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CMT is an inherited neurological disease characterized by a slowly progressive degeneration of the muscles in the foot, lower leg, hand, and forearm, and a mild loss of sensation in the limbs, fingers, and toes. The first sign of CMT is generally a high arched foot or gait disturbances.

Other symptoms of the disorder may include foot-bone abnormalities such as high arches and hammer toes, problems with hand function and balance, occasional lower leg and forearm muscle cramping, loss of some normal reflexes, occasional partial sight and/or hearing loss, and, in some individuals, scoliosis (curvature of the spine).

People with CMT disease usually begin to experience symptoms in adolescence or early adulthood. There is no cure for the disease, but there are treatment options, including physical therapy and bracing. Life expectancy is usually normal.

CMT disease can be divided into two classes, depending on where the dysfunction occurs in the peripheral nerves:

In CMT type 1, the peripheral nerves' axons - the part of the nerve cell that transmits electrical signals to the muscles - lose their protective outer coverings, their myelin sheaths. This disrupts the axons' function.

In CMT type 2, the axons' responses are diminished due to a defect within the axons themselves. CMT type 2, the less common of the two classes, can be further separated into at least six subtypes, caused by defects in different genes.

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CMT is an inherited neurological disease characterized by a slowly progressive degeneration of the muscles in the foot, lower leg, hand, and forearm, and a mild loss of sensation in the limbs, fingers, and toes. The first sign of CMT is generally a high arched foot or gait disturbances.

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Type 2 Diabetes Linked to Single Gene Mutation in One-In-Ten Patients | UC San Francisco

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A multinational study has identified a key gene mutation responsible for type 2 diabetes in nearly 10 percent of patients of white European ancestry.

The study, which originated in Italy and was validated at UCSF, found that defects in the HMGA1 gene led to a major drop in the body's ability to make insulin receptors - the cell's sensor through which insulin tells the cell to absorb sugar. This drop in insulin receptors leads to insulin resistance and type 2 diabetes, according to the paper.

Ira Goldfine, MD

Findings appear in the March 2 issue of the Journal of the American Medical Association and online at http://jama.ama-assn.org/content/305/9/903.short.

The results provide the unique opportunity for a test to predict potential for the disease in patients, as well as the possibility of identifying which of the current diabetes medications work best for people with this gene mutation, the authors said. Ultimately, it also could help drive research to find new and improved drugs for those patients.

While the study focused on Caucasians, it also lays the groundwork for similar analyses in patients of Asian, African and Native American descent, who suffer from higher rates of the disease, according to diabetes researcher Ira Goldfine, MD, a UCSF professor of medicine and of physiology who led the U.S. arm of these studies.

"This is a major breakthrough in type 2 diabetes," said Goldfine, noting that 26 million Americans have diabetes and an estimated 79 million have pre-diabetes. "Many of our current diabetes drugs are very effective in some patients and not in others. This finding could not only explain why that is, but also could help us target the right drug for the right person, so diabetics can manage their disease better and lead healthier lives."

Type 2 diabetes, which was previously referred to as "adult-onset" diabetes, is a growing global concern and is estimated to affect more than 250 million people worldwide. The disease has long been known to have both hereditary and lifestyle components, but until now, no single gene mutation has been pinpointed as playing a significant role in causing it.

The advance originated in 1993, when Antonio Brunetti, MD, PhD - at the time a postdoctoral fellow in Goldfine's laboratory - discovered that insulin receptors were turned on in cells by a certain protein, which is now understood to be produced by the HMGA1 gene. Brunetti, the senior author on this paper, continued his research at the University of Catanzaro, in Italy, and ultimately identified this gene mutation in a population of 3,278 Italians with diabetes, matched against a similar number of their compatriots who had neither diabetes nor pre-diabetes.

Brunetti's current study found at least one mutation on that gene in 9.8 percent of the diabetics in the Italian population, versus only 0.6 percent of the control group.

The UCSF team then ran a genetic analysis on 1,928 similar patients from the Genomic Resource in Arteriosclerosis, a DNA bank in the UCSF Cardiovascular Research Institute, a repository for 30,000 patient samples dating back to 1994. That data, mined in the UCSF laboratories of Clive Pullinger, PhD, and John Kane, MD, PhD, generated the same percentages as the Italian population, as did a subsequent study of 404 patients at the University of Reims, in France, by Vincent Durlach, MD.

"This is an excellent example of how international collaborations can find significant patterns in diseases," Brunetti said. "Diabetes is one of the most complex chronic diseases and it affects millions of people throughout the world. We hope to extend this research to see whether the same percentages hold true throughout the world population."

Brunetti said future research will include further study of variants within the HMGA1 gene, including studies in people with other racial heritages.

The international study included researchers from institutions in France, Italy and the United States, including Centre Hospitalo-Universitaire, Reims, France; Universita di Catanzaro "Magna Graecia," in Catanzaro, Italy; and UCSF. A full list of authors, their affiliations and funding sources, can be found in the published paper. No conflicts of interest were identified.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For more information, visit www.ucsf.edu.
Photo by Kristen Bole
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Type 2 Diabetes Linked to Single Gene Mutation in One-In-Ten Patients

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A multinational study has identified a key gene mutation responsible for type 2 diabetes, a finding that could lead to developing a predictive test for the disease, identifying which current medications work best and driving pharmaceutical research to find new therapies.

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Mutations in the , , and genes cause the forms of color vision deficiency described above. The proteins produced from these genes play essential roles in color vision. They are found in the retina, which is the light-sensitive tissue at the back of the eye. The retina contains two types of light receptor cells, called rods and cones, that transmit visual signals from the eye to the brain. Rods provide vision in low light. Cones provide vision in bright light, including color vision. There are three types of cones, each containing a specific pigment (a photopigment called an opsin) that is most sensitive to particular wavelengths of light. The brain combines input from all three types of cones to produce normal color vision.

The OPN1LW, OPN1MW, and OPN1SW genes provide instructions for making the three opsin pigments in cones. The opsin made from the OPN1LW gene is more sensitive to light in the yellow/orange part of the visible spectrum (long-wavelength light), and cones with this pigment are called long-wavelength-sensitive or L cones. The opsin made from the OPN1MW gene is more sensitive to light in the middle of the visible spectrum (yellow/green light), and cones with this pigment are called middle-wavelength-sensitive or M cones. The opsin made from the OPN1SW gene is more sensitive to light in the blue/violet part of the visible spectrum (short-wavelength light), and cones with this pigment are called short-wavelength-sensitive or S cones.

Genetic changes involving the OPN1LW or OPN1MW gene cause red-green color vision defects. These changes lead to an absence of L or M cones or to the production of abnormal opsin pigments in these cones that affect red-green color vision. Blue-yellow color vision defects result from mutations in the OPN1SW gene. These mutations lead to the premature destruction of S cones or the production of defective S cones. Impaired S cone function alters perception of the color blue, making it difficult or impossible to detect differences between shades of blue and green and causing problems with distinguishing dark blue from black.

Blue cone monochromacy occurs when genetic changes affecting the OPN1LW and OPN1MW genes prevent both L and M cones from functioning normally. In people with this condition, only S cones are functional, which leads to reduced visual acuity and poor color vision. The loss of L and M cone function also underlies the other vision problems in people with blue cone monochromacy.

Some problems with color vision are not caused by gene mutations. These nonhereditary conditions are described as acquired color vision deficiencies. They can be caused by other eye disorders, such as diseases involving the retina, the nerve that carries visual information from the eye to the brain (the optic nerve), or areas of the brain involved in processing visual information. Acquired color vision deficiencies can also be side effects of certain drugs, such as chloroquine (which is used to treat malaria), or result from exposure to particular chemicals, such as organic solvents.

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Color vision deficiency: MedlinePlus Genetics

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Mutations in the , , and genes cause the forms of color vision deficiency described above. The proteins produced from these genes play essential roles in color vision. They are found in the retina, which is the light-sensitive tissue at the back of the eye.

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Many women breathe a sigh of relief when they test negative for BRCA gene mutations, which raise the risk for breast, ovarian and other cancers. But that's not the end of the hereditary risk story.

Freelance journalist Susan Berger is a prime example. She was diagnosed with breast cancer in 1997 and learned she didn't have the BRCA gene mutations in 2009 when she underwent genetic testing.

She endured a lumpectomy, chemotherapy, radiation and years of the hormone therapy drug Tamoxifen to kill the cancer and keep it at bay - or so Berger thought.

In March, she received a frantic call from her 42-year-old daughter, Laura, who told her, "Mom, I have this genetic mutation. I don't even understand what it is. What am I supposed to do next?"

The genetic mutation was PALB2, which some experts call the third most important breast cancer gene. It increases the risk for breast cancer by 58% for those with a family history and 33% for those with no family history. It also increases a person's risk for ovarian and pancreatic cancers.

Doctors started testing for the PALB2 gene mutation in 2014, five years after Berger underwent genetic screening.

Berger's daughter, whose mutation was discovered as part of a fertility workup, now feared she was looking at the end of her life, instead of bringing a new one into the world.

Berger herself had never heard of the PALB2 mutation, even after doing health reporting for about 15 years.

"I'm sort of an information sponge, and I thought, 'If I don't know, people just don't know,'" she said. "I looked at my husband, and I said, ' I have to write about this.' I mean, people need to know."

Berger, 69, got tested, as did her two other daughters. Along with her oldest daughter, Laura, Berger has the PALB2 mutation, as does her middle daughter, Annie. Three more family members also have it and other relatives are being tested.

In July, Berger had her ovaries and fallopian tubes removed to prevent any cancer from developing. She also plans to have a prophylactic double mastectomy. Her daughters will both be monitored closely.

"I feel like I've had a really good life. There's been tough times, and this is certainly one of them. But it's been OK," she said, noting she's working on a memoir titled, "My Life on Deadline."

After The New York Times published Berger's article about PALB2 in August, doctors reported a flood of questions from patients.

"A lot of phone calls, mostly from women who we've taken care of in the last decade, who wanted to know if, in fact, they had been tested for this gene, said Dr. Elisa Port, chief of breast cancer surgery at Mount Sinai Hospital in New York.

"There was a lack, I would say, of general knowledge or general public knowledge about this gene because it is much less common."

Breast cancer patients who received genetic screens before 2014 should be tested for the PALB2 mutation. Those who have it, should understand steps they can take, such as preventive surgeries to remove the breasts or ovaries to reduce the risk of developing cancer.

There are also other gene mutations to be aware of, such as CHEK2. Women carrying it have a moderate risk for developing breast cancer, ranging from 23%-48% depending on their variant and family history, genetic experts said. Men with a CHEK2 mutation have an increased risk of developing prostate cancer.

In total, there are 11 breast cancer predisposition genes, with BRCA1 and BRCA2 carrying the highest risk.

Genetic testing used to be costly, and require doctor's orders and appointments. But anyone can now buy a fairly inexpensive testing kit online and receive some answers without leaving home as part of a growing industry known as direct-to-consumer genetic testing.

It usually means providing a saliva sample and sending it back to the company for lab analysis, with the results accessible via a secure online portal or sent in a letter. Depending on the company, a physician doesn't necessarily have to be involved to order the kit or get the findings.

A direct-to-consumer test is often not as comprehensive as screening done in a clinic and may look at just a few BRCA variants, when there are more than 1,000 with some clinical significance, for example.

If you're truly concerned about your risk and have a family history, a clinically validated test would be the best option, followed by a conversation with a genetic counselor, experts advised.

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She tested negative for BRCA, but had another dangerous breast cancer gene mutation

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Many women breathe a sigh of relief when they test negative for BRCA gene mutations, which raise the risk for breast, ovarian and other cancers. But that's not the end of the hereditary risk story. Freelance journalist Susan Berger is a prime example.