Does knowing the cause of autism in a child make a difference? Most children with autism do not have an identifiable cause for their disorder. Amy describes her journey, which leads to the identification of the cause of her daughter’s autism.

The First Three Years
My daughter, Emily, was born on October 21, 1988 via a repeat C-section. Her delivery took place at the same hospital where I worked as a neonatal ICU nurse. I loved working with challenged infants, and with my work came the realization that any child born healthy was a blessing. Fortunately, I already had one healthy child and was hopeful the second time around would result in the same. As soon as Emily was born, I heard her strong cry; a cry that was music to my ears, a cry so typical of a healthy rigorous newborn. I sighed with relief, and thought, "How much better could it get? Two healthy children, a boy and a girl." I had no idea of the turn my life was about to take.

Emily’s health concerns started when she was eight weeks old. After a 12 hour episode of vomiting, thought to be a virus, and 2 weeks of "chalky" colored stools, Emily’s pediatrician began a series of tests. Lab work showed that her liver function tests (LFTs) were very elevated and an ultrasound revealed a gallstone. Over the next few weeks, numerous tests were done to determine why Emily had a gallstone. However, no cause was ever determined, and the gallstone was considered to be "idiopathic."

However, by 9 months, Emily was having other problems. She now had a diagnosis of "failure to thrive," and appeared to be uncomfortable during and after her feedings. Further tests were done, including an abdominal X-ray, which indicated the gallstone had calcified. The abdominal discomfort and failure to thrive were thought to be due in part to the gallstone, and since an X-ray showed the gallstone had calcified, physicians felt it was best to remove Emily’s gallbladder. So, at nine months of age Emily underwent a cholecystectomy — fortunately, her surgery and recovery went well.

Over the next few months, Emily showed signs of developmental delay. She did not walk until 17 months, and when she did, her gait was broad based and unsteady. Her language did not progress and the few words she did have were poorly articulated. It was becoming quite evident that Emily’s problems were anything but "idiopathic."

As you might imagine, the next 2 years consisted of visits to new specialists (neurology, genetics, developmental pediatrics, ophthalmology, gastroenterology, speech, physical and occupational therapies) and many new tests, including three liver biopsies. Every specialty had its own ideas, but after everything was said and done, Emily still had no confirmative diagnosis.

I clearly remember all of Emily’s appointments with specialists; however, the one specialty that still sticks out in my mind is that of genetics. Although I had been a pediatric/neonatal nurse for many years, genetics was a field I knew little about. "Mrs. Whichello, your daughter has dysmorphic facial features. She has frontal bossing, flat nasal bridge, and epicanthal folds — let me point these out to you. Since Emily has these features, we need to do a chromosomal analysis. We would also like to send additional lab work, obtain a complete skeletal survey, and set up an eye exam…" Wow, I was feeling quite overwhelmed by this point. Much of Emily’s body was measured, pictures were taken to keep in her file, and a whole page of differential diagnoses were spit out of a computer program designed to aid in the diagnosis of children with rare disorders. The differential diagnoses were all ruled out, and while I was very relieved knowing what she did not have, her ongoing problems continued to baffle me.

At age 3, Emily began having complex partial seizures. Her neurologist informed me that Emily was also at risk for developing tonic clonic (grand mal) seizures. A little nervous about this new diagnosis, the neurologist put my mind at ease… "If by chance Emily has a tonic clonic — seizure, and it lasts more than 5 minutes, insert a Valium suppository, and if she stops breathing — you are a nurse, just start CPR." Thankfully, the Valium suppositories expired on the shelf.

The Diagnosis of Autism
I just thought things were difficult up to this point, but let me tell you, the next two years gave "difficult" a brand new meaning. When Emily was 4 ½ years old, she started to regress, especially behaviorally. She began to pinch, kick, and bite herself and those around her. Sensory issues heightened dramatically. She could sustain rages for 2 to 3 hours. What language Emily did have started to decrease and the aberrancy of her behaviors became very obvious. My daughter as I knew her quickly disappeared.

The next 1 1/2 years consisted of 3 hospitalizations, numerous medication trials, and last, but not least, a diagnosis of autism. Like many other parents whose children are newly diagnosed with autism, I started to read everything I could find. I soon realized that autism was basically a name for Emily’s inability to communicate, aberrant behaviors, and exaggerated reactions to sensory stimulation, but the diagnosis told me nothing about the underlying etiology of her problems. I still wanted to know.

Residential Placement
After three hospitalizations and no significant improvement in Emily’s condition, I was told by her physicians that she needed 24 hour support in a residential school (a kinder word for institution). The consensus was that Emily would not be able to survive, even in a group home setting, only a setting with more intense care. I was devastated and maybe in some sort of strange way, relieved. The recommendation validated the severity of Emily’s condition, and if someone else had not suggested residential placement, I would never have been able to make that decision on my own. The last thing I wanted to do was send my six-year-old daughter away. Yet, on the other hand, my family was crumbling right before my eyes. The stress was taking its toll on me, my husband, and Emily’s older brother, Brian. Every time I brought Emily home from the hospital, I so clearly remember Brian saying to me, "I thought the doctors were going to help Emily while she was in the hospital — maybe you should find better doctors." All I could do was reinforce to him that everyone was doing all they could, but that Emily challenged even the best. On February 1, 1995, my six-year-old daughter took up residence in a school that was one state and three hours away. Walking away that day was probably the hardest thing I have ever had to do.

The residential school was less than ideal, but as long as I felt Emily was safe, I tolerated her being there. I called and visited (sometimes unannounced) on a regular basis. And, as you might imagine, I was never given the "parent of the year" award for my vigilant eye.

Emily stayed at the residential school for approximately a year. Then, with the strong support of the school system, in-home services, and the positive effects of a new medication trial — naltrexone, we brought her home. The transition was with mixed emotions — we were extremely excited, but there was also the fear of Emily regressing again, as well as the realization of knowing the adjustment would not be easy. The transition went as smoothly as possible, and I am pleased to report that Emily has never deteriorated to that extent again, yet sadly, the Emily I knew before the age of 4 ½ has never returned. I will always miss that little girl.

During the next several years Emily was seizure free and actually came off of her anti-epileptic medication. She was making slight progress developmentally and behaviorally. Unfortunately, in 2001, Emily’s seizures returned, however, this time instead of complex partial, she had tonic clonic (grand-mal), absence, and myoclonic seizures, all of which still remain very difficult to control. Today, Emily is 16 years old and continues to live in our home. Although she has a developmental age of around two years, to me she is a beautiful and loving young lady.

The Missing Piece of the Puzzle
I continued to wonder about Emily’s problems; what could be so messed up? As Emily got older, her dysmorphic facial features seemed less noticeable, but I knew enough about genetics to know that dysmorphic features and genetic abnormalities typically went hand in hand. But, also in the back of my mind was the fact that Emily had been seen by three different geneticists, as well as had two "normal" (46, XX) chromosome studies.

Since Emily’s diagnosis of autism in 1994, I had been attending conferences, surfing the net for new information, and becoming quite interested in autism research. By this time, I was on the mailing list of many autism related organizations, including the National Alliance for Autism Research (NAAR). One particular issue of the NAAR newsletter included an article by Dr. Ed Cook regarding autism and chromosome 15. For some reason, the article caught my eye and the characteristics of the children discussed in the article reminded me of Emily. I contacted Dr. Cook and asked if he thought Emily might be an appropriate candidate for the "15" testing mentioned in his article. Dr. Cook suggested that with Emily’s medical history, multi-system involvement, and the possibility that this particular area of chromosome 15 was not closely examined with previous analyses, it might be a good idea to repeat the testing.

I quickly made an appointment with Emily’s new geneticist in Chapel Hill, Dr. Cynthia Powell, and spent the next few months anxiously waiting. Since Emily’s first two analyses had been done when she was two and three years of age, and at a different lab, I requested copies to take with me to the upcoming appointment. In February of 1999, I arrived at the genetics clinic with Emily, two karyotypes, and a NAAR newsletter… I discussed what I had found in the newsletter with Dr. Powell. Fortunately, she listened to what I had to say, and after she thoroughly examined Emily, recommended a number of tests, one of which was Emily’s third chromosomal analysis. The plan was that if this analysis came back "normal," a sample of Emily’s blood would be sent to a research lab for further testing, which would most likely be a long-term process and may or may not result in any significant findings. Knowing a little about research, I was satisfied with that answer. Emily’s blood was collected, and we returned home.

Patience was not my strength when it came to waiting on medical test results, but I knew I had no choice but to wait this one out. Several weeks went by — no news. Then, one day I received "the" call — Emily’s report was complete — a report I was not expecting to hear. "Emily has a translocation involving chromosomes 15 and 16. The breakpoint of the translocation may involve the interruption and/or deletion of an important gene that may be responsible for Emily’s phenotype." A lot of "maybes," but for the first time, my dream of knowing the etiology of Emily’s problems was much closer to a reality.

I shared the news about Emily’s translocation with everyone I knew. I was so excited. However, when I finally settled down long enough to think about the finding, brand new questions surfaced in my mind. How do we determine the breakpoint? How do we find the gene that was interrupted? Has the gene even been identified… so many questions. I knew the answers to these questions could only come through research…but how and by whom?

Emily’s Research
Initially, a researcher in England expressed an interest in Emily’s translocation. We collected and sent blood samples from everyone in the family to the United Kingdom. Unfortunately, a year later, the message was clear; this researcher had lost interest in Emily’s case. Emily’s breakpoint appeared to be outside of the researcher’s specific area of study and expertise, so no further work would be done regarding her case. While I understood his position, I was quite disheartened by the news.

Over the past year, I had continued to correspond with Dr. Cook regarding Emily’s case. I knew of Dr. Cook’s affiliation with Cure Autism Now (CAN) and the Autism Genetic Resource Exchange (AGRE), a DNA repository and family registry, but I also knew that Emily did not meet AGRE’s entry criteria of having two children in the same family with autism. Nonetheless, I was hopeful that since Emily had both autism and an already known genetic abnormality, AGRE just might make an exception. With some convincing, Dr. Cook agreed to ask AGRE, and excitingly, AGRE’s answer was yes — Emily’s sample could be admitted into the DNA repository and family registry. To add to the excitement, one of AGRE’s researchers expressed an interest in Emily’s translocation. Thrilled by the news, we once again collected blood samples from everyone in the family, and sent them to AGRE and to the interested AGRE researcher. The time now was Thanksgiving of 2000; I was definitely thankful…

The next two years passed, and unfortunately, the mapping of Emily’s breakpoint was still not complete. I was strictly at the mercy of the researchers because none of this testing was necessary for Emily’s treatment or care. I knew whatever was found would not help Emily, but what if information from her studies could benefit someone else? That was my hope.

Determined not to give up, I contacted the AGRE repository and asked the status of Emily’s sample. Had anyone else accessed her sample? Was anyone interested in her case? Surprisingly, a few weeks later, Emily’s sample was sent to Dr. Christa Martin’s lab at the University of Chicago. Somewhat reluctant to allow excitement, I was hopeful this time around would result in good news.

Emily’s Gene
In June 2003, approximately six months after Emily’s sample was sent to Dr. Martin’s lab, I received word that the breakpoint mapping of Emily’s translocation was finally complete!! The mapping revealed Emily’s breakpoint, which was on the short arm of chromosome 16, had resulted in a partial deletion of a particular gene, known as Ataxin-2 Binding Protein 1 (A2BP1). What did that mean? I quickly searched the gene using PubMed, and to my surprise, discovered there was very limited knowledge of A2BP1 in the literature, and even less information regarding its function.

Ataxin-2 Binding Protein 1 is a gene that was initially discovered by Dr. Stefan Pulst, at Cedars-Sinai Medical Center. To my knowledge, Emily’s case was the first report of an A2BP1 abnormality. However, in May 2004, a paper discussing two additional cases was reported (Bhalla, et al.), and my guess is that more cases are out there, not yet discovered. Emily’s case study was a poster presentation (#910) at the American Society of Human Genetics (ASHG) 2003 conference (Martin, et al.).

Does A Diagnosis Make a Difference?
I can without a doubt tell you that while the answer to this question is multifaceted, the bottom line is definitely "yes," it does make a difference. Through autism/genetic research, I now know the basis of Emily’s problems, and for that, I feel very fortunate. People sometimes say to me, "Why are you so excited about knowing the cause of Emily’s autism — how does this help her?" The answer to that question is, and always will be, "Short of a miracle, knowing the etiology of Emily’s autism and other problems will not help her, but Emily’s research is not just about Emily, it is about the possibility of someday helping others like her."

I suppose to more fully understand why Emily’s research has been so important to me; I need to complete the story. You see, since the time Emily was about four months old, I have had this gut feeling that she would someday make a contribution to the field of medicine, and what was learned from her may someday benefit someone else. While I am still not sure if or how Emily’s findings will benefit others, it has been the constant nagging of a gut feeling that has been my driving force for all of these years!

Special Thanks
I would like to say a special thanks to those directly or indirectly involved in Emily’s case study. Without the collaboration and work of others, finding the cause of Emily’s autism and other problems would never have become a reality. First of all, I would like to thank Dr. Powell for seeing Emily and listening to what I had to say. A special thanks to Dr. Ed Cook for his autism research, sharing his research findings with others, and his patience with my tenacious personality. I would also like to thank the National Alliance for Autism Research (NAAR) for their commitment to autism research, and keeping families updated through their very informative newsletter. Next, a grateful appreciation to the Autism Genetic Resource Exchange (AGRE) for their outstanding DNA repository and family registry, for accepting Emily’s sample and allowing me to be a part of Emily’s abstract, and to Dr. Christa Martin and her lab staff for completing the mapping of Emily’s breakpoint. Thanks to Dr. Stefan Pulst for identifying Ataxin-2 Binding Protein 1 (A2BP1) and his interest in continuing A2BP1 research. A special thanks to my family for their willingness to participate in Emily’s research. And, most of all, thanks to God for such a special daughter. You see, I believe Emily, like other children, is a special gift from God, and I am just the lucky one to whom the gift was given.

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