Clinical variability in Rett syndrome.
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.
Naidu
SakkuBai
S
Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA. naidu@kennedykrieger.org
Bibat
Genila
G
Kratz
Lisa
L
Kelley
Richard I
RI
Pevsner
Jonathan
J
Hoffman
Eric
E
Cuffari
Carmen
C
Rohde
Charles
C
Blue
Mary E
ME
Johnston
Michael V
MV
D000818:Animals; D002531:Cerebellum / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D005260:Female; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2; D009154:Mutation; D020125:Mutation, Missense; D009474:Neurons / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012097:Repressor Proteins; D015518:Rett Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D012720:Severity of Illness Index
D002868:Chromosomal Proteins, Non-Histone; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D016194:Receptors, N-Methyl-D-Aspartate; D012097:Repressor Proteins