Eva Andermann

Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy An MRI volumetric study

We performed MRI volumetric measurements of the amygdala (AM) and hippocampal formation (HF) in a group of 43 patients with temporal lobe epilepsy not controlled by optimal drug treatment. Fifteen patients (35%) had a history of prolonged febrile convulsions (PFC) in early childhood; 30 patients underwent surgery, and histopathology was available in twenty-four. The mean values of AM and HF volumes ipsilateral to the EEG focus were significantly smaller than those of normal controls. The volumetric measurements showed a more pronounced atrophy of the AM in patients with a history of PFC, although the HF volumes were also smaller in this group. Patients with a history of PFC had a higher proportion of more severe mesial temporal sclerosis (MTS) compared with those with no PFC. These findings confirm a correlation between early childhood PFC, the severity of atrophy of mesial structures, and MTS.

Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy

Laforas disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration. Onset occurs during late childhood and usually results in death within ten years of the first symptoms1,2. With few exceptions, patients follow a homogeneous clinical course despite the existence of genetic heterogeneity 3. Biopsy of various tissues, including brain, revealed characteristic polyglucosan inclusions called Lafora bodies4–8, which suggested LD might be a generalized storage disease6,9. Using a positional cloning approach, we have identified at chromosome 6q24 a novel gene, EPM2A, that encodes a protein with consensus amino acid sequence indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing alternatively spliced forms of EPM2A were found in every tissue examined, including brain. Six distinct DNA sequence variations in EPM2A in nine families, and one homozygous microdeletion in another family, have been found to cosegregate with LD. These mutations are predicted to cause deleterious effects in the putative protein product, named laforin, resulting in LD.

Congenital malformations due to antiepileptic drugs

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.

Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder

We describe a distinctive epilepsy syndrome in six families, which is the first partial epilepsy syndrome to follow single gene inheritance. The predominant seizure pattern had frontal lobe seizure semiology with clusters of brief motor attacks occurring in sleep. Onset was usually in childhood, often persisting through adult life. Misdiagnosis as night terrors, nightmares, hysteria, or paroxysmal nocturnal dystonia was common, and the inheritance pattern was often not appreciated. This autosomal dominant epilepsy syndrome is ideal for identification of partial epilepsy genes.

Sodium-channel defects in benign familial neonatal-infantile seizures

Ion-channel gene defects are associated with a range of paroxysmal disorders, including several monogenic epilepsy syndromes. Two autosomal dominant disorders present in the first year of life: benign familial neonatal seizures, which is associated with potassium-channel gene defects; and benign familial infantile seizures, for which no genes have been identified. Here, we describe a clinically intermediate variant, benign familial neonatal-infantile seizures, with mutations in the sodium-channel subunit gene SCN2A. This clinico-molecular correlation defines a new benign familial epilepsy syndrome beginning in early infancy, an age at which seizure disorders frequently have a sombre prognosis.

Concepts of absence epilepsies Discrete syndromes or biological continuum

There are two current approaches to the clinical conceptualization of the generalized epilepsies. The syndromic approach attempts to subdivide the patient population into relatively homogeneous groups, largely on the basis of clinical and EEG criteria. In contrast, the neurobiological approach aims to formulate a unique profile for each patient by incorporating particulars of the patient onto the background of knowledge regarding the etiologic factors important in generalized epilepsy. The value of these two approaches is discussed with regard to the dual aims of, first, improving the understanding of generalized epilepsy, and second, providing a precise diagnosis, an accurate prognosis, and optimal treatment for the patient.

Mutations in NHLRC1 cause progressive myoclonus epilepsy

Lafora progressive myoclonus epilepsy is characterized by pathognomonic endoplasmic reticulum (ER)-associated polyglucosan accumulations. We previously discovered that mutations in EPM2A cause Lafora disease. Here, we identify a second gene associated with this disease, NHLRC1 (also called EPM2B), which encodes malin, a putative E3 ubiquitin ligase with a RING finger domain and six NHL motifs. Laforin and malin colocalize to the ER, suggesting they operate in a related pathway protecting against polyglucosan accumulation and epilepsy.

X-linked malformations of neuronal migration

Malformations of neuronal migration such as lissencephaly (agyria-pachygyria spectrum) are wellknown causes of mental retardation and epilepsy that are often genetic. For example, isolated lissencephaly sequence and Miller-Dieker syndrome are caused by deletions involving a lissencephaly gene in chromosome 17p13.3, while many other malformation syndromes have autosomal recessive inheritance. In this paper, we review evidence supporting the existence of two distinct X-linked malformations of neuronal migration. X-linked lissencephaly and subcortical band heterotopia (XLIS) presents with sporadic or familial mental retardation and epilepsy. The brain malformation varies from classical lissencephaly, which is observed in males, to subcortical band heterotopia, which is observed primarily in females. The XLIS gene is located in chromosome Xq22.3 based on the breakpoint of an X-autosomal translocation. Bilateral periventricular nodular heterotopia (BPNH) usually presents with sporadic or familial epilepsy with normal intelligence, primarily in females, although we have evaluated two boys with BPNH and severe mental retardation. The gene for BPNH has been mapped to chromosome Xq28 based on linkage studies in multiplex families and observation of a subtle structural abnormality in one of the boys with BPNH and severe mental retardation. NEUROLOGY 1996;47: 331-339

Autosomal Dominant Nocturnal Frontal-Lobe Epilepsy: Genetic Heterogeneity and Evidence for a Second Locus at 15q24

Autosomal dominant nocturnal frontal-lobe epilepsy (ADNFLE) is a recently identified partial epilepsy in which two different mutations have been described in the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4). An additional seven families are presented in which ADNFLE is unlinked to the CHRNA4 region on chromosome 20q13.2. Seven additional sporadic cases showed no evidence of defective CHRNA4. One of the families showed evidence of linkage to 15q24, close to the CHRNA3/CHRNA5/CHRNB4 cluster (maximum LOD score of 3.01 with D15S152). Recombination between ADNFLE and CHRNA4, linkage to 15q24 in one family, and exclusion from 15q24 and 20q13.2 in others demonstrate genetic heterogeneity with at least three different genes for ADNFLE. The CHRNA4 gene and the two known CHRNA4 mutations are responsible for only a minority of ADNFLE. Although the ADNFLE phenotype is clinically homogeneous, there appear to be a variety of molecular defects responsible for this disorder, which will provide a challenge to the understanding of the basic mechanism of epileptogenesis.

Severe Myoclonic Epilepsy of Infancy: Extended Spectrum of GEFS+?

Summary:  Purpose: Severe myoclonic epilepsy of infancy (SMEI) is an intractable epilepsy of early childhood of unknown etiology. It is often associated with a family history of seizure disorders, but epilepsy phenotypes have not been well described. We sought to characterize the seizure phenotypes of relatives to better understand to the genetic basis of SMEI.