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Clinical Variability in Rett Syndrome

Department of Neurogenetics, Kennedy Krieger Institute, naidu{at}kennedykrieger.org., Departments of Neurology and Pediatrics, The Johns Hopkins School of Medicine

Genila Bibat, MD

Department of Neurogenetics, Kennedy Krieger Institute, Department of Pediatrics, The Johns Hopkins School of Medicine

Lisa Kratz, PhD

Division of Metabolism, Kennedy Krieger Institute

Richard I. Kelley, MD, PhD

Division of Metabolism, Kennedy Krieger Institute, Department of Pediatrics, The Johns Hopkins School of Medicine

Jonathan Pevsner, PhD

Department of Neurology, Kennedy Krieger Institute, Department of Neuroscience, The Johns Hopkins School of Medicine

Eric Hoffman, PhD

Center for Genetic Medicine Children's National Medical Center, Washington, DC

Carmen Cuffari, MD

Department of Pediatrics, The Johns Hopkins School of Medicine

Charles Rohde, PhD

Department of Biostatistics The Johns Hopkins Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD

Mary E. Blue, PhD

Department of Neuroscience, Kennedy Krieger Institute, Departments of Neurology and Neuroscience The Johns Hopkins School of Medicine

Michael V. Johnston, MD

Division of Neurology and Developmental Medicine Kennedy Krieger Institute, Baltimore,, Departments of Neurology and Pediatrics, The Johns Hopkins School of Medicine

The clinical variability of Rett syndrome, associated with mutations in the MECP2 gene, varies from classically symptomatic female patients to asymptomatic female patients, and male patients who have none of the diagnostic features considered pathognomonic of this disease. Multiple factors contribute to this variability. In our studies, mutations closer to the amino-terminus, prior to amino acid 255, led to severe clinical manifestations, such as inability to walk, severe dysphagia, and urinary organic acid abnormalities, compared with mutations toward the carboxyl-terminus. However, we found no correlation between severity and mutation type (missense versus nonsense). Despite the importance of mutation location to clinical severity, the widely varying severity within the same mutation suggests that in females, X-chromosome inactivation or other epigenetic phenomena also have roles in determining severity. We propose that stages 1 and 2 of the disease are a consequence of failed, time-linked, postnatal expression of MeCP2 in cerebellar neurons. This, in association with glutamate N-methyl-D-aspartate receptor—mediated neuroexcitotoxic injury to the differentiating neurons, results in the transient age-specific autistic-like behavior, motor, and cognitive dysfunction associated with these stages. (J Child Neurol 2003; 18:662-668).

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