The association of hereditary spino-ponto-cerebellar degenerations with tapetoretinal degenerations of varying types, and particularly with Stargardt's macular degeneration, is not rare, as at the present time more than 200 cases are known. Therefore the one-gene hypothesis seems to be the most plausible. The fact that there exist complex neuroophthalmological forms near purely neurological or purely retinal forms, is also in favour of one gene with polyphenic manifestation.

The clinical findings in a group of syndromes in which tapetoretinal degenerations are associated with systemic lipid disorders are described. This group includes abetalipoproteinemia (the syndrome of Bassen and Kornzweig), Refsum's syndrome, Neuronal Ceroid Lipofuscinosis, and Cockayne's syndrome. AII four are transmitted by single autosomal recessive genes. The pathological findings are discussed. If diagnosed early enough, abetalipoproteinemia should be treated by administration of vitamin A, and Refsum's syndrome by restriction of intake of phytanic acid and phytol.

Inherited tapetoretinal degenerations associated with, or caused by, abnormalities in lipid metabolism are discussed in terms of recent findings regarding their etiology. The biochemical basis of these tapetoretinal degenerations may be summarized as follows.

(a) In abetalipoproteinemia (the Bassen-Kornzweig syndrome) there is a complete absence of all plasma lipoproteins except HDL (alfalipoprotein; high density lipoprotein). In addition the levels of plasma lipids, including vitamin A, are grossly dimished. The genetically-caused basic defect in this disorder is the absence of a specific protein component, apoLP-ser, in the plasma lipoproteins.

(b) In a milder form of hypobetalipoproteinemia, transmitted as an autosomal dominant trait, there is little, if any, retinal degeneration.

(c) Refsum's syndrome is characterized by greatly increased plasma levels of phytanic acid, a 20-carbon branched-chain fatty acid. This substance is not synthesized in the body, but originates from dietary sources only. Patients with Refsum's syndrome lack the enzyme (phytanic acid oxidase) necessary to oxidize this fatty acid, and its accumulation in the tissues has severe consequences. Therapeutic measures, consisting of restriction of dietary phytanic acid, have given encouraging results.

(d) Three forms of Batten's disease (neuronal ceroid lipofuscinosis) are now recognized. These are (1) the rapidly progressive (Jansky-Bielschowsky) form, (2) the chronic (Batten-Mayou-Vogt-Spielmeyer-Sjögren) form, which is the most common, and (3) the late onset (Kufs') form. All are associated — to varying degrees — with an accumulation of autofluorescent ceroidlipofuscin pigments. The enzymatic defect is believed to consist of abnormalities in peroxidase enzymes.

(e) Other tapetoretinal degenerations thought to be associated with defects in lipid metabolism are discussed briefly. These include Hooffs disease, Cockayne's syndrome, and Alstrom's syndrome.

A study has been made of 35 patients belonging to 20 families, all diagnosed as Usher's syndrome (retinitis pigmentosa and deafness). The results indicate that there are four clinical types, which have been called Types I to IV. Genetically, they represent at least two, and possibly three or four, separate entities.

This review deals with CNS troubles and anomalies (excluding mental defects and oligophrenia, as well as primary muscular degenerations), that account for approximately 25 percent of all cases of genetic counseling in our material.

From a genetic-counseling perspective, CNS affections may be easily classed as follows: (1) congenital malformations; (2) monofactorial Mendelian affections; (3) diseases with a possibly hereditary disposition (e.g., arthrogryposis); (4) infant cerebral palsies; and (5) epilepsies.

In our own material, CNS congenital malformations account for approximately 60 percent of all cases of neurologic genetic counseling, whereas Mendelian affections account for only 20 percent and epilepsies for 15 percent. They mainly include cases of hydrocephaly, anencephaly, spina bifida, and microcephaly, for which the recurrence risk is mostly empirical. Emphasis is laid on the present possibilities of prenatal detection of some of these malformations.

On the basis of their genetic-counseling experience with 4000 propositi, the authors start by recalling in a first part the fundamental mechanisms of the appearance and heritability of chromosomal aberrations.

In a second part, they summarize the correlations between clinical cases and chromosomal abnormalities presently described in the literature. Only the syndromes in which a neurologic and/or an ophthalmologic history exists are reported.

In a third part, modalities of genetic counseling, with a summing-up of general risks for chromosomal rearrangements and of their principal circumstances of diagnosis, are related.

Genealogic and cytogenetic studies necessary for counseling are briefly recorded.

Prenatal diagnosis, although it has been introduced only a few years ago, has already become an important branch of genetics and cytogenetics.

Metabolites of certain monogenic diseases can be discovered in the supernatant of the amniotic fluid, although reliable results are obtained in later months of pregnancy only.

Determination of fetal sex is important if the mother is a proven carrier of a severe X-linked disease such as X-linked muscular dystrophies, Hunter's, Lowe's, Lesch-Nyhan disease. It can be done by the analysis of nuclear sex or sex chromosomal complement.

Biochemical studies of amniotic fluid cells, notably cultured amniotic fluid cells, permit prenatal diagnosis of some inborn errors of metabolism such as Tay-Sachs disease, Hurler's and Hunter's disease, and some rare monogenic diseases.

Numerically of greater importance is the prenatal chromosomal analysis of high-risk women. Provided it could be done in all so-called high-risk women, a considerable number of aneuploidies could be prenatally detected and ultimately prevented.

Religious and legal implications of eugenic abortions are discussed.

The geneticist faced with severe neuroophthalmological conditions should not only establish the prognosis on the basis of probability laws, but also take into consideration the prevailing affective and social situation of these patients and their families.

Huntington's chorea, e.g., manifests itself between 30 and 40 years of age, that is to say, when the patients often have already one or more children, who shall be exposed to the threat of becoming affected until rather an advanced age.

Among other dominant affections, myotonic dystrophy (Steinert) is discussed, which can nowadays be diagnosed in about 1/3 of cases before the first clinical manifestations, owing to slit-lamp examination and electromyography. Contrary to Huntington's disease, the affection can be detected at an early stage of life, so that the patients may still be dissuaded from having children.

In the field of ophthalmological conditions, the genetics of uni- and bilateral retinoblastoma, the three types of retinitis pigmentosa (recessive, dominant, sex-linked), the Lowe's and Waardenburg-Klein syndromes, as well as Tay-Sachs disease, are reviewed. As regards the latter condition, the importance of the discovery of a deficiency of hexosaminidase A is pointed out, since the detection of heterozygous carriers, and even prenatal diagnosis, have now become possible for this disease.

In the central nervous system, besides the neurotransmitters, the occurrence of substances which modify neuronal excitability has been proposed. Since their effect is a matter of modulating neuronal responsiveness, these substances may be called neuromodulators.

Examples of neurotransmitters or putative neurotransmitters in the central nervous system are acetylcholine, noradrenaline, dopamine, and aminoacids such as GABA, glycine, and L-glutamic acid. Under certain conditions, some of these (acetylcholine, L-glutamic acid, and GABA), as well as hormones and polypeptides (e.g., releasing factors) are considered to act as neuromodulators.

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.