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When Noah and Alexis Beery were diagnosed with cerebral palsy at age 2, their parents Reta and Joe thought they finally had an answer for the problems plaguing their twins from birth.
But their journey continued as the children's problems worsened. It took their mother's determination to dig deeper and find answers to her children's dilemma in the family's genome.
When the twins reached age 4, it became apparent to Reta and Joe that the diagnosis of cerebral palsy did not match what they were facing. Reta Beery began an extensive internet research and found a description that better fit her daughter dopa-responsive dystonia.
The muscles of people with dystonia contract and spasm involuntarily. In the twins case, the disease was responsive to a drug called L-dopa, which substituted for the neurotransmitter dopamine that each twin lacked. Neurotransmitters are critical to proper functioning of nerves including the control of muscle fiber response.
The Berrys' were also blessed with a father working in gene sequencing. Joe Berry is the chief information officer of Life Technologies, Inc., a company pioneering new methods and manufacturing the research equipment for next-generation sequencing. Within a few years, he and his family would enter the high tech world of next-generation sequencing on a very personal level.
In a report in the current issue of Science Translational Medicine, researchers from Baylor College of Medicine, and experts in San Diego and at the University of Michigan in Ann Arbor, describe how sequencing the children's whole genome along with that of their older brother and parents zeroed in on the gene causing the children's genetic disorder, enabling physicians to fine-tune their treatment.
The Berry's genome sequencing has taken human genome sequencing to a new level that of improving treatment on an individual level.
The Baylor Genome Sequencing Center pioneered whole genome sequencing of individuals, beginning with Nobel Laureate Dr. James Watson on May 31, 2007. The center followed the sequencing of Dr. Watson's genome by then sequencing in 2010, Dr. Richard Gibbs, director of the Baylor Human Genome Sequencing Center, and Dr. James Lupski, vice chair of molecular and human genetics at BCM. Gibbs and Lupski then published information on Lupski's whole genome sequence, identifying a gene mutation causing Lupski's inherited disorder - Charcot-Marie-Tooth Syndrome.
Dr. John Fink, professor of neurology at the University of Michigan, diagnosed first Alexis and then Noah with dopa-responsive dystonia disorder and started them on small doses of the drug L-dopa, which alleviated many of their symptoms. At age 6, they went to school and began to function as normal children.
"It's completely changed their lives," said Retta Beery.
However, about 18 months ago, Alexis began to have breathing problems. Dificulty breathing became so acute, twice paramedics were called to the Beery home. Alexis' inability to breathe began another desperate search for an answer by Reta Berry.
But this time, Reta inquired about whole genome sequencing to her husband Joe. That brought them to Baylor College of Medicine and Dr. Richard Gibbs at the Baylor Human Genome Sequencing Center.
A team of scientists began the search for the mutated gene that was causing the twins' problems. Existing single-gene tests were negative for the two genes known to cause the dopa-responsive dystonia. Then the Baylor team sequenced the whole genome of each twin (and studied their parents and brother for comparison), and found the twins had three genes with mutations that might be causing the problems.
Two of the genes had no known purpose, but one sepiapterin reductase (SPR) has been associated previously with dopa-responsive dystonia. The twins each inherited two mutated copies of that gene. One copy came from their mother and the other from their father.
Reta has a nonsense mutation, a mutation which stops the reading of messenger RNA, resulting in a shortened protein that does not work.
Joe has a missense mutation that results in the production of a different amino acid causing an alteration in the protein associated with the gene.
When SPR is mutated, it disrupts a cellular pathway that is responsible for not only the production of dopamine but also two other neurotransmitters serotonin and noradrenalin. Both dopamine and serotonin act at the synapse, the junction where one neuron passes electrical or chemical signals to the next.
These results meant that the twins were not only deficient in dopamine, they were also deficient in serotonin. In consultation with the twins' California pediatric neurologist, Dr. Jennifer Friedman of Rady Children's Hospital in San Diego, the Baylor doctors at Texas Children's Hospital advised adding a small dose of a supplement called 5-HTP to their medications. Friedman, a neurologist, had actually treated another child with the disorder.
"A month after adding the new therapy, Alexis's breathing improved dramatically," said Retta Beery. "She's been running track again." Noah has also benefited, as his handwriting has improved and he is able to focus more in school.
The Beery case has important implications for studying human genetics as their own genome sequencing resulted in a specific diagnosis and treatment plan based on a very specific inherited disorder. While the two mutated inherited genes caused profound disease in the twins, at least one mutation appears to be potentially associated with Retta Beery's family susceptibility to fibromyalgia, which has affected some members of her extended family.
"When the Baylor HGSC sequenced Watson's genome, it showed we could do a whole genome sequence," said Lupski. "When we sequenced my genome, it showed that whole genome sequencing was robust enough to find a disease gene among the millions of genetic variations. Now, not only have we found the variation that caused the disease, it enabled us to change therapy to improve their outcome."
Still, Dr. James Lupski, the physician who consulted on the Beery children at Texas Children's Hospital, credits the twin's mother, Retta Beery, with fighting for her children's future and her absolute determination to find an answer.
"Because of this mother, the children have a diagnosis and whole genome sequence that changed their diagnosis. Now they have additional therapy that works," he said.
The Beery family and the Lupski family share some similar outcomes from their genome research. Where some people on one side of Dr. Lupski's family with just one copy of the family mutated genes had carpal tunnel syndrome, some on the other side of his family with an additional mutated gene copy had axonal neuropathy (a disorder that affects the axon, the part of the neuron that extends away from the main body and carries messages to peripheral parts of the body). Only family members, like Lupski himself, who inherited both mutated copies were affected by the full Charcot-Marie-Tooth disease.
"I think we may find more examples of genes with mutations that cause disease, and when you look at family members who have only one of the mutated alleles, you may find other variations that result in milder common disease," said Dr. Richard Gibbs, co-author with Lupski on the gene mutation causing Lupski's inherited disorder - Charcot-Marie-Tooth Syndrome.
"This is an important finding," said Lupski. "We found evidence that sometimes, when you have a heterozygous state (only one of the mutated genes), you might be more susceptible to more common diseases."
"The key is that the children were correctly diagnosed clinically, but the molecular diagnosis offered a refinement that enabled better medical management which could further alleviate symptoms and improve quality of life for these terrific twins," said Lupski. "It answers the question of why do the genome sequence. I believe it also shows what we can all learn from a mother's persistence!"
Others who took part in this research include: Wojciech Wiszniewski, David R. Murdock, Claudia Gonzaga-Jauregui, Irene Newsham, Jeffrey G. Reid, Margaret B. Morgan, Marie-Claude Gingras and Donna M. Muzny, all of BCM, and Drs. Linh D. Hoang and Shahed Yousaf of Life Technologies in Carlsbad, California.
Funding for this work came from the U.S. Department of Veterans Affairs, the National Institutes of Health, the National Human Genome Research Institute, the National Institute of Neurological Disorders and Stroke, the Natural Sciences and Engineering Research Council of Canada and Life Technologies.
Original article: http://www.bcm.edu/news/features/item.cfm?newsID=4033