A National Multicenter Study of Leptin and Leptin Receptor Deficiency and Systematic Review

Area of Science:

• Genetics and Endocrinology
• Obesity Research
• Rare Diseases

Background:

• Leptin (LEP) and leptin receptor (LEPR) gene variants are known causes of severe childhood-onset obesity.
• Understanding genotype-phenotype relationships is crucial for managing these rare endocrine disorders.

Approach:

• This study presents new cases of LEP and LEPR deficiency and long-term follow-up data.
• A systematic literature review was conducted to consolidate findings from 47 studies.
• Genotype-phenotype correlations were analyzed in a cohort of 152 patients.

Key Points:

• Novel pathogenic variants in LEP and LEPR were identified.
• Frameshift variants were most common in LEP deficiency (48%), while missense variants predominated in LEPR deficiency (35%).
• LEP-deficient patients were diagnosed younger, had higher BMI SD scores, and more hyperinsulinemia compared to LEPR-deficient patients.

Conclusions:

• LEP deficiency is associated with earlier onset, higher BMI, and increased hyperinsulinemia, particularly with frameshift variants.
• Long-term metreleptin treatment was effective in 11 patients, though one developed neutralizing antibodies leading to loss of efficacy.
• Genotype-specific management strategies may be beneficial for patients with LEP and LEPR deficiencies.