Fundamentals of Medical Genetics - Buzhiyevska T.I. 2001

Hereditary Diseases
Disorders of Lipid Metabolism

This group of hereditary disorders includes storage diseases (intracellular accumulation of metabolic products, such as sphingolipidoses) and lipidoses, which are characterized by elevated serum lipid concentrations.

Tay-Sachs disease belongs to the group of gangliosidoses (GM2, type I) and represents one of the forms of amaurotic idiocy (early infantile). Clinically, it is characterized by progressive visual loss, intellectual degradation, and other neurological symptoms. At 4 to 6 months of age, a previously active infant begins to lose mobility and interest in the surroundings, stops recognizing parents, ceases to play or smile, fails to fixate gaze, and becomes blind. A hyperreaction to sound (even to the point of tonic seizures) is observed. Death typically occurs within 1.5 to 2 years from the onset of the disease. Fundoscopic examination reveals a characteristic cherry-red spot. The primary biochemical defect is a deficiency of hexosaminidase A activity (Prenatal Diagnosis of this condition is possible). Tay-Sachs disease is inherited in an autosomal recessive manner, with a predominantly high carrier and patient frequency among Ashkenazi Jews. It is hypothesized that heterozygotes may have increased resistance to tuberculosis. There is currently no effective therapy for the disease; Treatment remains purely symptomatic.

GM2-gangliosidosis type II (Sandhoff's amaurotic idiocy) follows a more malignant clinical course than Tay-Sachs disease, although their clinical presentations are similar. The primary biochemical defect is a deficiency of both hexosaminidase A and B. Treatment is symptomatic.

GM3-gangliosidosis type II (Norman-Wood amaurotic idiocy, congenital form) manifests During the first days of a child's life. It presents with progressive Hydrocephalus or microcephalus, seizures, paralysis, blindness, and developmental delay. This disorder is inherited in an autosomal recessive manner. There is no effective therapy, and management is symptomatic.

Kufs' late-onset amaurotic idiocy (adult ceroid-lipofuscinosis) manifests between the ages of 15 and 20. It is characterized by the slow progression of organic dementia. Visual impairment is typically absent, although pigmentary retinopathy may be detected in isolated cases. In the terminal stage of the disease, epileptic seizures, paralysis, and immobility are typical. This group of disorders also includes GM1-gangliosidosis type I (Norman-Landing disease, or familial neurovisceral lipidosis), which is characterized by The Development of hepatosplenomegaly after 6 months of age, kyphoscoliosis, brachydactyly, and multiple joint flexion contractures. Notable physical features include hypertelorism, a depressed nasal bridge, low-set ears, and gingival hypertrophy. In about half of the patients, a cherry-red spot is observed on fundoscopy. Death occurs by 2 to 3 years of age. The primary biochemical defect in this pathology is beta-galactosidase deficiency. The disease is inherited in an autosomal recessive manner, and treatment is symptomatic.

Derry disease (juvenile systemic lipidosis; GM1-gangliosidosis, type II) is characterized by delayed psychomotor development, spastic tetraparesis, seizures, ataxia, muscular hypotonia transitioning into rigidity, and dementia. Life expectancy for this condition ranges from 3 to 10 years. The primary biochemical defect is a deficiency of beta-galactosidase in Cells, lymphocytes, and urine. It is inherited in an autosomal recessive manner, and treatment is symptomatic.

Among the lipidoses accompanied by lipid accumulation in plasma, several forms of heterogeneous pathologies should be highlighted, including hyperlipoproteinemias, hyperlipidemias, hypercholesterolemias, and hypertriglyceridemias.

Plasma lipidosis type I (fat-induced hyperlipidemia, hypercholesterolemic xanthomatosis, Bürger-Grütz disease) manifests with xanthomas, hepatosplenomegaly, and occasionally pancreatitis before the age of 10. Blood tests show elevated levels of Cholesterol and triglycerides, with fasting chylomicrons present in the plasma. The Pathogenesis is based on lipoprotein lipase deficiency. It is inherited in an autosomal recessive manner. Treatment consists of a fat-free diet.

Plasma lipidosis type II (familial hypercholesterolemia, hyperbetalipoproteinemia) manifests in childhood with tendon and tuberous xanthomas, alongside atheromatous Changes in the coronary Vessels of the Heart. Xanthomas are located periorbitally, on the buttocks, and over the tendons. Blood cholesterol levels are significantly elevated, with a moderate increase in triglycerides. This pathology is inherited in an autosomal dominant manner with incomplete penetrance. Treatment involves a cholesterol-restricted diet. To lower cholesterol levels in the body, agents such as linetol, delipin, nicotinic acid, and cholestyramine are administered.

Adult plasma lipidosis type III manifests with tuberous xanthomas and early atheromatosis. Xanthomas appear on the soles of the feet, and yellow-orange streaks are noticeable on the palms. Laboratory findings reveal very low-density beta-Lipoproteins, hypercholesterolemia, and hyperuricemia. It is inherited in an autosomal recessive manner. Treatment is identical to that for type II lipidosis.

Plasma lipidosis type IV (endogenous hyperlipidemia, carbohydrate-induced triglyceridemia) develops in both children and adults. It affects the coronary vessels of The Heart. Affected individuals have a normal fat tolerance, but a reduced tolerance to CARBOHYDRATES. Blood levels of triglycerides are significantly elevated, alongside a minor increase in cholesterol. This disorder is inherited in an autosomal dominant manner.

Treatment involves restricting carbohydrate intake, with dietary plant oil recommended. Beneficial effects are achieved through the administration of linetol, delipin, nicotinic acid, lovastatin, lipostabil, Essentiale, and other lipid-lowering drugs.

Plasma lipidosis type V manifests between the ages of 20 and 40. Symptoms include abdominal pain, pancreatitis, xanthomas, hepatosplenomegaly, and hyperuricemia, accompanied by a marked increase in blood triglyceride levels. Autosomal dominant inheritance with variable expressivity has been described, although this condition is frequently associated with nephrosis, Myxedema, alcoholism, and other comorbidities. Management involves a diet low in carbohydrates and fats, as well as medications used in the treatment of other lipidosis forms.

In recent years, a link has been established between plasma lipidoses and Mutations in the Apo-A, Apo-B, Apo-C, and Apo-E genes. On this basis, DNA Diagnostics for family members of patients are proposed for the preclinical detection of specific mutation carriers and for preventive treatment.

Today, special attention is paid to Genetic Disorders OF Cholesterol METABOLISM that involve decreased bodily cholesterol levels, which can lead to the birth of a child with Smith-Lemli-Opitz syndrome (resulting from a 7-dehydrocholesterol reductase defect), as well as impairments in steroid metabolism, Nervous system myelination, and intellectual disability. When cholesterol synthesis is reduced, incorporating 2 to 3 egg yolks daily into the diet is recommended; however, these Conclusions are not yet definitive, and research is ongoing.