Hurler Syndrome

(Mucopolysaccharidosis I)

Hurler, Scheie and Hurler/Scheie syndromes are mucopolysaccharide disorders and are also known respectively as MPS-IH, MPS-IS, and MPS-IH/S. Hurler syndrome takes its name from Gertrud Hurler, the doctor who described a boy and girl with the condition in 1919. In 1962, Dr. Scheie, a consultant ophthalmologist, wrote about some of his patients who were more mildly affected. Patients who seem not to fit clearly in either the severe or the mild end of the disorder are said to have Hurler/Scheie syndrome.

There is no magic cure for MPS disorders, but there are ways of managing and treating the problems they cause.

What Causes the Disorder?

Mucopolysaccharides are long chains of sugar molecule used in the building of connective tissues in the body.

“saccharide” is a general term for a sugar molecule (think of saccharin)

“poly” means many

“muco” refers to the thick jelly-like consistency of the molecules

There is a continuous process in the body of replacing used materials and breaking them down for disposal. Children with these disorders are missing an enzyme called alpha-L-iduronidase which is essential in cutting up the mucopolysaccharides called dermatan and heparan sulfate. The incompletely broken down mucopolysaccharides remain stored in cells in the body causing progressive damage. Babies may show little sign of the disorder, but as more and more cells become damaged, symptoms start to appear.

How Common is the Disorder

Estimations

Scheie syndrome is 1 in 500,000

Hurler/Scheie syndrome it is 1 in 115,000.

There is an estimate in the United States that 1 in 25,000 births will result in some form of MPS. Other estimates state only 40 babies a year are born with Hurlers.

How is the Disorder Inherited?

We all have genes inherited from our parents which control whether we are tall, short, fair, etc. Some genes we inherit are “recessive,” that is to say we carry the gene, but it does not have any affect on our development. Hurler syndrome is caused by a recessive gene. If an adult carrying the abnormal gene marries another carrier, there will be a one in four chance with every pregnancy that the child will inherit the defective gene from each parent and will be affected with the disorder. There is a two in three chance that unaffected brothers and sisters of MPS I children will be carriers. They can be reassured; however, that, as the disorder is so rare, the chance of marrying another carrier is very slight provided they do not marry a cousin or other close family member. However, you can not find two more different genetic background’s than Joe and I. His family is all from Italy, and I like to say, I am 100% blond!!!!

Layman’s Explanation

The disorder is based on the bodies inability to produce a specific enzyme that is used to breakdown cellular byproducts into other molecules the body can use.  These molecules build up in the body and are stored in the cells where they were originally used.  Over time these molecules begin to get in the way and cause a slow down in the normal cellular processes that take place in the body.  The most common effects of this build up are mental deficiencies, skeletal and joint problems, vision and hearing impairment, heart, liver and lung disease. The end result is death.

Current Treatment Options

There are many treatment options available for Hurler’s.

  • Enzyme Replacement Therapy – Introduction of the missing enzyme back into the body through a central line or peripheral line.

Transplantation options:

  • Bone Marrow Transplants – Complete obliteration of the Childs malfunctioning bone marrow and replacement with healthy bone marrow that can produce the needed enzyme
  • Stem Cell Transplants – Introduction of stem cells into the body which produce the required cells in the treated organ to create the enzyme
  • Umbilical Cord Transplants:

Introduction

In the 1970s medical researchers discovered that human umbilical cord blood contained the same kind of stem cells found in bone marrow. (Stem cells get their name from their ability to develop into three types of blood cells: red blood cells, while blood cells and platelets). Because stem cells from bone marrow had already been used successfully to treat patients with life-threatening blood diseases, such as leukemia and immune system disorders, researchers believed that they could also use stem cells from cord blood to save patients.

In 1988, doctors transplanted human umbilical cord blood into a 5-year old boy suffering from Fanconi’s anemia. Ten years after the transplant, the boy is alive and seems to be cured of his disease. Based on this and other successful transplants, doctors and medical researchers began to collect, freeze and store cord blood units (CBUs) at cord banks throughout the world. As of October 1998, there were approximately 22,000 CBUs collected and frozen for use worldwide, and approximately 700 unrelated donor and 150 related (sibling) donor cord blood transplants had been performed.

Although today marrow transplants and cord blood transplants are often referred to by the same name — stem cell transplants — there are important differences between the two. This section will explain these differences and also discuss the kinds of decisions doctors and their patients must make to determine the best source of stem cells for transplantation. Before considering these issues, however, it is important to understand the challenges patients face in finding a donor.

Finding a Donor

Unfortunately, 70% of patients who need a stem cell transplant do not have a suitable donor in their family. The National Marrow Donor Program (NMDP) helps identify stem cell donors for patients who do not have a related donor.

Stem cell transplants require matching certain tissue traits of the donor and patient. Because these traits are inherited, a patient’s most likely match is someone of the same heritage. American Indian and Alaska Native, Asian, Black and African American, Hispanic and Latino, Native Hawaiian and Other Pacific Islander, and multiple-race patients face a greater challenge in finding a match than White patients.

The collection and storage of cord blood is one way to give patients of all racial and ethnic backgrounds greater access to stem cell transplantation. For that reason, beginning in the early to mid-1990s, medical institutions around the world began making a serious effort to collect and store cord blood units for use in transplantation.

Clinical Results

So far, clinical studies by John E. Wagner and others suggest that unrelated cord blood transplantation is a safe and acceptable alternative to bone marrow transplantation for many patients. However, these studies have also found that, as with bone marrow transplants, patients who receive cord blood from sibling (or related) donors generally have higher survival rates than those who receive cord blood from unrelated donors.

Studies have also found that banked cord blood (from both related and unrelated donors) often contains enough stem cells for transplantation. Physicians need to match the number of stem cells in a cord blood unit with the weight of the patient to be sure the unit is likely to be able to reestablish the patient’s immune system. Because there are fewer stem cells in cord blood than in marrow, until recently most cord blood recipients have been children or small adults. There is, therefore, some concern that the number of cells in an average cord blood unit may not be sufficient for engraftment in larger adults. Engraftment occurs when the transplanted stem cells — the “graft” — regenerate the blood and marrow and begin to function as the recipient’s new immune system.

One positive finding is that cord blood transplant patients appear to suffer less from acute graft-versus-host disease (GVHD) than patients who receive bone marrow transplants. GVHD is a very serious, and sometimes fatal, condition that occurs when the patient’s new immune system — which is made up of stem cells from the donor — starts attacking the patient’s body. GVHD affects the skin and internal organs such as the liver and intestines.

Despite the fact that cord blood recipients appear to suffer less from GVHD, it has not yet been proven that the risk of GVHD is less in all recipients after cord blood transplantation. Because children receive the most cord blood transplants, and because they also experience less GVHD than adults after bone marrow transplants, it may be that the success of cord blood transplants is at least partly attributable to the fact that they are used on more children than adults.

Understanding HLA Matching

With stem cell transplants, the better the match between the donor and the recipient, the less likely graft-versus-host disease is to develop. It is important, therefore, to understand how doctors determine the best, or most acceptable, match between the donor and the recipient. To understand how they do this, it helps to have a basic understanding of the human immune system.

Antigens, a kind of protein located on the outer surface of most cells in the body, help the immune system to identify foreign bacteria and viruses. The antigens that transplant doctors look for when matching patients and donors are located on a cell called a leukocyte, giving these antigens the name Human Leukocyte Antigens, or HLA. Every person has six groups of HLA antigens, but three groups (called A, B, and DR) are considered most important in a stem cell transplant. Each of these groups has two antigens, one inherited from the father and one from the mother, making a total of six antigens that determine a donor/recipient match. A perfect match is called a 6/6 HLA match.

Bone marrow transplants are usually not attempted unless the donor and recipient are a 6/6 or 5/6 HLA match. However, with cord blood transplants, doctors and medical researchers generally believe that a 4/6 match is sufficient. Because immune system cells contained in cord blood are less mature, they have not yet “learned” to attack foreign substances, and so would be less likely to attack the recipient’s immune system, even though the match isn’t perfect. Since matching requirements for cord blood are less strict, patients who are unable to find a 5/6 or 6/6 marrow donor may be able to find a suitably matched cord blood unit.

What is Known About Cord Blood Transplants

With its more than 30-year history, bone marrow transplants are a well-established, life-saving treatment for a wide range of blood disorders such as leukemia and aplastic anemia, as well as selected immune system deficiencies and genetic disorders. While the history of cord blood transplants is less extensive, there is evidence to suggest that these transplants can cure diseases, too. But with cord blood there are more unknowns, and doctors and their patients must carefully evaluate the situation before deciding on the best treatment.

The following lists explain what is known and not known about cord blood transplants. While these lists are not exhaustive, they do include aspects of cord blood transplants that are critical in the decision-making process:

What We Know About Cord Blood Transplants

  • Cord blood contains sufficient numbers of stem cells for engraftment in most recipients weighing less than 50 kilograms (about 110 pounds).
  • Collection of cord blood poses no health risk to the mother or infant donor.
  • Because it is stored and available for use, cord blood is sometimes more readily available than a potential marrow or blood stem donor, who may be unavailable for donation when it is needed.
  • Cord blood is rarely contaminated by viruses often found in marrow, such as cytomegalovirus (CMV) and Epstein-Barr virus.
  • Cord blood can cause severe GVHD, but possibly less frequently than in bone marrow transplants.

What We Think We Know about Cord Blood Transplants Based on Clinical Data

  • Compared to bone marrow transplants, cord blood transplants may have a lower rate of acute GVHD, at least in cases where a related (sibling) donor is used.
  • It appears that the transplant process using cord blood (from the time a search is started to the time donor cells are ready for transplant) is shorter than that for marrow cell donation because the cord blood units are in storage and ready for use.

What We Don’t Know about Cord Blood Transplants (because of lack of clinical evidence)

  • Whether cord blood is sufficient for engraftment in most adult recipients, although experience suggests that it may be sufficient for a significant proportion of these recipients.
  • Whether cord blood transplants pose a different risk of relapse (recurrence of an illness after a remission) compared to unrelated bone marrow transplants.
  • Whether focused cord blood collection will be successful in meeting the current challenge of finding a match for American Indian and Alaska Native, Asian, Black and African American, Hispanic and Latino, Native Hawaiian and Other Pacific Islander, and multiple-race patients, thus increasing the number of available transplants for these patients.

Clinical studies have demonstrated that stored cord blood is a sufficient source of transplantable stem cells, at least for young patients. Also, in addition to previously known advantages of cord blood (rapid availability and a low rate of virus contamination) studies have found that cord blood transplants may also lead to less GVHD than bone marrow transplants.

Clinical experience also shows that a high stem cell dose (a sufficient number of stem cells based on the patient’s body weight) is an important factor in recipient survival, and that cord blood transplants can be successful with as low as a 4/6 HLA match.

*Visit “Chemo Counting” to see what a typical hospital day will include*

Graph Versus Host Disease (GVHD)

GVHD is a frequent complication of an unrelated bone marrow or umbilical chord transplant.  The transplanted cells realize that they are in a new environment and attack the donor’s organs.  Approximately 50% of patients that receive an unrelated transplant contract GVHD, the numbers are less in umbilical chord transplants at 25%.  There are two types of GVHD, acute and chronic.  Acute GVHD occurs soon after the transplant between day 30 and day 60.  Chronic GVHD can occur much later after transplant and last much longer.  Both types of GVHD can be serious and range from level 1 through level 4 where level 4 is the most severe.  Most patients that contract GVHD are treated with steroids and a variety of anti-rejection medications.  The disorder has no long term side effects if treated properly.

T-Cells are the cells in the transplanted marrow that recognize foreign matter.  Their sole purpose is to fight off infections, viruses, and other foreign substances.  These T-Cells look for genetic markers, HLA markers, that distinguish them from foreign cells.  To T-Cells normal body cells can be foreign and are therefore considered bad.  The T-Cells will fight these cells trying to rid the body of them.  Obviously these small amount of T-Cells are not going to kill the entire human body but the side effects of GVHD can be uncomfortable.  Typical side effects are diarrhea, rashes, increased liver functions, stomach and intestinal problems.

**Information obtained from MPS website, and National Marrow Donor Program