[Unusual molecular changes in two families with Friedreich's ataxia]. / Alteraciones moleculares inusuales en dos familias con ataxia de Friedreich.

Friedreich's ataxia is an autosomal recessive disease generally characterized by the presence of microsatellite expansion in a GAA triplet. The patients inherit a pathologic allele from each one of their parents, that may sometimes show GAA triplet expansions or contractions. Two familial studies of typical Friedreich's ataxia are described. Their molecular study demonstrated marked intergenerational instability and an abnormally long expansion of the GAA triplet in the father in the other one. In the first case, there were expansions of 680/815 repetitions, being characterized by an expansion of 290 repetitions GAA in the father-patient transmission. The second case presented GAA of 1,260/1,095 expansions, while the expanded allele of the father was 1,350 repetitions. These cases illustrate that there can be both expansion as well as contraction of the GAA triplet from alleles of paternal origin in the disease, without any apparent phenotypic changes.

[Degree of association between serum levels and genotype in alpha-1-antitrypsin deficiency. Clinical usefulness]. / Grado de asociación entre valores séricos y genotipo en el déficit de alfa-1-antitripsina. Utilidad clínica.

AIM: To determine the degree of association between serum alpha-1-antitrypsin levels and its phenotypes as well as its clinical expression. PATIENTS AND METHODS: The alpha-1-antitrypsin genotype was identified using polymerase chain reaction followed by restriction enzyme digest in 212 patients in whom serum alpha-1-antitrypsin determination had been requested. The reasons for the request, the existence of pulmonary or liver disease, clinical diagnoses and functional repercussions were analyzed. RESULTS: Two hundred and twelve patients were evaluated (68% males; mean age: 34 20 years). In 23 patients (10.8%) a deficiency variant was found (one or two M alleles were lacking) and in 8 patients (3.8%) the genotype was ZZ. All patients with MM genotype had alpha-1-antitrypsin levels of 75 mg/dl or higher while none of the patients with ZZ genotype had levels higher than 40 ml/dl. All the patients with ZZ genotype showed alterations: 3 had pulmonary emphysema, 1 had chronic obstructive pulmonary disease and 4 had hypertransaminasemia. One patient with pulmonary emphysema had severe respiratory insufficiency while in the remaining patients with respiratory problems, respiratory insufficiency was slight or moderate. None of the patients with hypertransaminasemia showed echographic signs of portal hypertension or clinical or laboratory signs of reduced liver function. CONCLUSIONS: There is a close association between alpha-1-antitrypsin levels and the different genotypes. Consequently, in basal conditions with serum alpha-1-antitrypsin levels higher than 75 mg/dl genotyping is not required. The functional repercussions of deficiency variants in young adults is slight.

Impairment of metabolic function in chronic hepatitis C is related to factors associated with resistance to therapy.

OBJECTIVE: Liver disease causes a loss of hepatic function, and remission is associated with improved functional hepatic mass. The object of the present study was to investigate whether liver metabolic function assessed by antipyrine clearance is related to other disease characteristics influencing response to therapy in chronic hepatitis C. METHODS: Patients (n = 96) received three different treatment regimens: one group received interferon alfa-2b for 48 wk; in a second group with maintained positive hepatitis C virus (HCV) RNA after 12 wk, interferon was combined for 36 wk with oral ribavirin; and patients who were relapsers or nonresponders to a previous therapy with interferon alone received interferon alfa-2b plus ribavirin for 48 wk. RESULTS: Twenty-five patients (26%) showed sustained normalization of ALT levels and negative HCV RNA 6 months after therapy. The response was more likely to be sustained in patients with a genotype other than 1 (52.0% vs 15.5% in patients with genotype 1, p < 0.001), and the percentage of sustained responders was higher among patients who demonstrated negativity of HCV RNA at the end of 4 wk of treatment (64% vs 13% without negativity, p < 0.001). Sustained response was associated with significantly lower baseline serum ferritin (-46%, p < 0.01) and duration of infection (-33%, p < 0.01). Baseline antipyrine clearance was higher in sustained responders than in nonresponders (+19%, p < 0.05) and lower in genotype 1 patients than in those with a genotype other than 1 (-24%, p < 0.05). Antipyrine clearance increased by 12% at the end of the 48-wk course of treatment among sustained responders (+34% vs nonresponders, p < 0.001) and still remained elevated at the end of the follow-up (+35% vs nonresponders, p < 0.001). CONCLUSION: In summary, the present study shows that liver oxidative metabolism is related to antiviral response rates and suggests that much of the effect is explained by viral genotype.

C282Y and H63D mutations of the haemochromatosis gene in patients with iron overload.

OBJECTIVE: To determine the relevance of C282Y and H63D mutations of HEF gene in patients with iron overload. PATIENTS AND METHODS: Patients with iron overload referred to our Liver Unit were included in the study. The association of mutations to different diagnosis and their impact on the severity of the hepatopathy were explored. Sensitivity, specificity and positive and negative predictive values of mutations for the diagnosis of haemochromatosis were determined. RESULTS: The study included 78 patients with iron overload. The control group included 21 patients of similar age and sex ratio without iron overload nor hepatopathy. Twenty three patients had haemochromatosis, 22 alcoholic liver disease and 33 other diseases unrelated to iron metabolism. Seventy three per cent of patients with haemochromatosis were homozygous for the C282Y mutation. All the C282Y homozygous subjects had also haemochromatosis. Fifty three per cent of patients with alcoholic hepatopathy had some kind of mutation. This has been also observed in 70% of patients with iron-unrelated diseases. Such percentage was significantly greater than in the control group (24% with H63D mutation). C282Y homozygosity in patients with iron overload had a sensitivity of 73.9%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 89.6%. CONCLUSIONS: In our population, as in all the Western countries, haemochromatosis is mainly associated to homozygous C282Y mutation. The high frequency of mutations in patients with iron overload and without haemochromatosis suggests the involvement of such mutations in iron overload.

Mutaciones C282y y H63D del gen de la hemocromatosis en los pacientes con sobrecarga férrica / C282Y and H63D mutations of the haemochromatosis gene in patients with iron overload

Objetivo: conocer la utilidad de las mutaciones C282Y y H63D del gen HEF en los pacientes con sobrecarga férrica. Pacientes y métodos: se han estudiado los pacientes con sobrecarga férrica enviados a la Unidad de Hígado. Se han relacionado las mutaciones con los diferentes diagnósticos y su influencia en la severidad de la hepatopatía. Se ha determinado la sensibilidad, especificidad, valor predictivo positivo y negativo de las mutaciones para el diagnóstico de hemocromatosis. Resultados: se estudiaron 78 pacientes con sobrecarga férrica y 21 pacientes sin sobrecarga férrica ni hepatopatía, de similar edad y proporción de sexos. 23 padecían hemocromatosis, 22 hepatopatía alcohólica y 33 otras enfermedades no relacionadas con el metabolismo del hierro. El 73,21 por ciento de los pacientes con hemocromatosis eran homocigotos para la mutación C282Y. No hubo ningún homocigoto C282Y que no padeciese hemocromatosis. El 53 por ciento de los pacientes con hepatopatía alcohólica presentaba alguna mutación, lo que se ha objetivado en el 70 por ciento de los pacientes con otras patologías. Esto era significativamente más alto que lo que sucedía en el grupo control en que el 24 por ciento presentaba mutación H63D. En los pacientes con sobrecarga férrica, la situación de homocigoto C282Y tiene una sensibilidad del 73,91 por ciento, una especificidad del 100 por ciento, un valor predictivo positivo del 100 por ciento y un valor predictivo negativo del 89,65 por ciento. Conclusiones : en nuestro medio, como en todo el mundo occidental, la mayor parte de las hemocromatosis se asocian a la mutación C282Y en homocigosis. La elevada frecuencia de mutaciones en pacientes con sobrecarga férrica sin hemocromatosis sugiere responsabilidad de las mismas en dicha sobrecarga (AU)

A dominant negative protein kinase C zeta subspecies blocks NF-kappa B activation.

Nuclear factor kappa B (NF-kappa B) plays a critical role in the regulation of a number of genes. NF-kappa B is a heterodimer of 50- and 65-kDa subunits sequestered in the cytoplasm complexed to inhibitory protein I kappa B. Following stimulation of cells, I kappa B dissociates from NF-kappa B, allowing its translocation to the nucleus, where it carries out the transactivation function. The precise mechanism controlling NF-kappa B activation and the involvement of members of the protein kinase C (PKC) family of isotypes have previously been investigated. It was found that phorbol myristate acetate, (PMA) which is a potent stimulant of phorbol ester-sensitive PKC isotypes, activates NF-kappa B. However, the role of PMA-sensitive PKCs in vivo is not as apparent. It has recently been demonstrated in the model system of Xenopus laevis oocytes that the PMA-insensitive PKC isotype, zeta PKC, is a required step in the activation of NF-kappa B in response to ras p21. We demonstrate here that overexpression of zeta PKC is by itself sufficient to stimulate a permanent translocation of functionally active NF-kappa B into the nucleus of NIH 3T3 fibroblasts and that transfection of a kinase-defective dominant negative mutant of zeta PKC dramatically inhibits the kappa B-dependent transactivation of a chloramphenicol acetyltransferase reporter plasmid in NIH 3T3 fibroblasts. All these results support the notion that zeta PKC plays a decisive role in NF-kappa B regulation in mammalian cells.