PRESIDENT'S MESSAGE
by Randy Yudenfriend Glaser

It is with great pleasure that I write this column. The discovery of the ML4 gene is no longer a dream, but a reality that will allow researchers to concentrate on a treatment/cure for children affected with ML4. The most immediate benefits of the finding of the gene are prenatal and carrier testing for all at-risk individuals. The Foundation will be actively increasing its fundraising efforts in order to fund the now necessary broader range of research projects. Researchers are already planning and initiating studies that will elucidate the function of the gene. This will involve mouse and fruit fly models, development of antibodies to the ML4 gene and early gene therapy studies. You have made this dream come true by your generous support of the Foundation. Your belief in our cause has given us the determination to
continue to seek out prestigious researchers who are committed not only to ML4 research, but to the children suffering with ML4. Thank you for joining our efforts and making the first phase of our dream come true.

The Long and Winding Road
pathways to communication with an ML4 child.
by Diana Bensoul

How do I know what she wants? How do I know what happened to her today when I wasn't with her? How can she share her thoughts with me? These are just some of the many questions that come up when you realize that your child is not going to be able to communicate with you in the easily identifiable mode of "speech". An ML4 child is delayed in all areas of muscle development and function. What does a parent do to communicate with their child? How does one open the door to communication?

Communication involves knowledge of what needs to be communicated. Using the receptive abilities of Arielle, as well as her visual function, we were able to initiate communication from a very early age. Arielle listened to songs, as well as story tapes. In this way, language has always been present in her life. She responded to funny songs by laughing, and would appear to think about the meaning of more serious songs. Arielle would use vocal sounds to indicate that a song was ending even before we were aware of it! Her verbalization of "Uh-mah" and "Ah-bah" signified "Mom" and "Dad", and by reinforcing what those sounds meant to us, Arielle knew that those were mine and Daniel's names'.

Visually, Arielle loved to look at pictures, and we spent many hours looking at word picture books, and stories with pictures, the same as any young child. When she was 15 months old, she could give me tiles with pictures of many objects, as long as they were within her grasp and visually close enough. She had a very large receptive vocabulary. Then, we added letters and sight words. At this time, Arielle was in Early Intervention at Children's Specialized Hospital. She understood everything, but could only use basic gestures. When we presented her with sight words at age four, she was able to memorize them and point to correct match when asked. Picture boards were made up using categories of subjects such as food, animals and people. Large pictures were used with the name of the object printed below. She could point to words or pictures when asked, but the pointing wasn't always accurate, nor could Arielle initiate their use unless she urgently wanted something, such as "DADDY"! The boards were a frame of reference for those wishing to speak with Arielle, and for that purpose, they were terrific.

Where to go from here??? We found out about a device called the Digivox, which Arielle still uses. It is very easily programmable and has several overlays. Once again, overlays were made up in several categories for school use: class subjects, weather, news from home, playtime, etc. Arielle had more success with this device as the pictures were bigger and fewer in number, and the staff found it easy to program and use. It was lightweight and easy to carry, BUT .. .once again, it was not spontaneous and would not let us know what Arielle wanted to communicate at that moment.

Where to go from here??? SIGN LANGUAGE. We decided that Arielle could begin to use her gestures in a more defined way. We hired a speech therapist who was also a sign language interpreter. We wanted to find out if Arielle could learn a modified form of signing so that she would have a "vocabulary of words" with her at all times that would be understood by those close to her. No machine was necessary. She could use her signs spontaneously and we could give her choices in sign to help her make decisions and prompt her to speak with us.

This was a brilliant idea on the part of Daniel, her dad. He supported this direction, and Arielle took training at home for several years with a private tutor. She has developed a sign vocabulary that is quite extensive. She does not use all her words all the time, but we understand each other most of the time. Her teachers, therapists and caregivers were taught her signs as she learned them. THEN . . .

Arielle's eyesight began to fail. When Arielle's sight became more limited about two years ago, we gave up on her small picture board that she used to carry on her walker at all times. Now she is using a light box at school with larger pictures to facilitate her visual abilities. But, signing
remains her best mode of communication. At her new school, they are trying to use "Signing Exact English" with her because other children in the classroom use that system of signing. By keeping her basic signs, though, we try to avoid confusion. Picking and choosing signs was very difficult. We did not want to have any signs that would be too confusing, thus failing at this mode of communication. As with all ML4 children, Arielle's fine motor skills are weak, limiting her to certain movements that would be clear for sign interpretation. Too many signs near her mouth, or too many near her head, etc., would be difficult to interpret. Hours were spent deciding which words are important enough to warrant a sign, and which words could wait. We have put signs together as we had done for "Minspeak". Since she had learned that concept before, it was easier for her to grasp now.

Arielle tries to tell us things in sign language and sounds. We still have to prompt her a lot and give her many choices before we can get a clear picture of what she wants to say, unless it is something really important to her. She is very perseverant and will stick with a sign until we guess what she is trying to say. Once we understand, she just smiles and smiles and smiles! Many times she laughs out loud; it is worth the wait!

We know as much as we can about what Arielle is thinking through her signing, our intuition, and the ESP that comes with being a parent or loving sibling. We still don't know what she has done each day at school unless her teachers inform us, and we are very persistent in getting this information every day. Sometimes Arielle comes home from school and tries to tell us something that happened. If she's really excited about it, she'll stick with it until we figure it out. If we can't, we'll call the teacher that afternoon, or the next day at the latest, to find out what was on our daughters mind.

Because Arielle's eyesight has become more limited, the school is trying to work on some basic Braille skills with her. They are trying to get her to "see" by using her fingers and feel for information.

In learning to communicate with Arielle, we have gone from using her sounds for speech, listening to story tapes, using picture boards, reading basic sight words, the Touch Talker, the Digivox, modified sign language, a light box, and ultimately, learning basic Braille.

We always knew Arielle had lots to say even though she could not speak. We have always tried new ways to communicate and they have all worked in their own way. The signing seems to be the best way to go for us. As we say to Arielle while she is trying to sign something on the way downstairs each morning, "Gee, Arielle, for a girl who doesn't speak, you sure have a lot to say! Stop talking `til we get downstairs and I can really listen to what you have to say"!

GRANDPARENTS' Corner
Janet Price and her grandson Ryan Gale

We call Ryan our "hands-on" grandchild. As our other grandchildren live out of state, we were thrilled to have a new grandbaby to love and enjoy right in our own city.

Ryan is a beautiful child, with big blue eyes, long black lashes and a smile that knocks you over. We enjoyed him so much, but his slow development caused me considerable worry and anguish. I could not sleep at night and didn't know how, and if, to communicate my fears to his parents.

At about six months of age, the pediatrician noticed there were problems with Ryan's eyesight; cloudy corneas. Jon and Sandy, his parents, took him to a pediatric ophthalmologist and a developmental specialist. The ophthalmologist made several diagnoses, none of which were correct. The developmental specialist took a wait and see attitude.

Jon began to pour through neurological and developmental books, and was eventually in touch with a neurologist who came back with a bleak possibility, ML4. Biopsies of the cornea and skin behind the ear confirmed the diagnosis.

All of our lives changed. Ryan was about a year old and we all began a life of therapies: physical, occupational, speech and water therapies.

The water therapy was such a joy to both Ryan and his grandma. He shrieked and laughed, kicked and pounded the water. He felt a freedom he did not have on land. His water therapy has progressed very well. He walks with help in the shallow end, climbs the pool steps, and from a sitting position on the edge of the pool, goes into the water. He has learned to hold his breath, put his face under water and paddle with his hands.

In pre-school Ryan is very social and outgoing. He loves his teachers, the activities and the presence of the other children in his class. I try to visit his classroom often to see how he is progressing and to let his teachers and aids know we are interested and care about him. He has recently begun horseback riding therapy that he also enjoys, especially when the horse begins to trot.

At home Ryan loves to play with his toys, swing on his swings, ride his adaptive tricycle and listen to his music. Once a month we take him to Tot Sabbath. He loves the songs and music, clapping and dancing in my arms.

My own way of coping with his life challenge is to help my son, daughter-in-law and Ryan in whatever way I can. My other involvement has been to raise money for ML4 and educate the community about this genetic disorder. With multiple letter writing campaigns, speeches, a shopping bazaar (featuring 25 vendors, a bake sale and a silent auction), a cocktail party, dinner and entertainment, and a medical conference, Ryan's grandparents have raised over $100,000 for ML4 in the Kansas City, Missouri area.

Ryan is now 5 1/2 years old. He cannot speak or walk. At night, in my dreams, he calls to me and I run after him as he runs down the hall. Raising money for research and keeping in touch with other parents and grandparents involved with ML4 keeps my hopes alive, that my dreams will become a reality for my grandson Ryan, and for all of our beloved children.

Children Helping Children

The ML4 Foundation has received countless donations over the years to help us accomplish our goal of finding a treatment and a cure for ML4. Some of the most important contributions have come from the generosity of children. Whether by reading for the Read-A-Thon, walking in the Mitzvah Mile, or collecting change for charity in a classroom, children reaching out to help others has played a major role in reaching our goal. The following are the stories of three children who contributed to the foundation in honor of their bar/bat mitzvah.

My name is Alan Yaspan. A little over a year ago, I had donated $825 to the ML4 Foundation. It was in honor of my Bar Mitzvah. It says in Jewish law that you have to donate 10% of what you have to charity. So half the money I was donating to charity went to the ML4 foundation. I'm very glad to help and be a part of the effort to find the cure for this disease I was influenced to donate this money by our close family friends, the Shottenfelds. They have two great twins who have ML4. Seeing what they go through inspired me to take action. I hope my contribution helped the cause.

From Cassie Kornblau: I remember the first time I learned about this disease. I was young and my grandparents had friends with a grandson, Paul, who had ML4. My grandparents and his grandparents had grown up together. My grandmother Roz and his grandmother Pearl were friends since they were twelve. My dad, Marc, and his mom, Paula, knew each other as kids. As my dad and his mom grew up, they separated and had families of their own. They always had a close tie with the past and through their parents. When our family was visiting my grandparents, my dad told me that his friend, Paula, had a son, Paul, with this disease called ML4. I had never heard of it. It was not something we had been educated on like cancer, AIDS, and other major diseases of the world. My first impression when I saw him was that I began to see how lucky I was and how fortunate I am to have a regular childhood. He is not able at this time to run and play, or hang with friends, or even communicate the same way I do. So from that time forward I knew, because of the rareness of the disease, they were going to need help. Years went by and I still saw him but that thought was always in my head. While preparing for my Bat Mitzvah, I was going to have to do a Mitzvah, or good deed, as part of the responsibility of becoming an adult in the Jewish community. In Judaism we are taught to give tezdkah, money or necessities to those less fortunate or in need. In the back of my mind I had always remembered ML4. Fortunately, in my family, no one has a serious disease for which to donate money. My closest tie was this family and I knew this is where I wanted
to give my donation. I am happy to hear that the money I have given has helped for research of the gene that was responsible for this disease. This will prevent other children from living in a world different from my own. But to the children who do have it, I hope that this money will make their lives easier and better.

Brett Stokar: I made this donation to hopefully make Rachel Helmrich's life easier and to try to help find a cure for this disease.

NIH
Clinical Study
by Raffi Schiffman, M.D.

Since 1995, we, at the Developmental and Metabolic Neurological Branch at the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), have been conducting a study designated to characterize patients with Mucolipidosis Type IV (MLIV). This is the first such study in MLIV patients.

Our goals in this study are: 1. To identify the complete spectrum of the disease. This means that we would like to see what clinical problems MLIV patients have. We are interested in studying as many patients as possible of all degrees of severity. 2. The second goal is to follow our MLIV patients over time to find out if their neurological and eye problems remain stable or get worse as they grow older. 3. We would like to find clues as to the cause of MLIV. 4. This study is a crucial part of our effort to find the defective gene in this disorder. The main researcher working on this part of our MLIV research is Dr. Ehud Goldin who is working with Dr. Mei Sun. The ML4 Foundation supports both investigations. This work is done in  collaboration with Dr. Susan Slaugenhaupt at Massachusetts General Hospital in Boston.

How do we study patients with ML-IV? Patients usually spend 4-5 days on each visit to the Clinical Center of the NIH. An experienced medical team that includes a neurologist, and adult or pediatric nurse as appropriate and a neurologist examine the patient. The patient undergoes a number of blood and urine tests, an EEG, evoked potentials, a head magnetic resonance imaging (MRI) magnetic resonance spectroscopy developmental testing, rehabilitation consultation and speech and swallowing evaluation. A detailed eye examination by Dr. Janine Smith of the National Eye Institute is a very important part of our research protocol.

What have we learned from our MLIV patients and their families? To date, we have studied 22 patients. We found that MLIV is a developmental disorder; that is patients are born with some degree of neurological handicap already present. The patients have abnormalities on head MRI. The most distinctive abnormality consists of a paucity of white matter, and a malformation of the band of tissue that connects the two cerebral hemi spheres (corpus callosum). This structure is unnaturally thin and incompletely formed. We also noted that the degree of severity of the neurological and ophthalmologic (eye) abnormalities vary from patient to patient. The motor and cognitive deficit has remained stable in the majority of patients. The repeated eye examinations showed slow deterioration of the vision that is mostly due to retinal degeneration. Corneal cloudiness was stable or improved in some patients during our period of observation. A finding of iron deficiency anemia in some patients led us to the discovery that all MLIV patients are unable to secrete normal quantities of acid in their stomach (also called achloehydria). This is associated with elevation of a hormone called gastrin in the blood. This deficit of stomach acid secretion is benign. This finding is important for two reasons: elevated serum gastrin is a very useful test to confirm a suspected diagnosis of MLIV. Since the discovery of the phenomenon, we were able to diagnosis this disease in five patients from three continents. This finding is also an indicator of what goes wrong in the body of an MLIV patient and helps us to understand the disease. Finally, it provides a simple way to test future treatments, since an effective therapy should correct the acid secretion defect and can easily be monitored.

Prior to our study of MLIV patients at the NIH, the only means of diagnosing MLIV was a microscopic examination of tissue biopsy or cultured skin fibroblasts. Our work led to a significant expansion of diagnostic methods.Dr. Janine Smith developed a simple way to identify affected patients by using conjunctival swabs. A collaborative genetic study with Dr. Slaugenhaupt has yielded the chromosomal location of the ML-IV gene. This finding has made carrier testing in MLIV families possible. Recently, in collaboration with Dr. Slaugenhaupt's team, Drs. Sun Mei and Ehud Goldin at NIH found the MLIV gene. They also identified mutations in the gene in Jewish and non Jewish MLIV patients.

The MLIV gene is a new protein that is probably an ion channel but its exact function is not yet known.
The finding of this gene together with plasma gastrin will facilitate the identification of patients with MLIV. Identification of mutations in this new gene will also permit efficient prenatal diagnosis and carrier testing.

Where do we go from here? Our MLIV effort is still going strong. We would like to continue following patients and identify new patients. The true natural history of the disease will require a long term follow-up of existing patients. The discovery of the ML-IV gene will enable us to understand the mechanism of the disease and hopefully to develop rational and effective therapies.

Before concluding, I would like to thank the many families afflicted by ML-IV who participated in our study, and the ML4 Foundation, without all of whom this work would not have been possible.

Congress Urges NIH Support For ML4 Research

At the request of the ML4 Foundation the Appropriations Committee of the United States Senate and House of Representatives, in their reports on the budgets for the fiscal year 2000, urged the National Instituts of Neurological Disorders and Stroke (one of the Institutes forming the National Institutes of Health) to expand research into ML4 and, upon discovery of the gene, its treatment options. As this newsletter goes to press, similar action is expected from the Senate/House Conference Committee considering the NIH budget for fiscal year 2001. The ML4 team talking to Congress includes our directors Carol Turchin and Howard Monderer, and Washington representative Bob Hynes of Colling, Swift & Hynes, all of whom not only contribute their services but even pay their own expenses.

MAGIC ON BROADWAY

The curtain rose on the Broadway performance of Annie Get Your Gun starring Bernadette Peters on June 15, 2000. After enjoying a wonderful production, Bernadette Peters greeted ML4 Foundation supporters at a dessert reception in her honor. Ms Peters and her husband, Mike Wittenberg, recently became generous supporters of the Foundation. Ms Peters was escorted to the reception by a number of children and guests attending the performance. She graciously signed autographs and posed for photographs. Guests enjoyed the wonderful desserts and spent time mingling, enjoying a perfect New York evening. The Foundation wishes to extend their appreciation to Carol Turchin for her efforts in coordinating this successful fundraising event.

ML4 GREETING CARDS

The ML4 Foundation will again be offering greeting cards to help it meet its medical research commitments to Harvard Medical School, and the National Institutes of Health. ML4 greeting cards are printed in boxed sets of 20 cards with matching envelopes. The cards feature exquisite images reproduced from the Jewish Museum in New York City, are blank inside, and can be used for any occasion. Each set sells for $36.00 and is ideal for gifts.

We hope that recipients of this newsletter will consider purchasing ML4 greeting cards to help us continue to fund our vital research. To order your ML4 greeting cards, please enclose $36.00 per box by check, made out to the ML4 Foundation, and sent to: Roslyn Itzkowitz, 133 Laurel Lane, Wantagh, NY 112793.

Thank you for your continuing support!

A Long Awaited and Much Anticipated
Gala Event
to celebrate the discovery
of the ML4 gene!
Preparations are being made for a
Fund Raising Celebration
to support expanded and continuing research,
and ultimately find the cure.
Date and Location will be finalized in the Spring.
Please watch your mail for further details

Sibling Column

My name is Allison Glaser. I am fourteen years old, and going into ninth grade. I am the second oldest out of five children. My older sister Lauren and my younger brother Jonathan both have a Jewish genetic disease called ML4. When I was younger and it was just Lauren and I, we always used to play together. I even used to pretend I was handicapped to be like her. My mother tells me that I used to ask if Lauren would ever get better. Even though many years have passed, there is still hope for the future, now that the gene has been discovered. When Jonathan was born, I became an older sister. I understood that Lauren and Jonathan were different, but still had personalities and emotions just like me. Both of them have a great sense of humor and love to laugh. They love when we sing, dance or just hang out. Lauren goes to a school in upstate New York with other children like her. Jonathan has gone to the school to visit for short periods of time. Both Jonathan and Lauren go to sleepaway camp. They have their own social lives, just like other children their age. They have both taught me many things. I have learned that even though they cannot communicate as I can, I can still understand and relate to them. I know that even though they cannot say it, they love me, and I love them too.

ML4 ON THE WORLD WIDE WEB
Our new web site was set up by Gigi Baxter, mother of Greg Lipton, an ML4 child.
Please visit us at http://www.ML4.org e-mail address: ml4www@aol.com

The ML4 Foundation newsletter is edited and published by Randy Yudenfriend Glaser