OBJECTIVE Our objective was to study the long-term prognosis of sporadic hemiplegic migraine (SHM). METHODS We performed a longitudinal follow-up study in 18 patients who were diagnosed with SHM... Show moreOBJECTIVE Our objective was to study the long-term prognosis of sporadic hemiplegic migraine (SHM). METHODS We performed a longitudinal follow-up study in 18 patients who were diagnosed with SHM between 1993 and 1996. Follow-up time between the first and second survey ranged from nine to 14 years. These patients were included as part of a genetic study in which we systematically analysed the role of the three known familial hemiplegic migraine (FHM) genes. RESULTS In 12 out of 18 patients the clinical diagnosis was unchanged. In two of the six remaining patients the attacks were no longer associated with hemiplegia; one of them had an ATP1A2 gene mutation (E120A). In the four other patients, the diagnosis changed into FHM, because a family member had developed hemiplegic migraine since the initial diagnosis was made. In two of the four patients a mutation was demonstrated (CACNA1A [R583Q] and ATP1A2 [R834X]). CONCLUSION This study shows that the diagnosis of SHM changes into FHM in a considerable percentage of patients (22% [4 of 18]), almost a decade after the initial diagnosis. This indicates that a careful follow-up of SHM patients and their families is advisable for optimal care and counseling. Diagnostic screening of FHM genes in SHM patients can be of value. Our genetic and clinical follow-up studies reinforce the evidence that FHM and SHM are part of the same spectrum of migraine. Show less
Stam, A.H.; Louter, M.A.; Haan, J.; Vries, B. de; Maagdenberg, A.M.J.M. van den; Frants, R.R.; ... ; Terwindt, G.M. 2011
Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or... Show moreMigraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10(-9), odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(-11) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10(-5), permuted threshold for genome-wide significance 7.7 x 10(-5)). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine. Show less
The dynamics, computational power, and strength of neural circuits are essential for encoding and processing information in the CNS and rely on short and long forms of synaptic plasticity. In a... Show moreThe dynamics, computational power, and strength of neural circuits are essential for encoding and processing information in the CNS and rely on short and long forms of synaptic plasticity. In a model system, residual calcium (Ca2+) in presynaptic terminals can act through neuronal Ca2+ sensor proteins to cause Ca2+-dependent facilitation (CDF) of P/Q-type channels and induce short-term synaptic facilitation. However, whether this is a general mechanism of plasticity at intact central synapses and whether mutations associated with human disease affect this process have not been described to our knowledge. In this report, we find that, in both exogenous and native preparations, gain-of-function missense mutations underlying Familial Hemiplegic Migraine type 1 (FHM-1) occlude CDF of P/Q-type Ca2+ channels. In FHM-1 mutant mice, the alteration of P/Q-type channel CDF correlates with reduced short-term synaptic facilitation at cerebellar parallel fiber-to-Purkinje cell synapses. Two-photon imaging suggests that P/Q-type channels at parallel fiber terminals in FHM-1 mice are in a basally facilitated state. Overall, the results provide evidence that FHM-1 mutations directly affect both P/Q-type channel CDF and synaptic plasticity and that together likely contribute toward the pathophysiology underlying FHM-1. The findings also suggest that P/Q-type channel CDF is an important mechanism required for normal synaptic plasticity at a fast synapse in the mammalian CNS. Show less
Kaja, S.; Ven, R.C.G. van de; Broos, L.A.M.; Frants, R.R.; Ferrari, M.D.; Maagdenberg, A.M.J.M. van den; Plomp, J.J. 2010
Kaja S, Van de Ven RCG, Broos LAM, Frants RR, Ferrari MD, Van den Maagdenberg AMJM, Plomp JJ. Severe and progressive neurotransmitter release aberrations in familial hemiplegic migraine type 1... Show moreKaja S, Van de Ven RCG, Broos LAM, Frants RR, Ferrari MD, Van den Maagdenberg AMJM, Plomp JJ. Severe and progressive neurotransmitter release aberrations in familial hemiplegic migraine type 1 Cacna1a S218L knock-in mice. J Neurophysiol 104: 1445-1455, 2010. First published July 14, 2010; doi:10.1152/jn.00012.2010. Familial hemiplegic migraine type 1 (FHM1) is caused by mutations in the CACNA1A gene, encoding neuronal presynaptic Ca(V)2.1 (P/Q-type) Ca2+ channels. These channels mediate neurotransmitter release at many central synapses and at the neuromuscular junction (NMJ). Mutation S218L causes a severe neurological phenotype of FHM and, additionally, ataxia and susceptibility to seizures, delayed brain edema, and fatal coma after minor head trauma. Recently, we generated a Cacna1a S218L knock-in mutant mouse, displaying these features and reduced survival. A first electrophysiological study showed high susceptibility for cortical spreading depression, enhanced neuronal soma Ca2+ influx, and at diaphragm NMJs, a considerable increase of neurotransmitter release. We here assessed the function of S218L knock-in NMJs at several muscle types in great detail. Pharmacological analyses using specific Ca-V subtype-blocking toxins excluded compensatory contribution of non-Ca(V)2.1 channels. Endplate potentials were considerably broadened at many NMJs. High rate (40 Hz)-evoked acetylcholine release was slightly reduced; however, it was not associated with block of neurotransmission causing weakness, as assessed with grip strength measurements and in vitro muscle contraction experiments. The synaptopathy clearly progressed with age, including development of an increased acetylcholine release at low-rate nerve stimulation at physiological extracellular Ca2+ concentration and further endplate potential broadening. Our results suggest enhanced Ca2+ influx into motor nerve terminals through S218L-mutated presynaptic Ca(V)2.1 channels, likely because of the earlier reported negative shift of activation potential and reduced inactivation. Similar severe aberrations at central synapses of S218L mutant mice and humans may underlie or contribute to the drastic neurological phenotype. Show less
Klychnikov, O.I.; Li, K.W.; Sidorov, I.A.; Loos, M.; Spijker, S.; Broos, L.A.M.; ... ; Maagdenberg, A.M.J.M. van den 2010
Familial hemiplegic migraine type 1 (FHM1) is caused by missense mutations in the CACNA1A gene that encodes the alpha 1A pore-forming subunit of Ca(v)2.1 Ca2+ channels. Knock-in transgenic mice... Show moreFamilial hemiplegic migraine type 1 (FHM1) is caused by missense mutations in the CACNA1A gene that encodes the alpha 1A pore-forming subunit of Ca(v)2.1 Ca2+ channels. Knock-in transgenic mice expressing Ca(v)2.1 Ca2+ channels with a human pathogenic FHM1 mutation reveal enhanced glutamatergic neurotransmission in the cortex. In this study, we employed an ITRAQ-based LC-LC MS/MS approach to identify differentially expressed proteins in cortical synapse proteomes of Cacna1a R192Q KI and wild-type mice. All expression differences determined were subtle and in the range of 10-30%. Observed upregulated proteins in the mutant mice are Involved in processes, such as neurite outgrowth and actin dynamics, vesicle turnover, and glutamate transporters. Our data support the view that in Cacna1a R192Q KI mice, several compensatory mechanisms counterbalancing a dysregulated glutamatergic signaling have come Into effect. We propose that such adaptation mechanisms at the synapse level may play a role in the pathophysiology of FHM and possibly in the common forms of migraine. Show less
Gonzalez Inchauspe C, Urbano FJ, Di Guilmi MN, Forsythe ID, Ferrari MD, van den Maagdenberg AMJM, Uchitel OD. Gain of function in FHM-1 Ca(v)2.1 knock-in mice is related to the shape of the action... Show moreGonzalez Inchauspe C, Urbano FJ, Di Guilmi MN, Forsythe ID, Ferrari MD, van den Maagdenberg AMJM, Uchitel OD. Gain of function in FHM-1 Ca(v)2.1 knock-in mice is related to the shape of the action potential. J Neurophysiol 104: 291-299, 2010. First published May 19, 2010; doi:10.1152/jn.00034.2010. Familial hemiplegic migraine type-1 FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the alpha(1A) pore-forming subunit of Ca(V)2.1 Ca2+ channels. We used knock-in (KI) transgenic mice harboring the pathogenic FHM-1 mutation R192Q to study neuro-transmission at the calyx of Held synapse and cortical layer 2/3 pyramidal cells (PCs). Using whole cell patch-clamp recordings in brain stem slices, we confirmed that KI Ca(V)2.1 Ca2+ channels activated at more hyperpolarizing potentials. However, calyceal presynaptic calcium currents (I-pCa) evoked by presynaptic action potentials (APs) were similar in amplitude, kinetic parameters, and neurotransmitter release. Ca(V)2.1 Ca2+ channels in cortical layer 2/3 PCs from KI mice also showed a negative shift in their activation voltage. PCs had APs with longer durations and smaller amplitudes than the calyx of Held. AP-evoked Ca2+ currents (I-Ca) from PCs were larger in KI compared with wild-type (WT) mice. In contrast, when I-Ca was evoked in PCs by calyx of Held AP waveforms, we observed no amplitude differences between WT and KI mice. In the same way, Ca2+ currents evoked at the presynaptic terminals (I-pCa) of the calyx of Held by the AP waveforms of the PCs had larger amplitudes in R192Q KI mice that in WT. These results suggest that longer time courses of pyramidal APs were a key factor for the expression of a synaptic gain of function in the KI mice. In addition, our results indicate that consequences of FHM-1 mutations might vary according to the shape of APs in charge of triggering synaptic transmission (neurons in the calyx of Held vs. excitatory/inhibitory neurons in the cortex), adding to the complexity of the pathophysiology of migraine. Show less
Rooij, A.M. de; Gosso, M.F.; Alsina-Sanchis, E.; Marinus, J.; Hilten, J.J. van; Maagdenberg, A.M.J.M. van den 2010
Background: Mutations in the voltage-gated Na(V)1.7 Na+ channel alpha 1 gene SCN9A have been linked to pain disorders, such as inherited primary erythromelalgia and paroxysmal extreme pain disorder... Show moreBackground: Mutations in the voltage-gated Na(V)1.7 Na+ channel alpha 1 gene SCN9A have been linked to pain disorders, such as inherited primary erythromelalgia and paroxysmal extreme pain disorder. Both show clinical overlap with complex regional pain syndrome (CRPS), a condition that is characterized by pain in association with combinations of vasomotor, sudomotor, sensory, and motor disturbances. Therefore, we here investigated the involvement of the SCN9A gene in familial CRPS. Methods: We performed a mutation analysis of the SCN9A gene in four index cases of families with CRPS. All 26 coding exons and adjacent sequences of the SCN9A gene were analyzed for mutations using direct sequencing analysis. Results: No causal gene mutations were identified in the SCN9A gene in any of the patients. Conclusions: Despite the fact that the SCN9A gene is an excellent candidate, we did not find evidence that it plays a major role in familial CRPS. Show less
Facial expression is widely used as a measure of pain in infants; whether nonhuman animals display such pain expressions has never been systematically assessed. We developed the mouse grimace scale... Show moreFacial expression is widely used as a measure of pain in infants; whether nonhuman animals display such pain expressions has never been systematically assessed. We developed the mouse grimace scale (MGS), a standardized behavioral coding system with high accuracy and reliability; assays involving noxious stimuli of moderate duration are accompanied by facial expressions of pain. This measure of spontaneously emitted pain may provide insight into the subjective pain experience of mice. Show less
