Metabolic Genetics

Mechanisms of development and classification of dystrophies

Metabolic disorders are closely associated with the development of dystrophies. Depending on the influence of genetic factors, they are divided into two large groups:

• Hereditary. Based on a primary genetic defect of a specific enzyme (enzymopathy develops). Because of this, metabolic products cannot be normally metabolized; they remain in tissues and accumulate. This is how storage diseases (referred to in medical literature as thesaurismoses) are formed.
• Acquired. Develop against the background of secondary, acquired enzymopathies. As a rule, they are combined with impaired cellular energy supply and disruptions in substance transport.

According to the prevalence of the pathological process, any dystrophies can be generalized or local.

Features of inborn metabolic diseases

This is a huge group of anomalies in which normal metabolism is distorted due to hereditary factors. They are characterized by a colossal spread in the clinical picture: from mild forms to severe conditions. The age of manifestation and morphological changes also vary greatly.

From a genetics standpoint, most of these diseases are recessive. Autosomal recessive inheritance is most common, while X-linked pathologies are somewhat less frequent.

In the perinatal period, metabolic diseases are often represented by lysosomal storage diseases. These include Gaucher disease, Tay-Sachs disease, Niemann-Pick disease, Hurler syndrome, GM1 gangliosidosis, and mucolipidosis type 1. In addition to metabolic disorders, other genetic anomalies may manifest during this period: trisomies (Down, Edwards syndromes), Turner and Klinefelter syndromes, triploidy, Noonan syndrome, as well as skeletal dysplasias and congenital arthrogryposis.

Genetic factors in the etiology of liver cirrhosis

Hereditary metabolic disorders are a significant etiological factor in liver cirrhosis. Among the established genetic causes are:

1. Hemochromatosis.
2. Wilson's disease.
3. Alpha-1 antitrypsin deficiency.

Familial (hereditary) cirrhosis also exists, although the exact causes and detailed mechanisms of its formation are not fully understood. It is worth noting that metabolic (alimentary) cirrhosis can also develop without a genetic breakdown—with protein deficiency and a predominance of carbohydrates in the diet.

Nervous-arthritic diathesis (NAD)

This is a genetically determined anomaly of purine base and uric acid metabolism. The term was introduced into practice by J. Comby in 1901–1902. Clinically, NAD manifests as CNS hyperexcitability, a tendency to allergies, and spastic reactions.

The pathogenesis is based on hyperuricemia—an excess of uric acid and urates in the blood and tissues. It can be:

• Primary (genetic). Associated with mutations in genes encoding metabolic enzymes (e.g., defects in urate oxidase or phosphoribosyltransferase).
• Secondary (symptomatic). Occurs during massive purine and pyrimidine breakdown (a classic example is hemolytic states).

The formation of diathesis requires the imposition of an exogenous trigger onto an endogenous defect. Most often, the triggering factor is alimentary protein overload (especially meat) in early childhood or in the mother during pregnancy. In relatives of such patients, "metabolic diseases" (gout, cholelithiasis, urate nephrolithiasis, neurasthenia) are detected in 18–22% of cases, and the risk of developing atherosclerosis, coronary artery disease, diabetes mellitus, hypertension, and peptic ulcer disease is increased by 2.5 times.

Lymphatic-hypoplastic diathesis

Although this condition has a different nature, it is also associated with the constitutional features of the organism. Diagnosis is based on a clear triad:

• Clinical picture.
• Laboratory shifts: increase in circulating immune complexes (CICs), drop in thymic gland factors in the blood, and decrease in 17-ketosteroid excretion in the urine.
• Radiologically confirmed thymomegaly.

Differential diagnosis is carried out with HIV infection, hematological pathologies, and exudative-catarrhal diathesis. In most children, symptoms completely disappear by puberty. Only in rare cases does the condition persist lifelong as status thymicolymphaticus.

Class and exam questions

What else to study on this topic

• Lysosomal storage diseases (Gaucher, Tay-Sachs, Niemann-Pick diseases)
• Secondary hyperuricemia in hemolytic states
• Differential diagnosis of lymphatic-hypoplastic diathesis
• The effect of alimentary protein overload on the manifestation of diatheses
• Perinatal chromosomal anomalies (trisomies, Turner syndrome)

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