Systematics of the Age-Dependence of Some Neurological Disorders

Abstract

The age-dependence of malignant diseases has received various interpretations, whereas that of nonmalignant diseases has been relatively neglected. Nevertheless, the age-distributions of diseases in both categories conform to the same stochastic laws.Many, and perhaps all, natural disorders with a reproducible age-pattern can be described in terms of a simple model: The disease process is initiated in a genetically-predisposed person through the random occurrence of a small number (r) of somatic gene mutations in each of a small number (n) of growth-control stem cells. Each specifically-mutant stem cell propagates a “forbidden clone” of descendant cells. These cells, or their humoral products, attack those target cells that carry complementary recognition macromolecules. The resulting disturbance to target cells leads to the symptoms and signs of autoaggressive disease. In the classical infectious diseases, an extrinsic factor — the invading microorganism — is essential to the release of forbidden clones from restraints imposed by the host's endogenous defence mechanism.This general thesis is illustrated with reference to the age-distributions of. Wilson's disease; idiopathic facial (Bell's) palsy, recovery and denervation groups; poliomyelitis; Parkinson's disease; schizophrenia; and multiple sclerosis. Clinically-distinctive forms of a given disease, such as Huntington's chorea or Bell's palsy, often have a distinctive age-pattern.In addition to differences in n and/or r, it can be inferred that each such clinically-distinctive form of a disease is characterized by a distinctive predisposing genotype. The age-dependence of each stage of a progressive disease has a special interest.Thus, the onset of “definite and probable” cases of Parkinson's disease (Mayo Clinic data) requires two forbidden clones, each of which is initiated in a predisposed person by five specific somatic mutations. Late deaths from Parkinson's disease (as recorded by the Registrar General of England and Wales) require a third such forbidden clone.Progression in this neurological disorder, as in certain malignant diseases, corresponds to an increase in the number of pathogenic forbidden clones. The internal mathematical and biological consistency of this type of quantitative evidence powerfully corroborates the forbidden clone theory of age-dependent autoaggressive disease.