Abstracts

RATIONALE: Smith-Magenis syndrome (SMS) is a microdeletion syndrome of chr. 17p11.2. The neurological phenotype in children includes self-injurious behaviors, sleep disturbance, speech delay, mental retardation and EEG abnormalities. Seizures are present in up to 30%. We evaluated the epilepsy phenotype in SMS and a genetically engineered mouse model.
METHODS: Prolonged EEGs in SMS patients were obtained during an overnight sleep study. Intracranial EEG in freely moving animals with the deletion and wildtype littermates was recorded during both wake and sleep.
RESULTS: We examined a cohort of 60 SMS patients. Of the 60, 29 (48.3%) had abnormal EEGs, 27 were epileptiform in nature. Focal abnormalities were found in 8/27 (29.6%), and 21/27 (77.8%) showed generalized epileptiform features, including various 2-4 cps spike and slow wave patterns in single waveforms or bursts up to several seconds in duration. Seizures were reported by parents in 11 (18.3%), and included absence (7/11), generalized tonic-clonic (4/11) and drop attacks (2/11), but not febrile seizures. Half of these (54.5%) showed abnormal EEGs. When noted, seizures were reported to be infrequent.
Human chr. 17p11.2 is syntenic to the 32-34 cM region of murine chr. 11. Utilizing chromosomal engineering, we deleted a region on mouse chr. 11 that spans the syntenic region for the most commonly deleted interval in humans in order to generate a mouse model for SMS. In the F1 background (50% C57BL/6-Tyr c-Brd/50% 129S5/SvEvBrd) 8/27 deletion mutants had witnessed seizures. On a background of 75%/25% only 3/21 (14.3%) had seizures. Seizures occurred between the age of four weeks to 6 months and occurred infrequently. All witnessed seizures were generalized tonic clonic. We studied the EEG in freely moving animals with the deletion (n=5), and in wildtype littermates (n=3). Waking and sleep background activity appeared normal in all animals. Of the five mice recorded, witnessed seizures had occurred in two prior to recording. Bilaterally synchronous spike and slow wave activity occurred in 4/5 and generalized tonic clonic seizures occurred in 2/5. Of those with seizures, one had occasional myoclonic jerks without a clear EEG signature. Spike and wave activity occurred in singlets and occasional doublets; rare polyspikes were seen. In a recorded seizure, single spikes progressed to polyspike bursts of increasing duration which coincided with tail extension. Subsequently, a generalized seizure ensued with continuous spike and wave activity lasting 23 seconds, followed by post-ictal depression.
CONCLUSIONS: Epilepsy is a frequent component of SMS. In our study, nearly one-half of patients with SMS have abnormal EEGs, the majority of which show generalized spike and slow wave variants, however, the epileptiform EEG abnormalities do not correlate well with seizure history, which was positive in 11/60. We identified epilepsy in 14-29% (strain-dependent) of mice deleted for the syntenic region of SMS. Seizures were infrequent, but showed generalized features. Multiple genes are deleted in SMS. It is unclear which of these may underlie paroxysmal EEG activity and seizures. None of the genes identified within the commonly deleted region have a currently known role in epilepsy. This mouse model will be useful in characterizing the contribution of specific genes to the epilepsy of SMS.
[Supported by: NIH 1PO1CA75719 (JRL), 29709 (JLN) and T32-NS07399-04.]