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Presentation is typically in the first months of life with failure to thrive, hepatomegaly, generalized lipoatrophy, prominent musculature, umbilical prominence, acromegaloid features of extremities. Hypertriglyceridemia, insulin resistance, hyperglycemia and liver steatosis can be present in infancy, or diagnosed in late childhood, adolescence or adulthood. Accelerated growth in infancy, virilization of female patients and precocious puberty have been reported in some cases. High blood pressure, hypertrophic cardiomyopathy and bone cysts are frequent complications. Mild intellectual disability can be present, mainly in CGL related to BSCL2. Muscular dystrophy and cardiac arrhythmia are reported in CGL related to CAVIN1.

Two main causative genes have been identified: AGPAT2 (9q34), encoding a key enzyme in triglyceride biosynthesis (1-acyl-glycerol-3-phosphate-O-acyltransferase-2), BSCL2 (11q13), encoding the reticulum endoplasmic seipin protein. A few cases of CGL are due to biallelic pathogenic variants in CAV1 (7q31.2) and CAVIN1 (17q21.2), encoding respectively caveolin-1 and cavin-1, which are major components of specialized plasma membrane microdomains called caveolae. Generalized lipodystrophy is described in rare patients with biallelic pathogenic variants in the genes PPARG (3p25.2) or LMNA (1q22), for which heterozygous mutations are associated with familial partial lipodystrophy.

Diagnosis of CGL is based on recognition of the clinical picture and associated metabolic disturbances including low serum leptin levels. The differential diagnosis of each monogenic form of the disease requires genetic testing.

CGL may occur as a feature in other diseases. Differential diagnoses include acquired generalized lipodystrophy (which occurs mainly in the context of auto-immune diseases), monogenic syndromes of insulin resistance, autoinflammatory diseases, partial forms of lipodystrophy and premature ageing syndromes.

Prenatal diagnosis can be discussed in families with a known disease causing mutation.

Transmission is autosomal recessive. Couples in which each member carries at least one pathogenic variant should be informed that the risk of disease transmission to their offspring is 25%. A positive genetic test in an adult patient may lead to test the carriership of his/her partner.

Diet should be carefully managed, avoiding overfeeding in patients with CGL who are typically hyperphagic due to leptin deficiency. A low glycemic-index and low fat diet, supplemented with medium chain triglycerides in infants/children, is usually needed to manage insulin resistance, diabetes and hypertriglyceridemia. Exercise should be encouraged in the absence of cardiac complications. Insulin sensitizers (mainly metformin) and lipid-lowering drugs (statins, or fibrates in case of major hypertriglyceridemia) are helpful. Diabetes may require other non-specific treatments, along with insulin. The orphan drug metreleptin is authorized in Europe, as a therapeutic option in addition to diet, for the treatment of metabolic complications of generalized lipodystrophy associated with leptin deficiency, in adults and children above the age of 2 years. Regular metabolic, hepatic and cardiac monitoring is recommended. Ethinylestradiol should be avoided in women with CGL.

Prognosis depends on the presence of associated complications. Complications of diabetes, liver disease, and hypertrophic cardiomyopathy are significant causes of morbidity and early mortality.