Ever since Franklin Henry was a baby, doctors had diagnosed him with one condition after another, including Tourette syndrome and a range of disorders: autism spectrum, bipolar, obsessive-compulsive, oppositional defiant. Repeated genetic and psychological tests over the years couldn\u2019t narrow the diagnosis.<\/p>\n
But Joe and Karen Henry, his parents, believed something specific explained their son\u2019s explosive moods and compulsively repeated speech.<\/p>\n
\u201cWe knew from the get-go that it was not regular autism,\u201d Joe said.<\/p>\n
It wasn\u2019t until Franklin was a young adult, and technology had advanced, that a fifth genetic test finally gave his parents a name for their son\u2019s condition:\u00a0NR4A2-related neurodevelopmental disorder.<\/a><\/p>\n Franklin, now 29, has an extremely rare mutation on the NR4A2 gene.<\/p>\n Joe wanted to learn more about the disorder. He armed himself with the book \u201cGenetics for Dummies\u201d and dove into the scientific literature.<\/p>\n He emailed the author of a\u00a0particularly relevant study<\/a>\u00a0on rare mutations that contribute to autism spectrum disorder (ASD). That was Dr. Daniel Geschwind,<\/a>\u00a0a distinguished professor of human genetics, neurology and psychiatry at the David Geffen School of Medicine at UCLA.<\/p>\n Nearly a decade ago, Geschwind and his colleagues were the first to identify NR4A2 as an autism risk gene.<\/p>\n They wrote in the study that a mutated NR4A2 caused \u201ca highly penetrant form of syndromic ASD consisting of ID (intellectual disability), language delay and ASD-like behavioral and cognitive deficits.\u201d<\/p>\n They also noted the need to identify more individuals with the rare mutation.<\/p>\n The email correspondence between Geschwind and Joe provided an opening for that.<\/p>\n Last year, both Joe and Franklin had their blood drawn at home in Medford, Oregon, and delivered to Los Angeles. Franklin is the first patient in a new study by Geschwind\u2019s research group to understand how NR4A2 affects brain development, and ultimately, to develop therapeutics.<\/p>\n \u201cOur interests are very aligned,\u201d said Geschwind. \u201cThe Henrys want to understand this disorder, and so do we.\u201d<\/p>\n Autism genetics<\/p>\n Research on autism had once been confined to psychiatry and psychology, without much basic neuroscience. That changed with Geschwind\u2019s focus on investigating autism as a biomedical disorder.<\/p>\n Patients and families have been an integral part of his work since his lab\u2019s founding 27 years ago. Indeed, it was a group of dedicated and passionate parents who convinced him of a \u201chuge unmet need to bring genetics and neurobiology to the table,\u201d recalled Geschwind.<\/p>\n That launched the modern era of autism genetics.<\/p>\n He and the families, supported by the National Institutes of Health, created the\u00a0Autism Genetic Resource Exchange<\/a>. Biological samples from more than 2,000 families \u2014 most with two or more children on the autism spectrum \u2014 are included and available to researchers anywhere.<\/p>\n This data has helped scientists to identify more than 200 autism risk genes, which Geschwind likened to pieces of a jigsaw puzzle.<\/p>\n \u201cWe can begin to see parts of the image,\u201d he said. \u201cBut we certainly don\u2019t see the whole thing yet, so there\u2019s still a lot of gene discovery to go.\u201d<\/p>\n NR4A2 and a family<\/p>\n A mutation on one copy of his NR4A2 gene has had a profound impact on Franklin and his entire family.<\/p>\n The first hint came at less than a year old, when Franklin was late to reach milestones like rolling over, crawling and talking. Later, because he could not verbalize what was bothering him, there was constant screaming. For 18 years, Joe and Karen did not spend even one night apart from Franklin and his younger brother, Theodore.<\/p>\n Franklin\u2019s childhood was difficult, but every passing year after age 18 also saw marked improvements in his behavior.<\/p>\n These days, Franklin has a job at a local market. And he\u2019s one of Medford\u2019s most well-known and informed citizens. He regularly watches all city council meetings and local newscasts; joins a group of retired lawyers for their weekly lunches; and walks the town for miles, engaging anyone he can in conversation.<\/p>\n Brain organoids<\/p>\n NR4A2 and other risk genes can provide a roadmap to the mechanisms of autism. When and where a gene is expressed is crucial to understanding its function.<\/p>\n Geschwind explained that the first step is to study what happens when the gene is knocked out or reduced. The problem, he said, is that \u201cso many of these things are so rare. It\u2019s really hard to get patient lines.\u201d<\/p>\n That\u2019s where Franklin\u2019s mutated NR4A2 gene comes in.<\/p>\n Cells from his blood sample were reprogrammed to an embryonic state using induced pluripotent stem cell (iPSC) technology and then grown into organoids. These minuscule spheres mimic the cerebral cortex, the brain\u2019s \u201cgray matter\u201d responsible for language, memory, and conscious thought.<\/p>\n \u00a0<\/p>\n The organoids, floating in a Petri dish, are tiny and beige \u2013 \u201cnot particularly exciting,\u201d according to Dr. George Chen, an assistant project scientist in Geschwind\u2019s research group. But their lack of visual appeal belies the enormous information they convey about brain development.<\/p>\n Chen explained that the study will focus on the organoids\u2019 first 200 days, analogous to a brain developing in utero. Studying the role of NR4A2 will add to the understanding of how each risk gene contributes to neurodevelopment.<\/p>\n \u201cThat can give us a better picture of what genes are critical at which time points to lead to a neurotypical phenotype, or lead to a deleterious phenotype,\u201d said Chen.<\/p>\n He and his colleagues can assess changes in individual cells as well as their interactions with other cells, to provide a detailed look at the mutation\u2019s effects.<\/p>\n Geschwind, who is also a faculty member in the\u00a0Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA,<\/a>\u00a0cautioned that any understanding of NR4A2-related neurodevelopmental disorder cannot rely on studying one patient alone, but requires at least three, and preferably more.<\/p>\n Using his networks as a parent-advocate, Joe has introduced the research group to other families who may participate. He has also linked them with other investigators studying the gene.<\/p>\n