Obesity due to congenital leptin deficiency

Other Names: Obesity due to congenital leptin deficiency; Leptin deficiency or dysfunction; LEPD; Obesity, morbid, nonsyndromic 1

Congenital leptin deficiency is a form of monogenic obesity characterised by severe early-onset obesity and marked hyperphagia. Affected individuals are of normal weight at birth, but they are constantly hungry and quickly gain weight. Without treatment, the extreme hunger continues and leads to chronic excessive eating (hyperphagia) and obesity. Beginning in early childhood, affected individuals develop abnormal eating behaviors such as fighting with other children over food, hoarding food, and eating in secret.

Epidemiology

It has been described in less than 30 patients.

Cause

Congenital leptin deficiency is caused by mutations in the LEP gene. This gene provides instructions for making a hormone called leptin, which is involved in the regulation of body weight. Normally, the body's fat cells release leptin in proportion to their size. As fat accumulates in cells, more leptin is produced. This rise in leptin indicates that fat stores are increasing.

Leptin attaches (binds) to and activates a protein called the leptin receptor, fitting into the receptor like a key into a lock. The leptin receptor protein is found on the surface of cells in many organs and tissues of the body including a part of the brain called the hypothalamus. The hypothalamus controls hunger and thirst as well as other functions such as sleep, moods, and body temperature. It also regulates the release of many hormones that have functions throughout the body. In the hypothalamus, the binding of leptin to its receptor triggers a series of chemical signals that affect hunger and help produce a feeling of fullness (satiety).

LEP gene mutations that cause congenital leptin deficiency lead to an absence of leptin. As a result, the signaling that triggers feelings of satiety does not occur, leading to the excessive hunger and weight gain associated with this disorder. Because hypogonadotropic hypogonadism occurs in congenital leptin deficiency, researchers suggest that leptin signaling is also involved in regulating the hormones that control sexual development. However, the specifics of this involvement and how it may be altered in congenital leptin deficiency are unknown.

Congenital leptin deficiency is a rare cause of obesity. Researchers are studying the factors involved in more common forms of obesity.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Patients with congenital leptin deficiency are severely hyperphagic from early infancy and, although birthweight is normal, they rapidly become obese during early childhood. An increased susceptibility to infections has also been reported in these infants and appears to be associated with reduced numbers of circulating CD4+ T cells, and impaired T cell proliferation and cytokine release. Other features of the disorder include hyperinsulinaemia, advanced bone age, hypothalamic hypothyroidism and hypogonadotropic hypogonadism leading to a failure to undergo puberty.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 100% of people have these symptoms

• Decreased serum leptin
• Obesity(Having too much body fat)

80%-99% of people have these symptoms

• Absence of secondary sex characteristics
• Decreased proportion of CD4-positive helper T cells
• Decreased serum estradiol
• Decreased serum testosterone level(Decreased serum testosterone levels)
• Decreased T cell activation
• Decreased testicular size(Small testes)
• Gynecomastia(Enlarged male breast)
• Hypergonadotropic hypogonadism
• Hyperinsulinemia
• Hypoplasia of the ovary(Underdeveloped ovary)
• Polyphagia(Voracious appetite)
• Primary amenorrhea

30%-79% of people have these symptoms

• Accelerated skeletal maturation(Advanced bone age)
• Hypertriglyceridemia(Increased plasma triglycerides)
• Insulin-resistant diabetes mellitus(Insulin resistant diabetes)
• Orthostatic hypotension due to autonomic dysfunction
• Pituitary hypothyroidism(Low thyroid gland function due to abnormal pituitary gland)
• Recurrent upper respiratory tract infections

Diagnosis

Family history, severe hyperphagia and early-onset obesity may lead to suspicion of a monogenic obesity syndrome. The diagnosis of congenital leptin deficiency can be confirmed by analysis of serum leptin levels or identification of mutations in the ob gene.

Management and treatment

Congenital leptin deficiency can be successfully treated with daily subcutaneous injections of recombinant human leptin, resulting in sustained positive effects on weight loss, reducing appetite, appropriate pubertal development and hyperinsulinaemia.

Prognosis

As a result, the prognosis for patients undergoing treatment appears to be excellent. However, misdiagnosed patients are at risk of developing the complications normally associated with severe obesity (in particular type 2 diabetes), with the prognosis being hampered further by an increased rate of mortality due to childhood infection.

NIH genetic and rare disease info

• NIH info on Obesity due to congenital leptin deficiency

Obesity due to congenital leptin deficiency is a rare disease.

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