Association of a CA repeat polymorphism upstream of the Fas ligand gene with multiple sclerosis.

We have analyzed a CA repeat polymorphism localized 46-kb upstream of the Fas ligand gene in Spanish and American populations that include 139 healthy controls and a cohort of 177 unrelated relapsing and remitting multiple sclerosis (MS) patients. The MS patients consisted of two groups, one with a family history of MS and one without. The frequency of the 13 CA repeats (allele B) was lower (p=0.01) in MS patients than in controls, 0.45 and 0.55 respectively. The odds ratio (BB vs. AB/AA) for MS patients vs. healthy controls was 0.51 (95% CI 0.3-0.9; p=0.01). The odds ratio (BB vs. AB/AA) for MS patients extracted from multiply affected families vs. healthy controls was 0.22 (95% CI 0.07-0.62; p=0.002). The HLA DRB1*1501-DQB1*0602 haplotype is associated with B allele with a relative frequency higher than A allele (0.52 and 0.48 in patients vs. 0.68 and 0.32 in controls). The results suggest that chromosomes with B allele have a genetic background that reduces susceptibility to MS, particularly in the familial forms.

Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations.

Mutations in the Kritl gene have been recently discovered as the cause of hereditary cerebral cavernous angioma. We sought the possibility that de novo, noninherited mutations of Kritl also cause cavernous angioma. A patient with two cerebral malformations carries a heterozygous deletion of two base pairs (741delTC) in exon VI of the Kritl gene. The deletion initiates a frameshift mutation that, 23 amino acids downstream, encodes a TAA stop triplet replacing a CAT triplet of histidine at exon VII (H271X). Magnetic resonance images of the parents were normal, neither parent carries the 741delTC mutation, and both bear the wild-type sequence of exon VI. These findings document a de novo germline mutation in Kritl gene that causes cerebral cavernous malformations.

Serum endothelial adhesion molecules levels correlate with lesion burden in multiple sclerosis patients treated with interferon beta-1b.

The levels of serum-soluble intracellular adhesion molecule-1 and soluble endothelial-leukocyte adhesion molecule-1, and the Gadolinium-enhanced T1-weighted MRI were studied in a group of patients with relapsing-remitting multiple sclerosis treated with interferon beta-1b and compared to a non-treated control group. The levels of serum-soluble intracellular adhesion molecule-1 and soluble endothelial-leukocyte adhesion molecule-1 increased, after three months treatment, as compared to baseline and the non-treated MS patients. A significant correlation was found in the treated group between serum-soluble endothelial-leukocyte adhesion molecule-1 and the lesion area in the Gadolinium-enhancing (T2 weighted scan) MRI.

The oxidation-reduction state of serum proteins in multiple sclerosis patients: effect of interferon beta-1b.

The concentration of reduction equivalents in serum was studied in a cohort of healthy individuals, in a group of multiple sclerosis (MS) patients undergoing treatment with interferon beta-1b and another group of MS patients who refused treatment with interferon beta-1b. Two classes of sulfhydryl groups were detectable in serum: (1) the uncovered sulfhydryls, accessible to the oxidation-reduction substrate 5,5-dithiobis-(-2-nitrobenzoic acid) (DTNB); and (2) the hidden sulfhydryls that required previous heat denaturation of serum proteins to become accessible to DTNB. The concentration of the reduced form of both the uncovered- and hidden-type of sulfhydryls was higher in the serum of MS patients than in healthy individuals. Interferon beta-1b lowered the plasma concentration of the uncovered reduced sulfhydryls after 3 months of treatment. This was in contrast to a minor effect of interferon beta-1b in the hidden-form of sulfhydryl groups. The results suggest that the concentration of reduced sulfhydryls is a biochemical marker of the in vivo oxidation/reduction reactions in MS.