Abstract
In the quarter of a century since the first observation that patients with Down's syndrome exhibited an extra chromosome (24), numerous investigators have suggested the possibility of altered protein metabolism. Most of the subsequent effects of this additional chromosome were sought in alterations in serum and tissue proteins with particular emphasis placed on the electrophoretic separation of serum proteins and the estimation of serum and tissue enzymes. Most of the claims for significant changes in enzyme levels due to the extra chromosome were later to be shown to be due to morphological changes in the tissues themselves, and apparent changes in the serum fractions to be due to the crude techniques applied. The increasing availability of more refined techniques for the separation of serum proteins on more sophisticated support media, and the increasing use of immunological methods allows for a re-evaluation of the whole subject of possible changes in protein metabolism concomitant to the extra chromosome, and it is to this end that this thesis is directed. In the first section, the data on sixteen specific serum and plasma proteins in 150 subjects with Down's syndrome is compared with data on a similar number of mentally retarded control subjects. This section also contains data on electrophoretic fractionation of serum proteins and glycoproteins. The structure of some 30 individual proteins were screened using both immunoelectrophoresis and double diffusion techniques, and the IgG fraction after purification were subjected to papain hydrolysis and the F[AB ]and F[C] fragments of the Down's and control groups are compared. In the second section, the data on the frequency distribution of a number of serum and red cell polymorphisms and isoenzyme systems are compared, and the genotype and phenotype frequencies are estimated. In the third section, an investigation into the effects of parental age and some of the phenotype frequencies described in the second section are described, and a relationship between one system (haptoglobin) and the parental age at birth of the Down's subjects is proposed. In the fourth section, the screening of the Down's subjects for the presence of Australia antigen (hepatitis-associated antigen) are described, and possible relationships between the presence of this antigen, a suggested immunological defect and changes in proteins is considered In the fifth section, a comparison of the data from the first two sections with c group of 54 subjects with tuberous sclerosis is made. Both the affected groups of subjects show high mortality rates and similar patterns of infections and by comparing similarities and differences between these two groups possible changes in the Down's subjects due to selection by mortality are proposed. In the sixth section a mathematical model is derived and applied to phenotype frequency distributions in Down's syndrome, and by its use an attempt is made to assess the value of such phenotype distributions in locating gene loci situated on the additional chromosome. In the final section the data outlined in this thesis is summarised and in the light of the present findings suggestions are made for the continuation of this aspect of Down's syndrome.