The victims are called “silent angels” because they almost never speak; 50% can’t walk and most can’t make much use of their hands. In spite of severe disability, they enjoy social interaction and can often communicate through body language and their expressive eyes.
Rett’s syndrome – a rare and incurable neurodevelopmental syndrome that makes its presence felt after a seemingly normal first year of life – disables girls and usually kills off boys in the womb.
It presents both a curse and a blessing.
The bad news is that Rett strikes randomly; the birth of children with the syndrome cannot be predicted in advance by examining the parents’ genome because the genetic defect develops spontaneously in the uterus. The good news is that the parents have no reason to blame themselves – only fate – for having a severely disabled baby because they didn’t pass down a defective gene. The disease was first described by Austrian pediatrician Dr. Andreas Rett only in 1966; the condition existed before, of course, but no one had identified it. Dr.
Huda Zoghbi, an American pediatric neurologist and scientist of Lebanese origin, and her Israeli student Dr. Ruth Amir – working together in a lab at Baylor University in Texas – demonstrated in 1999 that the syndrome is caused by mutations in a gene called MECP2 on the X chromosome.
The severity of Rett syndrome in girls is in part a function of the percentage of their cells that express a normal copy of the MECP2 gene. It has been suggested that if the active X chromosome that is carrying the defective gene is turned off in a large proportion of cells, the symptoms will be mild, but if a larger percentage of cells have the X chromosome with the normal MECP2 gene turned off, onset of the disorder may occur earlier and the symptoms may be more severe.
As boys have XY chromosome pairs, when the X chromosome has a defect, the disease presents itself, but in girls, with two Xs, there could be a healthy one that makes survival possible. The syndrome occurs in every ethnic, racial and geographical group.
The risk of Rett is one out of 10,000 newborn girls, and an average of five are diagnosed in Israel each year. Although almost completely unknown to the public for many years, the disorder has become somewhat better known thanks to the Israel Rett Syndrome Association (www.rett.
org.il). It holds an annual run and distributes information to doctors and the general public. Along with its counterparts around the world, it marked International Rett Syndrome Awareness Day last month.
The national center for the diagnosis, treatment and supervision of Rett’s children functions out of the Safra Childern’s hospital in Sheba Medical Center at Tel Hashomer and was certified as such by the Health Ministry. It currently follows 160 girls from around the country under its wing and has treated a handful of boys, says its director, pediatric neurologist Prof.
Bruria Ben Zeev.
“We get fewer than nine new cases a year – closer to five. There may be some sectors, such as Beduins, where they aren’t brought in for medical diagnosis. About 16 of the 160 are Israeli Arabs. Some girls are brought in from the territories and Gaza for consultation and treatment. General practitioners generally know something about the syndrome, and some well-baby centers (tipot halav) as well. Every few years, said Ben Zeev, “we hold at Sheba a conference on Rett for physicians, parents and the general public.”
Born in Tel Aviv, she graduated from the Hebrew University Medical Faculty, specialized in pediatrics at Jerusalem’s Bikur Cholim Hospital and Rehovot’s Kaplan Medical Center. Then she went through her pediatric neurology fellowship at Toronto’s Hospital for Sick Children. She is currently the head of the pediatric neurology unit at Sheba.
Last year, the neurologist was a leading member of an Israeli-American team that identified mutations in genes responsible for two serious neurological disorders in infants and children of certain Oriental origins. The mutations were identified as part of research project to locate the genetic causes of some 100 serious diseases in the Israel population that have not been clear despite significant efforts to find the answers. Changes in the first gene causes a rare type of microcephaly in children of Iranian- Jewish origin; the symptoms include having a head with a smaller-than-usual circumference at birth, slow growth of the head afterwards, severe mental retardation and convulsions. The defect affects boys and girls equally and causes severe disability throughout their lives.
The second mutation causes a genetic disease in children of Bukharan-Jewish origin, with a high carrier rate in this group of one per 40. This mutation causes severe retardation and muscle problem and often prevents children from walking independently.
So far, there is no treatment for these, but the discovery is expected to lead to the identification of carriers and affected fetuses and prevent the severe diseases from being handed down to offspring.
“ONE CAN’T see any defect in an ultrasound scan of the Rett fetuses,” said Ben Zeev in an interview with The Jerusalem Post. “As it is sporadic and not inherited, it isn’t one of the genetic diseases for which couples are checked. But theoretically, one can test for it.”
Rett children are usually very good looking at birth. But later, the growth of the head slows, so its circumference is somewhat smaller than normal – but not something that most people would notice. As time passes, there is regression in speech, loss of the use of the hands and repetitive hand motions, difficulty walking, and sometimes difficult with earlier motor skills. “They almost can’t hold objects.
Motor difficulties,” said Ben Zeev, “stem from the combination of a muscle tone disorder , movement disorder and apraxia which may become more severe with age.
Epilepsy is frequent and may be difficult to control, as well as sleep, behavior, digestive, breathing and orthopedic disorders.”
She added that although some symptoms are similar to those in autism, “Rett’s is not autism. One of the most common characteristics among such children is their unique eye contact with others. It may have a functional meaning. They have a surprising ability to learn if you ‘reach’ them through the correct channels. Rett used to listed in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM) as autism, but it was removed from its last version ,” said Ben Zeev.
“They understand speech a little less than normal children, and some may have an IQ of around 70. They are definitely not profoundly mentally retarded,” said the Sheba neurologist. “They prefer to be with people, but they often show disquiet and cry. They may scream, especially when bored. Many are in special education schools, and very few are in regular schools with an adult helper. They see and hear well. Their lifespan is not very limited by the disease if well taken care of, and there are patients here in their 40s.”
Ben Zeev’s interdisciplinary clinic offers neurological, orthopedic , dietetic, gastroenterological and, if needed, endocrinological and cardiological treatment. Neurologists in the Sheba clinic also follow up children with uncommon variants of Rett, including those that affect boys. Including CDKL5, which is again on the X chromosome and affect mainly girls, and boys and girls with mutations in FOXG1, which is on a different chromosome.
ONE OF the leading advocates for Rett children is Shmuel (Shmulik) Zysman – a lawyer and businessman whose name is well known to Maccabi Tel Aviv basketball fans when the team won the Euroleague Cup in 1981. He serves as the voluntary head of the Israel Rett Research Foundation, devoting much time and money, with his wife Lilit, fighting the disorder, from which their fourth child, Hadar, suffers. In a published interview in Yedioth Aharonoth a few years ago, the Zysmans came forward and spoke about Hadar. “Every time she moves her mouth, I beg her: ‘Hadari, please just say Daddy,’ and she always laughs and remains silent. My greatest dream is for her to call me Daddy.” This is the most important game of his life.
“I have never hidden Hadar. She accompanies us to every function, and I want to make it clear that she is a member of our family.. But because I am known in Israel, thanks to my past as a basketball player, I was concerned that if our story were made public, people would think I sought pity, and that’s the last think I want. Hadar brings joy to our lives, despite the many difficulties,” he said.
He described her as an “exceptionally charming baby, and we were all excited to have her join our family. There was nothing to make us think that there was anything wrong with her. She developed and grew like any other child. Only afterward,” said Zysman, “when playing things back in my mind, did I recall saying goodbye to Hadar before leaving for work and asking her to wave goodbye, which she didn’t do.
I left the house thinking ‘She doesn’t know her father yet.’ But at some point, she’ll know and love me, and then she’ll wave goodbye wholeheartedly.” That scene was etched in his memory.
When Hadar was about a year old, her muscle tone had declined. Doctors assured the Zysmans that she was just developing slowly. But finally, one doctor mentioned Rett, and a group of physicians confirmed the diagnosis.
During the past decade and more, Hadar has been swimming with private instructors, and she can walk somewhat. She also rides horses and has been treated by a language clinician. She receives art and music therapy. The Zysmans also raise money for research.
“I worry about who will care for her as lovingly and understandingly as we do after we die – I have no answer.” But the couple still have hope. Seven years ago, an unexpected breakthrough was achieved when scientists abroad were able to completely reverse Rett symptoms in an animal model. It was included among the top 10 most important scientific breakthroughs of 2007. The researchers were optimistic that eventually they would find a cure for Rett and that this would speed up research into autism, Parkinson’s, schizophrenia and many other diseases.
Unlike inherited metabolic diseases like Gaucher’s, which is caused by a missing enzyme that can be synthetically replaced to restore function, Rett instead involves a protein needed for proper brain function early on. “Enzymes usually have a single function, but the MECP2 protein have multiple functions that make it more complicated,” said Ben-Zeev.
Rett’s does not occur naturally in animal models, but there are artificially made mouse models which are extensively studied and recently Chinese researchers published an article claiming they had created a Rett model in a monkey.
There is no cure, but various medications are being tested to relieve symptoms.
Copaxone, the medication for multiple sclerosis (MS) developed at the Weizmann Institute of Science and manufactured by Teva Pharmaceuticals, is being tested on Rett’s children. Brain-derived neurotrophic factor (BDNF) is low in Rett’s patients, and it has a role in MS. So injections are being given to girls in New York’s Montefiore Medical Center and Sheba. Teva provided the drug free, and the clinical trial in NY ended in September but continues in Israel.
The results have not yet been published, said Ben Zeev, but it seems it improved the girls’ communications, sleep and motor abilities. A double-blinded trial is being considered for the future. Other possible substances are Insulin growth factor (IGF- 1) and a tripeptide derivative.
In the meantime, there are expensive electronic devices made in Scandinavia that can identify the fixation of the eyes and identify objects on a board; some Rett’s girls – including Hadar Zysman – have been able to use it to produce sentences.
In contrast to the leadership of most organizations, concluded Zysman, “we yearn for the day when our foundation will no longer be in business; that will mean an end to Rett. Until that day comes we will continue to invest in high-quality scientific research.”