Studies Of Hereditary Neurological Disease: Disease Gene Identification

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The purpose of this research program is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. A genetic outreach program allows the identification and characterization of patients and families with hereditary neurological diseases. Specific research accomplishments in the past year include (1) characterization of a patient with spoinal and bulbar muscular atrophy and a longer repeat expansion mutation than previously reported, (2) collaboration in the H3Africa Consortium for genetic studies in Africa, (3) collaboration in gene identification and genotype-phenotype studies of Duchenne muscular dystrophy, MEGF10-associated myopathy, FBXO38-associated distal spinal muscular atrophy, distal myopathies, TRPV4-associated neuropathy, GRIN2A-associated epileptic encephalopathy, collagen VI-associated myopathy, and GNE-associated myopathy. Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a trinucleotide (CAG) repeat expansion in the androgen receptor gene. Patients with SBMA have weakness, atrophy, and fasciculations in the bulbar and extremity muscles. Individuals with CAG repeat lengths greater than 62 have not previously been reported. We evaluated a 29 year old SBMA patient with 68 CAGs who had unusually early onset and findings not seen in others with the disease. Analysis of the androgen receptor gene confirmed the repeat length of 68 CAGs in both peripheral blood and fibroblasts. Evaluation of muscle and sensory function showed deficits typical of SBMA, and in addition the patient had manifestations of autonomic dysfunction and abnormal sexual development. These findings extend the known phenotype associated with SBMA and shed new insight into the effects of the mutated androgen receptor. Our understanding of genome biology, genomics, and disease has advanced tremendously with the completion of the Human Genome Project. Technological advances coupled with significant cost reductions in genomic research have yielded novel insights into disease etiology, diagnosis, and therapy for some of the world's most intractable and devastating diseasesincluding malaria, HIV/AIDS, tuberculosis, cancer, and diabetes. Yet, despite the burden of infectious diseases and, more recently, noncommunicable diseases in Africa, Africans have only participated minimally in genomics research. If the dearth of genomics research involving Africans persists, the potential health and economic benefits emanating from genomic science may elude an entire continent. The lack of large-scale genomics studies in Africa is the result of many deep-seated issues, including a shortage of African scientists with genomic research expertise, lack of biomedical research infrastructure, limited computational expertise and resources, lack of adequate support for biomedical research by African governments, and the participation of many African scientists in collaborative research at no more than the level of sample collection. Overcoming these limitations will, in part, depend on African scientists acquiring the expertise and facilities necessary to lead high-quality genomics research aimed at understanding health problems relevant to African populations and to become internationally competitive in genomic science and its applications.