red Obesity is known to be a genetically mediated pathology. Of course, its degree is correlated with lifestyle and dietary patterns. However, studies on twins have shown that heredity plays an exceptional role in the etiology of obesity. More than 400 marker genes associated with obesity have been described. You will learn about rare forms of the pathology in this article.
Contents:
- Two groups of syndromes.
- Syndromal obesity.
- Monogenic pathologies.
- Conclusions.
Two groups of syndromes
Rare forms of obesity are divided into two large groups: syndromes accompanying obesity and monogenic pathologies. The first include obesity forms in Albright bone dystrophy, Prader-Willi syndrome, Down’s syndrome, Cohen’s syndrome and many others.
These diseases are characterized by a wide range of clinical manifestations. Moreover, these syndromes can debut at different ages, have varying degrees of severity and have specific features. However, as a rule, along with specificity, all patients with syndromal obesity demonstrate neurological disorders, delayed psychomotor development, and underdeveloped intelligence. Interestingly, the triggers of the syndromes are unknown, as is the underlying function, yet genetic defects and markers have been identified for most.
Syndromal obesity
Although we are talking about rare cases of obesity, there are many of them, so this article will present the most common ones. All of them are affiliated with adipose tissue, so they are directly related to its synthesis of leptin and other hormones.
Prader-Willi syndrome
Muscle hypotonia, which occurs at birth and persists through the first year of life, is typical of the pathology. Plus, there is psychomotor retardation, hypogonadotropic hypogonadism, cryptorchidism, undeveloped intelligence, short stature, insomnia, and thermoregulation disorders.
Phenotypically noted:
- acromyxia or dwarfism – minimal size of the feet and hands against a background of small stature;
- dolichocephaly – long and narrow head shape;
- almond-shaped eyes;
- Ear flaps that are lower than usual;
- wide nose bridge;
- thin upper lip.
Lawrence-Moon-Bardet-Biddle syndrome
Patients with this pathology are characterized at birth by polydictalism, that is, they have extra fingers and toes, plus muscle hypotonia. Obesity develops in the second year of life and is characterized by hypogonadism. Among other developmental abnormalities, polycystic kidney disease and retinitis pigmentosa are not uncommon. Intelligence is not developed. Presumably, the trigger of obesity in this case is a dysfunction of the satiety center in the hypothalamus, which provokes polyphagia. There is no need to prove the connection between hypothalamus and leptin, it is obvious, so the role of leptin in the development of this syndrome is probably significant.
Pseudohypoparathyroidism
This pathology is characterized by obesity against a background of short stature, short 4 and 5 metatarsals, short neck, round face, many ossificates under the skin, minimal calcium in the blood and high parat hormone levels. As a result, hypothyroidism and hypogonadism and diabetes mellitus develop. Intelligence is reduced. There are several types of pathology today, most of which are familial. Parate hormone resistance is always detected. The basis is a mutation of genes, including those controlling leptin.
Monogenic pathologies
However, if we are talking about leptin, its role is certainly more prominent when mutations in single genes lead to monogenic forms of obesity. For energy balance, energy expenditure and energy intake must balance each other. Caloric intake with food is controlled by the hypothalamus. There are two groups of peptides at work – the orexigenic peptides, which activate appetite, and the anorexigenic peptides, which suppress it.
It turns out that purely anatomically, the interaction of leptin with the cells of the arcuate nucleus of the hypothalamus activates two groups of neurons: those containing neuropeptide and those containing proopiomelanocortin, which transmit excitation to the paraventricular nucleus of the hypothalamus, where their axons contact the cells containing orexins. Fluctuations in leptin levels activate or block the activity of these centers. That is, it essentially makes a person eat more or less.
Mutations in the genes that control leptin can naturally lead to persistent obesity with polyphagia. Such obesity, which progresses from early childhood, is a common feature of all monogenic forms. This confirms the leading role of genes in the regulation of body weight.
Congenital Leptin Deficiency
Children with leptin deficiency from birth have normal weight, but already in the first months of life are characterized by an increased appetite, leading to rapid weight gain. They are characterized by aggressive polyphagia, early hyperinsulinemia with the development of type 2 diabetes in the first month of life. Clinically – it is a uniform deposition of fat, mainly in the subcutaneous fat. Intellect is not impaired.
Congenital leptin deficiency is combined with hypogonadotropic hypogonadism and secondary hypothyroidism, which requires replacement therapy. In this case, leptin plays an important role in the synthesis and secretion of thyroid hormone.
Such defects are accompanied by a lack of pubertal growth acceleration, so these adolescents end up with short stature. Another nuance is a pronounced T-cell immunodeficiency, which is clinically expressed by frequent acute respiratory infections and acute respiratory viral infections with a high mortality risk. The uniqueness of this genetic situation is the possibility of effective correction.
Parenteral administration of recombinant human leptin significantly minimizes polyphagia as early as the third day. Basic metabolism is normalized and weight is persistently reduced with reliable minimization of free fat mass. After one month of treatment the thyroid hormones are normalized and there is no need for replacement therapy. In addition, this treatment is accompanied by self-normalization of puberty and does not cause premature sexual development in children.
Such defects are accompanied by a lack of pubertal growth acceleration, so these adolescents end up with short stature. Another nuance is a pronounced T-cell immunodeficiency, which is clinically expressed by frequent acute respiratory infections and acute respiratory viral infections with a high mortality risk. The uniqueness of this genetic situation is the possibility of effective correction.
Parenteral administration of recombinant human leptin significantly minimizes polyphagia as early as the third day. Basic metabolism is normalized and weight is persistently reduced with reliable minimization of free fat mass. After one month of treatment the thyroid hormones are normalized and there is no need for replacement therapy. In addition, this treatment is accompanied by self-normalization of puberty and does not cause premature sexual development in children.
The clinical picture of congenital leptin receptor deficiency and hormone deficiency is similar: hyperphagia with the development of obesity during the first years of life, hypogonadotropic hypogonadism, frequent infections, and short stature. Therefore, the most surprising conclusion suggests itself: high leptin levels cannot be a marker of a gene mutation. Leptin levels correlate with body mass index.
Congenital proopiomelanocortin deficiency
The combination of rapidly progressive obesity, high appetite and adrenal insufficiency with no detectable cortisol or ACTH levels in the blood is characteristic of congenital ROMS (proopiomelanocortin) deficiency. All symptoms are relieved when glucocorticoid replacement therapy is administered, and severe obesity with polyphagia is formed from the first months of life. Another sign of pathology is the presence of red hair and pale skin. However, exceptions are possible if the child is not of European descent.
Conversase type 1 deficiency
Another example of monogenic obesity is a deficiency of an enzyme that transforms the inactive molecules proinsulin, proopiomelanocortin, and proglucagon into their active forms. Common symptoms of this pathology, which has been identified in only three patients worldwide, are early obesity, hypogonadotropic hypogonadism, hypoglycemia, and low serum cortisol levels combined with malabsorption.
Melanocortin receptor type 4 mutation
It is the most common of all known heterozygous mutations associated with the development of obesity. This form is characterized by a combination of polyphagia, early elevation of insulin in the blood, rapid growth of fat and muscle mass, and bone tissue, which, combined with high linear growth, creates the phenotype of a human mountain. At the same time, thyroid and adrenal gland function is preserved. Patients are normally developed, sexual development is not impaired, leptin levels correlate with body mass index. No correction as of today.
Hypothalamic obesity
This is the most severe non-genetic obesity. The most common triggers are hypothalamic and brainstem tumors or craniocerebral trauma, stroke, or hemoblastosis. As well as related radiation therapy. In this case, any dietary or pharmacological corrections are ineffective. They often provoke hypertension, nocturnal apnoea, dyslipidemia and psychosocial dysfunction. Life expectancy of patients with hypothalamic obesity is shorter.
Conclusions
Obviously, obesity is polyethyolgic and polygenic. The study of its rare forms will allow a better understanding of the mechanisms of control and correction of eating behavior.
