Familial Partial Lipodystrophy

Familial partial lipodystrophy is an inherited disorder with loss of fat from the limbs and buttocks, usually from puberty, and excess fat in the face, neck and trunk, with insulin resistance and its complications.

The commonest form (type 2, Dunnigan) is autosomal dominant, from LMNA variants (often R482). Type 3 is due to PPARG variants. Other genes include PLIN1, CIDEC, AKT2 and LIPE. Prevalence is about 1 in 100,000 or more, and it is often underdiagnosed.

Women are affected more severely than men, with earlier and more marked metabolic disease. LMNA variants can also cause cardiomyopathy, arrhythmia and muscle disease.

Pathophysiology.

Defective adipocyte differentiation and storage in the limbs and gluteal depots lead to ectopic fat and insulin resistance. Leptin is moderately low in women with marked fat loss.

Lamin A/C variants disrupt the nuclear envelope, affecting adipocytes and cardiac and skeletal muscle.

• Muscular, thin limbs with prominent veins, and a full face, double chin, neck and abdominal fat (Cushingoid appearance) after puberty.
• Acanthosis nigricans, hirsutism, oligomenorrhoea and polycystic ovaries, early diabetes, severe hypertriglyceridaemia with pancreatitis, hypertension and fatty liver.
• LMNA: palpitations, syncope, cardiomyopathy and conduction disease.

Red flags.

• Triglyceride over 10 mmol/L (880 mg/dL) with abdominal pain.
• Syncope, palpitations or heart failure.

• Examination, with fat distribution by DXA (high trunk to leg fat ratio, low limb fat).
• Fasting glucose, HbA1c, lipids, liver tests, liver elastography, urine albumin to creatinine ratio and leptin (reduced).
• Genetic testing (LMNA, PPARG, PLIN1, CIDEC, AKT2). Family testing.
• ECG, Holter monitoring and echocardiogram for LMNA variants.

Differential diagnosis.

• Cushing syndrome, polycystic ovary syndrome and simple obesity with insulin resistance.
• Acquired partial lipodystrophy and HIV-associated lipodystrophy.
• Madelung disease (symmetric lipomatosis).

• Diet and exercise as first measures.
• Diabetes: metformin first, pioglitazone 15 to 45 mg daily if needed, and insulin (often large doses, concentrated insulin up to 500 units/mL).
• Triglyceride: fenofibrate 145 mg daily, omega-3 fatty acids 2 to 4 g daily and a statin. Acute pancreatitis: intravenous insulin infusion. Avoid oral oestrogen.
• Metreleptin for selected patients with low leptin and severe, resistant metabolic disease (over 40 kg, men 2.5 mg and women 5 mg subcutaneously daily, titrated to 10 mg maximum).
• Hypertension: ACE inhibitor or angiotensin receptor blocker. Implantable defibrillator or pacing for LMNA conduction disease or ventricular arrhythmia by cardiology.
• Plastic surgery for facial fat if needed.

Special groups. Pregnancy: high risk of pancreatitis and diabetes; plan care with specialists. Genetic counselling: 50% risk for each child (LMNA and PPARG).

Monitoring. HbA1c, lipids and liver tests every 3 to 6 months, echocardiography and ECG every 1 to 2 years (yearly with LMNA), and urine albumin yearly.

Referral and escalation. Endocrinology with lipid service and cardiology; urgent admission for pancreatitis or arrhythmia.