Lipoidosis are hereditary diseases associated with impaired fat metabolism, deposition of lipids and their metabolites in various organs and tissues. General clinical manifestations are represented by a progressive disorder of intellectual and motor functions, damage to bones, skin, central nervous system, eyes and internal organs (liver, kidneys, spleen). Diagnosis of lipoidosis is based on laboratory studies of enzymatic activity, the amount of toxic substrate, the presence of mutations in genes. Treatment includes enzyme replacement, substrate-reducing and symptomatic therapy.
E75 Disorders of sphingolipid metabolism and other lipid accumulation diseases
Synonymous names of lipoidosis are reticuloendothelioses, lysosomal lipid accumulation diseases. This group includes sphingomyelinosis, Tay-Sachs disease, Gaucher disease, familial hyperlipidemia and some other diseases. A common characteristic is the pathological accumulation of lipids inside the cells of the body as a result of a defect in enzyme systems. Lipoidosis belong to a group of rare (orphan) diseases. Their prevalence is very low, for certain types of pathologies it ranges from 1:40 thousand to 1:1 million and less often. The total frequency is 1:7 thousand. Most lipidoses have a progressive course, lead to disability and early death.
The determining factor in the development of lipidoses is a genetic defect that causes complete or partial insufficiency of lysosomal enzymes that break down complex lipids. Inheritance of diseases occurs by an autosomal recessive mechanism. This means that a newborn turns out to be sick if he receives a mutated gene from each parent (has a pair of defective genes in the allele). When a mutation is transmitted only from the mother or father, the child is its carrier and remains healthy.
An exceptional mechanism of defect transmission in Fabry disease. Unlike other lipidoses, it is inherited by the X-linked recessive type. Hemizygous male patients are sick, pass the mutation only to their daughters. In girls, the disease always manifests itself in the presence of two recessive (altered) genes. Sometimes the symptoms of lipidosis appear in patients with one defective gene when the dominant gene is inactivated (the reasons for this have not been clarified).
The pathogenetic basis of most lipoidosis is a genetically determined enzymatic defect – enzymopathy. As a result, the lysosomes of cells accumulate lipids and intermediates of their metabolism, which leads to a progressive increase in organ dysfunction. With Wolman syndrome, acid etherase deficiency is determined, a complete cycle of cholesterol metabolism becomes impossible, the content of its esters in the lysosomes of the spleen, liver, adrenal glands, intestines and bone marrow increases. In patients with Gaucher’s disease, beta-glucosidase production is reduced or completely absent; sphingolipid cleavage products accumulate in the liver, spleen, and bone marrow. Niemann-Pick disease develops on the basis of sphingomyelase deficiency, characterized by an increase in the amount of sphingomyelin in many cells, especially in hepatocytes, neurons. With the Tay-Sachs idiocy, there is a defect of N-acetylhexosaminidase, gangliosides accumulate in the brain.
Hereditary disorders of the metabolism of complex lipids are represented by a group of diseases of different origin, which at the pathogenetic level are associated with the pathology of fat metabolism. Lipoidosis are characterized by the accumulation of complex lipid compounds inside the lysosomes of cells. Depending on which lipid is not completely broken down and deposited in the tissues, several types of diseases are distinguished:
- Glycolipidosis. With this type of disease, complete breakdown of glycolipids, compounds consisting of carbohydrates and fatty acids, is impossible. Glycolipidoses are represented by cerebrosidoses (Gaucher’s sphingolipidosis, Crabbe’s disease), sulfatidoses (metachromotic leukodystrophy), ceramidolygosidoses (Fabry’s disease, ceramidlactosidlipoidosis), gangliosidoses (Sandhoff’s disease, early childhood amaurotic idiocy).
- Lipoproteinemia. They are caused by a pathology of blood plasma lipid metabolism based on a genetic defect of enzymes or cell receptors. Plasma lipids – fatty acids, triglycerides, cholesterol. Lipoproteinemias include familial hypercholesterolemia, combined familial hyperlipidemia, and familial hyperlipidemia types I-V.
- Sphingomyelinosis. The synonymous name is Niemann-Pick disease. With the development of this disease, the content of the phospholipid compound sphingomyelin increases in reticuloendothelial cells.
The clinical picture of lipidoses is determined by the peculiarities of involvement of organs and systems in the pathological process. In Gaucher type I disease, the liver, spleen, bones and bone marrow are affected. Symptoms include an increase in the size of the liver, bone fragility, anemia, leukopenia, decreased blood clotting. Type II of the disease unfolds with predominant damage to the central nervous system and liver. There are convulsive seizures, muscle hypertonicity, spasticity, intellectual insufficiency, disorders of the act of swallowing. In people with galactosylceramide lipidosis (Crabbe’s disease) the functionality of the myelin sheath decreases. Hyperexcitability develops, vomiting, convulsions, delayed psychomotor development with a progressive decrease in intelligence and vision.
With metachromotic leukodystrophy, the myelin sheath pathologically changes. The main symptoms are hypotension of the muscles of the arms and legs, decrease (absence) tendon reflexes, ataxia, optic nerve atrophy, nystagmus, spastic tetraparesis, deafness, intellectual and motor underdevelopment. The clinical signs of Anderson-Fabry disease are diverse, one of the most common are neuropathic pain (moderate and mild severity, in the feet and palms) and Fabry crises – severe burning pains in the extremities of a paroxysmal nature. Additionally, hypohidrosis or anhidrosis, exercise intolerance, angiokeratomas, hearing disorders, cardiovascular and renal functions occur.
With the development of Sandhoff syndrome, general lethargy, hypotension of the muscles of the extremities, difficulty sucking and swallowing, progressive delay in motor and mental development, motor weakness, heart murmurs, convulsions, blindness, enlargement of the spleen are determined. In early childhood amaurotic idiocy, the central nervous system is most affected. By the end of the first half of the year, children’s reaction to external signals (faces of loved ones, toys) worsens, motor skills are lost, cognitive and gaming interest decreases. Vision is impaired up to blindness. Convulsive seizures are formed.
The first symptoms of sphingomyelinosis are lethargy, lack of mobility, apathy, refusal to eat, vomiting. Later, the abdomen increases (hepatomegaly), the limbs become thin, the skin acquires a brownish hue, periods of inhibition are replaced by hyperexcitation. Children lag behind in psychophysical development. Moderate hydrocephalus, hyperthermia, spastic paresis of the legs and arms, paroxysmal asphyxia are diagnosed.
Manifestations of hyperlipoproteinemia are detected at the age of 10 years. All forms of diseases are characterized by deposition of subcutaneous fat in the form of xanthus, as well as abdominal pain, pancreatitis, hepatosplenomegaly (accumulation of lipids in the spleen, liver). With combined familial hyperlipidemia and type II hyperlipidemia, early vascular atherosclerosis is possible. With hyperlipidemia of type IV and V – decreased sensitivity to glucose, coronary heart disease.
Lipoidosis occurs with the development of insufficiency of vital organs. The most frequent complications are diseases of the heart and blood vessels, central nervous system, kidneys, lungs, liver. Patients suffer from atherosclerosis of blood vessels, cardiac and respiratory insufficiency, coronary heart disease, chronic renal and hepatic insufficiency, adenomas and cirrhosis of the liver, strokes, transient ischemic attacks. With types of diseases compatible with life, motor and mental development are often disrupted. Many patients are incapable of self-care, training and mastering a profession, and need lifelong care from others.
Lipoidosis are not highly specialized diseases, therefore pediatricians, hematologists, gastroenterologists, rheumatologists, neurologists, psychiatrists and geneticists are engaged in their detection and treatment. At the initial stage of diagnosis, a family history is collected: with the hereditary nature of fermentopathy, the patient may have relatives with a confirmed diagnosis of lipidosis. When collecting clinical data, specialists pay attention to the time of onset of symptoms: most often the disease manifests itself during the newborn or the first year of life, rarely in older children or adults. Specific methods of examination of patients include:
- Analysis of the activity of the defective enzyme. Various biomaterials are examined – blood plasma, leukocytes, dry blood spots, skin fibroblast culture, kidney and liver biopsy material. With lipoidosis, a lack of activity of a certain enzyme is determined: from a slight decrease to complete absence.
- Quantitative study of lipids. The content of pathologically accumulated lipids and intermediate products of their metabolism is analyzed in the blood and biopsy material of organs. In patients with lipoidosis, the indicators exceed the norm. In parallel, changes in the structure of the affected cells are being studied.
- DNA sequencing. Detection of a defective gene in a chromosome is the most accurate, but time-consuming method of diagnosing hereditary diseases. It is widely used in the framework of perinatal and preimplantation diagnostics, in cases where the above analyses do not give an unambiguous idea of the diagnosis.
- Imaging studies of organs. Additionally, diagnostics of the condition of the affected organs – heart, liver, gallbladder, spleen, lungs, kidneys, brain – is carried out. Ultrasound, MRI, CT, ECG, EEG are used. Procedures allow you to assess the size, identify structural changes and neoplasms in the organ.
Therapy of this group of lipoidosis is a difficult task for doctors of different specialties. Treatment methods are imperfect and continue to be developed, with some types of diseases it is possible to achieve only a temporary improvement in the patient’s well-being, with others a stable remission is achievable. The general scheme of medical care for patients consists of three components:
- Enzyme replacement therapy. Drugs with artificially isolated deficiency enzyme are injected into the body of patients. Injections are performed for life, allow you to restore the metabolism of lipids.
- Substrate-reducing therapy. Treatment is aimed at reducing the intensity of formation of pathologically accumulated compounds (complex lipid, its metabolites). Low-mass molecules are used to stimulate the residual activity of the enzyme.
- Symptomatic therapy. The drugs are selected individually based on the clinical picture of the disease. The use of anticonvulsants, painkillers, ACE inhibitors, hepatoprotectors is widespread. In certain types of lipoidosis, the use of symptomatic medications is the only way to treat.
Prognosis and prevention
Lipoidosis are characterized by genetic defect heterogeneity and pronounced clinical polymorphism. Most of them have a continuous progressive course. Proper diagnosis and timely treatment can increase the life expectancy of patients, and in mild forms contribute to improving adaptation. Prevention is possible at the planning stage and in the first months of pregnancy. Married couples with a high risk of transmitting the disease to a child are recommended medical and genetic counseling, and in the first trimester – examination of amniotic fluid and chorionic biopsy material for the presence of gene mutations.