Hereditary Diseases

diseases caused by disturbances in the storage, transmission, and production of genetic information. With the development of human genetics, including medical genetics, the hereditary nature of many diseases and syndromes of undetermined etiology became known. The role of hereditary factors has been confirmed by the greater frequency of some diseases in certain families than in the population at large. The study of hereditary diseases in man is chiefly the concern of medical genetics.

Hereditary diseases are caused primarily by chromosomal and gene mutations; a distinction is made, accordingly, between chromosomal and strictly hereditary (gene) diseases. Mutation results in the disruption of the synthesis of a particular polypeptide (structural protein or enzyme). Limited or generalized disorder (change in the phenotype) arises in the patient depending on the specific function of this polypeptide for the vital functions of the organism.

The most rational classification of hereditary diseases is based on the type of metabolic disorder involved. Such disorders include those of amino acid metabolism (for example, phenylketonuria, tyrosinosis, alkaptonuria); of lipid metabolism (Nie-mann-Pick disease, Gaucher’s disease); of carbohydrate metabolism (galactosemia, fructosuria); of mineral metabolism (Wilson’s hepatoreticular degeneration); and of bilirubin metabolism (Crigler-Najjar syndrome, Dubinin-Johnson syndrome). However, the biochemical mechanisms of most hereditary diseases are still unknown; consequently, a pathogenetic classification cannot as yet be complete. This classification is therefore supplemented by a classification according to the organ or system of the body: hereditary diseases of the blood (hemolytic disease of the newborn, hemoglobinopathies); of the endocrine system (congenital adrenal hyperplasia, diabetes mellitus); of connective tissue (Marfan’s syndrome, mucopolysaccharidosis); of the neuromuscular system (progressive muscular dystrophies); and hereditary diseases chiefly affecting the kidneys (phosphate diabetes, Fanconi’s syndrome).

The following principal types of inheritance are distinguished according to the location of the pathological (mutant) gene—in an autosomal or in a sex chromosome—and according to its relations with the normal allele, that is, whether the mutation is dominant (the normal gene is suppressed by a pathological gene) or recessive (the pathological gene is suppressed by a normal gene): autosomal-dominant, autosomal-recessive, and sex-linked (or limited to sex). The type of inheritance is determined by analysis of the genealogy, which takes into account the prevalence of the disease under study in a family and the relationship between the persons afflicted with a hereditary disease. Clinical genealogical research deals with the construction and analysis of genealogies.

In hereditary diseases of the autosomal-dominant type, the mutant gene is manifested even in the heterozygous state. Boys and girls suffering from hereditary disease are born with equal frequency. Pathological heredity can be traced vertically in the genealogy. At least one of the patient’s parents was also afflicted. A genealogy characteristic of the autosomal-dominant type of inheritance is shown in Figure 1.

Figure 1. Autosomal-dominant type of inheritance

Other hereditary diseases of the autosomal-dominant type are arachnodactyly, brachydactyly, hereditary hemorrhagic telangiectasia (Osier’s disease), hyperbilirubinemia, neurofibromatosis (von Recklinghausen’s disease), Pelger-Huët nuclear anomaly, polydactyly, hereditary ptosis, idiopathic thrombocytopenic purpura, and ectopia lentis.

In hereditary diseases of the autosomal-recessive type, the mutant gene is manifested only in the homozygous state. Diseases of this type occur with equal frequency among boys and girls. The parents of the afflicted children are phenotypically healthy but act as heterozygous carriers of the mutant gene. Pathological heredity can be traced horizontally in the family genealogy. The probability of children being born with hereditary disease increases if the parents are blood relatives. A genealogy characteristic of the autosomal-recessive type of disease is shown in Figure 2.

Figure 2. Autosomal-recessive type of inheritance

If one of the parents is homozygous for a pathological recessive gene and the other is its heterozygous carrier, then children with hereditary disease may be born in half the cases. This creates the impression of a dominant type of hereditary disease (a genealogy is shown in Figure 3). This phenomenon is called pseudodominance. Pseudodominance differs from true dominance in that affected individuals homozygous for a recessive mutation when married to healthy persons will always have healthy offspring, but heterozygous, apparently healthy persons when married to other heterozygous carriers will have diseased children with a certain frequency (25 percent). If the genealogy shown in Figure 3 is traced back one more generation, it will look like that in Figure 4.

Figure 3. Pseudodominance

Hereditary diseases of the autosomal-recessive type include agammaglobulinemia, alkaptonuria, albinism, amaurotic familial idiocy, hepatolenticular degeneration, one of the forms of the pseudohypertrophic muscular distrophy, mucoviscidosis, and sickle-cell anemia.

Figure 4. The same genealogy as in Figure 3 traced back one more generation

Among the sex-linked diseases, of particular clinical significance are those caused by recessive mutations in the X chromosome (this type of inheritance is also called X-chromosomal disease). Women with this type of mutation are usually phenotypically healthy since the normal allele of the other X chromosome resists the pathological recessive gene. In men, however, the mutant gene is isolated and it determines the pathology of the phenotype. In X-chromosomal diseases, the effect of the mutant gene is manifested only in the heterogametic sex (that is, in males). In affected families, half the sons have the disease while half the daughters are carriers of the mutant gene (conductors), but the parents are clinically healthy. The disease is often seen in sons of the sisters of the patient (or propositus) or in his first male cousins on his mother’s side. The diseased father does not transmit the defective gene to his sons. A typical genealogy is shown in Figure 5.

Figure 5. X-chromosomal type of inheritance

X-chromosome linked hereditary diseases include hemophilia A, hemophilia B, periodic paralysis, retinitis pigmentosa, phosphate diabetes, and color blindness.

The aforementioned types of inheritance apply mainly to monogenic diseases (determined by the mutation of a single gene). However, a pathological condition may depend on two or more mutant genes. Some pathological genes have low penetrance. Their presence in the genome, even in a homozygous state, is essential but not sufficient for the development of the disease. Thus, not all the types of human hereditary diseases fit into the schemata listed above.

Inasmuch as any phenotype, normal or pathological, is determined not only by the genotype but is a result of the interaction of the genotype and its environment, considerable clinical polymorphism is inherent in hereditary pathology: different clinical syndromes may occur within a single nosologie entity and the severity of a disease may vary greatly. Wide variations in the clinical symptoms and course of a hereditary disease may occasionally be observed even in members of one family. In order to obtain an objective picture of the interaction of heredity and environment in the etiology and pathogenesis of hereditary diseases, it is important to conduct a clinical study of a hereditary disease as it occurs in identical and fraternal twins.

The nosologie classification of hereditary diseases is the result of comprehensive clinical (including clinical-genealogical) and laboratory examinations. Of great importance in diagnosis are biochemical, electrophysiological, cytomorphological, immunological, and other laboratory methods that frequently make it possible to identify not only the disease but the heterozygous carrier state of the mutant gene. The diagnosis is sometimes facilitated by the pleiotropic quality of genes, that is, the multiplicity of phenotypic effects for which a single gene is responsible. In particular, the effect of a pathological gene may be manifested not only in disease but also in a number of other traits that are usually harmless to the organism. The study of such traits is useful in determining the presence of the “guilty” gene in doubtful cases.

The progress of medical genetics and the growth of information about the nature of various hereditary diseases and about the influence of environmental factors on the manifestation of mutant genes have contributed greatly to the prevention and treatment of these diseases. Basic therapy for hereditary diseases includes the elimination or restriction of the intake of substances whose chemical transformation in the body, in the absence of an essential enzyme, results in a pathological condition; replacement therapy for a deficient enzyme or normal end product of a distorted reaction; and induction of deficient enzymes. Early treatment of hereditary disease is of considerable importance. Treatment must be started before the onset of pronounced disturbances in the patients. Some biochemical defects may be partly compensated with age. Great hopes rest on the future application of genetic engineering, that is, the planned intervention in the structure and function of the genetic apparatus, which entails the elimination or correction of mutant genes and their replacement with normal ones.

The prevention of hereditary diseases, mainly through genetic counseling, remains the most important task of medical genetics.