Mapping of monilethrix to the type II keratin gene cluster at chromosome 12q13 in three new families, including one with variable expressivity.

Monilethrix is an autosomal dominant disorder chiefly affecting hair. The degree of hair dystrophy is highly variable, as is the presence of additional features, such as follicular keratoses. In three British families of monilethrix, linkage has recently been reported to the type II keratin gene cluster at chromosome 12q13, and it has been suggested that the disease is due to a defect in the hard keratins of hair and nail. If monilethrix is a keratin disorder, we would predict that some pedigrees might map to the type I keratin gene cluster on 17q where hard keratin genes are also found. We have now studied clinically and by linkage analysis three new and unrelated pedigrees from England, Scotland and Spain, the first of which showed a variant phenotype. In this family the disease was expressed in four of 12 cases only as a follicular-keratosis of the neck, elbows and knees, and without clinical or historical evidence of hair anomalies; non-penetrance in an obligate carrier was also observed. In all three families, we have established linkage to a series of microsatellite markers at the type II locus at 12q13 (Zmax = 6.34 at theta = 0.00 for D12S368) and have excluded linkage from the type I keratin gene cluster on 17q. It remains probable that monilethrix is a disorder of hard keratins, but at present there is no evidence that it is due to defects in type I keratins.

A gene for monilethrix is closely linked to the type II keratin gene cluster at 12q13.

Monilethrix is an uncommon hereditary disorder of hair and nail which produces hair fragility and a variable alopecia. Many of the dystrophic hairs have a unique beaded morphology. Ultrastructural changes suggest a defect in the microfilament structure of the cortex of the hair shaft,and hence the cysteine-rich trichocyte keratins are candidate genes. Here, in two families with autosomal dominant monilethrix, we have excluded linkage to the type I keratin gene cluster on chromosome 17q, but show that the disorder is closely linked to the type II keratin cluster on 12q, where genes for basic trichocyte keratins are found. The combined maximum lod score for D12S96 was 12.27 at theta=0.0. This is the first mapping of a primary human hair disorder and the first evidence implicating a defect of the word 'hard' keratins of hair and nail disease.

A new locus for autosomal dominant retinitis pigmentosa on chromosome 7p.

Autosomal dominant retinitis pigmentosa (adRP) is known to result from mutations in two different retinal genes--rhodopsin and peripherin--while a third locus has been implicated by linkage data. However, families have been reported in which all three known loci have been excluded. We report linkage of adRP in one such family to two microsatellite markers on chromosome 7p. D7S435 has previously been localized to 7p13-15.1; D7S460, previously only localized to chromosome 7, maps to within 2 cM of D7S435 with a lod score of 12.15. Two point linkage analysis between these markers and adRP gave lod scores of 5.65 (theta = 0) and 4.19 (theta = 0.046) for D7S460 and D7S435, respectively. Multipoint analysis gave a maximum lod score of 8.22. These data strongly suggest a new adRP locus on chromosome 7p.

Exclusion of chromosome 6 and 8 locations in nonrhodopsin autosomal dominant retinitis pigmentosa families: further locus heterogeneity in adRP.

Genetic studies have revealed that 25 to 30% of autosomal dominant retinitis pigmentosa (adRP) families have mutations in the rhodopsin gene, while the remainder do not. More recently linkage data and mutation detection have demonstrated two further loci implicated in adRP, at an as yet unidentified gene on chromosome 8p and at the human gene homologue of the mouse Rds (Retinal Degeneration Slow) gene on chromosome 6p. We have previously reported exclusion of adRP from the rhodopsin locus on 3q in two large adRP families. We now report exclusion data for both families, on chromosomes 6 and 8, demonstrating that the adRP phenotype results from mutations in at least four locations.

Intravenous methylprednisolone in the treatment of Graves' ophthalmopathy.

Eleven euthyroid patients with severe Graves' eye disease were treated with intravenous methylprednisolone and followed up for six months or more by ophthalmological assessment, orbital computed tomography (CT), photographs, and antibody measurements. Papilloedema resolved in the single patient in whom it was present; visual acuity was abnormal in seven eyes initially and in only one eye after treatment; the intraocular pressure differential, which reflects muscle dysfunction, was initially abnormal in 18 eyes but showed a progressive and distinct improvement; nine patients showed substantial improvement in inflammatory signs. Exophthalmos improved early after treatment, but this improvement was not maintained. Orbital CT showed a pronounced reduction in the bulk of eye muscles after treatment in eight of nine patients. Autoantibodies to the thyroid stimulating hormone receptor declined. Adverse effects were trivial. Thus eight patients showed a clear response to intravenous methylprednisolone as judged by ophthalmic assessment and CT scan. The two patients who showed little response and one who had none all had a long history (more than a year) of ophthalmopathy. Results were better than those with oral steroids and adverse effects less. Treatment of Graves' eye disease is more likely to be effective if given early; patients should be referred promptly to specialist centres, where treatment with intravenous methylprednisolone should be considered.

Prediction of remission after antithyroid drug treatment in Graves' disease.

A prospective study was carried out to determine the factors which influence response to antithyroid drug treatment in Graves' disease and to assess their predictive value. Eleven variables were included in the assessment and were subjected to discriminant analysis, log rank test and "survival" analysis. The patients were observed for a considerable period (mean duration 51 months). Carbimazole (mean total dose 8 g) was given in combination with thyroxine for an average of eight months to 72 patients. Thirty-five patients relapsed and 37 remain in remission. Thyrotrophin binding inhibiting immunoglobulins (TBII) were detectable in 74 per cent of patients at diagnosis and thyroid stimulating antibodies detectable in 70 per cent. At the end of treatment thyrotrophin binding inhibiting immunoglobulins and thyroid stimulating antibodies were present in 36 and 27 per cent of patients respectively. Levels of thyrotrophin binding inhibiting immunoglobulins were significantly higher both before and after treatment in the group who relapsed, but were not of prognostic significance in an individual patient unless the value was extremely high (TBII index greater than 70). The presence of thyroid stimulating antibodies was of no value in predicting outcome. HLA typing confirmed the known association of Graves' disease with HLA B8 and HLA DR3 but neither of these antigens conferred and increased likelihood of relapse. The likelihood of relapse is shown to be directly related to the severity of the disease at the time of diagnosis, as measured by the serum total T3, and to the size of the thyroid gland; it is not affected by age, family history of thyroid disease or ophthalmopathy. The data indicate that antithyroid drug treatment can be expected to induce long-term remission in patients with mild disease (T3 less than 5 nmol/l) and small thyroids; carbimazole at this dose level is inappropriate for patients with severe disease (T3 greater than 9 nmol/) and large goitres.

Linkage studies of HLA and rheumatoid arthritis in multicase families.

The linkage of rheumatoid arthritis (RA) to the HLA-DR locus was investigated in 17 families with multiple cases of RA. Log odds scores were computed using the Liped program; sibship associations were examined by 2 methods. The results showed a trend toward linkage which was short of significance. The results were similar for patients with classic or definite RA, with or without the inclusion of probable RA patients. The finding of strong association and weak linkage would suggest that it is DR4, itself, that is important in RA.

Classification of rheumatoid arthritis: the importance of including data from the siblings.

A discriminant analysis has been applied to physical and laboratory data on a series of 37 patients with rheumatoid arthritis (RA). Good discrimination was found between RA when it was associated with organ-specific autoimmune phenomena and when it was not. When data from other members of the families was included there was consistently better discrimination than when using data from the patients alone. The results suggest that future studies of classification of variable diseases should include study of relatives.