Many chronological correlations in different plant and animal species, in populations, in human families, and between cotwins, prove the existence of characteristic biological times. Some such times also tend to be related to cosmic time, in which they develop and from which they are induced, resulting in peculiar composite times, such as the daily, monthly, or annual rhythms, that are the object of study of chronobiology.

Beyond these examples of exogenous chronological induction, the existence of a hereditary biological time is postulated, as the basic phenomenon in the relationship between time and life. The newborn scientific branch of “chronogenetics” is devoted to the study of the fundamental, endogenous genetic time, with its theoretical and practical, normal and pathologic implications. To explain and interpret the mechanisms of the hereditary biological time, the authors have developed a model based on the concepts of “ergon” (i.e., stability of the gene) and “chronon” (i.e., lifespan of the information). This Ergon/Chronon System is related to the gene, bringing into focus the fourth dimension and the dynamic aspects of unit of inheritance.

The applications of chronogenetics extend to every expression of life, from the most primitive unicellular to the higher plants and animals. In the area of normal human traits, the study of the hereditary biological time contributes significantly to the interpretation of such phenomena as development, reproduction, homeostasis, and senescence. In the area of medicine, chronogenetics interpretes, unifies, and develops the temporal phenomena of inheritance. In a future perspective, chronogenetics appears to be fundamental for eugenics, preventive medicine, and prognosis.

All living beings are variously conditioned by both continuous and repetitive chronological phenomena.

The greater biochemical complexity afforded by the genome of higher organisms contributes to increase their independence from environmental chronological phenomena (= increased homeostasis). Genetic variability (originated by mutations and required for evolutionary adaptation) extends its influence on the biochemical mechanisms of homeostasis.

Phenotypical variability, if prevailing environmental conditions are constant, is based on genotypical variability. Thus the variability observed in the duration of homeostatic mechanisms must be genotypical.

In current chronogenetical theory, Gedda and Brenci's concept of the Ergon) Chronon System provides the explanation for the observed variability in the duration of homeostatic phenomena; in this concept, the differential stability of genie information explains the variation of patterns of senescence in different individuals. From the viewpoint of the continuity of life, senescence must be considered as “physiological”, but its individual, especially initial degenerative manifestations are generally considered as pathological. The fundamental applications of chronogenetics to the human species are to be aimed in this direction.

Individual phenomena of senescence may be more or less linear; the pattern of the respective curves may be common to the entire species, or else it may afford varying degrees of variability. The ascertainment of the respective curves (for which some indicators may serve as examples) is a prerequisite for the application of chronogenetics to the individual, framing him within his genealogy and providing great potential developments for preventive medicine.

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.

Three sisters suffering from tapetoretinal degeneration and other eye anomalies, mental retardation, skeletal abnormalities, and unusual dermatoglyphs, are reported.

The family tree of four generations is presented which reveals the following other disorders: diabetes mellitus (2 M), rheumatoid arthritis (2 F), mental retardation (2 M), congenital heart disease (1 F). A great niece of the propositi is known to suffer from tapetoretinal degeneration, mental retardation, epilepsy, cerebellar ataxia, and deafness. One miscarriage and one infant death are also noted.

The mode of inheritance and relationship to other syndromes with tapetoretinal degeneration are briefly discussed. The chromosomal studies, relevant biochemical and other investigations, are within normal limits.

The neurological complications encountered in selected heritable skeletal dysplasias are described. The neurologic deficit may be caused by static (localized spinal cord compression; small spinal canal syndrome) or dynamic (atlantoaxial dislocation) involvement of the spinal cord. The neurologic symptoms have to be recognized early, as neurosurgical management is possible and may definitely improve the neurological condition.

Since the late thirties a syndrome has been progressively completing its description. It consists essentially in juvenile diabetes mellitus, diabetes insipidus, neurosensory hearing loss and optic atrophy. Neurosensory hearing loss, neurogenic bladder, autonomic dysfunction and hyperalanineuria have been added. The syndrome is generally familial.

Electrophysiologic and psychophysiological retinal studies have been done in these cases. Profound electrophysiological disturbance has been described. Cases under actual evaluation are presented. Physiopathologic processes remain a problem. The nature of the retinal affection is also open for discussion.

A case of oculo-auricolo-vertebral syndrome is presented.

A child, aged 8 months, was found to have epibulbar dermoid and subconjonctival lipodermoid in the right eye associated with preauricular appendices and a peculiar appendice located at the point of the nose.

Radiographic examination showed cuneiform anomalies of the cervical vertebrae, schisis of the dorsal vertebrae, and a marked calcification of the cerebral faulx. The child's mother presented similar vertebral anomalies and a supranumerary rib.

A new entity which belongs to the neuronal ceroid-lipofuscinoses has been delineated. The essential ophthalmologic features were absence of the ERG and progressive tapetoretinal degeneration leading to blindness at the age of 2 years. Electroretinography and fluoresceinangiography are of major importance for the diagnosis. The primary site of the retinal lesion seems to be the receptors and the pigment epithelium.

Attention was recently drawn to a progressive encephalopathy with early amaurosis. The disease has its clinical onset at the age of 8-18 months with rapid psychomotor deterioration, ataxia, muscular hypotonia. In the 45 cases examined microcephaly and myoclonic jerks were other prominent features; convulsions were few or did not occur at all. In all patients the disease reached a burnt-out stage during the third year. After the age of 5 years all children had a permanent increased flexor tonus in all limbs and flexion contractures were common. The mean age of death was 7.6 years. Early extinction of ERG, typical ophthalmological findings, and EEG records rapidly approaching isoelectricity were additional features.

The disease has an autosomal recessive mode of inheritance. A total of 52 cases are known in Finland. Histologically, an almost total destruction of cerebral and cerebellar neurons was observed. The surviving neurons and glial cells contained granular material which histochemically resembled lipofuscin but ultrastructurally differed from those in earlier reported patients with neuronal ceroid-lipofuscinosis. The cases observed seem to form a clearly separable infantile type of so-called neuronal ceroid-lipofuscinosis.

A 10-year-old girl with tapetoretinal degeneration, renal dysplasia similar to juvenile nephronophtisis, gradually increasing mental deterioration, walking incoordination, obesity, and ichthyosis is reported.

Hystochemical analyses of the liver, spleen, intestine, lungs, myocardium, kidney, and brain, showed a glycolipid storage. A triglyceride storage in the liver was identified.

Triglyceride lipase activity was about 1% and acid lipase activity 10% with respect to normal controls.

A genetic factor, rather than a secondary metabolic inhibition of triglyceride lipase, is indicated by the normal activity of this enzyme in fatty liver from patients with Reye's syndrome and alcoholic cirrhosis. No inhibitor was found in triglyceride storage disease.