Brennan Fieldler, 12, is gabby and a bit quirky, so her family calls her “Shelly” after the character Sheldon on the hit television show “The Big Bang Theory.” Aiden Coble, 6, started reading at age 3. Christian Chenault, 8, in his typically creative way, said something he ate recently tasted like “mustache.” Londyn Smith, 4, is so sociable that people thought she didn’t fit into the autism spectrum.
“When you’ve met one child with autism,” Aiden’s mother, Sally Coble, told a reporter, “you’ve met one child with autism.”
The condition, defined as a disorder of social communication combined with certain behaviors, should be known as “autisms” plural, Dr. Richard Frye of Arkansas Children’s Hospital Research Institute said.
Autism Spectrum Disorder — which now includes Asperger syndrome — is not simply a matter of a misfiring or tangled brain. It is a systemic condition, affecting the immune system, the metabolic system and the gut. Children with autism have problems relating to people around them. They exhibit behaviors that look like obsessive-compulsive disorder, like hand-flapping. They may be allergic to many foods, have trouble sleeping and be unable to speak. Serious gastrointestinal problems, like chronic constipation, are common.
Or they may be garrulous, like Brennan, or read early, or be able to tell you the make and model of every sort of truck, or make jokes.
Autism “is not a disorder,” Arkansas Children’s Hospital geneticist Dr. Stephen Kahler said. “It’s a description of how somebody looks to us, how they behave. They don’t relate to other people very well, they’re not good at communication. But those are descriptions about how somebody behaves. The only thing measureable is how old you are. If you are 2 months old, you can’t diagnose autism. If you are 50 with these characteristics, you wouldn’t call it autism. Everything else is a description of how you behave.”
And so there is no one treatment for autism. Now, however, Frye, who directs autism research at ACHRI and Children’s Hospital’s Autism Multispecialty Clinic and is associate professor of pediatrics at the University of Arkansas for Medical Sciences, is enlisting subjects to take part in a phase-three clinical trial of what could be the first FDA-approved drug treatment for autism that directly addresses gastrointestinal abnormalities. The drug, CM-AT, under development by the biotech company Curemark, is an enzyme that some individuals with autism are lacking, one that breaks down proteins into amino acids necessary to make neurotransmitters that affect such things as mood, learning, attention, memory and other health factors.
The clinics at Arkansas Children’s Hospital and at UAMS’ Dennis Developmental Center on the ACH campus are the state’s vanguard in the diagnosis and treatment of autism spectrum disorder. The Dennis clinic is the primary diagnostic center for the state and helps families find services; at the multispecialty clinic neurologists, geneticists, gastroenterologists, sleep specialists and other specialists treat patients and conduct research to identify and target some of the dysfunctions that afflict them.
There is a two-year waiting list to be seen in Children’s autism clinic. The wait for the diagnostic clinic has improved over the past three years to only four or five months. But the number of children being diagnosed with autism in Arkansas has increased exponentially in the past three decades. In the 1980s, one in 2,000 children nationally was diagnosed with autism. Now, that number is one in 68 nationally and one in 65 in Arkansas, according to the Centers for Disease Control and Prevention. The state has a lot of catching up to do.
Christian Chenault, who appears on the cover of this issue of the Arkansas Times, was “100 percent,” his mother, Heather, said, talking and hitting all the developmental milestones, until after a year of antibiotic treatments for intractable ear infections (which his mother believes played a role in his condition), his personality changed. He was just shy of his second birthday. ”All of a sudden he stopped making eye contact,” Heather Chenault said. “He started banging his head on the back of his high chair and on the tile floor.” The family pediatrician told her he was probably teething, which didn’t sound right to Heather; she had not seen her daughter, Abby, who is two years older than Christian, bang her head while teething.
Then Christian quit talking. He quit playing with his toys, though he would watch the wheels on his cars spin. It scared Heather and her husband, Nelson Chenault, “to death.” (Nelson Chenault, a professional photographer, took the photograph of his son that appears on the cover as well as another photograph for this article.) Heather knew about autism; she had a family member diagnosed with the disorder, but that child’s symptoms were “completely different” from Christian’s. Finally, though, the Chenaults raised their concerns about autism with their pediatrician. A checklist of behaviors suggested he fit into the spectrum.
After a five-month wait to get into the Dennis Developmental Clinic and another six-month wait for a hearing test the clinic ordered, the Chenaults finally got the diagnosis: autism and sensory processing disorder. Christian was 2 years and 8 months old. The Dennis clinic referred the Chenaults to a therapist at an early-intervention day school, but when the Chenaults called, they discovered the person had left the school. The autism clinic had not yet been created at Children’s. They felt “thrown to the wolves,” Heather said, though they were able to begin seeing geneticist Kahler.
Christian, at that point, quit sleeping, began crying and started running “like a track star” through the house. He quit eating most foods, accepting only crunchy carbohydrates, like pretzels.
“At that point I got Nelson’s credit card — as any wife and good mother would do [Heather still has a sense of humor] — and, honest to God, went to Barnes and Noble and Books-A-Million and bought every book on the shelves about autism.” With Christian in one arm and pumped up on Mountain Dew to stay awake, Heather plowed through 40 books. In this way, the Chenaults forged their own path based on what they read. Step one: They changed Christian’s diet, removing gluten and dairy products. In three days the crying lessened. They added in cod liver oil. “At least he wasn’t hurting as much,” Heather said.
But Christian was one sick little boy. He began to vomit often. He lost so much weight that the Chenaults had to consider putting him on a feeding tube.
Heather Chenault kept researching, eventually finding Dr. Julie Buckley, a Florida pediatrician who devoted her career to the study of autism because her daughter had the condition. But Buckley had a five-year waiting list. Undaunted, Heather called the clinic constantly, until she finally got lucky: A canceled appointment made room for the Chenaults, who hurriedly drove from North Little Rock to Florida to get to the suddenly available appointment with the doctor.
Blood tests showed that the toddler had such low cholesterol — crucial for brain function — that Buckley was shocked he was functioning as well as he was, Heather said. “His zinc had bottomed out” as well, and he was deficient in selenium.
Buckley was impressed with what the Chenaults had done for their son up to that point — it was just what she would have advised. Heather and Nelson Chenault both said meeting Buckley allowed them to breathe again; Buckley began to work with Kahler at Children’s to monitor Christian’s health.
The Chenaults had even more luck: At a conference on autism that Heather attended, Frye was a presenter. I “fell in love with his brain,” she said. Frye was not in Arkansas at the time, “but I was on a mission to add him to our team. He was my next target,” Heather said.
“I called Nelson and said I met the most amazing guy and he’s so smart and he understands mitochondrial dysfunction,” Heather said. He was unlike other doctors she’d met who “didn’t know what the hell I was talking about.” Imagine their delight when they discovered that Frye had been recruited to come to Children’s autism clinic.
Christian’s brain is also amazing. He can read, his therapists realized when he began following written instructions before they were read aloud to him. He’s artistic, and his drawings reveal a fascination with transportation. Earlier, before he began to speak again, he built an intricate object out of Tinkertoys. Heather posted it on Facebook, writing, “Just because someone can’t speak doesn’t mean he doesn’t have anything to say.”
Children’s is one of 20 sites conducting the phase-three clinical trial of CM-AT. The trial will test the drug for safety, efficacy and dosage in a wider population of autistic children than the preceding trials.
Candidates for the trial must be diagnosed, have a moderate “irritability score” — showing some mild aberrant behavior — and cannot be on other medications for a period of time until the trial. Though the drug is designed to replace an enzyme that some children do not have, it is being tested on all kids, whether they are lacking the enzyme or not.
Frye has completed the first two phases of a clinical trial on another therapy: folinic acid. “The folate story is the great story,” Frye said. Folate is a vitamin so important to the neurological system that folic acid is added to our food, and pregnant women take folic acid to prevent neural tube defects, like spina bifida, in their newborns. However, folic acid is the oxidized form of folate, which is not as fully accepted by the body as other types of what are called “reduced folates,” like folinic acid. Some people have trouble converting folic acid to reduced forms of folate.
In 2004, researchers discovered a link between a deficiency in folate and autism: By way of lumbar punctures, they found that while folate was present in the bloodstream of autism patients, it was not always present in the brain. Receptors for folates can be rendered dysfunctional by disorders in our cells’ mitochondria, where energy is generated. It can also be blocked from crossing the blood-brain barrier by antibodies that bind to or block the receptors.
There is, however a backdoor route for folate to get to the brain, by way of a “reduced folate carrier,” which admits folinic acid. Because folinic acid is used as a cell protectant in chemotherapy, doctors knew it was safe to give in high doses. Autistic children given folinic acid in high amounts, doctors discovered, “sometimes completely normalized, according to early case reports,” Frye said.
Patients at Frye’s clinic get blood tests to determine both mitochondrial disorders and whether or not there are folate antibodies present.
Brooklyn Fiedler, 18, who is both autistic and has Down Syndrome (about one in three children with Down Syndrome is autistic), was diagnosed at age 6 with leukemia. She was treated with the cancer-fighting drug methotrexate and the cell rescue drug leucovorin, a reduced folic acid.
“Here’s my daughter, lying on her deathbed, lifeless — you can’t imagine — and they come in and give her this rescue drug … and a few hours later she is sitting up asking for food and wanting to communicate,” Dana Fiedler said. After six years of silence, Brooklyn was making sounds, and Fiedler wanted doctors to keep giving her daughter leucovorin. She got the “brush off,” she said, because at that time physicians were unaware of the connection between folate deficiency and autism.
Like Heather Chenault, Fiedler, who has another autistic daughter as well, also did her own research into autism. (In fact, all the mothers interviewed for this article have done mountains of study — Kahler described it as “the heavy lifting” — on their own into Autism Spectrum Disorder.) Like Chenault, Fiedler was at a conference when she heard about Frye. Another researcher whose daughter had a dual diagnosis like Brooklyn told Fiedler “you need to get into that clinic as soon as possible.”
It took Fiedler a year, but she did get Brooklyn and her youngest daughter, Brennan, into Frye’s clinic. Brooklyn’s workup showed signs of oxidative stress that was suppressing the antioxidant glutathione, which manufactures vitamin B12 and is vital to cell health and folate absorption. Now, both she and Brennan get what Frye calls the “triple shot”: leucovorin, methyl B12 and the medication NAC (N-acetylcysteine), which boosts glutathione. Brooklyn’s speech “started to blossom,” Fiedler said.
“She doesn’t talk in complete sentences. … But what happened was she started to care, started to want to try. … It was unbelievable.” Brooklyn’s occupational and speech therapists noticed, calling Fiedler and asking if “we were doing something different. They said, ‘Something is going on here.’ “
Youngest daughter Brennan’s symptoms were so atypical she went undiagnosed for some time, Fiedler said. She’s a straight A student, started reading at 3, is big on math. What her teachers did not see at school was her abnormal need for control and order. For example, if she observed that someone at school was not following a rule, she would wait until she got home to “lose it,” Fiedler said, and could be upset for days. The doctor who diagnosed Brennan told Fiedler she believed many girls with autism weren’t being diagnosed.
Aiden Coble, 6, of Alma, also spoke until he was around 2 years old. Then he regressed, stopping speaking almost entirely. His mother, Sally, took him in for an evaluation, and he was diagnosed as autistic. Sally Coble did her research, and found out about Frye’s clinical trials of folinic acid. Once she was reassured that folinic acid was without potential side effects, she signed up Aiden to join the study. The study was double-blind, meaning Sally did not know whether Aiden was being given the drug or placebo. But a month and a half into the trial, “I got ‘Mama’ back for the first time in a year. He came home and he said, ‘Hi, Mama,’ and I cried. This trial was giving ‘Mama’ back to Mama.” At the end of the six-month trial, Dr. Frye started Aiden on the “triple shot.” Now, his mother said, while he may not converse, “his peers can understand him.” He will start first grade in the fall.
Aiden also likes to cuddle. “He’s very loving,” his mother said. “You don’t always see that.”
Children with autism may also have epilepsy, though their seizures are “subclinical” and go undetected except by electroencephalogram. Frye tests all patients in the clinic for these subclinical seizures.
Frye related a story about a 17-year-old patient he saw in Houston, where Frye was on faculty at the University of Texas Health Science Center. An electroencephalogram showed the nonverbal patient had “epileptic-form discharges,” Frye said. Frye put him on an anti-epileptic drug and the 17-year-old started talking.
“Now, about five years later, he’s not normal, but he makes jokes and speaks in sentences. He’s a functional part of the family. That’s a major thing for the family.”
You might think that at 17, a child would have endured so many insults to his complex, intertwined biological systems that nothing could help him. But Frye said no. “I would never say it’s too late for anybody.”
There is no single genetic defect, no single cause of autism. So, rather than try to solve the entire riddle, Frye and his clinic are looking at particular problems. “We are working backward,” Frye said, “from function to genes. How is the biological system broken? How can we fix this one piece?”
Little blonde Londyn Smith, 4, is one of the fortunate 100 to take part in a state Medicaid pilot program to see how well applied behavioral analysis (ABA) works to help improve the lives of children with autism.
Londyn was sociable; to the untrained eye, she did not fall into the autism spectrum. But Londyn did not speak and she did not play. She was hyperactive. Her mother, Sarah Smith, said Londyn could not slow herself down to fully connect with activities or people. She started going to an Easter Seals daycare starting at 10 months. She did not walk until she was 2; her muscle tone was poor, which is not typical for autistic children. At 3 and a half, she was formally diagnosed by specialists in speech, physiology and a doctor (required for the program) and found eligible for the ABA program through Medicaid.
ABA is intensive, a serious commitment for therapists and families. The three-year program includes up to 30 hours a week of therapy; right now, Londyn spends 20 hours Monday through Thursday with therapists.
Sarah Smith said the day starts with 15 minutes of “functional play,” in which Londyn chooses a toy and learns what to do with it.
“As a mom, you don’t think of having to teach a child to play,” Smith said. Like the problems that can arise when parents and teenagers try to do homework together, Smith said when she tried to get Londyn to play, “it ended up in a battle.” Not so with the three women who come to the Smith home in Stuttgart to help Londyn. Hearing “Pop Goes the Weasel” coming from a playroom might not mean much to many parents, but it was significant for the Smiths. Londyn was playing with her Jack in the Box.
The experience of raising an autistic child is “both fascinating and heartbreaking,” Smith said.
Londyn is also learning to follow directions. During “table time,” her therapists will ask her to do something — clap, for example — that will earn her a reward, like a gummy bear or 15 seconds on her iPad. (Londyn’s parents used to prop the iPad up on salt shakers when they went out to dinner to amuse her; now she can use a drop down menu with pictures to communicate what she needs. “It’s opened a whole new world,” Smith said.)
The analysis part of ABA means that therapists keep a record of daily interventions and how well they work. ABA is “an answer to a prayer,” Smith said. Londyn also takes medication to help her focus.
But, Dennis Developmental Center medical director Dr. Jill Fussell said, ABA could be answering more prayers. The legislature has not approved a Medicaid waiver for the program beyond 100 participants; the waiver is considered a pilot to show its worth.
Though private Arkansas insurance companies cover some autism services, few cover ABA therapy. Because reimbursement is infrequent, so is the number of ABA providers. It’s a Catch-22 for expansion of the program, which has been shown to be effective.
Whether diet is linked to autism is a subject of controversy. “There are certainly kids who benefit from dietary interventions,” Fussell said, but the scientific evidence is spotty, and a gluten-free diet, which many parents say is essential, can be expensive. She talks to patients about the various studies and what they’ve shown.
Children’s Hospital geneticist Kahler, however, believes the studies are flawed, not the notion that diet plays a big role.
“Here’s my take on this,” Kahler said. “Almost 25 years ago, I saw a patient who had autism. I knew nothing about autism.” The child, Evan, was frantic, not making eye contact. Genetic tests showed nothing extraordinary.
But when Kahler saw Evan again, “he was worlds better.” The mother told him she had taken Evan off milk and wheat and was giving him digestive enzymes, vitamin B6 and magnesium. “I said, ‘Tell me more.’ That’s when we began to learn about food” and its role in autism.
A year after Evan’s second visit, his parents asked how long he would have to be on the diet. They decided to give him a slice of pizza. In two hours, “he was flopping around like a chicken, doubled over on the floor. He was in absolute misery and that lasted for 18 hours.”
Heather Chenault doesn’t need convincing that her child’s diet must be limited to keep him healthy, even if some doctors do. She in fact once told a skeptical gastroenterologist to go get a saltine cracker and give it to her son “and see what’s going to happen.” She said if he had, Christian “would within 30 minutes begin kicking and screaming and having fits.” The doctor declined to take her up on the suggestion.
Kahler came to Arkansas in 2005, where he has worked with biochemist Dr. Jill S. James, who has studied the biomarkers and genetic factors of autism for more than 20 years; her research has shown a link between deficiencies in metabolic factors and oxidative stress. The autism clinic has taken shape since Kahler came, as specialists were added. Kahler said after he recruited Frye five years ago the clinic has become a “really fantastic operation.”
Depending on who you ask, Kahler said, genes play a picture in 20 percent to 40 percent of cases. Boys are far more likely to be diagnosed, so there is that genetic factor.
“Twenty years ago, if you tried to convince that this is a systemic illness with brain problems, they would say no, this is a brain disease,” Kahler said. “Now, I read something last month that said everybody knows intestinal problems are a major component of autism.”
Doctors would like to know the cause, but they are more concerned with the question, “What are we going to do with this patient here today?” he said.
Christian Chenault now talks; he even converses, which is a new thing, his mother said. He gets physical, speech and occupational therapy at the private All Children’s Therapy clinic, and sees Children’s Hospital allergist Dr. Stacie Jones, who is helping to expand his diet.
He also has “an emerging sense of self,” Heather said; recently he was reluctant to put on the headphones he sometimes wears in public to keep out stimulus, telling his mother, “Everyone will laugh at me.” He’s made great strides since he was a silent little boy who would throw a tantrum if one of the trucks he’d lined up through the entire house was moved out of place. (Though, don’t mess with his Tinkertoys, his mother says.)
For more information about autism interventions and the Medicaid waiver program, go to arkansasautism.org. To apply to enroll in the CM-AT study, contact Robin Gibson, RN, at 501-364-1542. Children between the ages of 3 and 8 and who meet other criteria are eligible; participants will get the enzyme sprinkled on their food three times a day, and will be followed by study visits every two weeks. Subjects will receive a stipend for their time.