Journal of the Neurological Sciences 162 (1999) 194–200 Comparison of clinical and demographic features between affected pairs of Italian Multiple Sclerosis multiplex families; relation to tumour necrosis factor genomic polymorphisms a, a a b b a a * M. Trojano , M. Liguori , F. De Robertis , A. Stella , G. Guanti , C. Avolio , P. Livrea a Department of Neurological and Psychiatric Sciences, University of Bari, Piazza Giulio Cesare, 70124 Bari, Italy b Department of Genetics, University of Bari, Piazza Giulio Cesare, 70124 Bari, Italy Received 27 February 1998; received in revised form 12 October 1998; accepted 8 December 1998 Abstract We conducted a comparative analysis of clinical and demographic findings between pairs of relatives (36 sibling and 9 parent / child), concordant for Multiple Sclerosis (MS), from 40 MS Italian Multiplex families. A genetic TNF ( a and b) loci typing in 51 affected and 69 healthy relatives belonging to 25 of these families was also performed. The sib pairs resulted significantly concordant for age at onset ( r50.414, P,0.013), Progression Index (r50.34, P,0.05) and sensory symptoms at onset (k50.37), and significantly not concordant for sex (k520.37), whereas no concordance was found for year at onset and disease course. The only significant result in the small group of parent / child pairs was that parents developed MS at an age of 18.74 years significantly ( P50.020) greater than their children. Genomic analysis identified 13 variants of TNF-a alleles, 7 of TNF-b, 6 of TNF-d and 3 of TNF-e. No differences in the frequencies of the various TNF alleles were observed between affected and healthy relatives. The two-point lod-score analysis of the TNF locus showed not significant or negative results for the TNFa loci and slightly positive results (Z 50.4 at u 50.2 cM) for the TNFb-b locus in the lowest max penetrance dominant model. The Sib pair analysis, using combined TNFa and TNFb haplotypes, demonstrated a TNF allele sharing between affected sib-pairs which did not exceed the expected 50%. These results suggest that genetic factors may partially influence the disease onset and the progression rate in sibling pairs. A recall bias and / or an ‘anticipation phenomenon’ could explain the development of MS at an older age in parents than in their children. In this small-sized cohort of MS Italian families no significant associations were confirmed between TNF polymorphism and MS.  1999 Elsevier Science B.V. All rights reserved. Keywords: Multiple Sclerosis Multiplex Families; Clinical features; Demographic features; Tumor necrosis factor a and b loci; Microsatellites 1. Introduction affected first-degree relative [32]; the concordance rate between monozygotic twins is higher (50%) than that Families in which two or more relatives have developed between dizygotic twins [23] which results to be approxi- Multiple Sclerosis (MS) provide a valuable source for mately the same as that for like-sex non-twin siblings testing the relative contribution of genetic and environmen- [29,32]. Studies of adoptees [5,6] and half sibs [35] tal factors in disease etiology and the possible existence of supported the hypothesis that familial aggregation of MS is clinical phenotypes that cluster within families. genetic. Population based-studies suggest that 20% of probands The evidence in support of genetic factors influencing have an additional family history of MS and 3.6% an the course and prognosis of MS is less strong. Some authors [1,3,33] found that age at onset tended to cluster in sibling pairs indicating a genetic control on the disease *Tel.: 139-80-5478519; fax: 139-80-5478532; e-mail: livrea@cimec.uniba.it onset; others [28] showed that sibling pairs share a similar 0022-510X / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X(98)00328-1