Proposed genetic classification of the “benign” familial neonatal and infantile epilepsies
Version of Record online: 11 MAR 2011
© 2011 International League Against Epilepsy
Volume 52, Issue 3, pages 649–650, March 2011
How to Cite
Mulley, J. C., Heron, S. E. and Dibbens, L. M. (2011), Proposed genetic classification of the “benign” familial neonatal and infantile epilepsies. Epilepsia, 52: 649–650. doi: 10.1111/j.1528-1167.2010.02953.x
- Issue online: 11 MAR 2011
- Version of Record online: 11 MAR 2011
The revised International League Against Epilepsy (ILAE) classification and terminology (Berg et al., 2010) acknowledges that the classification of epilepsy has historically rested on “astute observations and expert opinions,” and that in the future “advances being made in basic and clinical neurosciences” need to be incorporated. Benign familial neonatal epilepsy (BFNE) (Rett & Teubel, 1964), benign familial neonatal infantile epilepsy (BFNIE) (Kaplan & Lacey, 1983; Heron et al., 2002), and benign familial infantile epilepsy (BFIE) (Vigevano et al., 1992) are three clinical entities. Berg et al. (2010) recommended that BFNS (BFNC in earlier days) be renamed benign familial neonatal epilepsy (BFNE), that BFNIS be renamed benign familial neonatal infantile epilepsy (BFNIE), and that BFIS (BFIC in earlier days) be renamed benign familial infantile epilepsy (BFIE). Henceforth, in this discussion BFNS, BFNIS, and BFIS will be referred to as BFNE, BFNIE, and BFIE, respectively, distinguished by ascending average ages of seizure onset (mean age at onset of 2–3 days; 11 weeks; and 6 months, respectively) but with overlapping distributions of seizure age at onset (1 day to 6 months; 3 days to 6 months; and 2–20 months, respectively) (Berkovic et al., 2004; Herlenius et al., 2007). These overlapping phenotypic ranges are subject to expansion as additional patients with “atypical” BFNE and BFIE are delineated on the basis of confirmed mutations in known genes. When relying for classification on clinical features alone, the phenotypic overlap between patients blur the boundaries between these syndromes—despite unambiguous syndrome demarcation provided by different average age of seizure onsets determined from families that have been validated molecularly.
A molecular-based classification provides the framework for assessing the extended range of phenotypic variations associated with each syndrome, leading to a more complete clinical picture for these disorders and the prospect of exactness into the diagnosis of these syndromes. The overlapping ages at onset for the BFNE–BFNIE–BFIE cluster make it clear that objective classification for many of the presenting cases cannot be achieved through clinical evaluation alone. Accuracy without the application of genetic testing may be achieved, but only for large families with many affected individuals. Affected family members in mutation-positive families can be skewed in their clinical manifestations, providing biased clinical data. Isolated cases and small families may display only a small sample of the potential clinical variability associated with a given mutation and so provide misleading impressions. Moreover, different mutations in the same gene can vary in expressivity between families due to the position of the mutation affecting different functional domains of the protein. Even the identical mutation segregating in the same family or across different families can vary in phenotypic expressivity due to the effects of unidentified modifier loci. Total objectivity in clinical diagnosis can be achieved only by detection of mutations in the known genes: KCNQ2 and KCNQ3 for BFNE and SCN2A for BFNIE. There are as yet no known genes identified for BFIE. Observational assessment is entirely appropriate where the features observed can relate to only one recognized syndrome. When the observations can apply to more than one syndrome, then differential diagnosis is needed and clinical observation will direct the molecular laboratory to the most appropriate genetic testing regimen to minimize the time and expense for detection of the pathogenic mutation. Currently, sequencing of either the potassium channel subunit genes KCNQ2 and KCNQ3 and/or the sodium channel gene SCN2A provides clear molecular discrimination. Directed testing for separating the neonatal and the infantile epilepsies will be extended once the genes for what is currently referred to as BFIE are identified.
The patient–clinician interaction requires that patients and families formerly diagnosed as BFNE, BFNIE, and BFIE be grouped into a single group broad enough so that there can be no mistake as to their assignment when based on clinical observation alone (so as to avoid the use of technical terms that do not have meaning to the patients). We suggest that they could all be referred to as benign familial infantile epilepsy (BFIE), since that is a syndrome name already in widespread use and is not yet associated with a specific gene. The clinician–scientist interaction requires that the BFIE nomenclature (or an alternative if one can be devised that is more appropriate) could be molecularly refined to reflect the exact BFIE subsyndrome—for example, by addition of a suffix: namely, BFIE:KCNQ2, BFIE:KCNQ3, and BFIE:SCN2A if or when genetic tests are carried out. Such refinement is only needed for medical or research records where knowledge of the gene may direct treatment and prognosis. Therefore, for specificity and simplicity, two levels of nomenclature tailored to the situation would seem appropriate.
Distinction of subcategories no longer needs to rely on “astute observations and expert opinions” alone. Knowledge of the gene involved can have clinical and genetic counseling ramifications; 15% of patients with KCNQ2 mutations go on to develop seizures in later life (Scheffer et al., 2005), whereas patients with KCNQ3 and SCN2A mutations go on to normal development beyond infancy.
The recent ILAE classification and terminology report (Berg et al., 2010) sets the stage for the inclusion of genetic information in diagnosis. Indeed, inclusion of laboratory data to improve diagnostic accuracy is compatible with the recent ILAE concept of recognizing “genetic epilepsies” as a distinct group encompassing many syndromes previously referred to as “idiopathic.” Genetic testing is a legitimate adjunct to clinical diagnosis for the epilepsies, in the same way that electroencephalography (EEG) and imaging have been widely used. Genetic testing has been established in other areas of clinical genetics. The next step for the epilepsies is greater acceptance and more widespread application of genetic testing as an adjunct to syndrome description and clinical workup in situations in which knowledge of the defective gene can be useful for prognosis and patient management. The nomenclature style proposed for BFIE is sufficiently versatile for extension to similar situations in which causative genes have also been identified, such as for progressive myoclonus epilepsy (PME:SCARB2, PME:PRICKLE1) and genetic epilepsy with febrile seizures plus (GEFS+:SCN1A, GEFS+:SCN1B or GEFS+:GABRG2).
We thank the National Health and Medical Research Council of Australia, SA Pathology, MS McLeod Trustees, and Thyne-Reid Charitable Trusts for support and Professor Samuel F. Berkovic for critical comments and suggestions on the manuscript.
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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