Robert E. Shapiro

Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome

Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening. It was the first human, mendelian circadian rhythm variant to be well-characterized, and was shown to result from a mutation in a phosphorylation site within the casein kinase I (CKI)-binding domain of the human PER2 gene. To gain a deeper understanding of the mechanisms of circadian rhythm regulation in humans, we set out to identify mutations in human subjects leading to FASPS. We report here the identification of a missense mutation (T44A) in the human CKIδ gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKIδ-T44A gene showed a phenotype with lengthened circadian period. In contrast, transgenic mice carrying the same mutation have a shorter circadian period, a phenotype mimicking human FASPS. These results show that CKIδ is a central component in the mammalian clock, and suggest that mammalian and fly clocks might have different regulatory mechanisms despite the highly conserved nature of their individual components.

Connexin 43 (GJA1) Mutations Cause the Pleiotropic Phenotype of Oculodentodigital Dysplasia

Gap junctions are assemblies of intercellular channels that regulate a variety of physiologic and developmental processes through the exchange of small ions and signaling molecules. These channels consist of connexin family proteins that allow for diversity of channel composition and conductance properties. The human connexin 43 gene, or GJA1, is located at human chromosome 6q22-q23 within the candidate region for the oculodentodigital dysplasia locus. This autosomal dominant syndrome presents with craniofacial (ocular, nasal, and dental) and limb dysmorphisms, spastic paraplegia, and neurodegeneration. Syndactyly type III and conductive deafness can occur in some cases, and cardiac abnormalities are observed in rare instances. We found mutations in the GJA1 gene in all 17 families with oculodentodigital dysplasia that we screened. Sixteen different missense mutations and one codon duplication were detected. These mutations may cause misassembly of channels or alter channel conduction properties. Expression patterns and phenotypic features of gja1 animal mutants, reported elsewhere, are compatible with the pleiotropic clinical presentation of oculodentodigital dysplasia.

Randomized, controlled trial of telcagepant for the acute treatment of migraine

Background: The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In this large phase 3 clinical trial, we sought to confirm the efficacy of telcagepant, the first orally bioavailable CGRP receptor antagonist. Methods: Adults with migraine with or without aura (International Headache Society criteria) treated a moderate or severe attack with oral telcagepant 50 mg (n = 177), 150 mg (n = 381), 300 mg (n = 371), or placebo (n = 365) in a randomized, double-blind trial. The 5 co-primary endpoints were pain freedom, pain relief, and absence of photophobia, absence of phonophobia, and absence of nausea, all at 2 hours postdose. The key secondary endpoint was 2–24 hour sustained pain freedom. The prespecified primary efficacy analyses evaluated the 150 mg and 300 mg groups; the 50-mg group was included on an exploratory basis to further characterize the dose response but was not prespecified for analysis. Tolerability was assessed by adverse experience reports. Results: Telcagepant 300 mg was more effective (p ≤ 0.001) than placebo on all primary endpoints and the key secondary endpoint, as was telcagepant 150 mg (p ≤ 0.05). Telcagepant 300 mg showed a slight numeric advantage over telcagepant 150 mg on most measures. Telcagepant 50 mg values were numerically intermediate between placebo and telcagepant 150 mg and 300 mg. The percentages of patients with adverse experiences were 32.2% for telcagepant 50 mg, 32.0% for telcagepant 150 mg, 36.2% for telcagepant 300 mg, and 32.2% for placebo. Conclusions: This study confirmed previous findings that telcagepant 300 mg was effective at relieving pain and other migraine symptoms at 2 hours and providing sustained pain freedom up to 24 hours. In this study, telcagepant 150 mg was also effective. Telcagepant was generally well tolerated.

Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase

Mutations in casein kinase Iδ that are associated with migraine in patients cause changes in enzymatic function, pain behavior, cortical excitability, and astrocyte signaling in mice. The Pain of Sleep If you have experienced the excruciating pain of a migraine, chances are that some of your relatives have too. Despite this clear heritability, the genes that transfer this disease from generation to generation are known for only a few specialized types of migraine. While studying families with a sleep disorder called familial advanced sleep phase syndrome, Brennan et al. may have found another one of these genes. They discovered that mutations in a gene (casein kinase Iδ) that cause the sleep problems also seemed to cause migraine. In two families, everyone who carried the sleep-disrupting casein kinase Iδ mutation (each family had a slightly different mutation) also suffered from migraines, although there were several members who had migraines but not the mutation or the sleep disorder. To see whether the casein kinase mutation might really be contributing to migraine, the authors took their experiments in vitro and into mice. In a test of whether the two mutations affected casein kinase Iδ enzyme activity, the authors found that neither mutated form of casein kinase Iδ was able to properly phosphorylate its substrate. But does this weakened enzyme activity cause headaches? To see, the authors generated mice carrying mutated casein kinase Iδ. Because migraine is a pain syndrome, patients’ reports of their pain are important for characterizing the disease. Although mice cannot tell us if they hurt, the authors found some mouse phenotypes that suggest they are experiencing a migraine-like disorder: When treated with nitroglycerin (a migraine trigger), the mice were more sensitive to pain, just as humans are. The mice also more easily exhibited cortical spreading depression (a wave of ionic disturbance thought to be similar to migraine aura), and their arteries were abnormally dilated during the spreading depression—both phenomena similar to those seen during migraine in humans. The suggestive segregation of the casein kinase mutations in migraine patients and the ability of the same mutations to produce migraine-like phenomena in mice together make a strong case that casein kinase mutations can contribute to migraine, adding another gene to the small list associated with this debilitating headache syndrome. Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine.

Drug-induced serotonin syndrome: a review

Serotonin syndrome, or serotonin toxicity (ST), is a clinical condition that occurs as a result of an iatrogenic drug-induced increase in intrasynaptic serotonin levels primarily resulting in activation of serotonin2A receptors in the central nervous system. The severity of symptoms spans a spectrum of toxicity that correlates with the intrasynaptic serotonin concentration. Although numerous drugs have been implicated in ST, life-threatening cases generally occur only when monoamine oxidase inhibitors are combined with either selective or nonselective serotonin re-uptake inhibitors. The triad of clinical features consists of neuromuscular hyperactivity, autonomic hyperactivity and altered mental status, which may present abruptly and progress rapidly. The awareness of ST is crucial not only in avoiding the unintentional lethal combination of therapeutic drugs but also in recognizing the clinical picture when it occurs so that treatment can be promptly initiated. In this review, the pathophysiology, clinical features, implicated drugs, diagnosis and treatment of ST are discussed.

The FDA Alert on Serotonin Syndrome With Use of Triptans Combined With Selective Serotonin Reuptake Inhibitors or Selective Serotonin-Norepinephrine Reuptake Inhibitors: American Headache Society Position Paper

(Headache 2010;50:1089‐1099)

The Serotonin Syndrome, Triptans, and the Potential for Drug–Drug Interactions

The serotonin syndrome is an acute adverse reaction to medications that enhance serotonergic activity. The severity of cases ranges from mild to fatal. Recently, the U.S. Food and Drug Administration issued an alert that the risk of developing serotonin syndrome may be increased by the concomitant administration of triptan medications with certain other medications. However, a review of published data does not allow an accurate assessment of such risks related to triptans. We conclude that it is currently unclear whether administration of triptans with other serotonergic medications increases the risk of serotonin syndrome.

Migraine and mortality: A systematic review and meta-analysis

Objective: To evaluate the evidence on the association between migraine and mortality. Methods: Systematic review and meta-analysis of studies investigating the association between any migraine (all forms of migraine collectively) or migraine subtypes (e.g. migraine with aura) and mortality published until March 2011. Results: We identified ten cohort studies. Studies differed regarding the types of mortality investigated and only four presented aura-stratified results, limiting pooled analyses with regard to migraine subtypes and with regard to cause-specific mortality. For any migraine pooled analyses do not suggest an association with all-cause mortality (five studies; pooled relative risk (RR) = 0.90, 95% confidence interval (CI) 0.71–1.16), cardiovascular disease mortality (CVD; six studies; pooled RR = 1.09, 95% CI 0.89–1.32), or coronary heart disease mortality (CHD; three studies; pooled RR = 0.95, 95% CI 0.57–1.60). Heterogeneity among studies is moderate to high. Two studies suggest that migraine with aura increases risk for CVD and CHD mortality. Conclusion: This meta-analysis does not suggest that any migraine is associated with increased risk of mortality from all causes, CVD, or CHD. However, there is heterogeneity among studies and suggestion that migraine with aura increases CVD and CHD mortality. Given the high prevalence of migraine in the general population a definitive answer to the question of whether migraine or a subtype alters risk for mortality is of high public health importance and further targeted research implicated.

The Long Drought: The Dearth of Public Funding for Headache Research

Headache disorders are the most prevalent of neurological conditions, and migraine is the most prevalent disabling neurological condition (1). Migraine affects 12% and chronic daily headache 4% of Europeans and Americans (2, 3); these disorders also predominantly afflict women during their peak years of productivity. Headache disorders account for ~9% of total lost labour productivity (>r20 billion) (4, 5) and ~1% of total disability (6) in the United States annually. Severe migraine attacks are classified by the World Health Organization as among the most disabling illnesses, comparable to dementia, quadriplegia and active psychosis (7). Given the high global prevalence, enormous societal costs and substantial disability and suffering, one might assume that the alleviation of migraine and other headache disorders would be a major priority for the public research agencies of developed nations. Unfortunately, nothing could be further from the truth. In this issue of Cephalalgia, Olesen and coworkers (8) quantify for the first time the neglect of migraine among European public research funding agencies. Their data are stark: migraine is the least publicly funded of all neurological illnesses relative to its economic impact. Moreover, these authors found that anxiety and affective disorders, two of the most prevalent categories of disorders comorbid with migraine, rank nearly as low as migraine in European public research funding priorities relative to economic impact. The cumulative effect of these funding decisions is to deny migraineurs the promise of research developments to change the courses of their illnesses. The lack of public research support for migraine is not limited to European grant-giving agencies. The problem is equally profound in the USA. Although the precise dollar amounts of migrainerelated National Institutes of Health (NIH) research grants have not been reported, the Computer Retrieval of Information on Scientific Projects (CRISP) database of US federally funded biomedical research projects can be used to infer abysmal funding levels. CRISP includes a document for every year of every federally funded (mostly NIH) biomedical research grant. Analysis of the relative number of CRISP documents for prevalent chronic disorders provides an approximation of the relative weight of US federal funding for each disorder. The results are striking (Figure 1 and Table 1). A comparison of the number of CRISP documents (9) with actual NIH funding levels (10) for several disorders leads to an estimate of the mean annual federal funding for migraine research at ~r13M. This sum comprises <0.05% of the total current NIH budget of ~r28B. By comparison, ~21 times more NIH research funding is devoted to

Peripheral Autonomic Nervous System

Publisher Summary This chapter focuses on the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) as the first two aspects of the peripheral autonomic nervous system (ANS). The SNS is organized at a spinal and peripheral level such that cell bodies within the thoracolumbar segments of the spinal cord provide preganglionic efferent innervation to sympathetic neurons. Prevertebral ganglia are midline structures located anterior to the aorta and vertebral column, and are represented by the celiac ganglia, aortic–renal ganglia, and the superior and inferior mesenteric ganglia. The spinal cells of origin for the presynaptic input to sympathetic peripheral ganglia are located from the first thoracic to the second lumbar level of the cord, although minor variations exist. The postganglionic fibers in the SNS travel quite lengthy paths to arrive at target organs. For instance, fibers from the SCG traverse the extracranial and intracranial vasculature to reach such targets as the lacrimal glands, parotid glands, pineal gland, and pupils. Interactions between the adrenal cortex and adrenal medulla constitute a critical link between the autonomic and endocrine systems.