Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.      

Genome profiles of bilateral dysgerminomas, a unilateral gonadoblastoma, and a metastasis from a 46, XY phenotypic female

We present a case report of a 16-year-old, phenotypic female with bilateral dysgerminomas, a unilateral gonadoblastoma, and a peritoneal metastasis. The patient's constitutional karyotype was 46,XY. The chromosomal copy number, examined by the comparative genomic hybridization technique, showed 3 gains in the dysgerminoma of the right ovary, 6 gains in the dysgerminoma of the left ovary, and 2 gains and 1 loss in the gonadoblastoma of the left ovary. The metastasis showed 5 gains of which 4 were also observed in the dysgerminoma of the left ovary. The DNA ploidy classifications of the gonadoblastoma and the dysgerminoma in the right ovary were tetraploid, whereas the dysgerminoma in the left ovary and the metastasis were aneuploid. We therefore propose that the metastasis most probably developed from the dysgerminoma of the left ovary.     

The Gm-Pi linkage heterogeneity in view of Pi M subtypes

In this study linkage between the loci for Gm (γ-type heavy-chain immunoglobulin markers) and Pi (α₁-antitrypsin/α₁-protease inhibitor) has been shown in families segregating for the Pi M subtypes (Ml, M2, M3 and Msal) as identified by separator isoelectric focusing. The estimate for the Gm-Pi (M-type) recombination is 0-29 (95% limits 0-24-O37) at a peak lod score of 4-31 and with no sex difference. This value is not significantly different from updated recombination frequency estimates for Gm-Pi in Pi MS (0-26) and Pi MZ, SZ and FZ families (0 21). The overall Gm-Pi recombination fraction estimate of 0 26 (95 % limits O23-0-30) at a peak lod score of 20-75 must now be considered as solid. There is a significant heterogeneity within the male Pi MZ families in that the new Finnish families show a higher recombination between Gm and Pi. There is also a possible segregation distortion (Z:M = 23:8). The heterogeneity is discussed in terms of haplotypes, the behaviour of which could be determined by linked genes or chromosomal rearrangements. The possibility that the α₁-antitrypsin level influences recombination frequency has not been ruled out, but cannot explain the heterogeneity within Pi MZ families.     

Ramification of the portal vein at the porta hepatis in humans

The ramification of the portal vein at the porta hepatis was studied by anatomic dissection performed in 32 formalin fixed human livers. In all the specimens there were branches which ran towards the caudate lobe, arising from the portal vein and either from the left or the right portal branches. Tri-and quadrifurcation of the portal vein was observed. In 5 cases (16%) there were branches arising from left portal branch or portal vein and directed anteriorly to the quadrate lobe or to the region of the gall-bladder sulcus. These branches ranged from 1.0 to 6.0 mm in diameter. The portal caudate branches were divided into 3 groups.Group 1: Branches to the papillary process; 1 or 2 branches in 26 cases (82%), 3 or 5 branches in 3 cases (9%) and no branches in 3 cases (9%);     

Charcot-Marie-Tooth phenotype produced by a duplicated PMP22 gene as part of a 17P trisomy-translocation to the X chromosome

The Charcot-Mane-Tooth disease type 1A (CMTlA) phenotype is most often associated with a 1.5 megabase (mb), tandem duplication of chromosome 17 band p12 (17˜12). The prevailing hypothesis is that the demyelinating neuropathy results from a dosage effect of the peripheral myelin protein gene PMP22 which is included within this duplication. We present a patient with clinical and electrophysiological features ofCMTlA in whom an extra PMP22 gene resulted from a rare unbalanced translocation of 17p to the X chromosome. This finding further supports the hypothesis of gene dosage as the basis for CMTlA. More-over, this case highlights the importance of fluorescence in siiu hybridization (FISH) as an alternative molecular technique in the diagnosis of CMTlA.     

Myocardial ANP expression in Pompe's disease: An immunohistochemical study

The expression of atrial natriuretic peptide (ANP) was analyzed in the atrial and ventricular myocardium in three cases of Pompe's disease (glycogen storage disease of the myocardium), using an immunoperoxidase technique. The cytoplasm of almost all atrial myocytes and some subendocardial myocytes from the right and left ventricles were ANP-positive, excluding the typical central vacuole, which was occupied by glycogen. Ventricular ANP expression was usually more prominent in left ventricular samples, and its distribution was similar to that described in dilated, hypertrophic, restrictive, or ischemic heart disease; however, the enlargement of the myocytes in Pompe's disease is not caused by hypertrophy. We conclude that the atrial myocytes in Pompe's disease maintain ANP expression, despite severe cytoplasmic vacuolization. These results suggest that ventricular ANP expression may be related to mechanical stimuli, such as the increase in wall stress, and not directly related to myocyte hypertrophy.     

Neurophysiological and psychological predictors of genetic risk for schizophrenia

Mathematical genetic analyses were performed on a sample of schizophrenic families (25 probands and 58 first-degree relatives). Heritability coefficients were estimated for EEG power spectrum parameters and their topography, and also for psychological test data on thought and speech process disorder, designed to assess altered selectivity in cognitive activity. Multiple regression equations for genetic counseling regarding the prognosis of mental illness were derived from the neurophysiological and psychological measures.     

Inhibition of the Mixed Lymphocyte Culture Response by Antibody Following Successful Human Renal Transplantation

Immunoglobulin G, appearing after several months in the serum of a recipient of a successful kidney transplant from a closely matched sibling donor, was demonstrated to progressively inhibit unidirectional mixed lymphocyte cultures when donor lymphocytes were used either in responding or stimulating cell populations. The active recipient IgG had no effect in cultures in which donor cells were not used, nor did IgG obtained from other individuals show nonspecific inhibitory effects on cultures containing donor cells. It is suggested that the MLC inhibitory immunoglobulin may serve an immunoregulatory function after renal transplantation.