immune system. People with cystic fibrosis are missing a crucial immune system molecule that makes it possible for the immune cells to identify pathogens, in order to be able to hunt them down and destroy them. When the pathogens go unrecognized, they are allowed into the body to cause harm.

Fortunately, there is good news. Scientists are reporting that cystic fibrosis patients born in 2010 have a longer expected lifespan than their predecessors. Overall, only about half of cystic fibrosis patients live to 40—itself an improvement on the days when few reached elementary school age—but improvements in treatment and management mean those born this decade are expected to make it well into their 50s.

Race And Sickle Cell

Sickle cell disease is a genetic illness that causes chest and joint pain, anemia, poor blood circulation, and a tendency towards infection. The mutation responsible for the disease causes a flaw in the process of building red blood cells—rather than round and flexible, the cells are rigid and sickle-shaped, which is what gives the disease its name. The disease is present from birth, an symptoms begin to appear shortly thereafter. People with sickle cell often have vision problems and are at greater risk of hypertension and stroke.

When a disease is genetically linked, it tends to be more prevalent in certain populations and ethnic groups; in particular, sickle cell disease is mostly found in black communities. As a result, the ravages of the disease are often compounded by racism, including in treatment facilities—either the patients are overlooked, or the facilities themselves are neglected by politicians and philanthropists. This has an effect on the treatment these patients are able to receive. This, in turn, makes them skeptical that health care providers are on their side and willing to help them. As a result, sickle cell patients frequently get suboptimal care.

This is a particular issue with sickle cell because management of the disease is so complicated. Patients need regular blood transfusions from a young age—ideally from donors who are especially well-suited to match people with sickle cell—physical therapy to prevent the effects of poor circulation, regular screening for high blood pressure, and therapy to ward off kidney disease. Bone marrow transplants can help some patients; however, this is a dangerous and drastic measure and matches are hard to find, although researchers are looking into ways to broaden the pool of potential matches.

Scientists are also looking into gentler bone marrow transplant procedures that may be lower risk. Transplanted bone marrow is a source of stem cells, which can be used to create correctly shaped red blood cells, undoing the damage. The usual marrow transplant procedure starts with an intense course of chemotherapy to completely destroy the patient’s own bone marrow, which is then replaces with the donor’s. Recently, medical professionals have begun looking at partial transplant, which avoid the dangers of chemo. In initial testing, this has been successful, but there is larger-scale testing still to come.

Muscular Dystrophy Treatments May Be On The Horizon

Several possible new treatments for muscular dystrophy have been discovered in recent months, some rather surprising. For example a molecule in cola, when injected into laboratory animals with analogous conditions, alleviated the symptoms and arrested the progress of the degenerative disease. The substance, called THI, is found in caramelized sugar and brown sugar as well as cola; it boosts levels of a protein ordinarily responsible for muscle maintenance, which malfunctions in people with the form of muscular dystrophy referred to as Duchenne. THI was both injected into the experimental subjects and added to their drinking water—mimicking the way most humans who consume it do so.

Duchenne muscular dystrophy is only one form of the disease, but it is the most common, accounting for half of all cases. With muscular dystrophy, the muscles are not properly repaired after damage, even the wear and tear of ordinary life. In healthy people, muscles can be permanently weakened by severe injury, but more prosaic damage is repaired by cellular processes. In muscular dystrophy patients, these processes don’t work. This means the limbs slowly lose function, followed by the muscles responsible for respiration—most patients eventually need to rely on a ventilator to breathe.

There is no cure for muscular dystrophy currently available. There are medications to slow its progress, but these drugs cannot reverse the damage, or even stop it on a long-term basis, and so the focus is generally on management. Physical therapy can help maintain as much mobility as possible, and surgical treatments can minimize the effects of muscular contractures and curvature of the spine. In addition, a pacemaker may be used to maintain a regular heartbeat. One experimental treatment is looking at a slightly different approach to protecting the muscle-maintenance protein, by deactivating a quality control mechanism that destroys it in muscular dystrophy patients.

A third approach being studied looks at the genetics behind the disease. Muscular dystrophy is hereditary, with a complex inheritance pattern that means carriers of the mutations responsible may have no reason to be aware of it. Most Duchenne patients are male. Genetic editing techniques are being developed that may be able to fix the mutated genes early on, preventing proteins from being damaged and the disease from developing.

Growing Up With Sickle Cell

Doctors are increasingly able to control sickle-cell disease. The hereditary condition affects roughly 100,000 Americans, and can shorten life expectancy, though less so than in the past. People with sickle-cell disease have a genetic mutation that causes red blood cells to be rigid and misshaped, leading to excessive clotting. This means chest and joint pain and anemia, and greater risk of hypertension and stroke. The cells are also unusually fragile, with less than a quarter the life cycle of ordinary red blood cells, leaving people who have the disease unusually prone to infection. The rigidity and fragility are due to fibers that form in the cells of people who carry the mutation.

Advanced treatment techniques for sickle-cell disease are causing a good problem, that more and more children and adolescents with sickle-cell are becoming adults with sickle-cell, and are living with the condition as adults for longer. In studies, patients at the point of transition, who are becoming adults, lean more heavily on emergency rooms than pediatric patients do; researchers are looking into ways to get them the health care they need, without relying on emergency facilities that aren’t necessarily equipped to provide the kind of care these patients require.

One reason the condition has become more treatable is a finding that bone marrow transplants—a surgical procedure that can be a treatment of last resort in severe or intractable cases—don’t require the donor and recipient to be an exact match. Donor marrow produces healthy red blood cells to replace the misshapen ones, but transplantation can be hard on the immune system. Treatments for milder cases are drugs, including an anti-depressant, that manage the symptoms and effects but don’t fix the cell production.

Newer research has found a way to get the patient’s own boy to produce more correctly-shaped red blood cells. In sickle-cell patients, the problem is in the adult cells. Fetal cells—those present at birth—are shaped normally. The genetic mutation affects only the adult cells. The chemical that regulates which type of cell is produced is a common one with a variety of functions in the body, but scientists may have found a way to target it only in red blood cells, leaving it alone elsewhere.

Duchenne Muscular Dystrophy

Muscular dystrophy refers to a group of genetic diseases that prevent the muscles from developing properly. The muscle fibers are more easily damaged and do not get repaired fully, meaning the muscles weaken faster. In the skeletal muscles, this typically leads to limbs being fixed in position and to using a wheelchair; in other parts of the body, it can cause difficulties in breathing or swallowing. The most common type, Duchenne muscular dystrophy, accounts for half of all cases. Most people with Duchenne are male; about one in 3,600 boys are born with the disease. Duchenne is a hereditary disease that, due to the genetics of the condition, seldom affects girls.

Duchenne symptoms generally appear before the age of six. Boys with the condition tend to walk late, and have trouble standing up, climbing stairs, and running. Not only do these children start walking late, they gradually lose the ability to walk after developing the skill, often by the time they reach their teens. Duchenne boys usually have across-the-board motor skill deficiencies, as well as an increased risk of neurological and learning difficulties. Duchenne does not affect the ability to feel pain or other sensations, though it is generally not painful itself. The condition also affects breathing, and men with Duchenne are not expected to live much past 40—often, 30—due to respiratory difficulties.

Treatment for the forms of muscular dystrophy is the subject of ongoing research. A study involving nanoparticles to deliver a medicine called rapamycin the function of the faulty protein—as opposed to other treatment approaches that focused on the protein itself—has proven successful in experimental animals.

"The nanoparticles tend to penetrate and be retained in areas of inflammation," study author author Samuel A. Wickline, M.D., said in a statement. "Then they release the rapamycin over a period of time, so the drug itself can permeate the muscle tissue." Rapamycin cannot be administered orally because in small doses, it is ineffective in the muscles, while in large doses, it has too drastic a suppressive effect on the immune system to be safely administered. When smaller doses are targeted to muscle tissue directly, it might be possible to see an effect without compromising the patient’s safety.

Fixing Cystic Fibrosis

Around 30,000 people in the United States have been diagnosed with cystic fibrosis. This is a condition in which a genetic flaw affects the way the body uses water and salt, causing the mucous that lines the lungs and digestive organs, rather than being slick as it normally is, to turn sticky. When this happens, it makes breathing and digestion difficult. Cystic fibrosis is typically diagnosed in childhood, though it is a lifelong condition. Symptoms in children include poor growth, poor weight gain despite a normal appetite, and chest infections, as well as the mucous itself.

People with cystic fibrosis are prone to a type of lung infection called bronchiectasis, an abnormal stretching of the passages of the lungs that causes coughing fits and bad breath. The lung damage from cystic fibrosis can also lead to people coughing up blood, chest pain, and even collapsed lung or respiratory failure. Cystic fibrosis also affects fertility, particularly in men, who may become completely infertile. The condition can open the door to diabetes, nasal polyps, osteoporosis, malnutrition, gallstones, certain kinds of bowel obstruction, and liver disease.

In fact, one pathogen that commonly causes illness in people with cystic fibrosis is a quite common one in healthy people—but it is primarily in people whose lungs are already affected by cystic fibrosis that the bacterium has an effect. In people with the condition, the pathogen, Pseudomonas aeruginosa, causes a form of pneumonia. The reason this bacterium is active in cystic fibrosis patients is that it feeds on the waste products of another bacterium, Enterobacter aerogenes, that is associated with cystic fibrosis.

Fortunately, while there is nor permanent cure for cystic fibrosis, new, more effective treatments may be on the horizon. While thousands of gene mutations have been identified as underlying cystic fibrosis, one in particular is responsible for 70 percent of cases. Interestingly, the damaged protein produced by the mutated gene can still function normally—but it gets destroyed by other proteins tasked with eliminating proteins that are damaged. Researchers in France used computer modeling to find ways to disguise the damage, so the damage-fixing proteins leave the ones produced my the mutated gene alone. Thus far it only works on this one common mutation.

Gene Therapy Helps Restore Sight For Some

The degenerative eye disease choroideremia affects about one in 50,000 Americans. It is a progressive form of blindness in which parts of the eye called the choroid and the retinal pigment epithelium, along with the retina, gradually decay. Ordinarily the epithelium provides materials and protection for the choroid and the retina, while the choroid lines the eye and helps get nourishment to the retina. When these layers start to break down, they can no longer support optical function and vision loss results. The disease runs in families, but the rate and degree of loss varies from person to person. The degeneration is irreversible, and there is currently no treatment that can stop its progress.

Now, however, researchers say a new approach using gene therapy may hold the key to not just stopping the degradation of the eye layers, but restoring sight already lost. Patients are injected with a clean copy of the gene that is damaged in people with the disease. This is intended to supplant the damaged gene and stop the destruction of cells in the eye. The treatment has only been tested in half a dozen patients, but all of them report success. In fact, one of the two patients in the study who had the most advanced choroideremia, with the most profound vision loss, was able to read four lines further down an eye chart six months after treatment, and night vision, in which the loss generally starts, improved in all six subjects.

Researchers warn, however, that these are only preliminary results, and it remains to be seen how well the treatment will work in the long term. In particular, scientists suspect that the treatment slows degeneration, but does not stop it entirely. Even if that is the case, however, the added years of functioning vision are a benefit to patients. Furthermore, the scientists note that the success of this genetic therapy for choroideremia suggests both other avenues to pursue in efforts to battle the disease—which has not proven treatable until this study—and ways to use gene therapy or similar approaches to treat other eye diseases, which may have similar pathologies, be likewise genetically linked, or both.

Gene Therapy For Down Syndrome

When women have children late in life, there is an increased risk that those children will have a condition that results in stunted growth, significant cognitive deficits, a flat face with a protruding tongue, and often short fingers and poor muscle tone. Down syndrome occurs in one in 35 babies born to women over 45, as compared to one in 400 babies born to women under 35; having a baby with Down syndrome is itself a risk factor, raising the chances of subsequent children also having the condition.

The most common form of Down syndrome is called trisomy 21 because it is caused by an extra 21st chromosome, three rather than the usual two. The other, vastly rarer, forms can also be traced to excess 21st-chromosome material, either present in some cells but not others (called mosaic Down syndrome) or attached to other chromosomes (called translocation Down syndrome). The translocation type accounts for about one in 25 cases of the condition and is the only type that can be inherited.

The extra chromosomal material, scientists now believe, appears to affect stem cell regulation. The primary culprit appears to be a gene on the chromosome called Usp16; an extra copy of the gene means more stem cells are used in development. While that one gene is almost certainly not solely responsible for all the symptoms of the condition, treatments that dial it back causes neural cells that typically grow slowly in Down patients to instead grow in the usual way.

This suggests a possible direction for research into genetic-based treatments for Down syndrome. The study that identified the role of Usp16 included tests in human cells, so there is some insight into how it works in people. Current treatments for Down syndrome are focused on early intervention and team care to address the symptoms and possible complications—specialists in developmental pediatrics, cardiology, speech therapy, neurology, and all the other areas the condition touches—but gene therapy may in the future prevent the condition from showing symptoms in the first place.