Phenotypic and genetic data collected from patients with Lennox-Gastaut syndrome of unknown cause suggest that the condition has a broad range of epilepsy onset, predominantly affects males, and often is associated with normal development prior to the onset of seizures.
The study, conducted by Dr. Peter Widdess-Walsh of UPMC Beacon Hospital in Dublin, Ireland, and his colleagues, is the largest to date to describe the phenotype of patients with Lennox-Gastaut syndrome of unknown cause (LGSu), which accounts for about 25% of cases. It is part of the Epilepsy
Dr. Peter Widdess-Walsh
Phenome/Genome Project, a collaborative effort of 27 epilepsy centers in the United States, Australia, New Zealand, and Argentina to collect detailed phenotypic and genetic data on large numbers of patients with epilepsy. Dr. Widdess-Walsh was at St. Barnabas Medical Center in Livingston, N.J., when he conducted the analysis.
"Systematic definition of the clinical phenotype of LGSu is critical to expand our knowledge of this distinctive subgroup of LGS and to correlate with genetic studies. ... By collecting comprehensive phenotypic data on these subjects, we will be well positioned to understand the consequences of the mutations identified in a future genomic analysis," many of which are suspected to occur de novo, the investigators wrote.
Dr. Widdess-Walsh and his associates reviewed medical history and records of 135 patients with LGSu and their parents from 19 centers in the United States and Australia. These data included a representative EEG and brain MRI, and all patients and their parents contributed blood samples processed for DNA extraction and creation of immortalized cell lines. The investigators excluded patients with autism, moderate to severe developmental delay prior to the onset of seizures, a history of epilepsy in either parent, known genetic syndrome, TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus) infection, metabolic disease, premature birth before 32 weeks, structural MRI lesion, hypoxic-ischemic encephalopathy, meningitis/encephalitis, stroke/intracerebral hemorrhage, microcephaly less than 2.5 standard deviations from normal, and significant head trauma (Epilepsia 2013 Oct. 7 [doi: 10.1111/epi.12395]).
The median age at enrollment was 14 years (range, 2-51 years), and 66% of patients were male. The 2:1 preponderance of males affected by the syndrome in this series "suggests that the vulnerability of the male brain extends to epilepsy in early life," possibly because of early exposure to pulses of testosterone or mutations involving genes on the X chromosome, according to the investigators.
Overall, 33 patients (24%) had mild developmental delay before onset of seizures, while 80 (59%) had normal development. Records did not clearly state whether the remaining 22 patients had developmental delay prior to their first seizure. Despite the invariable decline in development seen in patients with LGSu, 21 of the 50 patients who were age 18 or older were secondary school graduates and 2 had completed some college. This group had no developmental delay prior to seizure onset, and no history of special education as reported by parents. Twenty patients did not complete high school; 13 of them had some mild developmental delay documented prior to seizure onset and had a history of special education. Information about schooling for the remaining seven patients was not known or not asked.
However, the schooling data were biased by the study’s exclusion of patients with moderate to severe developmental delay prior to the onset of seizures, the investigators said, and inclusive education programs to promote school completion may have contributed to their educational achievements. A bias toward enrolling patients with higher cognitive function also could have contributed to these findings.
The most common seizure types were absence (80%), atonic (65%), generalized tonic-clonic (60%), and tonic (55%). All patients had EEG recordings with generalized epileptiform abnormalities. Specific EEG phenotypic features could be assessed from digital EEG data of 71 patients, including generalized single spike and wave complexes seen in 39 (55%) with a frequency range of 1-5 Hz.Sixteen patients had West syndrome, which evolved to LGS by a median age of 2 years.
The median age at first seizure was 1 year, with a range of less than 1 year to age 13. Most patients (93%) were diagnosed with LGSwithin a year of seizure onset. Within 3 months of the first seizure, 17 patients (12%) had an abnormal neurologic exam. No abnormalities were detected in genetic studies of 32 patients and metabolic evaluations of 39 patients. Another 37 patients had normal chromosomes.
The parents of patients in the study had no higher rates of febrile seizure history or family history of epilepsy than did the general population, and their slightly higher age at the time of birth than that of the general population likely reflects their sociodemographic and educational background. "These findings are consistent with an effect of de novo mutations on risk for LGSu, in patients selected on the basis of the absence of a parental history of epilepsy," the investigators wrote.