PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine.

OBJECTIVE: Whole genome sequencing and the screening of 103 families recently led us to identify PRRT2 (proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKD/IC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKD/IC or PKD/IC with migraine. METHODS: We performed Sanger sequencing of all PRRT2 coding exons and of exon-intron boundaries in the probands and in their relatives whenever appropriate. RESULTS: Two known and 2 novel PRRT2 mutations were detected in 18 families. The p.R217Pfs*8 recurrent mutation was found in ≈50% of typical PKD/IC, and the unreported p.R145Gfs*31 in one more typical family. PRRT2 mutations were also found in PKD/IC with migraine: p.R217Pfs*8 cosegregated with PKD associated with HM in one family, and was also detected in one IC patient having migraine with aura, in related PKD/IC familial patients having migraine without aura, and in one sporadic migraineur with abnormal MRI. Previously reported p.R240X was found in one patient with PKD with migraine without aura. The novel frameshift p.S248Afs*65 was identified in a PKD/IC family member with IC and migraine with aura. CONCLUSIONS: We extend the spectrum of PRRT2 mutations and phenotypes to HM and to other types of migraine in the context of PKD/IC, and emphasize the phenotypic pleiotropy seen in patients with PRRT2 mutationsjournal articleresearch support, non-u.s. gov't2012 Nov 202012 10 17importedComment in : Paroxysmal disorders associated with PRRT2 mutations shake up expectations on ion channel genes. [Neurology. 2012

Applying response surface methodology to optimize nimesulide permeation from topical formulation

Nimesulide is a non-steroidal anti-inflammatory drug that acts through selective inhibition of COX-2 enzyme. Poor bioavailability of this drug may leads to local toxicity at the site of aggregation and hinders reaching desired therapeutic effects. This study aimed at formulating and optimizing topically applied lotions of nimesulide using an experimental design approach, namely response surface methodology. The formulated lotions were evaluated for pH, viscosity, spreadability, homogeneity and in vitro permeation studies through rabbit skin using Franz diffusion cells. Data were fitted to linear, quadratic and cubic models and best fit model was selected to investigate the influence of permeation enhancers, namely propylene glycol and polyethylene glycol on percutaneous absorption of nimesulide from lotion formulations. The best fit quadratic model explained that the enhancer combination at equal levels significantly increased the flux and permeability coefficient. The model was validated by comparing the permeation profile of optimized formulations’ predicted and experimental response values, thus, endorsing the prognostic ability of response surface methodology

Clinic–based study of family history of vascular risk factors and migraine

The objective was to evaluate the presence of a positive family history (FH) of vascular risk factors between patients with migraine with aura (MA) and migraine without aura (MO), and in chronic migraine (CM) compared to other headache types. As migraine patients are typically too young to have developed vascular events, studying older relatives of migraine patients may be a practical means of evaluating associations between vascular risk factors and migraine. A cross-sectional study of a clinic-based sample of adults with migraine headache was carried out at the University of Utah. Predictor variables comprised first or second degree relatives with stroke, hypertension, diabetes or hypercholesterolaemia. Outcome measures comprised diagnosis of MA, MO or CM according to the revised International Headache Society criteria. There was no significant difference in FH of vascular risk factors in MA compared to MO (adjusted OR 1.04, 95% CI 0.61-1.78). CM was associated with a decreased risk of FH of stroke (OR=0.11, 95% CI 0.02-0.87, p=0.036). There was no significant difference in FH of vascular risk factors in MA patients compared to MO. CM patients were more likely to have a negative FH of stroke compared to other headache types, suggesting that CM is likely a neuronal disease rather than a vascular one

Genotype-phenotype correlations of DHP receptor alpha 1-subunit gene mutations causing hypokalemic periodic paralysis

Hypokalemic periodic paralysis (hypoKPP) is an autosomal dominant or sporadic disorder characterized by periodic, reversible attacks of muscle weakness. Mutations in the skeletal muscle dihydropyridine receptor alpha 1-subunit that functions as a calcium channel (CACNL1A3) cause hypoKPP. We studied a group of 45 hypoKPP probands and demonstrated mutations in 30 of them. When compared with patients in whom CACNL1A3 mutations were not identified, those with mutations had an earlier age of onset and more often had a family history of hypoKPP. To date, three mutations have been identified. The R1239G mutation has only been found in one family. Of the 30 probands with recognized mutations, R528H accounted for 43% and R1239H was seen in 53%. Age of onset and potassium levels during attacks were lower in patients with the R1239H mutation than those with R528H. Cardiac dysrhythmias co-segregated with hypoKPP in one small kindred with the R528H mutation. No mutations were identified in exons of the gene encoding the S4 segments of domains one and three or the cytoplasmic loop between domains two and three. In addition to the 45 hypoKPP probands, an additional 11 probands with clinical variants of hypoKPP (three thyrotoxic hypoKPP and eight Andersen syndrome patients) were examined for CACNL1A3 mutations and none were found