Mirella Mochi

A genetic association study of dopamine metabolism‐related genes and chronic headache with drug abuse

To assess the role of dopamine metabolism‐related genes in the genetic liability to chronic headache with drug abuse (DA). We performed a genetic association study using four functional polymorphisms of the dopamine receptor 4 (DRD4), dopamine transporter (DAT), mono‐amino‐oxidase A (MAOA) and cathecol‐O‐methyl‐transferase (COMT) genes in 103 patients with chronic daily headache associated with DA (CDHDA). Control samples were 117 individuals without headache or DA (controls) and 101 patients with episodic migraine without aura and without DA (MO). No differences were found at the COMT and MAOA genes among the three groups investigated. Allele 4 of DRD4 was significantly overrepresented in patients with MO compared with both controls and CDHDA. Allele 10 of the DAT gene was significantly underrepresented in patients with CDHDA when compared with the MO group. Genetic variability at the DRD4 gene is involved in the predisposition to episodic MO but not to DA, while liability to CDHDA may involve genetic variability at the DAT gene in comparison with episodic MO.

Abnormal platelet mitochondrial function in patients affected by migraine with and without aura

To investigate energy metabolism in migraine, we determined platelet mitochondrial enzyme activities in 40 patients with migraine with aura and in 40 patients with migraine without aura during attack-free intervals and in 24 healthy control subjects. NADH-dehydrogenase, citrate synthase and cytochrome-c-oxidase activities in both patient groups were significantly lower than in controls (p < 0.01), while NADH-cytochrome-c-reductase activity was reduced only in migraine with aura (p < 0.01). No alteration in succinate-dehydrogenase was observed. Monoamine-oxidase activity differed between sexes (p < 0.05) but within each sex group no difference was observed between patients and controls. We hypothesize that the defect in mitochondrial enzymes observed indicates a systemic impairment of mitochondrial function in migraine patients.

Testing Models for Genetic Determination in Migraine

We collected two clinically matched samples of patients, one sample affected by migraine with aura the other by migraine without aura, to investigate the genetic determination of these conditions. A maternal and X-linked transmission for both these diseases was considered unlikely after pedigree analysis. Classical segregation analysis indicated a likely autosomal recessive kind of transmission for both. Reduced penetrance and the h2 values, however, imply the presence of additional genetic and/or environmental factors controlling the phenotypic expression of migraine.

A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes

Abstract. We assessed the role of some dopamine metabolism genes in the genetic susceptibility to migraine. We performed an association study using three functional polymorphisms: a 48-base-pair (bp) tandem repeat in the D4 dopamine receptor gene (DRD4), a 40-bp tandem repeat in the dopamine transporter gene (DAT) and a dinucleotide repeat in the dopamine beta-hydroxylase (DBH) gene. Allelic and genotypic frequencies for each polymorphism were assayed in two migraine populations (93 individuals with migraine with aura (MA) and 101 with migraine without aura (MO)) and were compared with those in a control group (117 individuals). No significant differences were found between control and migraine groups for DAT and DBH polymorphisms. Instead, the distribution of alleles for the DRD4 gene in the MO group was significantly different from those in both MA and control groups, with the shortest and longest alleles being less frequent in MO. Our data indicate that MO, but not MA, shows significant genetic association with DRD4.

Genetic polymorphism of catechol-O-methyltransferase and levodopa pharmacokinetic–pharmacodynamic pattern in patients with Parkinson's disease†

We explored the potential effect of catechol‐O‐methyltransferase (COMT) genetic polymorphism on the pharmacokinetics and pharmacodynamics of a standard oral dose of levodopa in patients with Parkinsons disease (PD). We prospectively collected blood samples for COMT genotyping from a population of 104 PD patients. Each patient was examined by a standard oral levodopa/benserazide test, based on simultaneous serial measurements of plasma levodopa concentrations, finger‐tapping motor effects and dyskinesia ratings, up to 4 hours after dosing. The main levodopa pharmacokinetic outcome variables were time to peak and peak plasma concentration, plasma elimination half‐life, and the area under the plasma concentration–time curve. The main outcome levodopa pharmacodynamic variables were latency, duration, and magnitude of the motor effect elicited by the levodopa test dose, the area under the tapping effect–time curve, and the presence of dyskinesias. Nineteen patients (18%) harbored the low‐activity homozygous COMT genotype (A/A), 63 patients (61%) carried the intermediate‐activity heterozygous COMT genotype (A/G) and 22 patients (21%) had the high‐activity homozygous COMT genotype (G/G). The three groups were comparable for vital and clinical characteristics. No significant difference was found in levodopa main pharmacokinetic–pharmacodynamic variables and dyskinesia incidence among the three subgroups of patients. We failed to identify clinically relevant levodopa pharmacokinetic–pharmacodynamic response patterns associated with the COMT polymorphism in PD patients.

Familial hemiplegic migraine: clinical features and probable linkage to chromosome 1 in an Italian family

We describe an Italian family with familial hemiplegic migraine (FHM), subtle cerebellar signs and probable linkage to chromosome 1. FHM is genetically heterogeneous; in about 50% of families it is caused by mutations within the CACNA1A gene on chromosome 19. Linkage to 1q31 and 1g21–23 has also been established. Other families do not link either to chromosome 19 or 1. Chromosome 19-linked FHM may display nystagmus and cerebellar ataxia. Affected family members were neurologically examined; linkage analysis was performed with markers for chromosomes 19p13, 1q21–23, and 1q32. Five family members had hemiplegic migraine, and 3 displayed additional cerebellar signs (scanning speech and nystagmus). In 1 patient, episodes of hemiplegic migraine triggered by mild head trauma. Epilepsy and mental retardation were also found in 1 affected relative each. Lod scores for linkage to 19p13 were negative, while the maximum two-point lod score was 1.81 to 1q21–23. This family with FHM and associated subtle cerebellar signs, epilepsy and mental retardation showed probable linkage to 1q21–23.

Dopamine transporter gene polymorphism, SPECT imaging, and levodopa response in patients with Parkinson disease

Objectives:To assess the potential association between dopamine transporter (DAT) genotype, single photon emission CT (SPECT) measures using [123I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([123I]-FP-CIT) of striatal dopaminergic function, and oral levodopa response pattern in a cohort of patients with Parkinson disease. Methods:Thirty-six patients at different disease stages enrolled in the study. Each patient was examined by [123I]-FP-CIT SPECT and a standardized oral levodopa test on 2 separate days in a randomized order within 3 weeks. The main outcome variables were the specific-to-nonspecific tracer uptake ratio in the contralateral putamen for SPECT analysis; latency, duration, and magnitude of the motor effect; and presence of dyskinesias for the levodopa test. The variable number of tandem repeat (VNTR) polymorphisms of the gene coding for DAT were detected for each patient by standard methods. Results:Contralateral putamen [123I]-FP-CIT uptake ratios were similar in the patients carrying the 9-copy allele (n = 20) of the DAT VNTR compared with 10-repeat homozygotes (n = 16). No significant difference was found in levodopa main outcome variables and dyskinesia incidence between the two groups of patients stratified by DAT VNTR polymorphism. Conclusions:The study did not identify clinically relevant in vivo DAT neurochemical function phenotypes or levodopa response patterns associated with the DAT polymorphism.

The genetics of chronic headaches.

Abstract. Patients with chronic daily headaches (CDH) bear similarities to drug or substance abuse patients, for whom genetic liability loci have been implicated. We reviewed papers dealing with the metabolic and the genetic aspects of CDH. The relative risk for CDH in first-degree relatives is 2.1- to 3.9-fold increased compared to the general population. Genetic variation at the dopamine receptor 2 has been associated with co-morbidity of migraine with aura with major depression and anxiety, and allele D of the angiotensin converting enzyme increases the frequency of migraine without aura attacks. In CDH, analgesic abuse was significantly associated with specific functional polymorphisms at the DRD 4 and at the dopamine transporter (DAT) genes, findings implicating dopamine-related genes in CDH with drug abuse. CDH carries a substantial genetic predisposition. Molecular genetic studies are, however, still few and preliminary.

Investigation of an LDLR gene polymorphism (19p13.2) in susceptibility to migraine without aura

We performed a genetic association study with the LDL receptor gene (LDLR) on chromosome 19p13.2 in 360 migraine patients, 220 with migraine without aura (MO) and 140 with migraine with aura (MA), and 200 controls, by analysing two polymorphic markers, a G142A transition in exon 10 and a triallelic (TA)n repeat in exon 18. The allelic distribution of the (TA)n polymorphism was significantly different between migraine without aura (MO) and both controls and migraine with aura (MA). We suggest a possible predisposition to MO in the studied population through this polymorphism or another polymorphism in linkage disequilibrium with (TA)n.

Investigation on early divergence between populations of Drosophila melanogaster kept at different temperatures

An experiment was performed on Drosophila melanogaster populations kept at two temperatures (25°C and 28°C) with the aim of providing further evidence that:1phenotypic differentiation between the two populations is already detectable in earlier generations of selection;2the divergence is more related to a changed body shape than to body size;3this divergence is correlated with fitness and, therefore, natural selection may operate on these differences. The results obtained by univariate and multivariate statistical analysis imply that:(i)progress in the phenotypic divergence is observed from the first to the sixth generation as based on the discrimination by a linear function of nine metric traits of the wing, while, as expected, divergence is not detected on mean values and variance estimates;(ii)differential reproductive fitness is associated with these differences and not with single traits. It is suggested that the kind of variation observed is the outcome of a rearrangement of the developmental pattern of the wing in the population kept at different temperatures and that the reproductive fitness values are more dependent on the developmental pattern than on the genetic basis of a given character.The results are discussed in terms of population dynamics.