Hyperekplexia exacerbated by occlusion of posterior thalamic arteries.

A 65-year-old man with the onset of hyperekplexia at 37 years of age experienced resolution of the illness at the age of 45 years. Twenty years later after a posterior thalamoperforate artery occlusion that produced a "rubral tremor," severe hyperekplexia redeveloped. The patient's symptoms were controlled with clonazepam, except for brief periods. Interruption of the rubrothalamic pathways or neuronal aggregates at the level of the red nucleus seemed to disinhibit the startle reflex.

Susceptibility for multiple sclerosis is determined, in part, by inheritance of a 175-kb region of the TcR V beta chain locus and HLA class II genes.

Genetic makeup thought to affect susceptibility to multiple sclerosis (MS) and current evidence suggests that multiple genes may be involved. We have mapped a potential susceptibility gene or genes in the germ-line T cell receptor (TcR) V beta region of multiple sclerosis (MS) patients. Six restriction fragment length polymorphisms (RFLPs) spanning approximately 600 kb of the TcR V beta region were used to define TcR haplotypes in 197 Caucasian controls and 83 Caucasian MS patients in the chronic progressive stage of the disease. The distribution of TcR subhaplotype frequencies was significantly different only in the approx. 175-kb region between RFLPs defined by V beta 8.1 and V beta 11. Stratification of the MS patients into HLA-DR2+ (n = 51) and HLA-DR2- (n = 32) populations demonstrated that the subhaplotype frequencies differed from the control population significantly only in the HLA-DR2+ (corrected P = 0.00007) and not in the HLA-Dr2- (corrected P = 0.46) population. Subhaplotypes which are rare in the normal population are overrepresented in the HLA-DR2+ MS patient population and confer a relative risk of 4.06. These results indicate the existence of an MS susceptibility gene within the TcR V beta region, and provide new evidence for gene complementation between a HLA class II gene and TcR V beta gene(s) in conferring susceptibility to MS.

Further localization of a multiple sclerosis susceptibility gene on chromosome 7q using a new T cell receptor beta-chain DNA polymorphism.

Multiple sclerosis (MS) has been associated with particular HLA haplotypes and has recently been reported to also be associated with the T cell receptor (TCR) beta-chain complex. We have tried to determine the source of the TCR-beta/MS association by exploiting the pattern of linkage disequilibrium within the TCR-beta complex. We describe a new DNA polymorphism with the TCR variable region gene segment V beta 15 which appears to localize between the constant region and V beta 11. When the distribution of V beta 11-V beta 15 haplotypes in MS patients was compared to healthy controls, the strength of the V beta 11-V beta 15 MS association (p = 0.107) was much less than the MS association with the adjacent V beta 8-V beta 11 haplotype (p = 0.0010). On the basis we exclude an MS susceptibility gene telomeric to V beta 11. The reported MS association with the TCR-beta gene complex therefore does not appear to be due to genes within the diversity, joining, or constant region but more likely involves a specific gene(s) within the variable region.

The germline repertoire of T cell receptor beta-chain genes in patients with chronic progressive multiple sclerosis.

The T cell receptor (TcR) beta-chain germline gene repertoire of multiple sclerosis (MS) patients was compared to that of 100 normal individuals. No differences in the number of gene segments defined by probes representing 14 different human V beta subfamilies and the constant region genes were found. The distribution of haplotypes defined by restriction fragment length polymorphism (RFLP) alleles detected with V beta 8, V beta 11, and C beta probes in the MS patients was significantly different from that found in normal individuals. Because 84% of the MS patients were DR2+, the findings in these patients were compared to a second group of 43 normals who were DR2+. The distribution of TcR haplotypes in MS patients was also significantly different from that in the DR2+ normals. The data suggest that an MS susceptibility gene(s) may be located in the region of the TcR beta-chain gene complex.

Susceptibility to relapsing-progressive multiple sclerosis is associated with inheritance of genes linked to the variable region of the TcR beta locus: use of affected family-based controls.

We tested the hypothesis that susceptibility to relapsing-progressive (RP) (but not to relapsing-remitting [RR]) multiple sclerosis (MS) is associated with a gene linked to the TcR beta-chain variable region delimited by the Vbeta8-BamHI and Vbeta11-BamHI RFLP alleles in DRw15+ MS patients, using a contingency-table test of patient data and affected family-based controls. Control alleles and haplotypes were composed of parental marker alleles and haplotypes not transmitted to the affected child, in 90 simplex and 31 multiplex families from British Columbia. A total of 6,164 alleles at 11 loci were segregated through families of probands with RP MS or RR MS. The Vbeta8-Vbeta11 subhaplotype frequencies in the DRw15+ RP MS (but not RR MS) patients differed from control frequencies, because of an increase of the 2-1 subhaplotype (P=.02). Vbeta8-BamHI and Vbeta11-BamHI allele frequencies (P=.05 and .009, respectively) in the DRw15+ RP MS (but not RR MS) patients differed from control frequencies. The Vbeta1-Vbeta8 subhaplotype frequencies in the DRw15- RP MS (but not RR MS) patients differed from control frequencies (P=.03), with a significantly increased frequency of the 1-1 subhaplotype (P=.01; RR=7.1) in RP MS versus RR MS patients. Susceptibility to RP MS is associated both with a recessive inheritance of a gene linked to the 3' (Vbeta11) end of the 2-1 subhaplotype defined by the Vbeta8-BamHI and Vbeta11-BamHI alleles in DRw15+ patients and with a gene, located on the 1-1 subhaplotype, defined by the Vbeta1-TaqI and Vbeta8-MspI alleles of the TcR beta-chain complex in DRw15- patients.

Abnormal systemic metabolism of iron, porphyrin, and calcium in Fahr's syndrome.

Striopallidodentate calcinosis (Fahr's disease) is characterized clinically by seizures, rigidity, and dementia and pathologically by mineral deposition in the basal ganglia, dentate nucleus, and cerebral cortex. Disorders of iron and calcium-phosphate metabolism are thought to play a role in its pathogenesis. We present the case of a patient with familial striopallidodentate calcinosis who had porphyria cutanea tarda, refractory anemia, and pseudohypoparathyroidism type 2. The serum level of ferritin was markedly increased, serum iron and iron-binding capacity were below normal, and at autopsy she had deposition of iron in liver, spleen, bone marrow, and brain. She showed intermittent mild hypocalcemia, increased serum values of parathyroid hormone, elevated renal tubular reabsorption of phosphate, and low serum levels of 1,25-dihydroxyvitamin D, suggesting blunted renal responsiveness to endogenous parathyroid hormone. Pseudohypoparathyroidism type 2 was confirmed by infusion of synthetic parathyroid hormone, which gave a normal urinary cyclic adenosine monophosphate response, but a blunted phosphaturic response. After splenectomy for hypersplenism and weekly phlebotomies, she showed progressive improvement in function, mental status, weight, and seizure control. The hypothesis advanced is that the underlying pathophysiology of the separate diseases contributed to the formation of the brain stones through mechanisms of defective iron transport and free radical production.

Beta-chain gene rearrangements and V beta gene usage in DPw2-specific T cells.

The diversity of human T cell receptor beta-chain gene rearrangements and variable region gene usage in the T cell response to a single allogeneic class II HLA gene product has been investigated. Nine clones of cytotoxic T lymphocytes (8.2 to 8.10) that are specific for the class II specificity DPw2 were analyzed for their T cell receptor beta-chain gene rearrangements using a constant-region probe. A minimum of seven different clonotypes were present in this panel of clones. The beta-gene expressed by one clone, 8.9, was isolated and the variable (V), diversity (D), and joining (J) segments were sequenced. The sequence of the V beta 8.9 segment is identical to the V beta 14 sequence, and is joined to D beta 1.1 and J beta 1.1 segments. Northern analysis revealed that three of the eight clones analyzed, 8.5, 8.7, and 8.9, expressed a 1.3 kb transcript that hybridized with the V beta 8.9 probe, indicating that these clones were using the same V beta gene (these clones shared common DNA rearrangements). The remaining five clones did not express V beta 8.9. Southern analysis of DNA obtained from a DPw2-specific tertiary mixed lymphocyte reaction bulk culture from which the clones were derived showed a prominent rearrangement of the V beta 8.9 gene that was indistinguishable from those observed for clones 8.5, 8.7, and 8.9. This prominent rearrangement of V beta 8.9 was not observed in DNA obtained from normal peripheral blood lymphocytes. These results suggest that although the number of V beta genes which can contribute to a DPw2 specificity may be relatively large, only a limited number of clonotypes ultimately predominate in the response to certain class II HLA antigens.

The germline repertoire of T-cell receptor beta-chain genes in patients with multiple sclerosis.

The T-cell receptor (TCR) beta-chain gene repertoire of 40 multiple sclerosis (MS) patients was compared to that of 100 normal individuals. V-beta probes that represent 14 different V-beta subfamilies plus a C-beta probe were used to identify 53 separate beta-chain gene segments. No duplication or deletion of any of these 53 gene segments was found in the MS patients. Restriction fragment length polymorphism (RFLP) alleles detected by V-beta 8, V-beta 11 and C-beta probes defined 8 different beta-chain haplotypes. The distribution of these haplotypes in Caucasian MS patients and normal individuals was significantly different (p = 0.012). Comparison of the DR2+ subset of MS patients (n = 32) to a second group of 43 Caucasian DR2+ normal individuals revealed that the distribution of these beta-chain haplotypes was significantly different in these two populations (p = 0.015). These results suggest that an MS susceptibility gene(s) may be located in the region of the TCR/beta-chain gene complex.

Magnetic resonance imaging of cerebral lesions in patients with the Sjögren syndrome.

Thirty-eight patients with the primary Sjögren syndrome, 16 with active neuropsychiatric manifestations and 22 without clinical evidence of central nervous system involvement had magnetic resonance (MR) imaging. Eight patients had focal neurologic deficits (6 of these also had psychiatric, or cognitive dysfunction), and 8 had psychiatric or cognitive abnormalities alone. Magnetic resonance imaging showed abnormal results in 12 of 16 (75%; 95% CI, 48 to 93) patients with active central nervous system disease (67 focal lesions predominantly within the subcortical and periventricular white matter), and in 2 of 22 (9%; 95% CI, 1 to 29) patients without clinical evidence of central nervous system disease (P less than 0.0001). Seven of eight patients with focal neurologic deficits and 5 of 8 patients with psychiatric or cognitive dysfunction alone had abnormal results on MR imaging. Magnetic resonance imaging was more sensitive in the subgroup with focal deficits, (sensitivity, 88%; 95% CI, 44 to 97) than computerized axial tomography or cerebral angiography. Magnetic resonance imaging detects focal cerebral lesions in patients with the Sjögren syndrome and central nervous system involvement, including patients with psychiatric and cognitive dysfunction alone.