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Tissue inhibitor of metalloproteinases 1 (TIMP-1) inhibits several proteinases including a disintegrin and metalloproteinase 10 (ADAM10), a major alpha-secretase that cleaves the beta-amyloid precursor protein within its amyloidogenic Abeta domain. The gene encoding TIMP-1 (TIMP 1) maps to the short arm of the X chromosome, in a region previously suggested as conferring genetic susceptibility for Alzheimer's disease (AD). To determine whether genetic variability of TIMP 1 contributes to the pathogenesis of AD, we analysed one single nucleotide polymorphism within TIMP 1 and one single nucleotide polymorphism in the 5'-untranslated region of TIMP 1 in patients with AD and control subjects from two independent and ethnically different populations. We did not observe any association between TIMP 1 genotypes and the diagnosis of AD in men or women. We also measured TIMP-1 protein levels in the cerebrospinal fluid of patients with AD, healthy control subjects, and patients with other neurological disorders. TIMP-1 levels were similar in all groups. In addition, no significant differences were observed after stratification for TIMP 1 genotypes. Our data show that neither genetic variability nor protein levels of TIMP-1 are associated with AD.

Objectives: To characterize MS patients with the earliest onset of disease. Background : MS—primarily a disease of young adulthood—begins in childhood in 3 to 5% of cases. However, onset before 10 years of age is considered exceptional. Accordingly, inclusion age at onset is generally between 10 and 59 years. Methods : Information was obtained on patients with MS treated at our institution (n = 6) or from reports in Medline or bibliographies. Onset of disease was before 6 years of age, for a total of 49 patients (29 girls, 20 boys). Results : All patients had clinically defined MS according to Poser’s criteria; 22 were also laboratory supported. The female/male ratio (1.4) was lower than that usually recorded for adult onset MS (2.0) and that of MS with onset between 6 and 15 years (2.2 to 3.0). The group of patients (n = 5) with onset before 24 months of age showed the lowest ratio (0.6) and carried the most unfavorable prognosis. Among initial symptoms, ataxia was preponderant (61%). Optic nerve involvement became more frequent with age. Generalized or partial seizures occurred in 22% of cases. First inter-attack interval was less than 1 year in 63% of the cases. The yearly relapse rate ranged from 1.1 at disease onset to 0.2 after 9 years from disease onset. At follow-up (mean length 6.8 years), the disease was relapsing-remitting in 84% patients and the grade of recovery was complete in 64%. Conclusions : Definite MS can be consistently diagnosed by current criteria for adult onset MS in patients with the earliest onset of disease who show peculiar clinical features and natural history. These findings may suggest a reconsideration of current lower limits for MS diagnostic criteria.

Objective: To verify linkage to chromosome 19p13, to detect mutations in the CACNA1A gene, and to correlate genetic results to their clinical phenotypes in Italian families with familial hemiplegic migraine (FHM). Background: FHM is an autosomal dominant disease, classified as a subtype of migraine with aura. Only a proportion of FHM patients have been associated with chromosome 19p13. Among these, four missense mutations within the CACNA1A gene in five unrelated families have been described. Methods: A linkage study was performed in 19 patients affected by FHM from five families by studying microsatellite markers associated with the 19p13 region. All familial and seven additional sporadic patients with FHM were analyzed to search for mutations within the CACNA1A gene by applying the double gradient–denaturant gradient electrophoresis technique. Results: Lod score values did not establish significantly linkage to chromosome 19. However, seven new genetic variants were detected: six were new polymorphisms. The seventh was a missense mutation present in family 1, and it was associated with a hemiplegic migraine phenotype without unconsciousness and cerebellar ataxia. Because this missense mutation is absent in the general population and cosegregates with the disease, it may be a pathologic mutation. Conclusions: Genetic heterogeneity of FHM has been shown in familial and sporadic FHM patients of Italian origin. The new missense mutation—G4644T—is associated with milder clinical features compared with typical FHM.

CSF oligoclonal IgG bands are often found in MS or cerebral diseases in which there is chronic antigenic stimulation. Using agarose isoelectric focusing followed by immunoblotting, we found oligoclonal IgA bands in CSF from 16 of 20 randomly selected patients with MS, 7 of 7 with subacute sclerosing panencephalitis (SSPE), and 0 of 10 with noninflammatory neurologic or psychiatric disease. IgA bands did not correlate with the course or stage of MS. Serial samples from two patients with MS and one with SSPE demonstrated only minor changes in IgA banding pattern. One MS patient without oligoclonal IgG bands had oligoclonal IgA bands, indicating that the latter test may be helpful in the diagnosis of MS.