We have a diagnosis.
Those words — spoken to me over the phone in October by a nurse practitioner at the National Institutes of Health — were a long time coming, almost the entire life span of my sons, Alex, 18, and George, 17. I sat in my chair, trembling, waiting to hear more.
It was September 1992 when we realized Alex, a pudgy, adorable 6-month-old, wasn’t rolling over or reaching out for toys, the developmental milestones that every proud parent looks for and brags about.
A shadowy picture on an MRI scan showed his brain was smaller than normal, something the doctors called “moderate cerebral atrophy.” The best experts in Los Angeles, where my former husband and I lived at the time, could not understand why. Nor could they forecast what lay ahead.
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When I saw Alex’s brain scans, I was already pregnant with my third child, George. My daughter, five years older than Alex, had walked, talked and read ahead of her peers. With no family history that we knew of, we believed Alex’s delays were an isolated anomaly and that George would progress like his sister. We also hoped that Alex would eventually catch up with the norm, rendering the scans meaningless.
But George at 2 months had a major epileptic seizure as he lay beside me in bed one night. His follow-up MRI showed he too had cerebral atrophy.
Since that time, the boys have not progressed beyond the level of infants. They are — without a doubt — charming, loving boys, smiling when being sung or read to and laughing as they play peekaboo.
But birthday after birthday added one more candle on the cake and nothing more; they can’t talk, toilet or walk independently. Instead of climbing trees or playing with friends, the boys have spent their childhoods in wheelchairs, doctors’ offices and laboratories, with needles and blood draws and humming machines, subject to every test doctors could think of.
As the cause of the boys’ arrested development eluded us, I reconciled myself to the reality that they may never progress and worked to keep them an integral part of the family, school and community. With the help of local organizations, such as UCP (formerly known as United Cerebral Palsy) and the YMCA, they became poster boys for recreation programs that included all kids regardless of their abilities.
Thinking ahead, I fashioned a will with a special needs trust, and I set up in-home supportive services and respite funding from the state’s regional center to help provide us with an aide for the boys, knowing they will need total care, 24 hours, seven days a week, for the rest of their lives. If I die before they do, my husband and daughter promise to look after the boys (their father is no longer involved in their lives).
As the years have gone by, the boys’ skills and robustness have deteriorated. George, 5-foot-2 and under 100 pounds, used to walk but now can’t stand without support.
Alex, also 5-foot-2, is losing his sight and appears to be wasting away. He lost weight this past year and now weighs only 78 pounds.
My daughter, 22, wants to know the odds of her giving birth someday to similarly affected children.
A simple survey
About a year ago, I answered a survey from the National Institutes of Health through an Internet disability awareness network I had tapped into. Among other things, it asked how it felt to have a child with an undiagnosed disorder.
By the time I finished filling out the form, the answer was clear: It was hell not knowing. I needed to do more — for the sake of all three of my children.
As soon as I hit the send button, I called the NIH’s phone number listed at the bottom of the survey. Could my children become candidates for their studies?
I was referred to the National Institutes of Health’s Undiagnosed Disease Program, a relatively new effort formed under the National Human Genome Research Institute.
Although the NIH is best known for advances in cancer research, it also strives to find answers to other health issues, including heart disease, neurodegenerative illnesses, autism, and other chronic, acute and rare diseases.
The undiagnosed disease program began in 2008 as “the place of last hope,” as its director Dr. William Gahl told CNN earlier this year.
The institute agreed to consider the boys but warned that it would take months to process their medical records before I would hear back — and that they couldn’t accept everyone who applied.
Also, they warned, the program has had only a 10 percent to 15 percent success rate in uncovering the mysteries of its patients’ diseases.
I remained hopeful. Having two children with similar delays pointed to a probable genetic cause — and therefore fit into several of the researchers’ interests.
Six months later, we received a letter accepting us into the program. And last September, I shepherded the boys on a plane to Washington, D.C., near the NIH campus in Bethesda, Md.
Reason for hope
The campus is huge, encompassing more than 1 million square feet, with 75 buildings and 2,600 laboratories on 350 acres.
The boys became inpatients — with me on a couch beside them — in the clinical hospital’s pediatric unit for 10 days and sleepless nights of exhaustive investigation, brain scans, nurses, all sorts of doctors, nutritionists, electroretinagrams, bone scans, occupational and physical therapists, X-rays, electroencephalograms, urinalyses, blood draws, IV drips and spinal taps. Never had the boys received such concentrated attention nor been in a hospital for so long where every idea could be tested within hours. We did not have to worry about insurance. We had the best doctors and equipment, every test at our disposal. The government paid for everything.
After 10 days we left for home knowing that, given the elusiveness of the boys’ disorders, it still could take years — if ever — to discover the root cause.
But to everyone’s surprise, the diagnosis took less than 10 days.
The researchers had sourced the boys’ disease from a spinal tap, a test that they’d never before been given. The spinal fluid, which washes the brain, showed an extraordinarily high level of a substance called succinyladenosine.
This in turn pointed the NIH to a mutant gene that failed to make an important enzyme, called adenylosuccinate lyase or ADSL, critical to the boys’ brain development. It is a rare autosomal recessive disorder, meaning both the boys’ father and I are carriers of the mutant gene.
This also means my daughter may be a carrier, as well as any and all members on both sides of our family. If they are carriers, and their mate is also a carrier, they have a 1 in 4 chance of having a child (regardless of gender) with the same disorder.
According to the NIH, the first case of the ADSL enzyme deficiency was documented in the 1980s, and fewer than 100 people in the country within the mental retardation-autism spectrum have been diagnosed with it. Given the rarity of the boys’ condition, it is unlikely that my daughter — even if she is a carrier — will pair up with someone carrying the same mutant gene.
Researchers hope studying the boys’ genetic differences will help them better understand why the condition occurs and how it manifests itself — as well as help find treatments for other children with mental retardation of unknown origin.
The NIH also believes it’s possible other children with severe mental retardation could have a similar deficiency but haven’t been tested for it because the diagnosis is so new. A simple urinalysis that screens for the enzyme is also a less-invasive test, although it is not as sensitive to picking up the disorder as a spinal tap.
On a personal level, we’re still figuring out what to do next.
Genetic specialists who research this disorder at Prague’s Charles University in the Czech Republic are mapping the boys’ ADSL gene. This month they should finish examining samples of the boys’ and my daughter’s DNA to find out how much of the boys’ genes have been affected and whether my daughter is a carrier.
Also, more results from the institute’s battery of tests are coming in.
We have learned, for example, that Alex has retinitis pigmentosa, which is affecting his sight and for which there is no known cure. George is deficient in a substance called cerebral folate, a condition that causes irritability, seizures, wobbly gait (ataxia), spasticity and poor development. It can be supplemented with folinic acid, so we have started both boys on the drug and are watching for signs of improvement. Already they seem more alert and energetic.
Unfortunately, we are further away from treatment for the ADSL deficiency, which is probably the determining cause of the boys’ condition. Research regarding enzyme and gene replacement therapies are in the beginning stages and are not available for this type of disorder.
Because this rare disease wasn’t diagnosed until the 1980s, no one has been willing to predict the boys’ life expectancy. “Everyone’s learning about this condition,” said Dr. David Adams, research head of the team handling the boys’ case at the NIH. “We have very little to go on about what the condition looks like as the boys age, and there is a wide range of variables.”
Doctors do know it is a progressive metabolic disorder, meaning the boys’ condition may worsen and that the disease can be fatal, Adams said.
Out of three recently documented cases in the United Kingdom, two of the children died before they turned 2.
However, because the boys have shown strength and resilience to get through their teens, that is a good sign for the future, said Gretchen Golas, the nurse practitioner who handled the case at the NIH. Alex, for instance, gained 8 pounds after returning from his hospitalization, with increased fats and carbohydrates in his diet and vitamin supplements in his milk. We also have a specialist, a pediatrician, gastroenterologist and nutritionist now monitoring his weight.
At the boys’ age, the chances of reversing the damage are slim, but they are on the front lines of research into a little-understood condition.
Perhaps their experience will one day lead to treatments or a cure for others in what is truly a rare and unlucky genetic group.
While we still have much to learn, I remain thankful for the joy the boys give me — and that my daughter will now be able to find out if she too is a carrier.
Nothing much else has changed.
I will continue to care for my boys at home to ensure that they are as happy and safe as possible — and use every resource available to supplement their losses and boost their rebounds.
I hope that more answers will soon be on the way.
Melanie Cleveland is a former Tribune staff writer.