The Genetic Basis of Pediatric Brain Disorders
Unlike adult disorders, which are frequently due to dominant genetic or multifactorial causes, many pediatric disorders, especially severe or life-threatening types, are due to recessive genetic mutations. In such families, in the absence of environmental influences, two healthy parents have one or more children with a severe disease. Having such a child frequently leads the parents to a genetic counselor, to ask how their genetic makeup could have led to their child's condition, and whether the condition could be repeated in future children.
Many pediatric brain diseases have no known causes. Most human genes are expressed in the developing brain but have no known function. These observations led us to the hypothesis that permeates our work: many of these connections between diseases and genes remain to be established. If we can elucidate these connections and understand how these mutations give rise to a specific disease, we hope to understand more about the assembly of the human brain. Synergy between clinical and basic science allows for advances in human health, fundamental mechanisms of disease, and allows for discovery of potential treatments.
Focus on the Middle East, North Africa, and Asia
To understand the function of recessive disease genes, we study populations where both copies of a gene are missing. In most cases of recessive disease in the United States, physicians assume that two different mutations in the same gene were inherited. However, in practice, to identify the causes of such diseases, it is most useful to have a situation in which we can assume that the child inherited the same mutation from both parents. Such inheritance is typical in regions of the world with high rates of inbreeding, as when a grandparent passes the mutation to relatives who marry within the family, and their child inherits the same mutation in a homozygous state.
For this reason, we have established collaborations with physician-scientists in major cities in many countries with high rates of consanguinity rates. Physicians from our group make regular visits to counterparts in Egypt, Lebanon, Libya, Kuwait, Jordon, Saudi Arabia, Pakistan, Turkey, Morocco, Qatar, Oman, and neighboring countries to evaluate patients, ascertain for research participation, and subsequently to link disease to gene. These discoveries are then translated in a "bench-to-bedside" approach to develop new diagnostic tests, consider potential points of treatment, and help clarify basic mechanisms of brain development. Having enrolled over 3,000 families and studied over 3,000 exomes, we leverage expertise in bioinformatics and stem cell modeling to make new discoveries.
Molecular Mechanisms of Cerebellar Development
One focus of our research is the development of the cerebellum, the main brain region that controls balance. Surprisingly, we now know that the cerebellum is responsible for much more than just balance: it establishes much of our basic bodily rhythms and a lot of higher cognitive processing. In Joubert syndrome, the most common inherited cerebellar malformation, the midline, or vermis, is underdeveloped. We have contributed to the identification of more than six different genetic causes of this disease, and there appear to be many more causes yet to identify. We found that the gene products appear to localize to the region of the cell known as the primary cilium, an organelle that, until recently, was thought to be vestigial. It is now established, however, that the primary cilium plays critical roles in most regions of the body. We are exploring how dysfunction of Joubert syndrome genes can lead to cerebellar development disorders and whether defective signaling at the primary cilium is a major contributor.
Potentially Treatable Diseases
The entries for most conditions in pediatric neurology textbooks nearly always end with the sad truth that most of these conditions have no treatment other than supportive care. As our list of candidate genes grows through expanded patient recruitment, we prioritize study of mutations that predict treatment might be possible. We recently uncovered several different conditions, previously considered untreatable, for which potential treatments emerged. We found mutations in SRD5A3 link with a defect in protein N-linked glycosylation due to a biochemical block in the conversion of polyprenol to dolichol, essential for synthesis of the precursor glycan. We found that mutations in BCKDK lead to a depletion of branched chain amino acids, and result in autism. We found that mutations in AMPD2 lead to a depletion of GTP, a key cellular energy source, resulting in neurodegeneration. In each condition, nutritional supplementation with the depleted cellular metabolite rescued at least some aspects of disease. We are researching whether such novel forms of treatment are feasible in patients, and interested to apply this approach to other poorly understood, untreatable conditions.
The Gleeson lab also receives funding from the NIH, the Simons Foundation and the California Institute for Regenerative Medicine.
As of February 21, 2014