Search

Objective Fibromyalgia (FM) patients have signs of relentless sympathetic hyperactivity associated with hyporeactivity to stress. Adrenergic receptors (ARs) are parts of the sympathetic nervous system that are fundamental for maintenance of homeostasis. We undertook this study to correlate α-AR and β-AR gene polymorphisms with the presence of FM and with different domains of the FM syndrome as measured by the Fibromyalgia Impact Questionnaire (FIQ). Methods We studied 78 Mexican FM patients and 48 age-matched controls as well as 78 Spanish FM patients and 71 controls. All subjects studied were women. Single-nucleotide polymorphisms (SNPs) of α1A-AR (rs574584, rs1383914, rs1048101, and rs573542), β2-AR (rs1042713 and rs1042714), and β3-AR (rs4994) were analyzed by 5′ exonuclease TaqMan polymerase chain reaction. Polymorphic haplotypes were constructed after linkage disequilibrium analysis. Results The β2-AR AC haplotype was a risk factor for the presence of FM. This haplotype had an increased frequency in Mexican patients compared with Mexican controls (42.1% versus 30.5%; P = 0.04). Similarly, 50.4% of Spanish patients had this haplotype compared with 40.0% of Spanish controls (P = 0.05). In Spanish patients, the α1A-AR SNP rs1383914 was associated with the presence of FM (P = 0.01), and the α1A-AR SNP rs1048101 was linked with FIQ disability (P = 0.02). Mexican patients with the rs574584 GG genotype presented the highest FIQ score compared with Mexican patients with other genotypes (P = 0.01), and in Mexicans SNP rs574584 was associated with FIQ morning stiffness (P = 0.04) and with FIQ tiredness upon awakening (P = 0.02). Conclusion AR gene polymorphisms are related to the risk of developing FM and are also linked to different domains of the FM syndrome.

Fundamento y objetivo: Determinar la posible relacion entre los genotipos Val158Met del gen catecol O-metiltransferasa (COMT) y la severidad del sindrome de fibromialgia (FM). Pacientes y metodos: El estudio incluyo 110 pacientes de edades comprendidas entre 45 y 55 anos diagnosticados de FM (ACR 1990) y 110 muestras de controles sanos sin dolor ni fatiga anormal (Banco Nacional de ADN). Como medida de gravedad de la FM se utilizo el cuestionario de impacto de fibromialgia (FIQ), y se establecio el valor FIQ = 70 para determinar FM severa, criterio que cumplieron el 35,5% de pacientes. Los polimorfismos se analizaron mediante tecnicas de reaccion en cadena de la polimerasa (PCR) estandar. Todos los grupos cumplian el equilibrio de Hardy-Weinberg. Resultados: La frecuencia del genotipo Met/Met es mas baja en controles (20,9%) que en casos (34,5%), mientras que la de Val/Val es mas alta en controles (30,9%) que en casos (20,0%), y las diferencias son significativas (p = 0,048). Los valores medios de FIQ son mas altos en los genotipos Met/Met (71,67) y Val/Met (68,27) y mas bajos en el genotipo Val/Val (58,93). El test de Tukey de comparaciones multiples indica que los valores de FIQ presentan diferencias significativas cuando se compara Met/Met/Val/Val (Tukey, p < 0,001) y Val/Val/Val/Met (Tukey, p = 0,003). Conclusiones: Nuestros resultados parecen indicar que el genotipo Met/Met esta asociado a cuadros clinicos de FM mas graves.

Segawa disease is a rare dystonia due to autosomal dominant guanosine triphosphate cyclohydrolase I (adGTPCH) deficiency, affecting dopamine and serotonin biosynthesis. Recently, the clinical phenotype was expanded to include psychiatric manifestations, such as depression, anxiety, obsessive–compulsive disorder, and sleep disturbances. Although cognitive and neuropsychiatric symptoms may be attributable to dopamine deficiency in the prefrontal cortex and frontostriatal circuitry, intelligence is considered normal in Segawa disease. Our aim was to investigate neuropsychiatric symptoms and intelligence quotients (IQ) in a series of individuals with adGTPCH deficiency. The assessment included a structured clinical interview following the DSM-IV-TR’s guidelines, Beck’s Depression Inventory, the State-Trait Anxiety Inventory, the Maudsley Obsessive–Compulsive Questionnaire, the Barratt Impulsiveness Scale-11 (BIS-11), the Oviedo Sleep Questionnaire, the Pittsburgh Sleep Quality Index, and the Wechsler Adult Intelligence Scale-Third Edition. Equivalent tests were applied to pediatric patients as appropriate for their age group. Fourteen patients with adGTPCH deficiency were evaluated (seven adult and seven pediatric patients). Depression, anxiety, and obsessive–compulsive symptoms were not more common than expected in the general population. However, the seven adults showed impulsivity in the BIS-11; nine individuals had an IQ in the range of borderline intellectual functioning to mild mental retardation, and sleep disturbances were found in four individuals. We found no differences between these results and the motor impairment. In conclusion, our findings would suggest that cognitive impairment, and impulsivity in adults, may be associated with Segawa disease.

Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency is an inborn error of neurotransmitter metabolism, with a prevalence of 0.5 per million, caused by mutations/deletions in the GCH1 gene. The finding of the mutation Q89X in the GCH1 gene in 23 patients from two pedigrees in an area inhabited by a population of 800,000 prompted us to consider that our cohort may have descended from a single founder. Twelve Q89X mutation-positive cases belonging to two families and 100 unrelated control subjects from the same geographical region were studied. Six microsatellite markers located near GCH1 were analyzed to validate a possible mutation-related founder haplotype. Haplotype analysis revealed two different haplotypes for six microsatellite markers that segregated with the Q89X mutation. A common haplotype in 10 out of 12 mutation carriers studied was identified. Two subjects carried a second haplotype, most probably because of a recombination event. However, at least 186 different haplotypes were established in the control subjects. In contrast with the frequencies of 83.3% and 16.7%, respectively, found for both mutation-segregating haplotypes, the frequency of none of the control haplotypes exceeded 1.5%. Dystonia was the most frequent symptom in our series, and parkinsonism was present in five patients. The large number of Q89X mutation carriers in our community is because of a founder effect. The same mutation in GCH1 causes a wide phenotypic spectrum of clinical variability occurring in this population of affected patients.

Autonomic dysfunction is frequent in patients with fibromyalgia (FM). Heart rate variability analyses have demonstrated signs of ongoing sympathetic hyperactivity. Catecholamines are sympathetic neurotransmitters. Catechol-O-methyltransferase (COMT), an enzyme, is the major catecholamine-clearing pathway. There are several single-nucleotide polymorphisms (SNPs) in the COMT gene associated with the different catecholamine-clearing abilities of the COMT enzyme. These SNPs are in linkage disequilibrium and segregate as 'haplotypes'. Healthy females with a particular COMT gene haplotype (ACCG) producing a defective enzyme are more sensitive to painful stimuli. The objective of our study was to define whether women with FM, from two different countries (Mexico and Spain), have the COMT gene haplotypes that have been previously associated with greater sensitivity to pain. All the individuals in the study were female. Fifty-seven Mexican patients and 78 Spanish patients were compared with their respective healthy control groups. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Six COMT SNPs (rs2097903, rs6269, rs4633, rs4818, rs4680, and rs165599) were genotyped from peripheral blood DNA. In Spanish patients, there was a significant association between three SNPs (rs6269, rs4818, and rs4680) and the presence of FM when compared with healthy controls. Moreover, in Spanish patients with the 'high pain sensitivity' haplotype (ACCG), the disease, as assessed by the FIQ, was more severe. By contrast, Mexican patients displayed only a weak association between rs6269 and rs165599, and some FIQ subscales. In our group of Spanish patients, there was an association between FM and the COMT haplotype previously associated with high pain sensitivity. This association was not observed in Mexican patients. Studies with a larger sample size are needed in order to verify or amend these preliminary results.

We report on a GTP cyclohydrolase 1 mutation-confirmed heterozygous case presenting with an infantile hypokinetic rigid syndrome and delay in attainment of motor milestones starting from the first year of life. He had a family history of dopa-responsive dystonia-parkinsonism. CSF neopterin, biopterin and HVA values were decreased. Molecular study of GCH-1 gene showed the Q89X mutation in exon 1. Treatment with l-dopa resulted in a complete remission of symptoms.

To determine the possible relationship between Val158Met genotypes of the COMT gene and the severity of fibromyalgia (FM) syndrome.The study included 110 patients aged between 45 and 55 years old diagnosed with FM (ACR, 1990) and 110 samples from control subjects with no pain and no abnormal fatigue (National DNA Bank, Spain). To measure the severity of fibromyalgia, the Fibromyalgia Impact Questionnaire (FIQ) was used. Severe FM was defined as an FIQ of ≥ 70 and was found in 35.5% of the patients. Polymorphisms were analyzed using standard polymerase chain reaction techniques. All the groups met the Hardy-Weinberg equilibrium.The frequency of the Met/Met genotype was lower in controls (20.9%) than in patients (34.5%), whereas that of the Val/Val genotype was higher in controls (30.9%) than in patients (20.0%), with significant differences (p=0.048). The mean FIQ values were higher in the Met/Met genotypes (71.67) and Val/Met genotypes (68.27) and were lower in the Val/Val genotype (58.93). Tukey's multiple comparison test indicated that FIQ values presented significant differences when Met/Met/Val/Val (Tukey, p0.001) and Val/Val/Val/Met (Tukey, p=0.003) were compared.Our results appear to indicate that the Met/Met genotype is associated with greater severity of FM symptoms.

In Familial Alzheimer’s disease (FAD), a devastating neurodegenerative process mainly characterized by loss of learning and memory, the genetic contributions are been clarified day by day. Mutations on chromosome 21 and 19 AD-related have been described and well documented in some patients and their relatives (St. George-Hyslop et al., 1987; Murrell et al., 1991; Chartier-Harlin et al., 1991; Pericak-Vance et al., 1991). Further studies have shown mutations on chromosome 14, the locus FAD-3 placed in 14q24.3, as responsible of about 70% of the early-onset FAD (Schellenberg, et al., 1992; Bonnycastle et al, 1993). In this locus, the S182 gene (presenilin 1 gene) has been recently mapped and postulated as a possible FAD gene (Selkoe et al., 1995). Another gene, the STM2 on chromosome 1 (presenilin 2 gene), has also been related with some pedigrees of AD; and, curiously, this gene is very close related in its function with the S182 (Levy-Lahad et al., 1995). At the cytogenetic level, some authors have reported certain chromosomal abnormalities associated with this disorder. In two sisters with late-onset AD, an unusual elongated short arm of chromosome 22 has been described, and this marker was also demonstrated in other 24 biological relatives of these patients (Percy et al., 1991). Other reports postulate that a nondisjunction, mainly affecting chromosome 21, may lead to AD through the same mechanism by which Down syndrome patients develop the disease (having an extra copy of chromosome 21) (Potter, 1991). An increase of chromosome breaks, acentric chromosomes, chromatid exchanges and high sensitivity to damage induced by chemical o physical agents reveal the fragility of the chromosomes in these patients (Nakanishi et al, 1979; Noderson et al., 1980; Ettinger et al., 1994). Another age-related cytogenetic event more recently described was the formation of micronuclei and a significant increase in the loss of chromosomes in both males and females with age, especially involving chromosome X in females and chromosome Y in males (Hando et al., 1994). In this paper, we present some cytogenetic findings observed in metaphases of AD lymphocytes in comparison with an age-matched healthy eldery controls.

Summary. An accurate diagnosis of a mentally retarded patient is a crucial step to design a successful treatment. The effects ofgenetic and environmental influences have to be clarified in the etiological approach. For that reason, we have to record a moreappropiate family information, detailed prenatal, birth and postnatal patient history, and perform a thorough clinical examina-tion to check for associated major and minor malformations. One of the major question to be resolved when faced with a mentallyretarded patient is whether the disease is genetically or environmentally determined. The main purpose of this paper is to describea general methodology we apply in genetic counselling of mental retardation including diagnosis, risks evaluation and psychologicalsteps that we have to consider when we inform family members at risk. [REV NEUROL 2001; 33 (Supl 1): S1-6] Key words. Diagnosis. Environment. Etiology. Genetic counselling. Human. Inheritance models. Mental retardation. Riskfactors. Syndromes.