Hope for familial dysautonomia sufferers

Judy Siegel Itzkovich

Could you please tell me if there is current research on myelin cells? My daughter has familial dysautonomia, and in FD, there are fewer myelin cells than normally. Please tell me more about the disease.  I also want to know if there was any progress in the growth of myelin cells. B.F., New York City, US.

Prof. Channa Maayan, a pediatrician and pediatric pulmonologist who was the director of the Israel Center for Familial Dysautonomia for 32 years since it was established in 1981 at the Hadassah Hospital on Jerusalem’s Mount Scopus and continues to work there in her retirement, replies.

Familial dysautonomia (FD) ; also known as Riley-Day syndrome and autonomic neuropathy type III, is a genetic disorder that affects the development and survival of certain nerve cells and causes sensory and autonomic dysfunction. The autonomic nervous system controls involuntary actions such as digestion, breathing, production of tears and the regulation of blood pressure and body temperature. It also affects the sensory nervous system, which controls activities related to the senses, such as taste and the perception of pain, heat and cold.

FD is very rare and occurs almost exclusively in Jews of Ashkenazi origin; in this population, the carrier rate has been estimated to be 1 in 30. The incidence of all diagnosed cases of FD in Israel among Jews of Ashkenazi origin from 1977 to 1981 was 27/100, 000 or 1/3,703 live births. In January 2001, researchers at Massachusetts General Hospital and Fordham University in New York simultaneously reported finding the genetic mutation that causes FD, a discovery that opens the door to many diagnostic and treatment possibilities.

The defective FD gene IKBKAP/Elp   (I-kB kinase-associated protein), provides instructions for making a defective protein – IKAP ( IkB kinase complex-associated protein) (IKAP/Elp1). There are three mutations in the gene. The IKBKAP gene located at the long arm of chromosome 9q31. The defective protein as well as the normal proteins, are found in a variety of cells throughout the body, including brain cells.

Myelin is a lipid-rich (fatty) substance formed in the central nervous system by special cells called glial cells and in the peripheral nervous system. Myelin sheaths are sleeves of fatty tissue that protect many nerve cells and function like insulation on an electric wire. As these cells are part of the central nervous system, which carries messages back and forth between your brain and the rest of the body, when the myelin is damaged (demyelination), the nerves have a difficult time carrying messages that tell the body to move and function.

In FD, there is damage of myelinated and unmyelinated nerve fibers. Nerve conduction can be slowed or blocked, resulting in the damaged information networks between the brain and the body or within the brain itself. Because multiple sclerosis also involves demyelination, MS research canbenefit from FD research, and vice versa. There is still a lot of research to do and some are being done or planned to be done here, but I cannot report on this as it is still not published.

FD patients show defective function and degeneration of the autonomic nervous system as well as the sensory and motor nervous systems. The gene regulates expression of genes involved in oligodendrocytes differentiation and/or myelin formation and maintenance in humans and other functions some of which are not known yet. More understanding in gene and protein function and its role in the nervous system should contribute to the possible treatment of FD.

Signs and symptoms of FD are in most of the body systems and are very complex and severe. First start during infancy and include poor muscle tone, feeding difficulties, poor growth and developmental delay, lack of tears after three months, holding their breath for prolonged periods of time can last until age six or seven that may cause a bluish appearance of the skin or lips or fainting.

Later, the major symptoms manifested in FD patients are: defective coordination of the gastrointestinal tract including the area of naso-esophageal region causing difficulty in sucking, swallowing and gastro-esophageal reflux. All of which lead to recurrent pneumonia and chronic lung disease. Other clinical signs are constipation, diarrhea, less tearing from the eyes and optic atrophy, which develops with time.

FD patients also have unstable blood pressure. They may experience a sharp drop in blood pressure upon standing, which can cause dizziness, blurred vision or fainting. They can also have episodes of high blood pressure when nervous or excited, or during vomiting crisis. There is also an increased frequency of convulsions, abnormal insensitivity to pain and temperature and difficulty maintaining body temperature, poor balance and unsteady gait and more.

About 40% of patients will react to stress (infection or emotional events) with a combination of symptoms termed the “dysautonomia crisis.”; In addition to nausea and vomiting, there is an increased heart rate and higher blood pressure, marked sweating, red blotching of the skin, drooling and sometimes negative changes in personality with nervousness and aggressiveness.

FD patients have a high incidence of multiple fractures or insensitivity to pain in bones can result in unrecognized fractures. Swelling or mild discomfort with movement may be the only sign of a fracture. The fractures in FD sufferers are associated with reduced bone mineral density. Spinal curvature (kyphosis, scoliosis) develops in 95% of the patients by the time they reach their teens.

About one-third of children with FD have learning disabilities, such as a a short attention span, that require special-education classes. The number and severity of symptoms are variable from patient to patient and at different ages during life. Clinical diagnosis of FD is based upon the clinical symptoms and signs However, a firm diagnosis can be made now with a genetic test that shows the mutations in the IKBKAP gene.

Since the discovery of the gene, genetic screening became available for couples before marriage or pregnancy, and as a result, many fewer babies are born with FD, as with Tay-Sachs disease and cystic fibrosis, which are also genetic disorders found mostly in Ashkenazi Jews (because of their close genetic background over the millennia).

Even though it could take many years until stem-cell therapy can be offered for FD, it probably will occur, and eventually, treatment could be given to the fetus in the uterus.

In the meantime, various foundations and three medical centers in the US and Israel (New York UniversityHadassah University Medical Center in Jerusalem and Sheba Medical Center at Tel Hashomer) devote themselves to FD treatment and research.

The survival rate and quality of life have increased since the mid-1980s mostly due to a greater understanding of the most dangerous symptoms. At present, although there is no definitive but only symptomatic treatment, FD patients can be expected to function independently if treatment is begun early and major disabilities avoided. Because of the FD-causing mutation, individuals with FD make insufficient amounts of the normal protein, IKAP, which is encoded by the IKBKAP gene. Someresearch is directed toward finding treatments that will increase the levels of the functional IKAP protein in FD patients and promote autonomic stability in these individuals.

There are substances called tocotrienols (vitamin E) that increase IKAP protein levels in cells derived from individuals with FD at the laboratory. Fifteen years ago, it was discovered that EGCG, a compound in green tea, alters the splicing of the IKAP RNA and increases the amount of normal IKAP protein produced in cells of FD patients. The combined treatment of EGCG and tocotrienols results in a synergistic (greater than additive) increase in the amount of the IKAP protein produced in cells from individuals with FD.

Vitamin A and beta-carotene also increase IKAP levels in cells derived from individuals with FD and in blood cells isolated from individuals ingesting these compounds. Isoflavones found in soy have been found to correct the irregular splicing of the IKAP RNA in FD-derived and neuronal cells and mediate an increase in the level of the IKAP protein. Researchers are also working on inducing stem cells from FD patients.

At New York University’s FD center as well as at Hadassah and Tel Hashomer centers, researchers are conducting a study to understand the clinical features of FD and how they evolve over time. Participants with FD are being followed on a yearly basis (or more often) to assess their autonomic and neurological function.

So as basic researchers and clinicians in the field work together, there is hope that effective treatments and even a cure will eventually be found for FD.

If you want an Israeli expert to answer your medical questions, write to Breaking Israel News health and science senior reporter Judy Siegel-Itzkovich at judy[at]israel365.com with your initials, age, gender and place of residence and details of the medical condition, if any.