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The prevalence of familial partial lipodystrophy (FPLD) is estimated at less than 1/100,000 in Europe; however, this is likely an underestimate.

Whilst FPLD is clinically and genetically heterogeneous, each form of FPLD shows a varying degree of lipoatrophy of trunk and/or extremities with sparing subcutaneous fat or even fat accumulation in the cervico-facial and/or truncal region. Patients appear normal at birth and throughout childhood regarding fat distribution but develop clinically apparent changes near puberty. Metabolic complications appear progressively in adolescence or in adulthood and include insulin resistance, diabetes, hepatic steatosis, acanthosis nigricans, high blood pressure, and premature atherosclerosis with an increased risk of coronary heart disease. Some females may display the features of polycystic ovary syndrome such as hirsutism, oligomenorrhea, polycystic ovaries and infertility. Patients are typically predisposed to early cardiovascular diseases. Other manifestations may include complications of diabetes, recurrent acute pancreatitis and liver steatohepatitis or cirrhosis. FPLD3 is frequently associated with severe hypertension.

FPLD2, the most common form of FPLD, is caused by a mutation in the LMNA gene (1q22) encoding the nuclear intermediate filaments A-type lamins. Other mutations in this gene can lead to atypical lipodystrophies, more frequently associated with other laminopathic phenotypes (muscular and/or cardiac dystrophies, accelerated aging) such as autosomal codominant severe lipodystrophic laminopathy. Other genes associated with rarer genetic variants of FPLD include PPARG (3p25; FPLD3), AKT2 (19q13.1-q13.2), PLIN1 (15q26; FPLD4), CIDEC (3p25; FPLD5) and LIPE (19q13.1-q13.2; FPLD6). FPLD1 is probably of oligogenic or polygenic origin including different etiological subtypes . Many patients with a FPLD phenotype do not display any pathogenic variants in these genes and thus other disease-causing genes are yet to be discovered.

Diagnosis is made by clinical examination, analysis of fat distribution by imaging (MRI, CT-scan and whole-body dual-energy X-ray absorptiometry) and evaluation of metabolic status (hypertriglyceridemia, low levels of high density lipoprotein (HDL)-cholesterol in the blood, hyperinsulinemia, altered glucose tolerance, low circulating levels of leptin and adiponectin). Body mass index is usually normal. Liver enzyme levels should be measured and ultrasonography of liver should be performed, and with transient elastography if a fatty liver disease is suspected. Cardiovascular investigations are needed to search for rhythm and conduction disturbances, and early atherosclerosis. Molecular genetic testing confirms diagnosis.

Differential diagnoses include other forms of FPLD as well as Cushing syndrome, type 2 diabetes, metabolic syndrome and acquired lipodystrophy.

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

Depending on the causal mutation involved, FPLD can be inherited in an autosomal dominant or recessive manner. Genetic counseling is possible in families with a known disease-causing mutation.

Treatment consists of correcting metabolic abnormalities and managing complications. Monitoring diet (reduced intake of dietary fats and carbohydrates) and maintaining daily physical activity can improve the metabolic complications of lipodystrophy. Insulin sensitizers (mainly metformin) and lipid-lowering drugs (statins, or fibrates in case of major hypertriglyceridemia) can also be helpful. Diabetes may require other non-specific treatments, along with insulin. The orphan drug metreleptin is authorized under exceptional circumstances in Europe for the treatment of metabolic complications of partial forms of lipodystrophies, in adults and children above the age of 12 years, where standard treatments have failed. Further studies are required to investigate the benefits and risks of treatment. Regular cardiac monitoring is recommended. Ethinylestradiol should be avoided in women with FPLD and hypertriglyceridemia. Plastic surgery can help some patients.

Prognosis is linked to the severity of associated comorbidities (diabetes, pancreatitis, cardiovascular diseases).