Congenital generalized lipodystrophy

Overview

Congenital Generalized Lipodystrophy (CGL), also known as Berardinelli–Seip syndrome, is a rare genetic disorder characterized by the near-total absence of adipose (fat) tissue from birth. As a result, individuals are unable to properly store fat, leading to the abnormal accumulation of fat in non-adipose tissues such as the liver and muscles. This causes severe insulin resistance, diabetes mellitus, hypertriglyceridemia, and hepatic steatosis (fatty liver disease). CGL also presents with a muscular appearance, acromegaloid features, and accelerated growth during childhood.

Causes

CGL is caused by mutations in genes that are essential for the development and function of adipocytes (fat cells). There are four main subtypes of CGL, each associated with a different gene:

• CGL type 1: Caused by mutations in the AGPAT2 gene

• CGL type 2: Caused by mutations in the BSCL2 gene (typically more severe)

• CGL type 3: Caused by mutations in the CAV1 gene

• CGL type 4: Caused by mutations in the PTRF gene (may involve muscle weakness and arrhythmias)

CGL is inherited in an autosomal recessive manner, meaning a person must inherit two copies of the faulty gene (one from each parent) to be affected.

Symptoms

Symptoms typically present at birth or within the first year of life. Hallmark features include:

• Generalized lack of subcutaneous fat: Leading to a muscular and vascular appearance

• Prominent veins and musculature

• Acromegaloid features: Enlarged jaw, hands, and feet

• Accelerated linear growth in childhood

• Severe insulin resistance: Often leading to early-onset diabetes

• Hypertriglyceridemia: Elevated triglyceride levels in the blood

• Hepatomegaly: Enlarged liver due to fat accumulation (hepatic steatosis)

• Acanthosis nigricans: Dark, thickened patches of skin, typically around the neck or armpits

• Hyperphagia: Increased appetite in early childhood

• Cardiac abnormalities: Including hypertrophic cardiomyopathy in some types

• Intellectual disability: May occur in type 2 and type 4

Diagnosis

Diagnosis of CGL is based on clinical features, biochemical findings, and genetic testing. Steps may include:

• Physical examination: Noting absence of fat, prominent muscles, and acanthosis nigricans

• Blood tests:

  • Elevated triglycerides and cholesterol

  • Elevated insulin and glucose levels (indicative of insulin resistance or diabetes)

  • Low leptin and adiponectin levels

• Liver imaging: To assess hepatomegaly and fatty infiltration

• Genetic testing: Confirms the diagnosis by identifying mutations in one of the known CGL-associated genes

• Family history assessment: Especially useful in consanguineous families

Treatment

There is no cure for CGL, so treatment focuses on managing metabolic complications and preventing long-term organ damage. A multidisciplinary approach is essential. Key treatment strategies include:

• Dietary management: Low-fat, high-fiber diet to manage hypertriglyceridemia and control blood glucose levels

• Diabetes management: Use of insulin or insulin sensitizers such as metformin

• Leptin replacement therapy: Metreleptin is an FDA-approved treatment for metabolic complications in patients with generalized lipodystrophy

• Lipid-lowering medications: Such as fibrates or omega-3 fatty acids to reduce triglyceride levels

• Liver monitoring: Regular screening for fatty liver disease and progression to cirrhosis

• Cardiac monitoring: Especially in patients with known cardiac involvement (types 2 and 4)

• Endocrinology and nutrition support: To guide treatment and optimize metabolic control

• Genetic counseling: For affected families to understand inheritance and future pregnancy risks

Prognosis

The prognosis of Congenital Generalized Lipodystrophy depends on the severity of metabolic complications and the effectiveness of treatment. With early diagnosis and proper management, many individuals can live into adulthood. However, untreated or poorly managed CGL can lead to life-threatening complications such as diabetes, pancreatitis, liver failure, or cardiac issues. Leptin therapy has shown significant promise in improving metabolic outcomes and quality of life in affected individuals. Lifelong monitoring and a proactive treatment approach are essential for improving long-term outcomes.