6 research outputs found
Rett Syndrome: Revised diagnostic criteria and nomenclature
No full textObjective: Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials. Method: RettSearch members, representing the majority of the international clinical RTT specialists, participated in an iterative process to come to a consensus on a revised and simplified clinical diagnostic criteria for RTT. Results: The clinical criteria required for the diagnosis of classic and atypical RTT were clarified and simplified. Guidelines for the diagnosis and molecular evaluation of specific variant forms of RTT were developed. Interpretation These revised criteria provide clarity regarding the key features required for the diagnosis of RTT and reinforce the concept that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. We recommend that these criteria and guidelines be utilized in any proposed clinical research
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No full textMany postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-function mutations in MECP2, display impaired excitatory neurotransmission, the RTT phenotype can be largely reproduced in mice simply by removing MeCP2 from inhibitory GABAergic neurons. To determine what role excitatory signaling impairment might play in RTT pathogenesis, we generated conditional mouse models with Mecp2 either removed from or expressed solely in glutamatergic neurons. MeCP2 deficiency in glutamatergic neurons leads to early lethality, obesity, tremor, altered anxiety-like behaviors, and impaired acoustic startle response, which is distinct from the phenotype of mice lacking MeCP2 only in inhibitory neurons. These findings reveal a role for excitatory signaling impairment in specific neurobehavioral abnormalities shared by RTT and other postnatal neurological disorders
Loss of MeCP2 function contributes to kidney failure in male <i>Mecp2</i><sup><i>tm1</i>.<i>1Bird/Y</i></sup> mice.
No full textMoribund NULL mice (mori) exhibited evidence of kidney failure compared to normal serum chemistry values in WT or healthy NULL littermates before they become moribund. Moribund NULL mice exhibited (A) normal Na+, (B) increased K+, (C) increased serum osmolarity, (D) decreased bicarbonate, (E) increased creatinine, and (F) increased blood urea nitrogen levels. (WT N≥17, NULL healthy N≥9, NULL moribund N≥7). *ppost hoc correction for multiple comparisons.</p
Micturition is impaired by loss of MeCP2 function.
No full text(A,A’) male Mecp2tm1.1Bird/Y (NULL) and female Mecp2tm1.1Bird/+ (HET) mice showed abnormal micturition patterns with an increase in the number of micturition bouts, (B,B’) despite similar total volume of urine expelled during the test interval. (C,C’) Thus, the average volume voided per bout was decreased in NULL and HET mice relative to their WT littermates. (D,D’) Furthermore the maximum volume voided during the session was also reduced in the NULL and HET mice relative to WT littermates. Male 129B6F1 WT N = 8, NULL = 7; Female 129B6F1 WT = 5, HET = 6. *p<0.05 ANOVA for effect of genotype. ns not significant.</p
Strain dependent survival in <i>Mecp2</i><sup><i>tm1</i>.<i>1Bird/Y</i></sup> mice and penetrance of urethral obstruction.
No full text(A) Survival plots of male Mecp2tm1.1Bird/Y (NULL) mice show premature lethality across all strains tested. FVB NULL mice died significantly earlier than all strains and 129 NULL mice lived significantly longer than 129B6F1 mice. *ppost hoc correction for multiple comparisons (15 comparisons). (B) Penetrance of urethral obstruction in male moribund NULL mice varied by strain (p<0.001 determined by Chi-Square) with pure strains showing lower penetrance than isogenic F1 strains. (C) Similarly, penetrance of distended bladder while moribund also varied by strain (p<0.001 determined by Chi-Square) and was lower in the pure strains and highest in the isogenic F1 strains. N for each strain is indicated on the respective graphs. Median survival in days is indicated in the key for panel A.</p
Representative urological pathology of 129B6F1 <i>Mecp2</i><sup><i>tm1</i>.<i>1Bird/Y</i></sup> mice.
No full text(A-A’) Gross examination of moribund NULL mice revealed severely distended bladders compared to WT littermates. Bladders indicated by black arrows. (B) A plug of seminal coagulum was present within the penile urethra of the moribund NULL mice. (C-C’) Coronal H&E stained sections through the penile urethra showed that this plug occludes the urethra, effectively limiting urine outflow. Occlusion of the urethra is indicated by * in C’. (D-E’) The kidneys exhibited moderate hydronephrosis observable at both the gross level (D-D’), and in coronal H&E stained sections taken through the middle of the kidney (E-E’). Scale bars: A-A’ 1cm, B 5mm, C-C’ 250μm, D-D’ 5mm, E-E’ 2mm.</p
