Abstracts & Commentary
Sources: Walz R, et al. Surgical outcome in mesial temporal sclerosis correlates with prion protein gene variant. Neurology. 2003;61(9):1204-1210; Mastrianni JA, Roos RP. Wrinkles and folds of the prion protein. Neurology. 2003;61(9): 1168-1169.
Allelic variants of the cellular prion protein (PrPc), the product of the prion protein gene (PRNP), are best known for their role in spongiform encephalopathies. In an entirely novel observation, Walz and associates describe a PrPc variant associated with hippocampal sclerosis that seems to be partially predictive of seizure-free outcome in patients undergoing surgery for medically refractory mesial temporal lobe epilepsy (MTLE).
Walz et al studied a population of 100 consecutive patients surgically treated for medication-resistant MTLE. These patients underwent resection of the anterior-lateral temporal pole on the epileptogenic side to a maximum of 4-5 cm posteriorly, further allowing access to removal of mesial temporal structures up to 3 cm back. One hundred and eighty control individuals, without a history of neurologic or psychiatric disease, were also included. DNA samples were obtained, and 4 PRNP polymorphic alleles, occurring at different frequencies, were identified among the cases. Among these, a heterozygous genotype (Asn/Ser) involving an asparagine to serine substitution at codon 171 (Asn171Ser) was found among the epilepsy cases. This genotype was present in 23 of the patients, compared to none of the controls (P < .0001). While the Asn/Ser genotype did not correlate with any of the demographic or presurgical data, the Asn171Ser allele was associated with a lower rate (68.2% vs 91.8% for Asn/Asn) of seizure freedom at 18 months postoperative follow-up (P = .005).
PrPc is a glycoprotein expressed on the cell surface of neurons, including synapses. Its normal function is unknown, but it is clear that certain allelic variants create protease-resistant forms that lead to the prion diseases: Creutzfeldt-Jakob disease (sporadic, iatrogenic, and variant), kuru, fatal familial insomnia, etc. Two important preclinical observations motivated the current study investigating the possible association of PRNP polymorphisms with MTLE: 1) PRNP knockout mice appear to have enhanced sensitivity to developing seizures;1 and 2) hippocampal slices prepared from these animals demonstrate neuronal hyperexcitability.2
As suggested by the accompanying editorial by Mastrianni and Roos, the human data need to be interpreted with caution, specifically relating to population sampling (eg, inadequate sample sizes or sample populations that have different ethnic origins or skewed genetic backgrounds). While Walz et al indicate that the ethnic backgrounds of patient and control groups were similar, it is still critical to replicate their findings among different ethnic groups.
The current report shows the promise of using a different level of genetic study for non-Mendelian presumably multigenic diseases, such as epilepsy. Older methods are certainly complementary, such as linkage analysis, coupled with looking for candidate genes located close to associated polymorphisms. These studies, however, require large pedigrees of affected individuals surrounding an index case. On the other hand, Walz et al’s analysis allows us to look at broader populations of affected individuals. While not used in the current study, microarray analysis will also allow screening larger samples of candidate genes. While patient populations studied in this way may be more phenotypically heterogeneous, this may provide a subtle benefit in allowing investigators to begin to tease out the different contributions of nature vs nurture that can account for the fact. For example, the Asn171Ser allele leads to 68.2% surgical cure rather than complete surgical failure. — Andy Dean, Assistant Professor of Neurology and Neuroscience; Director of the Epilepsy Monitoring Unit, Department of Neurology, New York Presbyterian Hospital Cornell Campus; Assistant Editor, Neurology Alert.
1. Walz R, et al. Epilepsia. 1999;40:1679-1682.
2. Mallucci GR, et al. EMBO J. 2002;21:202-210.