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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.

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.

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