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1.  Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype 
Neurology  2011;77(22):1960-1964.
Objectives:
Acetazolamide has been the most commonly used treatment for hypokalemic periodic paralysis since 1968. However, its mechanism of efficacy is not fully understood, and it is not known whether therapy response relates to genotype. We undertook a clinical and genetic study to evaluate the response rate of patients treated with acetazolamide and to investigate possible correlations between response and genotype.
Methods:
We identified a total of 74 genotyped patients for this study. These included patients who were referred over a 15-year period to the only UK referral center or to a Chinese center and who underwent extensive clinical evaluation. For all genotyped patients, the response to acetazolamide therapy in terms of attack frequency and severity was documented. Direct DNA sequencing of CACNA1S and SCN4A was performed.
Results:
Only 46% of the total patient cohort (34 of 74) reported benefit from acetazolamide. There was a greater chance of benefit in patients with mutations in CACNA1S (31 responded of 55 total) than in those with mutations in SCN4A (3 responded of 19 total). Patients with mutations that resulted in amino acids being substituted by glycine in either gene were the least likely to report benefit.
Conclusions:
This retrospective study indicates that only approximately 50% of genotyped patients with hypokalemic periodic paralysis respond to acetazolamide. We found evidence supporting a relationship between genotype and treatment response. Prospective randomized controlled trials are required to further evaluate this relationship. Development of alternative therapies is required.
doi:10.1212/WNL.0b013e31823a0cb6
PMCID: PMC3235354  PMID: 22094484
2.  The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment 
Brain  2009;133(1):9-22.
The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.
doi:10.1093/brain/awp294
PMCID: PMC2801326  PMID: 19917643
ion channels; neuromuscular; genetics; EMG
4.  Private sector financing for medical education. 
Western Journal of Medicine  1984;141(5):687-688.
PMCID: PMC1011193  PMID: 6516345
5.  Decreased insulin sensitivity of forearm muscle in myotonic dystrophy. 
Journal of Clinical Investigation  1978;62(4):857-867.
Previous studies of patients with myotonic dystrophy have demonstrated hyperinsulinism after glucose loading. This hyperinsulinism has been attributed by some investigators to tissue insulin resistance. We have directly studied insulin sensitivity of forearm muscle in patients having such hyperinsulinism. The effect of an intrabrachial arterial insulin infusion (100 mu U/kg per min) on glucose uptake was determined in six cases of myotonic dystrophy, six normal subjects, and in seven disease control subjects with myotonia or wasting from other disorders. There was no significant difference in insulin tolerance comparing myotonic dystrophy patients to the normal and disease control groups. Glucose tolerance and basal insulin levels were normal in the myotonic dystrophy patients, but hyperinsulinism occurred after glucose ingestion. After 25 min of intra-arterial insulin, the mean peak muscle glucose uptake in myotonic dystrophy was 2.54 +/- 0.54 mu mol/min per 100 ml forearm compared to 5.24 +/- 0.86 mu mol/min per 100 ml for disease controls (P is less than 0.05). Myotonic dystrophy patients showed a peak glucose uptake increment of only 2.6 +/- 0.2-fold over basal contrasted with the disease control value of 6.5 +/- 1.0-fold (P is less than 0.02) and the normal control value of 8.8 +/- 1.1-fold (P is less than 0.01). Thus, there was an absolute as well as a relative decrease in muscle insulin sensitivity in myotonic dystrophy patients compared to both control groups. The peak increments in arterio-superficial venous glucose concentration differences after insulin infusion were not significantly different comparing myotonic dystrophy and control groups. These data suggest that in myotonic dystrophy, there is insulin insensitivity of skeletal muscle.
PMCID: PMC371838  PMID: 701484

Results 1-5 (5)