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J J Vílchez

Publications and source records attributed to J J Vílchez.

At least 19 recordsLinked to original sources
PubMed2006

Dysferlin expression in monocytes: a source of mRNA for mutation analysis.

Dysferlin protein is expressed in peripheral blood monocytes. The genomic analysis of the DYSF gene has proved to be time consuming because it has 55 exons. We designed a mutational screening strategy based on cDNA from monocytes to find out whether the mutational analysis could be performed in mRNA from a source less invasive than the muscle biopsy. We studied 34 patients from 23 families diagnosed with dysferlinopathy. The diagnosis was based on clinical findings and on the absence of protein expression using either immunohistochemistry or Western blot of skeletal muscle and/or monocytes. We identified 28 different mutations, 13 of which were novel. The DYSF mutations in both alleles were found in 30 patients and only in one allele in four. The results were confirmed using genomic DNA in 26/34 patients. This is the first report to furnish evidence of reliable mutational analysis using monocytes cDNA and constitutes a good alternative to genomic DNA analysis.

DNA Mutational Analysis↗
PubMed2004

[Different phenotypes of Charcot-Marie-Tooth disease caused by mutations in the same gene. Are classical criteria for classification still valid?].

Molecular genetic research is leading to the continuous discovery of new genes and protein involved in peripheral nerves function. Simultaneously, extended clinical, neurophysiological and pathological research has yielded new genotype-phenotype correlation on Charcot-Marie-Tooth disease (CMT). This has made it possible to know that several genes can cause both demyelinating (CMT1) and axonal (CMT2) phenotypes. Those observations have questioned the validity of some current criteria for CMT classification and raise the need for new strategies for diagnosis. The discovery of Schwann cell-axon interaction is a challenge for coming years. In this review, we extensively analyzed mutations of genes that give rise to CMT1 or CMT2 phenotypes. There are at least three forms of genetic variability. MPZ gene mutations yield a real allelism, that is, CMT1 or CMT phenotypes associated to specific mutation by site or quality. GADP1 and probably NF-L gene manifest different phenotypes but only in terms of nerve conduction velocity (CV). Evidence is provided that indicates that CV reduction in GADP-1 neuropathy may be the result of axonal loss. Finally a third form of variability is present in CMTX due to the degree of clinical expression in females related with the inactivation of chromosome X.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Genotype and phenotype analysis of Friedreich's ataxia compound heterozygous patients.

Friedreich's ataxia is caused by mutations in the FRDA gene that encodes frataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygous for the expansion of a GAA triplet repeat within the FRDA gene, but a few patients show compound heterozygosity for a point mutation and the GAA-repeat expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. Patients heterozygous for the GAA expansion were screened for point mutations within the FRDA coding region. Molecular analyses included the single-strand conformation polymorphism analysis, direct sequencing, and linkage analysis with FRDA locus flanking markers. Seven compound heterozygous patients were identified. In four patients, a point mutation that predicts a truncated frataxin was detected. Three of them associated classic early-onset Friedreich's ataxia with an expanded GAA allele greater than 800 repeats. The other patient associated late-onset disease at the age of 29 years with a 350-GAA repeat expansion. In two patients manifesting the classical phenotype, no changes were observed by single-strand conformation polymorphism (SSCP) analysis. Linkage analysis in a family with two children affected by an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich's ataxia patients are null mutations. In the present patients, clinical phenotype seems to be related to the GAA repeat number in the expanded allele. Complete molecular definition in these patients is required for clinical diagnosis and genetic counseling.

Adult↗
PubMed1999

Early onset cerebellar ataxia and preservation of tendon reflexes: clinical phenotypes associated with GAA trinucleotide repeat expanded and non-expanded genotypes.

The aim of this study was to determine phenotypie characteristics of patients with early onset cerebellar ataxia (EOCA) with preserved tendon reflexes. The series comprises 25 patients, representing 10% of all ataxic patients who have been genetically studied in our laboratory since 1990. There were 11 males and 14 females. Fourteen patients were homozygous for the GAA expansion on chromosome 9q13 (group 1) and therefore a diagnosis of Friedreich's ataxia with retained reflexes (FARR) was given. The remaining 11 patients had two normal non-expanded alleles (group 2) and a working diagnosis of EOCA with retained reflexes (EOCARR) was established. Mean ages of onset were 13.7 +/- 5.9 years (3-25) for group 1 and 10.3 +/- 7.3 for group 2; the difference was not significant. Frequencies of symptoms and signs were also comparable for both groups the only significant differences being the higher frequency of nystagmus, cardiomyopathy and sensory neuropathy in group 1 patients. There was a tendency for FARR patients to have higher frequencies of hypopallesthesia in the lower limbs and skeletal deformities. In none of the cases diabetes mellitus was observed. We conclude that differentiation of FARR and EOCARR may be suspected by classical clinical and electrophysiological data and confirmed by analysis of the GAA repeat.

Adolescent↗
PubMed1997

Mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies.

Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsies (HNPP) are two inherited peripheral neuropathies. The most prevalent mutations are a reciprocal 1.5-Mb duplication and 1.5-Mb deletion, respectively, at the CMT1A/HNPP locus on chromosome 17p11.2. Point mutations in the coding region of the myelin genes, peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) or connexin 32 (Cx32) have been reported in CMT patients, including CMT type 1 (CMT1), CMT type 2 (CMT2) and Déjérine-Sottas neuropathy (DS) patients, and only in the coding region of PMP22 in HNPP families lacking a deletion. We have investigated point and small mutations in the MPZ, PMP22 and Cx32 genes in a series of patients of Spanish ancestry: 47 CMT patients without duplications, and 5 HNPP patients without deletions. We found 15 different mutations in 16 CMT patients (34%). Nine different mutations in ten patients were detected in the Cx32 gene, this being the most frequently involved gene in this series, whereas five mutations involved the MPZ gene and only one the PMP22 gene. Six out of nine nucleotide substitutions in the Cx32 gene involved two codons encoding arginine at positions 164 and 183, suggesting that these two codons may constitute two Cx32 regions prone to mutate in the Spanish population. Analysis of HNPP patients revealed a 5' splicing mutation in intron 1 of the PMP22 gene in a family with autosomal dominance, which confirms allelic heterogeneity in HNPP. Ectopic mRNA analysis on leukocytes suggests that this mutation might behave as a null allele.

Charcot-Marie-Tooth Disease↗
PubMed1997

Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat.

The Friedreich ataxia (FA) mutation has recently been identified as an unstable trinucleotide GAA repeat present 7-22 times in the normal population but amplified as many as > 1,000 times in FA. Since it is an autosomal recessive disease, FA does not show typical features observed in other dynamic mutation disorders, such as genetic anticipation. We have analyzed the GAA repeat in 104 FA patients and 163 carrier relatives previously defined by linkage analysis. The GAA expansion was detected in all patients, most (94%) of them being homozygous for the mutation. We have demonstrated that clinical variability in FA is related to the size of the expanded alleles: milder forms of the disease-late-onset FA and FA with retained reflexes-are associated with shorter expansions, especially with the smaller of the two expanded alleles. Absence of cardiomyopathy is also associated with shorter alleles. Dynamics of the GAA repeat has been investigated in 212 parent-offspring pairs. Meiotic instability showed a sex bias: paternally transmitted alleles tend to decrease in a linear way that depends on the paternal expansion size, whereas maternal alleles can either increase or decrease. A different pattern of intergenerational variation was also observed, depending on the genetic status of the sib: patients had shorter expansions than were seen in heterozygous carriers. This finding has been interpreted as a postzygotic event. Finally, we have observed that the size of the expansion remains constant in the population through carriers.

Adolescent↗
PubMed1997

[Analysis of the situation of Valencian neurology by the Commission of Analysis of the Quality of Valencian Neurological Society].

INTRODUCTION: The Comision de Analisis de la Calidad de la Sociedad Valenciana de Neurologia has made a proposal of Neurology care requirements, based on the findings of various studies done in this region. There studies suggest that there should be a proportion of 3 neurologists per 100,000 inhabitants. METHOD: An analysis of requirements was made, based on evaluation of the public health service, private practice and trainee specialists (MIR) regarding this problem. The need for emergency neurological attention, and the place of a hierarchy and a system for referral was also considered. RESULTS: It was calculated that 109 neurologists are required, 11 in Castellon, 63 in Valencia and 35 in Alicante. This would mean a proportion of 2,66 neurologists per 100,000 inhabitants in Castellon, 2,90 in Valencia and 2,70 in Alicante. The total figure for the whole Community would be 2,82 per 100,000 inhabitants. CONCLUSIONS: At the present time neurological care is expensive, since a lack of specialists means waiting lists, poor patient care and high costs due to inappropriate use of technical resources.

Emergency Medical Services↗
PubMed1997

[Predictive value of the study of cerebro-spinal fluid in neurological diseases. Discriminant analysis of 733 cases].

INTRODUCTION: The study of cerebrospinal fluid (CSF) gives very valuable data for the diagnosis of certain neurological disorders. Objective. To discover the discriminative value of different tests and their usefulness in the study of neurological disorders. MATERIAL AND METHODS: Discriminative multivariate analysis was used for the group of parameters obtained from study of CSF and serum in a sample of 733 patients. BO was included, CSF cytobiochemical data and five of the equations used for calculation of the synthesis of intrathecal IgG. RESULTS: The best discriminative function was expressed as the intrathecal IgG with normal BHE. The formula of Tourtellotte was noteworthy for overestimation of the synthesis of intrathecal IgG when the albumin index indicated BHE rupture. Prospective reclassification of the 733 cases showed that these tests are well worthwhile to rule out immunologically mediated disorders (93% of the cases were correctly reclassified); they suggest the diagnosis in multiple sclerosis (66% correctly reclassified) and give very poor reliability when trying to distinguish between inflammatory infectious processes. CONCLUSIONS: In spite of their undoubted use in supporting the clinical diagnosis, the tests used for study of the synthesis of IgG, even complemented by cytobiochemical examination of the CSF, are not in themselves sufficient for use as a discriminative test in the differential diagnosis of neurological processes.

Albumins↗
PubMed1996

[Magnetic resonance of the brain in encephalitis due to Epstein-Barr virus].

Encephalitis due to Epstein-Barr virus (EEBV) is rare and the debate on possible pathogenic mechanisms has remained open in the absence of structural changes in brain images and discrepancies in serology and viral culture results. We describe an EEBV case in which magnetic resonance images in T1 and T2 potentiated sequences were normal, although intense meningeal captation and a destructive parenchymatous lesion could be observed after administration of gadolinium. These findings suggest direct infiltration of the central nervous system by the virus as well as a meningeal infiltrative type reaction, supporting the hypothesis that the pathogenic mechanisms involved is invasive rather than infectiously or immunologically mediated. The pattern of involvement seen in EEBV by magnetic resonance is different from that of other forms of viral encephalitis.

Adult↗
PubMed1995

[The diagnosis and prevalence of locus CMT1A duplication in Charcot-Marie-Tooth disease type 1].

BACKGROUND: The Charcot-Marie-Tooth (CMT) disease or hereditary motor-sensitive neuropathy (HMSN) is the most frequent hereditary neuropathy. The demyelinated or type 1 form (CMT1) is the most frequently presented, commonly being of a dominant autosomic inheritance. CMT1 is heterogeneous genetically and the subjacent mutation found in most of the cases is a duplication of 1,500 kb in the CMT1A locus of chromosome 17p11.2. The aim of the present study was to determine the prevalence of CMT1A duplication in patients with CMT1 and evaluate its usefulness as a biological diagnostic marker. METHODS: The study was carried out in a group of patients with HMSN who were not related, and were distributed according to the following diagnostic categories: CMT1 (n = 49), CMT2 (n = 9), untyped CMT (n = 11) and Déjérine-Sottas (DS) disease (n = 4). To detect three alleles confirming the presence of duplication the DNA of the patients was analyzed with four polymorph markers, VAW409R3a, RM11-GT, VAW412R3HEc and EW401HE localized in the CMT1A locus. RESULTS: CMT1A duplication was found in 68.7% of the patients with CMT1 and in 27.2% of untyped CMT patients. None of the individuals in the CMT2 and DS categories showed duplication. Cases pertaining to families with dominant autosomic inheritance and genetically sporadic cases were confirmed to show a high prevalence of duplication, being of 83.3% and 85.7%, respectively. CONCLUSIONS: Duplication of the CMT1A locus is the most prevalent mutation found in Charcot-Marie-Tooth type 1 disease. It is a specific mutation of this disease among the different forms of hereditary motor-sensitive neuropathy. This mutation is useful as a biological marker in the diagnosis of these neuropathies.

Alleles↗
PubMed1995

Friedreich's ataxia: an epidemiological study in Valencia, Spain, based on consanguinity analysis.

Epidemiological studies performed directly on the population show a prevalence of Friedreich's ataxia (FA) from 1 to 4.7 cases/100,000 inhabitants. An indirect epidemiological approach can be achieved using genetic methods like consanguinity studies to determine the frequency of a mutated gene and the incidence of certain diseases in the population. We obtained consanguinity data of a series of FA patients in Valencia, Spain and the figures on consanguinity in the general population that were estimated according to the Archive of Dispensations given by the Catholic church for consanguineous marriages. From these data, the frequency of the FA gene was calculated as 1/127. From these data, applying the Hardy-Weinberg principle, the frequency of the carriers was 1/64 and the incidence was 6.18/100,000 live births. Assuming a life expectancy of FA of 45 years, the prevalence was 3.83/100,000 inhabitants. These figures are in the same range as those obtained in population studies.

Consanguinity↗
PubMed1995

[Deletion of 17p11.2 chromosome in Spanish families with hereditary neuropathy and abnormal sensitivity to pressure].

Hereditary neuropathy with abnormal liability to pressure palsies (HNPP) is a dominant autosomally transmitted disease that gives rise to foci of peripheral nerve myelination, reducing conduction and leading to episodes of palsy and sensory changes that are all linked to sensitivity to pressure and traction on the affected nerve roots. The molecular basis of HNPP has been identified as a submicroscopic deletion of the 17p11.2 chromosome in exactly the same region that it is duplicated in Charcot-Marie-Tooth disease, type 1A (CMT1A). We report genetic analyses of 13 patients (belonging to 3 families) diagnosed of HNPP by means of physical examination and electrophysiologic and morphologic tests (the last in 3 cases only). Inter- and intrafamilial variation in symptomatology was studied. Some patients presented the usual clinical signs, such as recidivating brachial plexus palsy, permanent sensory polyneuropathy, foot deformities and others that might also be found in patients with CMT1A. All the patients showed electrophysiologic signs of underlying demyelinating polyneuropathy. Genetic study centered on detecting the deletion of 17p11.2 by segregation analysis with the polymorphic markers VAW409R3a (D17S122) and EW401HE (D17S61). Our results confirmed deletion at the CTM1A location of chromosome 17p11.2 in all 13 patients examined. These data suggest that the deletion of 17p11.2 plays a causal role in HNPP and that it is the most prevalent mutation in this disease; our findings constitute new evidence of the importance of the CMT1A/HNPP locus in the formation and control of peripheral myelin and in the ultimate functioning of peripheral nerves.

Adult↗
PubMed1993

[Scleromyxedema associated with myopathy].

We describe a 45 year-old man, with scleromyxedema associated to systemic manifestations, including myopathy. After 6 years of dermatologic manifestations, muscular weakness, with proximal predominance resulting in incapacity, was established. Corticosteroids plus cyclophosphamide treatment suppressed muscular symptomatology, and a second biopsy was normal. The common association between scleromyxedema and myopathy and other systemic alterations suggest that this entity should probably be considered as a systemic disease instead as a skin disease.

Cyclophosphamide↗
PubMed1990

[Genetic analysis of Friedreich's ataxia using polymorphic DNA markers].

Friedreich's ataxia (FA) is a progressive degenerative disease involving both central and peripheral nervous system. It is an autosomal recessive hereditary disorder, which begins around puberty and has an unknown genetic basis and biochemical defect. The recent mapping of FA locus in human chromosome 9 by means of the analysis of the molecular genetic linkage has permitted to evaluate FA genetics with polymorphic genetic markers (RFLPs) that are secreted linked with the FA gene. The normal and mutant allele secretion of FA was evaluated in ten Spanish families with one or two members with FA by means of several cloned probes (MCT112, DR47, D9S1 and HHH220), localized in chromosome 9 and strongly linked to FA gene, with the aim of achieving a predictive diagnosis of relatives in the pediatric age and to detect healthy carriers. In 9 out of 10 families some totally or partially informative RFLP were found. In 5 of 6 relatives in pediatric age the future development of the disease could be ruled out. By contrast, the carrier status could only be identified in three relatives. In a family with two affected children a genetic recombinant for D9S1 was found. Remarkably, one of them had a better clinical evolution and preserved tendon reflexes in lower limbs.

Adolescent↗