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Biomedical subjects

A M Cobo

Publications and source records attributed to A M Cobo.

27 records · Page 2Linked to original sources
PubMed1995

[Diseases due to instability of DNA].

The catalog of genetic diseases whose mutational mechanisms are based on the expansion of nucleotide triplets includes 8 disorders classified in terms of type of triplet sequence and the mechanism by which the mutation manifests clinically. To date there are 3 groups. The first is made up of several mental retardation syndromes linked to fragility in the X chromosome (FRAXA, FRAXE, FRAXF, FRA16), with CGG type triplets and large growth expansions located close to a CpG island whose methylation determines degree of chromosome fragility as well as the size of expansion. The second group encompasses diseases arising from CAG triplets. Examples are spinal bulbar atrophy, Huntington's chorea (HC), type 1 dominant cerebellar ataxia (DCA1), dentatorubral-pallidoluysian atrophy (DRPLA) and Machado-Joseph's disease. In this group the expansion codes a polyglutamate residue that gives rise to clinical manifestations by way of functional gain. Myotonic dystrophy (MD) remains in a separate group, with large-size expansion but no chromosomal fragility, and clinical manifestations in multiple systems. All entities encompass phenotypic variation or tendency to inter-generational growth of the expanded fragment that triggers the anticipation phenomenon to varying degrees--greater for some diseases (MD) in cases of maternal transmission and for others (DCA1, HC and DRPLA) when transmission is paternal. The mechanisms by which expansions occur is unknown but the decisive element in some entities may be failure to correct errors in DNA duplication and errors in the integrity of the repeated sequence. We review the difficulties inherent in establishing correlations between genotype and phenotype and in providing genetic counseling.

Chromosome Aberrations↗
PubMed1994

Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy.

In myotonic dystrophy (DM), the size of a CTG repeat in the DM kinase gene generally increases in successive generations with clinical evidence of anticipation. However, there have also been cases with an intergenerational contraction of the repeat. We examined 1,489 DM parent-offspring pairs, of which 95 (6.4%) showed such contractions in peripheral blood leukocytes (PBL). In 56 of the 95 pairs, clinical data allowed an analysis of their anticipation status. It is surprising that anticipation occurred in 27 (48%) of these 56 pairs, while none clearly showed a later onset of DM in the symptomatic offspring. The contraction occurred in 76 (10%) of 753 paternal transmissions and in 19 (3%) of 736 maternal transmissions. Anticipation was observed more frequently in maternal (85%) than in paternal (37%) transmissions (P < .001). The parental repeat size correlated with the size of intergenerational contraction (r2 = .50, P << .001), and the slope of linear regression was steeper in paternal (-.62) than in maternal (-.30) transmissions (P << .001). Sixteen DM parents had multiple DM offspring with the CTG repeat contractions. This frequency was higher than the frequency expected from the probability of the repeat contractions (6.4%) and the size of DM sib population (1.54 DM offspring per DM parent, in 968 DM parents). We conclude that (1) intergenerational contractions of the CTG repeat in leukocyte DNA frequently accompanies apparent anticipation, especially when DM is maternally transmitted, and (2) the paternal origin of the repeat and the presence of the repeat contraction in a sibling increase the probability of the CTG repeat contraction.

Adolescent↗
PubMed1993

[Direct genotypic analysis of myotonic dystrophy: detection of an unstable DNA fragment in carriers].

BACKGROUND: Myotonic dystrophy (DM) is an inherited autosomal dominant disorder. The molecular defect responsible for the disease is the expansion of a CTG triplet at the 3' end of the DM gene. We report the analysis of the gene expansion, its correlation with the clinical severity and with the phenomenon of anticipation. METHODS: Using the cDNA25 probe, we have analyzed 140 affected DM patients from a total of 42 families comprising 303 individuals. According to the clinical status, the affected DM patients were classified as follows: group I, congenital form; group II, classical form, and group III, mild form. RESULTS: A larger than normal fragment was detected in all the DM patients but in none of the controls. The expansion size is 2.5-6 kb in group I, 0.3-5 kb in group II and 0.2-1.5 kb in group III. In 49 parent-child couples which show clinical anticipation, 47 have an increase in size of the fragment from one generation to the next. CONCLUSIONS: Our results show a clear correlation between the severity of the disease and the expansion size. We confirm at the molecular level the phenomenon of anticipation. The direct gene analysis of the DM families allows the diagnosis of all the at-risk individuals and facilitates the genetic counselling of these families.

Adult↗
PubMed1991

[Application of the polymerase chain reaction technique (PCR) to the molecular diagnosis of myotonic dystrophy].

We report the application of the PCR technique to study the CKMM polymorphisms in 39 Spanish Myotonic Dystrophy affected families. We have studied 255 subjects comprising 116 clinically affected DM patients. The molecular study was informative in 64% of the DM patients. For the 76 at risk individuals, the study was informative in 46 of them, confirming the non carrier status in 34 individuals and demonstrating the at risk haplotype in 12. In the remaining 30 subjects, it was not possible to establish a diagnose with this technique exclusively. The use of the CKMM probe in the DM genetic studies was extremely useful because of the close linkage with the gene (1 cM) and the high heterozygosity (PIC = 0.33). The allelic frequencies detected by the TaqI enzyme (allele I = 0.27; allele i = 0.73) and NcoI enzyme (allele J = 0.29; allele j = 0.71) are similar to the previously reported in other european populations.

Base Sequence↗
PubMed1990

[Prenatal diagnosis of myotonic dystrophy: the first experience in Spain].

We report the first prenatal diagnosis of myotonic dystrophy (MD) in Spain by DNA techniques. The previous familiar study allowed us to determine the DM haplotype in this family with the following probe/enzyme combinations: p4.1/Msp I, LDR 152/Bgl II, Apo CII/Ban I, Taq I, Bam HI, pSCII/Bgl I. In the tenth week of amenorrhea, a transabdominal biopsy was done to obtain chorionic villi. One part of the sample was processed for the cytogenetic analysis that revealed a 46 XY karyotype. The other part was used to perform the molecular analysis with two probes, p4.1 and LDR 152, determining that the fetus was a DM gene carrier with a 96% probability.

Family Health↗
PubMed1990

[Genetic analysis of Spanish families with myotonic dystrophy].

Myotonic dystrophy (MD) is the most common form of muscular dystrophy in adult life, with a clinical prevalence of 5.5/100,000, being the gene prevalence of 13.5. The disease is autosomal dominant with variable expressivity, existing a congenital form with a severe prognosis. Recent genetic studies revealed that the DM gene is localized in the chromosome's 19 proximal long arm and with recombinant DNA techniques, several polymorphic markers have been isolated near the gene, the closet being Apo-CII, LDR 152 and p 4.1. We have studied clinically, electrophysiologically and by genetic analysis 6 families with 32 individuals. We have diagnosed the disease in 16 individuals and after the molecular analysis, the DM gene was totally excluded in 6 clinically healthy individuals. In our preliminary study, the use of Msp I/p 4.1, Bgl II/LDR 152 y Ban I, Bgl I, Taq I/Apo-CII c-DNA and genomic was found the most informative combination. These molecular analysis seem to be very useful as a complement to the diagnosis of myotonic dystrophy.

Adolescent↗
PubMedDate not supplied

[Alterations in functional proteins. Calpaine-3 deficiency].

INTRODUCTION: Muscular dystrophies due to calpain deficiency are the first example of a muscular dystrophy due to the mutation of a gene codifying for a non-structural enzymatic protein of unknown function and substrate. DEVELOPMENT: More than 70 mutations have been described in the gene structure, localized to chromosome 15. Although the time course and topography is fairly homogeneous, correlation between the different mutations and the phenotype has still to be analyzed. The age of onset of symptoms is usually between 8 and 14, with no difference between the sexes. There is a slow but uniformly progressive course starting in the pelvis and extending to the shoulder and the distal musculature. Almost all patients are confined to a wheelchair twenty years after onset of the disease. There is no facial, oculomotor or bulbar involvement and gemellar pseudohypertrophy is rare. However, a winged scapula and marked lumbar hyperlordosis is universal. No cardiac or cognitive changes have been observed. Muscle CT shows a pattern of atrophy, mainly of the posterior and medial muscle compartments and of the posterosuperficial group of the legs, which varies depending on the time the disorder has been present. This condition is the commonest etiological group of the dystrophy syndromes, especially of those of late infancy or juvenile onset, in the open populations studied to date. Muscle biopsy, stained by all methods available, is essential to rule out other types of progressive dystrophies secondary to deficiencies of structural proteins.

Adult↗