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A Novel GLRA1 Mutation Associated with An Atypical Hyperekplexia Phenotype

J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, Department of Neurosciences (Neurology), Medical University of South Carolina, Charleston, South Carolina

Greg F. Guzauskas, BS

J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina

Terence S. Edgar, MD

Department of Neurosciences (Neurology), Medical University of South Carolina, Charleston, South Carolina

Kate B. Clarkson, MD

J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina

Anand K. Srivastava, PhD

J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, anand{at}ggc.org

Kenton R. Holden, MD

Department of Neurosciences (Neurology), Medical University of South Carolina, Charleston, South Carolina,kholden{at}ggc.org

Hyperekplexia (MIM #149400) is a rare neurological disorder characterized by an exaggerated startle response, infantile hypertonia and hyperreflexia without spasticity, a hesitant gait that usually improves by 3 years of age, and nocturnal myoclonus. Familial hyperekplexia is usually autosomal dominant resulting from mutations in the inhibitory glycine receptor subunit alpha 1 (GLRA1) gene on chromosome 5q. We identified a 3-generation family with progressively severe phenotypes of hyperekplexia. All affected family members were found to be heterozygous for a novel arginine271proline mutation in GLRA1. Long-term follow-up of the affected members of the third generation, now aged 6 and 7 years, reveals enhanced startle responses and persistent hypertonia of the extremities without clonus or a catch, tight heel cords and abnormal toe-walking gait, and plantar flexor reflexes. The 7-year-old child recently reponded well to a benzodiazepine. Future studies are warranted to examine whether this new missense mutation is solely responsible for this atypical phenotype.

Key Words: gene mutation • GLRA1 • hyperekplexia • startle • neurodevelopment • stiff-boy

Journal of Child Neurology, Vol. 23, No. 12, 1433-1438 (2008)
DOI: 10.1177/0883073808320754


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