Graves’ Disease: Pathophysiology, Genetics and Management

Graves’ disease is an autoimmune disorder in which hyperthyroidism (over active thyroid) is caused by the autoantibodies against the TSH receptor. It is mainly characterized by the appearance of goiter. The symptoms are wide ranging as thyroid hormone affects many body systems. It is common in women and in people with age below than 40. Graves’ disease is caused by a combination of genetic and environmental factors while genetics being the main cause. Graves’ disease is not a single gene defect but has a complex pattern of inheritance. Today it is clear that genetic predisposition to Graves’ disease is caused by multiple genes. HLA gene is one the most studied gene predisposing to Graves’ disease. Lot of polymorphisms in this gene has been to be associated with the disease. Lymphoid tyrosine phosphatase encoded by the gene PTPN22 has been found to increase the risk of many autoimmune diseases including Graves’ disease. The best documented association of PTPN22 variants to autoimmune disorders including GD is rs2476601 (C1858T). Other genes associated with the risk of GD are thyrotropin receptor (TSHR), thyroglobulin gene, FCRL3, SCGB3A2, and CTLA4. This chapter will discuss in detail the genetics, pathophysiology, diagnosis and treatment of Graves’ hyperthyroidism.

A Case of Neonatal Diabetes Mellitus Due to INS Gene Mutation with Maternal Mosaicism and Atypical Presentation

Neonatal diabetes mellitus is a single gene defect that results in diabetes mellitus in the first 6 months of life. We report a child who was diagnosed to be hyperglycemic at 13 months of life and assumed to have type 1 diabetes mellitus and started on insulin. The child came to us at 2 and 1/2 years of age. He had exceptionally good blood glucose control. His history revealed that he was symptomatic with a voracious appetite and poor weight gain since the second half of infancy. Genetic testing revealed a heterozygous mutation of the INS gene (the gene that codes for insulin). The condition has autosomal dominant inheritance. Testing the parents revealed that the mother had 7.8% mosaicism for this variant in her lymphocyte DNA. Though this did not alter the management of the patient, it did help in counseling the parents regarding risk of recurrence in future pregnancies.

Porphyria

This chapter discusses six diseases caused by inborn errors of metabolism affecting the biosynthesis of haem. Haem is a tetracyclic metal-binding compound involved in oxygen transport (in haemoglobin and myoglobin) and redox reactions (e.g. in the cytochrome P450 system). Each of these conditions is caused by a single gene defect in one of the enzymes involved in the biosynthesis of haem. Inheritance is usually autosomal dominant with incomplete penetrance. The enzyme defect results in disease, not as a result of deficiency of the reaction product, but as a result of accumulation of precursors. Early, soluble precursors, 5-aminolaevulinic acid, and porphobilinogen (not porphyrins as such) are neurotoxic and, when present in great excess, as occurs when flux through the haem synthetic pathway is increased in response to particular medications or hormones, lead to acute neurovisceral crises. Later cyclical precursors (porphyrins) in the pathway are also water soluble and excreted in urine, but are susceptible to activation by electromagnetic radiation in the visible spectrum and are converted to free-radical metabolites that cause pain, inflammation, and tissue damage in the skin. The final haem precursors (also porphyrins) are hydrophobic and excreted in the bile and faeces and are also activated by light to toxic metabolites.

Complex cardiovascular diseases: the genetics of arterial hypertension

Arterial hypertension appears as two genetic types: primary hypertension is to a substantial extent determined by a large number of genetic risk variants, whereas rare patients with a familial hypertensive syndrome have a single gene defect that drives the elevated blood pressure. The familial hypertensive syndromes have been instrumental in highlighting blood pressure-regulating pathways that almost exclusively cluster in the kidney and in the mineralocorticoid pathways. Conversely, hundreds or more genetic variants cause the genetic component of primary hypertension and each risk variant causes a small blood pressure increase. The blood vessels appear to be one tissue in which these variants principally act and surprisingly there is little overlap with pathways of kidney and hormone pathways. Genetic testing is useful for the rare familial hypertensive syndrome, but in primary hypertension cardiovascular risk prediction can currently not be improved by genotyping.

Genetics of susceptibility to tuberculosis in humans

There is substantial epidemiological evidence that host genetic factors in part determine susceptibility to mycobacteria, and many approaches have been applied to identify the specific genes involved. These include the study of single genes in ‘knockout’ mouse models and rare human families in which increased susceptibility to mycobacterial infection segregates as a single gene defect. Several genes have now been studied in many different populations. This review gives an overview of the progress made in the field of genetic susceptibility to tuberculosis and highlights more generally some of the challenges involved in the identification of complex disease genes.

Deficiency in CD22, a B Cell–specific Inhibitory Receptor, Is Sufficient to Predispose to Development of High Affinity Autoantibodies

CD22 is a B cell–specific transmembrane glycoprotein that acts to dampen signals generated through the B cell antigen receptor (BCR): B cells from CD22-deficient mice give increased Ca2+ fluxes on BCR ligation. Here we show that this B cell hyperresponsiveness correlates with the development of autoantibodies. After the age of eight months, CD22-deficient mice developed high titers of serum IgG directed against double-stranded DNA; these antibodies were of multiclonal origin, somatically mutated, and high affinity. Increased titers of antibodies to cardiolipin and myeloperoxidase were also noted. The results demonstrate that a single gene defect exclusive to B lymphocytes is, without additional contrivance, sufficient to trigger autoantibody development in a large proportion of aging animals. Thus, CD22 might have evolved specifically to regulate B cell triggering thresholds for the avoidance of autoimmunity.

Dense cells in sickle cell anemia: the effects of gene interaction

In an attempt to uncover potential genetic sources of the clinical diversity of sickle cell anemia, we have characterized homozygous SS patients in the following ways: percentage of dense red blood cells (% F4) as determined from Percoll-Stractan continuous density gradients, alpha gene deletion, average percentage of hemoglobin F (% HbF), hemoglobin in g/dL, age, and sex. We find that alpha 4 individuals have a higher % F4 (mean 24% +/- 15%) than alpha 3 individuals (mean 12% +/- 8%) (P less than .005). Multivariate analysis demonstrated a significant correlation among % F4 levels and alpha-gene number and % HbF, and an interaction between the last two variables. The other variables considered did not significantly alter this model. As reported before, with fewer samples, we find that in the first ten years of life of SS individuals, the frequency of alpha gene deletion is 17%, which is comparable to that in the general black population, while in the group over 20 years of age, the frequency rises to 49%, implying that alpha thalassemia is associated with longer survival. These results indicate that it is necessary to consider sickle cell anemia not only as a single gene defect, but also as a disease whose clinical expression is the result of a group of genes capable of interacting at the phenotypic level.