Familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2.

BACKGROUND: The mechanisms of genotype-phenotype interaction in Familiar Hemiplegic migraine type 2 (FHM2) are still far from clear. Different ATP1A2 mutations have been described, with a spectrum of phenotypes ranging from mild to severe. No genotype-phenotype correlations have been attempted. CASE PRESENTATION: We describe an Italian family with FHM and a missense ATP1A2 variant (L425H) not previously described. The clinical picture was mild in all the affected members. CONCLUSIONS: Co-segregation of the variant with the aura phenotype was complete in this family, suggesting a 100% penetrance. In silico protein prediction softwares indicate that this variant may change the 3D structure of ATPA1A2 at the cytoplasmic loop between the two central transmembrane helices. Milder FHM phenotypes are rarely reported in literature, likely because case reports are biased towards the most severe phenotypes, with milder forms possibly misdiagnosed as sporadic migraine with aura forms (MAs), even with complex auras. Further studies taking into account intra-familiar variability and functional consequences on the channel protein may help clarify genotype-phenotype correlations.

Genetics Influences Drug Consumption in Medication Overuse Headache, Not in Migraine: Evidence From Wolframin His611Arg Polymorphism Analysis.

Background: The Wolframin His611Arg polymorphism can influence drug consumption in psychiatric patients with impulsive addictive behavior. This cross-sectional study aims to assess the prevalence of the Wolframin His611Arg polymorphism in MOH, a secondary headache belonging to the spectrum of addictive disorders, episodic migraine (EM), and healthy subjects (HS), and its influence on drug consumption. Methods: One-hundred and seventy-two EM, 107 MOH, and 83 HS were enrolled and genotyped for the Wolframin His611Arg polymorphism. Subjects were classified as homozygous for allele His (H/H subjects), homozygous for allele Arg (R/R subjects), and heterozygous (H/R subjects), regrouped as R/R and carriers of allele H (non-R/R), and matched for clinical data. Results: There were no differences in allelic distributions between the three groups (p = 0.19). Drug consumption and other clinical characteristics were not influenced by the Wolframin His611Arg polymorphism (p = 0.42; ß = 0.04) in the EM group. Among the MOH population, R/R subjects consumed more analgesics (p < 0.0001; ß = -0.38), particularly combination drugs (p = 0.0001; d = 2.32). Discussion: The Wolframin His611Arg polymorphism has a similar prevalence between the MOH, EM, and HS groups. The presence of the R/R genotype does not influence symptomatic drug consumption in EM, whereas it determines an increased use of symptomatic drugs in the MOH group, in particular combination drugs (i.e., drugs containing psychoactive compounds). Conclusions: Our findings are consistent with the hypothesis that the Wolframin His611Arg polymorphism plays its effect only in the MOH population, influencing the impulsivity control underlying addictive behavior.

Possible Involvement of the CACNA1E Gene in Migraine: A Search for Single Nucleotide Polymorphism in Different Clinical Phenotypes.

OBJECTIVE: To search for differences in prevalence of a CACNA1E variant between migraine without aura, various phenotypes of migraine with aura, and healthy controls. BACKGROUND: Familial hemiplegic migraine type 1 (FHM1) is associated with mutations in the CACNA1A gene coding for the alpha 1A (Cav 2.1) pore-forming subunit of P/Q voltage-dependent Ca2+ channels. These mutations are not found in the common forms of migraine with or without aura. The alpha 1E subunit (Cav 2.3) is the counterpart of Cav 2.1 in R-type Ca2+ channels, has different functional properties, and is encoded by the CACNA1E gene. METHODS: First, we performed a total exon sequencing of the CACNA1E gene in three probands selected because they had no abnormalities in the three FHM genes. In a patient suffering from basilar-type migraine, we identified a single nucleotide polymorphism (SNP) in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760; Minor Allele Frequency 0.2241) hitherto not studied in migraine. In a second step, we determined its occurrence in four groups by direct sequencing on blood genomic DNA: migraine patients without aura (N = 24), with typical aura (N = 55), complex neurological auras (N = 19; hemiplegic aura: N = 15; brain stem aura: N = 4), and healthy controls (N = 102). RESULTS: The Asp859Glu - rs35737760 SNP of the CACNA1E gene was present in 12.7% of control subjects and in 20.4% of the total migraine group. In the migraine group it was significantly over-represented in patients with complex neurological auras (42.1%), OR 4.98 (95% CI: 1.69-14.67, uncorrected P = .005, Bonferroni P = .030, 2-tailed Fisher's exact test). There was no significant difference between migraine with typical aura (10.9%) and controls. CONCLUSIONS: We identified a polymorphism in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760) that is more prevalent in hemiplegic and brain stem aura migraine. This missense variant causes a change from aspartate to glutamate at position 859 of the Cav 2.3 protein and might modulate the function of R-type Ca2+ channels. It could thus be relevant for migraine with complex neurological aura, although this remains to be proven.

The Revolution in Migraine Genetics: From Aching Channels Disorders to a Next-Generation Medicine.

Channelopathies are a heterogeneous group of neurological disorders resulting from dysfunction of ion channels located in cell membranes and organelles. The clinical scenario is broad and symptoms such as generalized epilepsy (with or without fever), migraine (with or without aura), episodic ataxia and periodic muscle paralysis are some of the best known consequences of gain- or loss-of-function mutations in ion channels. We review the main clinical effects of ion channel mutations associated with a significant impact on migraine headache. Given the increasing and evolving use of genetic analysis in migraine research-greater emphasis is now placed on genetic markers of dysfunctional biological systems-we also show how novel information in rare monogenic forms of migraine might help to clarify the disease mechanisms in the general population of migraineurs. Next-generation sequencing (NGS) and more accurate and precise phenotyping strategies are expected to further increase understanding of migraine pathophysiology and genetics.

Pharmacogenomics of episodic migraine: time has come for a step forward.

Migraine is characterized by heterogeneous behavior in response to drugs. Many resources have been invested in attempting to unravel the genetic basis of migraine, while the role of genetics in responses to currently available drugs has received less attention. We performed a systematic literature search identifying original articles pertaining to pharmacogenomics of episodic migraine. Few primary studies on the pharmacogenomics of symptomatic and preventive medication in episodic migraine were found. The number of patients studied in the individual articles ranged from 40 up to 130. There was a strong heterogeneity among these studies. We believe that pharmacogenomics studies, if properly designed, could contribute towards optimizing the treatment and reducing the burden of migraine, in turn helping patients and optimizing resources. Our knowledge on the pharmacogenomics of migraine is growing too slowly, and concerted measures should be undertaken to speed up the process.

The upstream Variable Number Tandem Repeat polymorphism of the monoamine oxidase type A gene influences trigeminal pain-related evoked responses.

Monoamines have an important role in neural plasticity, a key factor in cortical pain processing that promotes changes in neuronal network connectivity. Monoamine oxidase type A (MAOA) is an enzyme that, due to its modulating role in monoaminergic activity, could play a role in cortical pain processing. The X-linked MAOA gene is characterized by an allelic variant of length, the MAOA upstream Variable Number Tandem Repeat (MAOA-uVNTR) region polymorphism. Two allelic variants of this gene are known, the high-activity MAOA (HAM) and low-activity MAOA (LAM). We investigated the role of MAOA-uVNTR in cortical pain processing in a group of healthy individuals measured by the trigeminal electric pain-related evoked potential (tPREP) elicited by repeated painful stimulation. A group of healthy volunteers was genotyped to detect MAOA-uVNTR polymorphism. Electrical tPREPs were recorded by stimulating the right supraorbital nerve with a concentric electrode. The N2 and P2 component amplitude and latency as well as the N2-P2 inter-peak amplitude were measured. The recording was divided into three blocks, each containing 10 consecutive stimuli and the N2-P2 amplitude was compared between blocks. Of the 67 volunteers, 37 were HAM and 30 were LAM. HAM subjects differed from LAM subjects in terms of amplitude of the grand-averaged and first-block N2-P2 responses (HAM>LAM). The N2-P2 amplitude decreased between the first and third block in HAM subjects but not LAM subjects. The MAOA-uVNTR polymorphism seemed to influence the brain response in a repeated tPREP paradigm and suggested a role of the MAOA as a modulator of neural plasticity related to cortical pain processing.

Migraine headache: a review of the molecular genetics of a common disorder.

This tutorial summarises the state-of-the-art on migraine genetics and looks at the possible future direction of this field of research. The view of migraine as a genetic disorder, initially based on epidemiological observations of transmission of the condition within families, was subsequently confirmed by the identification of monogenic forms of "syndromic" migraine, such as familial hemiplegic migraine. We are currently witnessing a change in the way genetic analysis is used in migraine research: rather than studying modalities of inheritance in non-monogenic forms of migraine and in the persistent modalities of migraine headache, researchers are now tending to focus on the search for genetic markers of dysfunction in biological systems. One example of the evolution of migraine genetic research is provided by the recent efforts to shed light on the pharmacogenomic mechanisms of drug response in migraineurs. In addition, novel molecular approaches about to be introduced are expected to further increase knowledge on this topic and improve patient management.

The Val66Met polymorphism of the BDNF gene influences trigeminal pain-related evoked responses.

UNLABELLED: Cortical pain processing is associated with large-scale changes in neuronal connectivity, resulting from neural plasticity phenomena of which brain-derived neurotrophic factor (BDNF) is a central driver. The common single nucleotide polymorphism Val66Met is associated with reduced BDNF activity. Using the trigeminal pain-related evoked potential (tPREP) to repeated electrical painful stimuli, we investigated whether the methionine substitution at codon 66 of the BDNF gene was associated with changes in cortical processing of noxious stimuli. Fifty healthy volunteers were genotyped: 30 were Val/Val and 20 were Met-carriers. tPREPs to 30 stimuli of the right supraorbital nerve using a concentric electrode were recorded. The N2 and P2 component latencies and the N2-P2 amplitude were measured over the 30 stimuli and separately, by dividing the measurements in 3 consecutive blocks of 10 stimuli. The average response to the 30 stimuli did not differ in latency or amplitude between the 2 genotypes. There was a decrease in the N2-P2 amplitude between first and third block in the Val/Val group but not in Met-carriers. BDNF Val66Met is associated with reduced decremental response to repeated electrical stimuli, possibly as a result of ineffective mechanisms of synaptic memory and brain plasticity associated with the polymorphism. PERSPECTIVE: BDNF Val66Met polymorphism affects the tPREP N2-P2 amplitude decrement and influences cortical pain processing through neurotrophin-induced neural plasticity, or through a direct BDNF neurotransmitter-like effect. Our findings suggest that upcoming BDNF central agonists might in the future play a role in pain management.

Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy.

OBJECTIVE: To test the effect of the single nucleotide polymorphism -66 T>G (rs28357094) in the osteopontin gene (SPP1) on functional measures over 12 months in Duchenne muscular dystrophy (DMD). METHODS: This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the north star ambulatory assessment (NSAA) and the 6-minute walk test (6MWT) at study entry and after 12 months. Genotype at rs28357094 was determined after completion of the clinical evaluations. Patients were stratified in 2 groups according to a dominant model (TT homozygotes vs TG heterozygotes and GG homozygotes) and clinical data were retrospectively compared between groups. RESULTS: Eighty patients were selected (age 4.1-19.3 years; mean 8.3 ± 2.7 SD). There were no differences in age or steroid treatment between the 2 subgroups. Paired t test showed a significant difference in both NSAA (p = 0.013) and 6MWT (p = 0.03) between baseline and follow-up after 12 months in patients with DMD carrying the G allele. The difference was not significant in the T subgroup. The analysis of covariance using age and baseline values as covariate and SPP1 genotype as fixed effect showed that these parameters are significantly correlated with the 12-month values. CONCLUSIONS: These data provide evidence of the role of SPP1 genotype as a disease modifier in DMD and support its relevance in the selection of homogeneous groups of patients for future clinical trials.

Drug consumption in medication overuse headache is influenced by brain-derived neurotrophic factor Val66Met polymorphism.

Medication overuse headache (MOH) can be considered a clinical condition at the boundaries between drug addiction and chronic pain disorder. The common 196G > A single-nucleotide polymorphism of BDNF gene, resulting in a valine 66 to methionine (Val66Met), is related with behaviour disorders and substance abuse. With the aim of identifying a worsening factor in MOH, rather than the detection of a specific risk factor for the development of the disease, we investigated whether the presence of a functional BDNF polymorphism might determine clinical differences within a group of 90 MOH patients, particularly in monthly drug consumption, that is the hallmark of disease. Directly comparing MOH patients homozygous for G allele (G/G) with carriers of A allele (non-G/G), we have observed 47 G/G genotypes and 60 non-G/G genotypes. Non-G/G had a higher consumption of monthly drug number (Cohen's d = 0.76) than G/G patients. At multiple regression analysis, the Val66Met BDNF polymorphism emerged as a significant independent predictor of analgesic drug consumption (Beta = 0.33, Cohen's f(2) = 0.134). These findings showed an influence of examined BDNF polymorphism in the MOH clinical features, supporting the idea that MOH is a substance abuse disorder.

The interplay of two single nucleotide polymorphisms in the CACNA1A gene may contribute to migraine susceptibility.

Migraine is a common disorder with a significant genetic component. Mutations in the CACNA1A gene are found in hemiplegic migraine (HM). Basilar-type (BM), another subtype of migraine with aura, differs from HM only by the absence of motor deficits. BM and HM may thus share common genetic features. In the present study, two single nucleotide polymorphisms (SNPs) of the CACNA1A gene were characterized in a population of migraine patients and healthy controls. The polymorphisms, E918D, predicting a glutamic acid-to-aspartic acid substitution at codon 918 and E993V, predicting a glutamic acid-to-valine substitution at codon 993, were frequently detected among patients and controls. Seven BM, 10 SHM, 5 FHM, 57 migraine with typical aura, 32 migraine without aura patients and 107 healthy controls were screened. The E918D and E993V SNPs were found in 30/117 (25.6%) and 32/117 (27.3%) migraine patients, respectively. The prevalence of these SNPs taken separately was not significantly different from that of control subjects (n=28/107, 26.2% for E918D; n=29/107 for E993V, 27.1%) neither for the total migraine population nor for the various migraine subtypes. By contrast, coexistence of both SNPs was more frequent in migraineurs (25/117, 21%) than in healthy controls (12/107, 11%; p=0.048), a difference that was significant for every migraine subtype. This result suggests that the interplay of minor genetic variants such as single nucleotide polymorphisms may influence the P/Q-type calcium channel function in several subtypes of migraine.

An inherited large-scale rearrangement in SACS associated with spastic ataxia and hearing loss.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a neurodegenerative disorder characterized by early-onset, spastic ataxia and peripheral neuropathy, with or without mental retardation. The array of mutations in SACS has expanded worldwide after the first description in Quebec. We herein report the identification of an unconventional SACS mutation, a large-scale deletion sized approximately 1.5 Mb encompassing the whole gene, in two unrelated patients. The clinical phenotype of the patients was similar to more canonical ARSACS cases, though it is was complicated by the unusual presence of hearing loss. Our findings suggest that a "microdeletion" on chromosome 13q12 represents a novel allelic variant associated with ARSACS, stressing the need for an expanded testing in molecular diagnostic laboratories.

Six novel mutations of the RUNX2 gene in Italian patients with cleidocranial dysplasia.

We report clinical and molecular findings in 14 patients with cleidocranial dysplasia (CCD), a well defined skeletal disorder with characteristic clinical findings and autosomal dominant inheritance. We identified ten heterozygous base changes in the RUNX2 gene, including six novel mutations [c.522insA, c.389G>A (W130X), c.662T>G (V221G), IVS2+T>A, c.1111_1129del19, and c.873_874delCA]. We did not establish a clear correlation between clinical features and genotype, the phenotypes of all patients analyzed falling within the range of variation described in CCD without an effect related to the length of the predicted protein. In two cases, however, a limb-girdle myopathy affecting the shoulder muscles was also identified. Our data add new variants to the repertoire of RUNX2 mutations in CCD.

Current insights into familial spastic paraparesis: new advances in an old disease.

Hereditary spastic paraparesis (HSP) comprises a clinically and genetically heterogeneous group of disorders characterized by progressive spasticity and hyperreflexia of the lower limbs. The past few years have witnessed an exponential increase in knowledge of this disease and we can now list 19 loci mapped on the human genome and eight genes cloned. However, this wider knowledge of the molecular basis of HSP has had limited impact on clinical practice: the use of antispastic drugs and regular physiotherapy still remain crucial in the therapeutic management of patients. Nonetheless, the identification of new genes mutated in HSP furthers comprehension of the pathomechanisms involved and helps in genetic counseling, especially of asymptomatic individuals who request molecular analyses.