August 24, 2011 | 11:38 pm

Crohn’s Disease:  An interview with Ron Bahar, MD

Posted by Norman Lavin, M.D, PhD., UCLA Medical School

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Ron Bahar, MD is a board-certified pediatric gastroenterologist and Assistant Clinical Professor of Pediatrics at The UCLA David Geffen School of Medicine.  He is a native of Lincoln, Nebraska.  He completed his undergraduate studies at the University of Wisconsin-Madison, and medical school at the University of Nebraska College of Medicine.  He then moved to Los Angeles to complete pediatric residency and pediatric gastroenterology fellowship training at UCLA.  He was an attending physician at UCLA for three years before opening a private practice in Encino in 2000.  His areas of interest include inflammatory bowel disease and irritable bowel syndrome in children.

Dr. Lavin:  What is Crohn’s Disease?

Ron Bahar: Crohn’s disease is a chronic inflammatory bowel disorder which can involve the entirety of the gut, from lips to anus.  In addition, other organs, including skin in the form of erythema nodusom (red nodules), joints in the form of arthritis, and kidney disease in the form of stones, are commonly concurrently affected. 

Dr. L.: How do patients with Crohn’s disease present, and how is the diagnosis confirmed?

R.B.: Crohn’s disease most commonly presents in patients in their second and third decades of life, but also occurs in children.  Symptoms typically include abdominal pain, diarrhea, rectal bleeding, poor appetite, weight loss, and oral ulcers.  With regard specifically to children, individuals frequently display poor linear growth (short stature) and poor weight gain, along with failure of the development of secondary sexual characteristics (delayed puberty). 

Patients are usually referred from their generalist (pediatrician or internist) to a pediatric or adult gastroenterologist.  Based on history and physical examination, along with screening blood and stool studies, which commonly show evidence of anemia, inflammation, low blood protein, and white blood cells in the stool, the diagnosis is often strongly suspected.  However, Crohn’s disease cannot be confirmed without diagnostic upper gastrointestinal endoscopy, colonoscopy and biopsy.  If the diagnosis is still equivocal, or if the extent of the disease in the small intestine has not adequately been quantified, wireless capsule endoscopy (pill camera) can then be employed. 

Dr. L.:  Discuss the incidence, prevalence, genetics, and immunology of Crohn’s disease:

R.B.: The incidence (the number of new cases in the population) is approximately 5 per 100,000 in the United States.  The prevalence (the total number of patients in the population) has been estimated at between 26 and nearly 200 per 100,000 in this population.  The incidence of Crohn’s disease amongst Ashkenazi Jews is 2-8 times that of the general population, and also affects Sephardic Jews more than the general population, but not as frequently as the Ashkenazi families.  The relative risk of Crohn’s in siblings of an individual with the disease is 17 to 35 times that of this same group.  It is slightly more common in males than in females.

In 2001, the mutations in the gene NOD2/CARD15 (which encodes for a protein seen in white blood cells and plays a role in the regulation of the immune response) was determined to be associated with a significant increased risk of severe, penetrating disease in patients with Crohn’s disease.  Various additional gene mutations have since been implicated as well. 

The body’s antibody reactivity to microbes, such as brewer’s yeast and E. coli bacteria, has also been associated with an increased risk for more serious manifestations of Crohn’s disease.  Through this research, physicians can now specifically target therapy based on individual genetic and immunological profiles.

Dr. L.:  Discuss the treatment of Crohn’s disease:

R.B.: Crohn’s disease is not curable.  However, advancements in medical therapy over the last several decades have made it more “livable” than ever, and patients generally lead entirely “normal” lives.  Medications used in the treatment of Crohn’s disease in both FDA-approved and off-label fashions are divided into broad categories.  They include 5-ASAs (sulfasalazine derivatives), anti-inflammatory steroids, immune-system modulators such as 6-mercaptopurine and methotrexate, and biologic agents (antibodies) such as Remicade and Humira.  In addition, liquid dietary formula typically delivered via tube feeding as a sole source of nutrition is now used as an alternative to traditional medical therapy in selected patients. 

For patients with intractable Crohn’s disease, surgery is an option.  The most common of these procedures is removal of the end of the small intestine called the terminal ileum. 

To find a pediatric gastroenterologist who is a member of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, please refer to the following link:
http://www.naspghan.org/aspModules/PublicLocateDoctor/PublicLocateDoctor.asp

For support group information for patients with Crohn’s disease, visit the Crohn’s and Colitis Foundation of America’s official website at:
http://www.ccfa.org/

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August 11, 2011 | 10:51 am

Jews, industrial pipe cleaners, and osteoporosis

Posted by Norman Lavin, M.D, PhD., UCLA Medical School

Chances are that you or a family member are taking a medication to reverse or improve Osteoporosis – a condition of poor bone density. The most common class of treatment is the Biphosphonates for which Fosamax is a prime example.  The purpose of this article is not to discuss the clinical uses of this drug, but rather to review the history of Biphosphonate development by several Jewish scientists and physicians.  I will specifically focus on “The Stumble” effect – that moment when a basic observation is recognized for its greater relevance, as with Alexander Fleming’s work with Penicillium molds or the story of Isaac Newton and the apple.

“Stumble” is not meant to imply a lack of awareness but, to the contrary, the sudden insight of a connection between apparently unrelated concepts.  In this context, the story of the clinical uses of Biphosphonates may be more akin to a serendipitous revelation – the enlightening discovery of something important that was not deliberately sought.

In 1897 in Germany, two Jews – Baeyer and Hofmann - first synthesized Biphosphonates for medical use, but for 63 years this compound sat idle on chemists’ shelves receiving scant attention.  In the 1930’s, phosphates were recognized as crystal inhibiting substances.

A few years later, L. Rothstein accidently added phosphate to an irrigation system which prevented blockage by inhibiting crystal formation which led to derivatives for scale prevention.  In 1960, it was used for water softening and prevention of deposits in plumbing.  Procter and Gamble then bought it for detergent research.

Three more Jews working in Berne, Switzerland demonstrated that soft tissue calcifications could be prevented by the intravenous injection of polyphosphates. The major clinical break through, however, occurred in 1968 when a child with severe calcification of his respiratory muscles leading to inability to breathe was treated with Etidronate (a bisphosphonate) and surprisingly recovered. This led to the use of this class of drugs in the treatment of metabolic bone disease.  The child survived and grew into adulthood – testimony to a fortuitous juxtaposition of basic science, clinical skill, and recognition of potential benefit – in other word, an informed “Stumble”.

Is what has been said so far a contradiction?  Biphosphonates inhibit calcification and inhibit bone resorption, therefore, how can they increase bone density? Paradoxically, these medications have two distinct biologic effects.  At high doses, there is inhibition of calcification, whereas at lower doses, there is inhibition of bone resorption.  This latter effect proves beneficial in osteoporosis which led to a new understanding of bone formation:  bone requires reshaping for optimal mechanical function.  This process is initiated by recruiting ‘cleaning’ cells (osteoclasts) which leads to bone resorption followed by ‘building’ cells (osteoblasts) that lead to new bone synthesis.  Biphosphonates exert their major biologic action on bone resorption through inhibition of osteoclasts.

The history of the Biphosphonates – from detergents to pipe cleaners to pharmaceutical agents – demonstrates with remarkable clarity that the application of these associations requires perseverance and sound scientific judgment.  At the same time, we are witness to Jewish researchers and scientists and physicians who unknown to each other are now inextricably linked in helping prevent fractures, deformities and in some cases- death.

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April 24, 2011 | 11:07 am

KAFKA, MODIGLIANI, HITLER, AND TUBERCULOSIS

Posted by Norman Lavin, M.D, PhD., UCLA Medical School

What do these names have in common? Simply stated, Modigliani and Kafka died from tuberculosis, and Hitler (Who else?) delivered a medical discourse on Jews and tuberculosis.

What is Tuberculosis?
Tuberculosis is an infectious disease caused by a bacterium called Mycobacterium tuberculosis, which often affects the lungs, but may involve any organ and may infect anyone at any age. Tuberculosis is spread from person to person, usually through the air when someone with active disease coughs and sprays the bacteria. Left untreated, TB can kill approximately one-half of patients within five years and produce significant morbidity in others. Inadequate therapy for TB can also lead to drug-resistant strains of M. tuberculosis that are more difficult to treat.

In the United States, TB is much less common than it used to be. Of approximately 13,000 new cases of active disease each year, over half occur in persons born outside of the country; it is very common in the developing world. It is estimated that as much as one-third of the world’s population is infected with M. tuberculosis, and worldwide about 1.6 million people die of this disease every year. TB and HIV are closely associated; people with HIV are much more likely to develop active disease if they are infected with the bacteria that cause TB.

Jewish Immunity (or Not) –
From a book on Anti-Semitism
Many “physicians” in the late 1800s and early 1900s, particularly in Germany and other
European countries, characterized the Jewish individual as physically vulnerable to developing tuberculosis and “is the reason for the spread of this disease throughout the world.” But there is a basic contradiction of many of these so called “experts”.

On the one hand, Jews have an immunity to certain diseases, including tuberculosis, though an affinity for others. On the other hand, the male Jewish body is depicted in terms of the habitus phthisicus (body type). But how can the Jew be both immune to and defined by tuberculosis? Here, the stereotype’s peculiar power to accommodate antithesis comes into play. At the turn of the century, Jews are both the arch-bankers and the arch-revolutionaries, both the false nobility of Paris and the wandering Eastern Jews of Warsaw. “All Jews to all groups who need to define outsiders.” Thus, their supposed immunity, whether racial or acquired, is a sign of their “nature,” as is the assumption that the Jew, because of his body form, is predisposed to tuberculosis.

The Tubercular Jew
Many public officials and physicians describe physical characteristics that they said made Jews more prone toward tuberculosis. This may have been a reflection of the fact that many very famous Jewish individuals did contract tuberculosis, such as Modigliani and Kafka. But, in fact, the Jews were more immune to tuberculosis than most any other group, and were more immune to many other infectious diseases. According to statistical data concerning the occurrence of tuberculosis in Jews and non-Jews in various countries, the mortality from tuberculosis in Jews is lower, and the course of the disease is slower and more favorable. Hereditary predisposition may contribute to immunity or susceptibility. Tuberculosis exhibits the character of an acute epidemic with a preponderantly rapid and grave course in the case of ethnic groups which come in contact with it for the first time.

During the course of generations, however, the sickness takes on more and more of the character of a chronic, insidious, ethnic epidemic. Those who are predisposed are killed off by the disease with an increased incidence, in large part before the end of their reproductive age. For that reason, the number of those who are resistant increases more and more in the population. It is called, selective resistance. The Jews are now the group which has been exposed longest to the conditions of urban life. For that reason, they have been subjected longest to the selection process just described. The result is similar to a “genuine racial characteristic” (Racial Biology of the Jews, by Barron Otmar von Verschuer, M.D.).

Racial Tuberculosis
The following is a speech delivered by Adolf Hitler in Salzburg on August 7, 1920:

“This is not a problem you can turn a blind eye to – one to be solved by many
concessions. For us, it is a problem of whether our nation can ever recover its health,
whether the Jewish spirit can ever really be eradicated. Don’t be misled into thinking you can fight a disease without killing the carrier, without destroying the bacillus. Don’t
think you can fight racial tuberculosis without taking care to rid the nation of the carrier
of that racial tuberculosis. This Jewish contamination will not subside. This poisoning
of the nation will not end until the carrier himself, the Jew, has been banished from our
midst.”

In Hitler’s diatribe against the Jews, he described the Jews as “carriers of tuberculosis”, and, therefore, “they should be eliminated”. Since, in fact, they were not carriers and not seeds of tuberculosis dissemination, he used the term “Racial Tuberculosis” to justify the extermination of the Jewish people.

Modigliani
Amedeo Modigliani was an Italian artist who worked mainly in France. Primarily a figurative artist, he became known for paintings and sculptures in a modern style characterized by mask-like faces and elongation of form. He died in Paris, at age 35 of tubercular meningitis, exacerbated by poverty, overwork, and addiction to alcohol and narcotics.

Modigliani was born in 1884 in Livorno, Italy to a Sephardic Jewish line of intellectual aristocrats, tracing their lineage to Spinoza. It was said that Modigliani was immersed in alcoholism and drug addiction, but he consciously used intoxicants as a cover to hide a “great secret”—that being tuberculosis. In remission since childhood, it returned when he was an adult accompanied by symptoms like spasmodic coughing, stretches of lassitude, and bouts of erratic behavior. He was terrified of the social ostracism that would result if he were known to have the highly contagious disease, which is similar to having AIDS today. He deliberately fostered a reputation as an alcoholic and addict to prevent detection. This allowed him to freely drink the wine that soothed his coughing and use the drugs that gave him energy to work. Modigliani died on January 24, 1920. There was an enormous funeral, attended by many from the artistic communities in Montmartre and Montparnasse.

Kafka
Franz Kafka was born to middle class German-speaking Jewish parents in Prague, Bohemia, then part of the Austro-Hungarian Empire. Contemporary critics and academics regard Kafka as one of the best writers of the 20th century. The term “Kafkaesque” has become part of the English vernacular. During World War II, Kafka’s three younger sisters were sent to their deaths at Theresienstadt and Auschwitz.

“The Metamorphosis” – by Franz Kafka
The most obvious parallel between Kafka and Gregor Samsa, (the main character), is the fact that they die early deaths alone. The name of the book “die Verwandlung,” translated as the conversion or change, is an indication of a life changing moment in time. Gregor’s life is completely altered by the fact that he becomes a vermin. Becoming an insect, Gregor crosses over an imaginary line to a point where there is no turning back, much like that of any person with a chronic illness. Kafka was afflicted with various illnesses throughout his life that contributed to his health conscious vegetarian diet. He suffered from insomnia, recurring coughs, night sweats, and similar difficulties, all of which are symptoms of tuberculosis. He spent much of his time during these bouts in a sanitarium with only the company of his journals. With his illness and isolation, Kafka felt like vermin, unwanted, reviled. Kafka demonstrates this in his unpublished “Letter to His Father,” where he refers to himself as “Ungeziefer,” that is translated specifically as vermin.

Summary
Unlike most Jews, these two giants succumbed to tuberculosis. But, I’m sorry (not) Mr. Hitler – there is no racial tuberculosis – certainly not in the Jewish people. In spite of or because of this disease, Franz Kafka and Amedeo Modigliani became exemplary scholars and artists who contributed immensely to our civilization.

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February 23, 2011 | 2:56 pm

Tay-Sachs disease: An interview with Stephen Cederbaum, M.D.

Posted by Norman Lavin, M.D, PhD., UCLA Medical School

Dr, Stephen Cederbaum has recently retired from his position as Professor of Psychiatry, Pediatrics and Human Genetics at UCLA. He is former Chief of the Division of Genetics in the Pediatrics Department at UCLA and Associate Director of the Mental Retardation Research Center. He is a founding member and past-president of the Society for Inherited Metabolic Disorders, and founder and first chair of the California Newborn Screening Advisory Committee. Dr. Cederbaum specializes in the diagnosis, treatment and study of human biochemical disorders.

Dr. L.  What is Tay Sachs Disease?

Dr. C.  Tay sachs disease is a disorder in which an enzyme called hexosaminidase A is deficient in the body of affected individuals resulting in the accumulation of a fatty substance in the brain which leads to neurological deterioration and eventually death.  An enzyme is a protein that catalyzes (i.e. increases or decreases) the rate of a chemical reaction.  Almost all metabolic processes in a biological cell need enzymes to regulate the rate of metabolism

The children appear normal at birth, but by 4-6 months of age, normal developmental progress ceases and a steady deterioration and loss of abilities evolve. The patients are usually blind and immobile by 1 year of age, are hypersensitive to sound and develop seizures. Death often occurs by age 2 although modern support programs can prolong life for several years longer.  A characteristic finding on physical examination is a “cherry red spot” in the eye. This is due to a general atrophy and pallor in most of the eye, but the retention of function and the blood supply in one round area distinguishes it from the pale appearance around it.

Dr. L. Explain the Genetics.

Dr. C.  Tay-Sachs Disease is inherited in what geneticists describe as an autosomal recessive manner. This means that both parents are carriers of one abnormal gene, which is balanced by one normal one. In these circumstances, when the egg and sperm combine to form the new individual there is a 25% chance that the offspring will inherit both non-functional (abnormal) genes. In this form of inheritance, the normally functioning genes prevent the carriers from showing any symptoms. The carrier frequency for Tay Sachs disease amongst Jews of Ashkenazi origin is as high as 1 in 27 and the disease frequency is one in 2500 to 1 in 3000. It is about 100 times less frequent in a non-Jewish population.

Dr. L. Are other groups affected and why?

Dr. C.  As I mentioned in response to the previous question, the frequency of Tay Sachs disease is highest amongst Ashkenazi Jews, but also amongst the French Canadian population that migrated to what is now Quebec from Brittany in the 17th and 18th centuries. Although a number of different explanations have been proposed, it appears most likely that the condition in both of these groups arose when a small founder population happened to carry a gene for a defective form of the enzyme hexosaminidase A.  It is also possible that there was some evolutionary pressure that caused this gene to be favored and therefore increased in the population, but that has not been demonstrated.

In both instances, the gene defects are complete enough so that the disorder invariably occurs in infancy with little variation in the time of onset.

Dr. L. What are the different types and what is the late onset type?

Dr. C.  The name Tay-Sachs disease refers to the specific and typical presentation in infancy. It was only many years later that the defect was demonstrated in Hexosaminidase A. Other forms of the disorder have a later onset. They are due to a less complete block of the enzyme and consequently progress at a slower rate.  Because the brain has already developed by this time, the symptoms are those of a degenerative neurological disorder but does not resemble the infantile disease. While the name “late-onset Tay-Sachs disease” is often used, it should more properly be called late-onset hexosaminidase A deficiency.

Dr. L. What is the mechanism that causes the disease?

Dr. C.  The disorder is due to the failure of the enzyme to degrade a complex lipid, found in the brain that must be synthesized and degraded on a regular basis. Consequently, this complex lipid accumulates in the brain and destroys the nerve cells in a manner that is incompletely understood. The nerve cells become bloated with the fatty material and the head becomes larger than normal.

Dr. L. How is the diagnosis made?

Dr. C.  Until 40 years ago, the diagnosis was made based on ethnicity, typical clinical symptoms, and the presence of the cherry red spot in the eye - and in some instances with confirmatory microscopic study of a biopsy. With the discovery of the enzyme defect, determination of the enzyme activity level in the white blood cells replaced this approach and enabled the diagnosis to be made more easily.  More recently still, DNA analysis of the genes has replaced enzyme analysis as the method of choice.

Dr. L. Please discuss the screening program.

Dr. C.  Shortly after the discovery of the deficiency of the enzyme hexosaminidase A as the cause of the disease, it was shown that carriers of the disease, especially in the higher risk communities could be detected with high efficiency. This paved the way for a then revolutionary strategy of detecting carriers in these communities, and allowing couples planning marriage or already married to plan their futures with the knowledge of the 25% risk to each of their children. Options included ignoring this knowledge, deciding to choose another mate who was not a carrier, or performing amniocentesis and prenatal diagnosis with the option of terminating affected pregnancies. Intensive publicity and outreach programs in houses of worship and schools have resulted in the virtual elimination of Tay-Sachs disease in these higher risk communities. In populations at lower risk, such screening would be extremely inefficient and ineffective. Because only a small number of mutations causes Tay-Sachs disease in these higher risk communities, screening is now accomplished using DNA, rather than enzymatic techniques.

Dr. L. Discuss prevention.

Dr. C.  Screening programs were first carried out on a population basis, but were always reenforced in obstetrical practice. It is now customary for obstetricians to ascertain the ethnicity of a couple who come to them with a pregnancy. If both members of the couple are of Ashkenazi Jewish background, they are asked to present evidence that they have had screening for Tay-Sachs disease carrier status (and that of other disorders known to be more frequent in this population group) or at least one member of the couple is advised to have such screening. In case only one member of the couple is of Ashkenazi Jewish origin and no testing has been done previously, it is often recommended that the non-Jewish member have Tay-Sachs screening by enzymatic testing. Other strategies are of course possible.

Dr. L. What is the management and is there a treatment?

Dr. C.  There is no generally recognized treatment for Tay-Sachs disease or the later onset form of hexosaminidase deficiency. There have been some patients treated with bone marrow transplantation. This approach may prolong life but has generally been disappointing. The management is limited to treating specific symptoms such as seizures, ensuring that the patients receive adequate nutrition, usually through a tube in the stomach as the disease progresses, and keeping the patients comfortable. The disorder can be very distressing to families and support for them is important.

Dr. L. What is the impact on Jewish communities?

Dr. C.  Jewish communities are, in the main, well educated and medically sophisticated. They accepted this higher risk of Tay-Sachs disease as a challenge and a problem with a solution and embraced screening. In very Orthodox communities in which pregnancy termination was frowned upon and arranged marriages common, the results of testing became part of the basis for arranging a marriage. There was no perception in this community that carrying these disorders was a black mark and one of which to be ashamed

Dr. L. Discuss the future for this disease focusing on research, such as enzyme replacement therapy, gene therapy, and substrate reduction therapy.

Dr. C.  Much research is going on in Tay-Sachs disease and in other allied disorders. Nothing resembling a breakthrough seems to be on the horizon. Enzyme replacement is an unpromising approach (although is used in Gaucher Disease – see upcoming blog). The enzymes would not cross from the blood into the brain because nature has provided a barrier between the two compartments. In unaffected individuals, this is a protective mechanism. Unfortunately, in those with brain disorders it also serves as a barrier to effective enzyme therapy. In principle, the enzyme could be injected repeatedly into the spinal fluid, but this too would be inefficient and likely to be ineffective in the long run. The enzyme would have to reach all the brain cells and would have to be re-injected at intervals to account for its normal degradation and the reaccumulation of the complex lipid. Gene (and stem cell) therapy have been associated with great hype and hope, but so far the manipulation and delivery of these therapies has posed a challenge and the solution to these issues is unlikely to arrive in the near or intermediate-term future.

Another approach in active study is substrate reduction therapy. By inhibiting the synthesis of the complex lipid accumulating in this disorder, and, incidentally, other complex compounds needed by the body and brain, the progress of the disease may be slowed. This approach cannot prevent the progression - only slow it. Stopping the synthesis, even if it were possible would have serious consequences for the body. This form of therapy is approved for another, more mild, complex-lipid storage disorder, but is only in research trials for Tay-Sachs.

Dr. L. Thank you Dr. Cederbaum for sharing your expertise and for your many years of caring for thousands of special needs kids.

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February 14, 2011 | 12:04 pm

Preimplantation diagnosis of Jewish genetic diseases: An interview with Snunit Ben-Ozer, M.D.

Posted by Norman Lavin, M.D, PhD., UCLA Medical School

Dr. Lavin: There are several methods to prevent genetic diseases generally and in Jewish people specifically. (See my previous blog on Jewish Genetic Diseases.) I have the distinct pleasure of interviewing an expert in Infertility and Reproductive Endocrinology who will discuss various options for prevention. Before we delve into preimplantation diagnosis, Dr. Ben-Ozer, can you explain amniocentesis and CVS sampling?

Dr. Ben-Ozer: Amniocentesis (Amnio), Chorionic Villous Sampling (CVS) and Preimplantation Genetic Diagnosis (PGD) are all procedures that detect chromosomal (genetic) abnormalities in the fetus. Amnio, in which amniotic fluid from around the baby is collected by passing a needle through the mother‘s abdomen and the uterus, is generally performed around 14-16 weeks of gestation. CVS is a placental biopsy obtained through the vagina, usually at 10-12 weeks of gestation, but may be of higher risk than the Amnio.

Dr. Lavin: Very simply, what is fertilization and what is an embryo? What is in vitro fertilization and what is preimplantation diagnosis?

Dr. Ben-Ozer: In vitro fertilization is a process by which oocytes (eggs) are retrieved from a woman, combined with sperm in a specialized laboratory, and the resulting fertilized eggs, called embryos, are grown for several days until they are either transferred back into the womb (uterus) or frozen for future use. PGD is a process by which a chromosome analysis is performed on embryos prior to transferring them into the uterus, in order to select normal embryos. This is performed by a highly skilled embryologist who under the microscope makes an opening in the shell surrounding the embryo, removes a single cell (sometimes a few) from each embryo, and fixes it on a slide in preparation for a DNA analysis.

Dr. Lavin: In PGD, how do you tell a good cell from a bad cell?

Dr. Ben-Ozer: Two days following the biopsy, we receive a detailed report of the chromosome analysis of each embryo, so we can select a normal embryo to transfer into the uterus.

Dr. Lavin: How successful is this procedure and are there risks?

Dr. Ben-Ozer: When done properly, the embryo at the early stages of development does not appear to be harmed by the absence of a single or several cells. This is a highly technical procedure and should only be performed in specialized IVF laboratories by specially trained embryologists. The DNA analysis is also very complex, and the DNA biopsy slides are sent to specialized laboratories around the country, depending on the specific genetic analysis needed. The accuracy of the testing is close to 100%.

Dr. Lavin: What is your role in these procedures?

Dr. Ben-Ozer: My role is to review the appropriate genetic options available to the couple, stimulate the woman to produce multiple eggs, perform the egg retrieval procedure, review the chromosome analysis, and perform the embryo transfer procedure, in which the embryo(s) are placed back into the uterus by passing a special catheter through the vagina, usually under ultrasound guidance.

Dr. Lavin: Let’s discuss the religious, ethical and moral aspects. Do we need a Rabbi’s opinion at this point?

Dr. Ben-Ozer: Many IVF cycles are done with Halachic blessing and supervision. Because In vitro Fertilization was obviously not available in Biblical times, certain Rabbis evaluate the couple’s specific needs and history in relation to the intent of the Halachic laws, and decide if the couple is religiously supported in proceeding with IVF, surrogacy, and even egg donation.  Thus, Jewish couples are encouraged to speak with their local Rabbi if they are having fertility issues.

Snunit Ben-Ozer, M.D. is board certified in both Reproductive Endocrinology, Infertility and Ob/Gyn and is Founder of the Tree of Life Center for Fertility in Tarzana, and Beverly Hills. She is also Associate Clinical Professor at the University of California Los Angeles, Dept Ob/Gyn and has a special interest in fertility in advanced maternal age, PCOS, and recurrent pregnancy losses.

For Further Information Contact:
Snunit Ben-Ozer, M.D.
18370 Burbank Blvd., Suite 514
Tarzana, CA 91356
Phone #: 818-344-8522

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February 3, 2011 | 12:05 am

Introduction to Jewish Genetic Diseases: Part 2

Posted by Norman Lavin, M.D, PhD., UCLA Medical School

In Part 1 on Jewish Genetic Diseases, I described concepts of genetic testing, the Genome Project, preimplantation diagnosis, genetic engineering and gene therapy.  The following questions and answers explain in more detail how these programs are implemented.

Questions

1.  What is genetic testing?

These tests are examinations of an individual’s DNA found in chromosomes which are the chemical alphabets that spell out genes just as letters spell out words.  But, what are genes?  Genes are the blueprints or instructions used to make the body’s building blocks or cells.  Genetic testing enables physicians to check for defects in the DNA that may cause a disease. 

2. How do genes cause disease?

Most genes determine critical components that must function correctly in order for your body to be healthy. Genes that spell out a defective component can cause a disease, which can be handed down through generations just like eye color.
 

3. How are genetic diseases passed from one generation to the other?

Everyone has two copies of each gene.  Therefore, when a man and woman have a child, each contributes one copy of their genes to that child.  As a general rule, a disease is expressed only if the child has two copies of the defective gene, although there are exceptions.  A normal copy of the gene tells the body how to correctly build the product that is controlled by that gene, and this type of gene is called an autosomal recessive gene.  Autosomal means that it is not associated with the sex of the offspring, which implies that the risks are equal for boy and girl babies.  Recessive means that if one copy of the gene is normal, the damaged gene recedes (does not appear) into the background and cannot cause the disease.

4.  What is a carrier?

A carrier is an individual who has one copy of the defective gene and one of the normal gene because, as discussed above, having one normal copy of the gene is enough to prevent the disease.  Therefore, the person would not have an autosomal recessive disease.  However, if the carrier mates with another carrier who also has one copy of this same defective gene, there is a chance that the baby would have two copies of the defective gene and, therefore, be affected.  That is the reason that couples who suspect they could be carriers may decide to undergo genetic testing. 

5.  What information can genetic testing provide?

Genetic testing can determine whether one or both partners carry a specific autosomal recessive gene defect.  In other words, if neither is a carrier or if only one is a carrier, then there is no risk of having a baby with that disease.  If, however, both people are carriers, then there is one chance in four (25%) that their baby would be affected by the disease.  Therefore, testing before a couple decides to have a baby can determine what chance there is of the offspring having that specific genetic disease.  Genetic testing can also be performed during pregnancy using two procedures: amniocentesis (obtaining a specimen of fluid from the vicinity of the fetus) or chorionic villus sampling (obtain actual cells from the fetus). 

6. How is testing usually performed?

The test is most often performed on a sample of blood, which is sent to a specialty laboratory for the specific genetic diagnosis. 

7. What if you are identified as a carrier?

If you are found to be a carrier, other members of your family could also be carriers, or they may even be at risk of having the disease.  Genetic counseling, therefore, is available to determine these risks. 

8. Which diseases can be detected?

There are several disorders that have been called “Jewish genetic diseases,” -  not because they are specifically Jewish, but because they are much more common in the Jewish community. It is important to note that these diseases are not limited to Jewish individuals, but often occur in people who are or have been in areas from which Jews have emigrated..  Thus, they also occur in the non-Jewish community.  Some examples are Gaucher disease, cystic fibrosis, Tay-Sachs disease, Canavan disease, Niemann-Pick disease, and Fanconi anemia.  (A more complete list is found at the end of this article.) 

9. Are there more genetic diseases that affect Jews?

Over the next several months, we will look at genetic diseases in several subgroups of Jewish people, which include the Samaritans, the Oriental Jews, Yemenite Jews, Karaites, African Jews, Sephardic Jews, and Ashkenazim.

Every resource that I have checked lists some, but not all disorders.  I will list the majority of genetic diseases that I am familiar with in the following tables. 

A). At the present time, there are at least 18 genetic diseases for which population screening is available for Ashkenazi Jews:

Bloom Syndrome
Familial Dysautonomia (Riley-Day Syndrome)
Gaucher Disease type 1
Mucolipoidosis type 4
Nieman-Pick Disease (type A:acute neuropathic form)
Tay-Sachs Disease
Canavan Disease
Fanconi Anemia
Glycogen Storage Disease type 1a
Maple Syrup Urine Disease
Joubert Syndrome
Spinal Muscular Atrophy
Usher Syndrome type 1
Usher Syndrome type 2
Nemaline Myopathy
Lipoamide Dehydrogenase Deficiency (E3)
Congenital Hyperinsulinism
Cystic Fibrosis

B).  Additional Genetic Disorders Common Among Ashkenazim

A- beta lipoproteinemia
Primary torsion dystonia
PTA deficiency (plasma thromboplastin antecedent, or factor XI deficiency)
Spongy degeneration of the central nervous system
Congenital Adrenal Hyperplasia

C). At the present time, there are 4 genetic diseases that can be screened for in the Persian Jewish Community ( please refer to my article on the Persian Jewish Community in a previous Blog)

Pseudocholinesterase Deficiency
Congenital Hypoaldosteronism
Autoimmune Polyendocrine Hormone Deficiency
Hereditary Inclusion Body Myopathy

D). Additional Genetic Disorders Among non-Ashkhenazi Jews including Sephardic and Oriental Jews

Ataxia-telangiectasis
Cystinosis
Cystinuria
Down syndrome
Dubin-Johnson syndrome
Familial deafness
Familial Mediterranean fever
Glanzmann thrombasthenia
Glucose-6-phosphate dehydrogenase deficiency
Glycogen storage disease type 3 (deep branch or enzyme deficiency)
Ichthyosis vulgaris
Metachromatic leukodystrophy
Phenylketonuria
Pituitary dwarfism
Selective vitamin B12 malabsorption
Thalassemia
Werdnig-Hoffman disease
Acute hemolytic anemia
Aldolase A deficiency
Blue sclerae and keratoconus
Chronic airway disease
Cleidocranial dysplasia
Combined factor V and factor VIII deficiency
Congenital deafness
Onychodystrophy
Congenital hepatic fibrosis
Congenital ichthyosis with atrophy
Cutis laxa
Deaf-mutism with total albinism
Familial infantile renal tubular acidosis with congenital nerve deafness
Familial syndrome with a central nervous system and ocular malformations
Glycinuria associated with nephrolithiasis
Glycoproteinuria
Osteopetrosis
Hidrotic ectodermal dysplasia

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January 24, 2011 | 10:15 am

An introduction to Jewish genetic diseases: Part I

Posted by Norman Lavin, M.D, PhD., UCLA Medical School

The following is an introduction to Jewish genetic diseases, which I will explore in greater detail with you – the reader – over the next two years.  I will attempt to provide answers to some of the many questions asked by potential parents and others in the Jewish community on genetic testing, screening, diagnosis, and treatment. At the end, I will provide resources to seek additional genetic information and counseling.

The first step towards unraveling the mysteries behind genetic disorders is to find the defective gene.  Over 4000 genetic diseases are known and many of these cluster among members of specific ethnic groups such as the Jewish people. Unfortunately, many of these diseases are debilitating and may result in early death.

 
Why Perform Genetic Testing?

Genetic testing is a procedure that analyzes genes which can provide information about the health of an individual or the potential health of a newborn baby.  The Human Genome Project,  (launched in 1988), was an attempt to characterize specific genes allowing detection of specific diseases, as well as diagnosis, screening, counseling, prevention, treatment, and theoretically cure by gene replacement or other correction procedures. Geneticists seek to understand the inherited basis of human diseases enabling improved diagnostic tests and ultimately the cure for these horrific disorders.  This genetic project invites ethical, legal, and social questions with literally tens of thousands of responses by ethicists, philosophers, professors, and clergy.  After many years in which the study of complex human traits was mired in false claims and inconsistencies in methodology, this genomic program has brought not only better understanding of human variation, but also welcome rigor in the interpretation of statistical evidence.

Why would an individual want Genetic Testing?

If a genetic disease exists in a particular family, a family member might want to know if he or she might get the disease or they may want to know what the possibility is of getting the disorder because of their affiliation with a particular ethnic group such as Judaism. On the other hand, an individual might be experiencing signs or symptoms reflecting an underlying genetic disease.

The Genome Project and Judaism

Does genetic engineering change the Divine arrangement of Creation?  Some rabbis say yes, but most consider the acquisition of knowledge for the sake of providing cures for human illnesses to be divinely sanctioned, if not, in fact, mandated.  The pursuit of scientific knowledge is not considered to constitute prohibited eating from the Tree of Knowledge (Genesis 2:17).   

Ancient Jewish Writings

The subject of genetics is sprinkled throughout the Bible and Talmud.  One writer describes how the laws of Mendelian genetics were applied by Jacob in the biblical narrative (Genesis 30:32) of the speckled and spotted sheep.  Hemophilia (described in one of my previous articles on the Blog)) and its precise genetic transmission is described in the Talmud (Yevamot 64b).  The sages had a surprisingly remarkable knowledge of the genetics of this sex-linked disorder and the rabbis at the time recognized that females transmit the disease, but do not suffer from it, although a few rabbis also considered the possibility of its transmission through males.  Genetic disease was also recognized by Maimonides.

Premarital Screening/Amniocentesis

Debate continues about the screening of large populations of Jewish people for the carrier state of Tay-Sachs disease, as well as other genetic disorders, to prevent inappropriate “marriage to carriers.”  Another controversy is the performance of amniocentesis for the prenatal detection of this fetal disease with possible abortion of an affected fetus.  Termination of these fetal diseases by abortion may not be acceptable in Judaism, although some rabbis might sanction such a procedure. Rabbi Eliezer Yehuda Waldenberg allows abortion following amniocentesis during the first trimester if Tay-Sachs disease is diagnosed.  Conversely, Rabbi Jay David Bleich states that abortion may not be sanctioned.

Should a carrier of the Tay-Sachs gene, for example, refuse to marry a mate who has not been tested?  Should two carriers break up an engagement if they learn that both are carriers as a result of a screening program?  Should a young person inquire about the Tay-Sachs status of a member of the opposite sex prior to meeting that individual on a social level?  Must a person who knows that he or she is a carrier divulge this fact to an intended spouse?

Newborn Screen

Newborn screening shortly after birth can detect certain genetic diseases, such as phenylketonuria or hypothyroidism, and can be treated immediately with the infant growing up physically normal. 

Preimplantation Diagnosis  

Genetic testing can also be performed at different stages of human development and life.  One example is pre-implantation diagnosis of several genetic disorders whereby individual cells of a fertilized egg are tested for a mutant gene or a gene product.  For example, two married carriers of the Tay-Sachs gene can choose to discard an affected zygote, (an early embryonic structure), and then only implant an embryo free of the genetic disease into the mother’s womb to prevent the birth of an affected baby.. 

There are many pitfalls, including inconclusive linkage studies, insensitivity of the specific test, variable expressivity of the gene, laboratory quality control, and misinterpretation of test results.  There are also concerns about genetic discrimination and confidentiality of test results.

There are many more questions, such as who owns genetic information, how should genetic information be used, and who decides who should be screened?  Should there be limits to pre-implantation, prenatal and neonatal screening?  And how should employers and insurers utilize genetic information?

Commentary on Genetic Screening

There are two methods to eliminate the need for prenatal screening for Tay-Sachs disease and the Halachic objections to abortion if the fetus is found to be affected.  The first is to perform confidential premarital screening and to strongly discourage the marriage of the two carriers.  This approach has been used in Israel since 1986 and has resulted in no Tay-Sachs children being born to newlywed couples in the ultra-Orthodox Ashkenazi Jewish community.  The second method, which we will discuss in greater detail, is to prevent the birth of a Tay-Sachs baby by pre-implantation screening of the in vitro fertilized zygote.  This procedure is performed if both the husband and wife are known carriers and then use only the healthy zygote for implantation.  The discarding of the affected zygote is not considered as abortion since the status of a fetus or a potential life in Judaism applies only to a fetus implanted and growing in the mother’s womb.

Gene Therapy/Genetic Engineering

Gene therapy, such as the replacement of the missing enzyme in Tay-Sachs disease or the missing hormone in diabetes or the repair of the defective gene in hemophilia or Huntington’s disease is probably sanctioned in Jewish law because it is meant to restore health and preserve and prolong life. 

Another argument supporting genetic manipulation is the fact that the sperm or ovum or even the fertilized zygote is not a person.  The potential human being status in Jewish law is only bestowed upon a fetus implanted in the mother’s womb.  Rabbi Moshe Hershler supports genetic engineering and gene therapy, but still asks the question whether these procedures may be prohibited because he who changes the Divine arrangement of Creation is lacking faith in the Creator.  Rabbi Shlomo Zalman Auerbach and Yeshua Jaynuerth support these procedures – they believe that the main purpose of gene therapy is to cure disease, restore health, and prolong life -  all goals within the physician’s divine license to heal. 

I believe that genetic engineering and gene therapy can and should be used to treat, cure, and prevent disease, but the question arises whether these techniques should be allowed to alter human traits, such as eye color, height, personality, intelligence, or facial features

Conclusion

The scientific community is moving forward in the quest of curing Jewish genetic diseases, but current rabbis should examine these issues from the Jewish viewpoint and offer Halachic guidance to the medical and lay communities.

Judaism supports premarital screening for the purpose of discouraging at-risk marriages for a fatal illness such as Tay-Sachs disease.  Neonatal screening is encouraged as it can provide avenues of treatment for disorders such as Phenylketonuria.  Pre-implantation screening, using only healthy zygotes for implantation into the mother’s womb, is also probably sanctioned in Jewish law, but further discussion is ongoing.  Prenatal screening with a specific intent of aborting an affected fetus is not allowed according to most rabbinic authorities.  Not to have   children if both parents are carriers of genetic diseases, such as Tay-Sachs, is not a Jewish option.  Pre-implantation screening is preferable.  To improve physical traits, such as height, eye and hair color is frowned upon in Judaism if it serves no useful medical or psychological purpose.  Finally, the cloning of man is prohibited as a violation of the Divine arrangement of the world and the creation of man in the image of God.

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December 14, 2010 | 11:01 am

The Shofar saves a Rabbi’s life

Posted by Norman Lavin, M.D, PhD., UCLA Medical School

Shofar: Ram’s horn sounded during the month of Elul, on Rosh Hashanah and at the close of Yom Kippur, reminiscent of the ram “tangled in the   bush by its horns” during the Binding of Isaac (Genesis 22), the shofar sounded at Sinai (Exodus 19) and the shofar of Moshiach (Isaiah 27:13).
                                     
The Concern

My patient, an esteemed Rabbi, recently underwent major abdominal surgery lasting several hours.  Within one day postoperatively, he was instructed to blow into a mechanical device to help prevent respiratory complications. 

Pulmonary problems are not uncommon after surgery, and they include pneumonia, atelectasis, respiratory failure, prolonged mechanical ventilation, pneumothorax, acute respiratory distress syndrome (ARDS), pleural effusion, and pulmonary embolus. 

Atelectasis ( collapse of part or all of the lung) is perhaps the most common, particularly in those patients with neuromuscular or chest wall disease.  Because atelectasis in some patients appears to be due to repeated small inspirations, deeper breaths may be helpful.  Incentive spirometers encourage expansion of the lungs as much as possible above spontaneous breathing -  these have proved to be beneficial in controlled studies.

The Dilemma

The Rebbe blew and blew into the spirometer, but his profound weakness precluded successful deep respiratory excursions.  Several doctors and nurses hovered over this frail, gentle, brilliant scholar, but could not coax him into breathing deeply.  As his attempts increased in frequency, his frustrations grew since he knew failure could possibly transform into pneumonia or atelectasis with their attendant consequences.  More importantly, Rosh Hashanah and Yom Kippur were a few days away, and he was emphatic about not missing these High Holy Days; he never missed blowing the shofar during the Days of Awe.

I spoke to the Rebbe.  He shared his concerns, his fears, his hopes, but focused on his love for all humanity.  He conveyed his dream immediately prior to surgery when he “stood in court and was being judged.”  He argued that he is merciful – that he is a good person.  Because he is merciful, he wants to help others.  He wants to “stay alive to continue to do good things.” 

In this same dream, he is moved to another room, surrounded by books, thousands of books that help convey the word of God (this array of books is exactly a replica of every room in his house).  He continues to teach: “In Genesis, God blows breath in man.”  “He gives him the ‘soul of life’.”  “Life is ‘God blowing in and out of man’.” 

“I have the answer,” he cries out.  “The answer to what?” I asked.

The Solution

“It is Rosh Hashanah!” he bellows.  “I need a Shofar.  Bring me a Shofar!” 

He put the shofar to his lips, and the wailing sound permeated the hospital corridors.  His respirations deepened: full expansion of his lungs was successful.  This new “breathing apparatus” may have saved his life.  “How do you have the strength?” I asked.  He replied, “The shofar is blowing itself.”  Days later, he walked unaided to Shul.  He stood on the bima, almost glowing, and he blew the shofar better than anyone could imagine.  He felt strong.  He felt connected to God. 

The physical shofar is nothing more than the hollow horn of a ram.  When the breath of a human being is blown through it, however, it undergoes a transformation.  It becomes a living embodiment of the heart and emotion of the human being expressing the Divine Self, its sense is pulsing within, crying out to its Maker.

The shofar has an aura of awe and holiness about it.  Its blasts can shatter hearts of stone and wash away layers of complacency.  Its call is capable of bringing us back to places inside ourselves, impenetrable by any other means.  The Baal Shem Tov teaches that the shofar is an emotional, intuitive way of gaining access to the deepest recesses of our heart and of divine experiential knowledge.  Its blast – a wordless sound – speaks to the heart in a way all the greatest words and insights cannot approach.

May this wonderful Rebbe live a full and healthy life , and continue to blow the Shofar for many more years to come.

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