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Gambardella et al. report a genetic association between nonlesional temporal lobe epilepsy (TLE) and a missense (G1465A) polymorphism in the GABA (B) receptor gene. Moreover, patients carrying the GABA (B) G1465A polymorphism are also reported to have an increased odds of developing drug refractory TLE.
see page 560
GABA receptors and refractory temporal lobe epilepsy
Commentary from Michael R. Johnson
New antiepileptic drug development will be made possible by better understanding of molecular mechanisms underlying epilepsy. Genetic influences on 
-aminobutyric acid (GABA) are likely to be of importance. The report from Gambardella et al. in this issue of Neurology provides novel evidence concerning a GABA receptor and temporal lobe epilepsy. The neuronal response to GABA has two phases. Inotropic (GABAA) receptors produce a rapid, chloride-mediated postsynaptic membrane hyperpolarization. Metabotropic (GABAB) receptors generate a long lasting, G-protein–mediated, inhibitory hyperpolarization of postsynaptic membranes as well as inhibition of neurotransmitter release from presynaptic terminals. The GABAA receptor is a heteromeric complex of subunits including 
1-6, ß13-3, 13, 
, and 
.1 GABAB receptors comprise a heterodimer of GABABR1 and GABABR2 subunits, with R1 providing the binding domain and R2 responsible for second messenger processing.2 A central role for GABAA receptors in epilepsy, long suspected from pharmacologic studies, was firmly established with the identification of mutations in 2(GABRG2) and 1 (GABRA1) subunits in familial generalized epilepsy.3-5 Despite a series of pharmacologic studies in animal models suggesting that GABAB receptors play a critical role in the genesis of spike wave discharges, clear evidence for a role of the GABAB receptor in human epilepsy has been lacking. The Gambardella et al. report of an association between a polymorphism in the GABABR1 subunit gene (GABBR1) and temporal lobe epilepsy (TLE) is therefore important, not least because the association is, surprisingly, with partial and not generalized epilepsy. In a study population of 141 mostly MRI negative TLE patients (with some patients having MRI evidence for hippocampal sclerosis), a GABABR1 polymorphism was associated with an impressive risk for TLE. A second intriguing observation was that the polymorphism is associated with a significantly higher risk of drug-refractory epilepsy. These important findings suggest GABAB-mediated genetic mechanisms contribute increased risk for epilepsy and offer a new insight into genetic mechanisms of poor epilepsy outcome.
References
1. Mehta AK, Ticku MK. An update on GABAA receptors. Brain Res Rev 1999;29:196–217.
2. Jones KA, Borowsky B, Tamm JA, et al. GABAB receptors function as a heterodimeric assembly of subunits GABABR1 and GABABR2. Nature 1998;396:674–679.
3. Baulac S, Huberfield G, Gourfinkel A, et al. First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the 2-subunit gene. Nat Genet 2001;28:46–48.
4. Wallace RH, Marini C, Petrou S, et al. Mutant GABAA receptor 2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet 2001;28:49–52.
5. Cossette P, Liu L, Brisebois K, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 2002;31:184–189.
Major fetal malformations in pregnant women with epilepsy
In a prospective follow-up study of 970 pregnancies in women with epilepsy, Kaaja et al. noted major malformations in 3.8% exposed to maternal AEDs and only 0.8% in those not exposed. Carbamazepine, valproate, and oxcarbazepine well as low serum folate concentrations were all associated with major malformation.
see page 575
Variability of phenytoin in elderly nursing home residents
Birnbaum et al. studied total phenytoin levels obtained while subjects remained on the same phenytoin dose. They followed 56 elderly residents residing in nursing homes across the US and found levels varied as much as two to threefold. This variability suggests that phenytoin levels alone should not be used to guide treatment.
see page 555
The accompanying editorial by Lesser and Sundaram points out that while drug levels are of particular value in detecting noncompliance, there is a large number of defined variables that produce changes in drug levels. However, the two- to threefold variation in the Birnbaum study are unexplained (noncompliance being unlikely in their population). Whatever the reason, the results imply that drug levels are not useful to guide dosage adjustments except in well-defined situations such as pregnancy, where predictable changes are anticipated.
see page 534
Sporadic hemiplegic migraine
Thomsen et al. identified 105 persons with migraine with aura that included motor weakness without a family history. These persons had symptoms identical to familial hemiplegic migraine and different from migraine with typical aura and are classified as a separate entity termed sporadic hemiplegic migraine.
see page 595
The accompanying editorial by Peter Goadsby notes that this large series of patients in whom major motor symptoms proved to be related to migraine provides important data for the clinician confronted with a patient with acute symptoms. Rapid onset and duration <60 minutes point to migraine, but even longer duration symptoms can occur.
see page 536
Dietary factors in AD and PD
In a "Medical Hypothesis" review of studies of human populations and animal models, Mark Mattson notes that high-calorie diets and diets that increase homocysteine levels increase the risk of AD and PD. Low-calorie diets may reduce disease risk by stimulating the production of neurotrophic factors and stress proteins, while dietary folate lowers homocysteine levels and decreases DNA damage in neurons.
see page 690
Randomized controlled trial of pergolide for tics
Gilbert et al. randomized 56 children and adolescents with Tourette’s syndrome or chronic motor tics to pergolide or placebo. Pergolide reduced tics and ADHD symptoms without causing weight gain or sedation. These results corroborate those obtained in smaller studies of dopaminergic medications for tic suppression.
see page 606
Pneumonia complicating acute stroke
Katzan et al. found that after adjustment for severity of illness and other patient factors, pneumonia conferred a threefold increase risk of 30-day mortality in patients hospitalized for acute stroke.
see page 620
Intranasal sumatriptan is effective in cluster headache
In a placebo-controlled, multicenter study, van Vliet et al. demonstrated that sumatriptan 20 mg nasal spray is effective within 30 minutes in the treatment of acute cluster headache. The study adds a further evidence-based option to the treatment of this disabling headache.
see page 630
Neutralizing antibodies (NABs) effect on IFNß bioavailability
Bertolotto et al. studied the effect of NABs on IFNß bioavailability by MxA mRNA quantification. MxA mRNA increases 11-fold from basal level in NAB-negative patients, whereas MxA mRNA was not increased in NAB-positive patients. NABs abolish IFNß bioavailability.
see page 634
Weekly MRI of new brain lesions in relapsing-remitting MS
Cotton et al. performed weekly MRI studies of 113 new enhancing MS lesions. Over 50% enhanced for only 2 weeks or less. Early lesion growth may predict final lesion size. Within-patient heterogeneity of lesion evolution suggests that individual lesions develop independently from each other.
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see page 640
Clinical findings of myotonic dystrophy type 2
Myotonic dystrophy type 2 (DM2) results from a CCTG repeat expansion in intron 1 of the zinc finger protein 9 gene. Here, the authors who identified the gene lesion, Day et al., describe the clinical features of 133 families confirmed to have DM2 by an improved molecular diagnostic method. Clinical features mirror adult-onset DM1, with myotonia, muscular dystrophy, cataracts, and endocrine and cardiac involvement.
see page 657
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