Berardinelli-Seip Congenital Lipodystrophy (BSCL) is an extremely rare, inherited disorder characterized by a near-total absence of adipose tissue, which is the body’s fat storage. This condition is apparent from birth or early infancy and is classified as a generalized lipodystrophy because the fat loss occurs across the entire body, including subcutaneous and visceral fat stores. The scarcity of functional fat tissue disrupts the normal regulation of energy metabolism, leading to severe metabolic complications and a distinctive physical appearance.
The Underlying Genetic Cause
BSCL is caused by mutations in genes that govern the development and function of adipocytes, the cells responsible for fat storage. The condition follows an autosomal recessive inheritance pattern, meaning an affected individual must inherit a mutated copy of the gene from both parents. Carriers, who have only one mutated copy, typically do not show symptoms.
BSCL Type 1 is caused by mutations in the AGPAT2 gene, which encodes the enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2. This enzyme plays a role in the biosynthesis of triglycerides, the primary form of fat stored in the body, and in the development of fat cells. Dysfunction of AGPAT2 reduces the ability of adipocytes to synthesize and store fat, resulting in the generalized lack of adipose tissue.
BSCL Type 2, the most common form, results from mutations in the BSCL2 gene, which codes for the protein seipin. Seipin is understood to be an essential regulator of adipogenesis, the process by which fat cells differentiate and mature. When seipin is defective, the development of functional fat cells is impaired, severely limiting the body’s capacity for lipid storage. While other gene mutations have been linked to congenital generalized lipodystrophy, AGPAT2 and BSCL2 are the most frequently implicated genes in BSCL.
Physical Appearance and Metabolic Complications
The near-total absence of subcutaneous fat tissue gives individuals with BSCL a characteristic physical appearance, often apparent at birth. Since the underlying musculature is not covered by fat, affected individuals often present with a highly muscular or “pseudo-athletic” look. This lack of insulation also makes veins appear prominent beneath the skin, particularly on the limbs and trunk.
Many individuals also exhibit acromegaloid features, involving accelerated growth in childhood and the enlargement of body parts like the hands, feet, and jaw. A common skin manifestation is acanthosis nigricans, where the skin in body folds becomes thick, dark, and velvety. This skin change is related to the high levels of insulin circulating in the bloodstream.
The core health issues in BSCL stem from ectopic fat deposition, where fat that cannot be stored in adipocytes is forced into non-adipose tissues like the liver and muscle. This misplacement causes severe metabolic derangements, including profound insulin resistance. Cells become unable to respond effectively to insulin, leading to high blood glucose levels and often the early onset of diabetes mellitus, sometimes starting in the teenage years.
Hypertriglyceridemia, or extremely high levels of triglycerides in the blood, is a consistent feature of BSCL and can lead to severe complications. High blood fat levels increase the risk of acute pancreatitis, a painful and potentially life-threatening inflammation of the pancreas. The accumulation of fat in the liver causes hepatic steatosis, or fatty liver disease, which results in an enlarged liver (hepatomegaly) and can progress to severe liver damage like cirrhosis.
The metabolic stress also affects the cardiovascular system, with many affected individuals developing hypertrophic cardiomyopathy, where the heart muscle thickens. This condition can lead to heart failure or abnormal heart rhythms, posing a risk of early mortality. Bone abnormalities, such as bone cysts, and endocrine disturbances, like precocious puberty in females, are also associated with the systemic nature of the disorder.
Diagnosis and Current Treatment Approaches
Diagnosis for BSCL typically begins with a clinical assessment based on characteristic physical features, such as the generalized absence of subcutaneous fat and the muscular appearance. Blood tests detect metabolic abnormalities, including severe hypertriglyceridemia, high fasting glucose, and elevated insulin levels due to insulin resistance. Low serum levels of leptin, a hormone normally produced by fat cells, also support the diagnosis.
Imaging studies, such as Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) scans, are used to visualize the lack of adipose tissue and assess the extent of ectopic fat deposition in organs like the liver. Genetic testing provides definitive confirmation by identifying pathogenic variants in the AGPAT2 or BSCL2 genes. Identifying the specific gene mutation is important for accurate genetic counseling and understanding clinical presentation differences.
Management of BSCL focuses on controlling the severe metabolic complications arising from the lack of fat storage. Treatment involves strict dietary modification, including restricting total fat intake to manage high triglyceride levels. Standard medications for diabetes and hypertriglyceridemia, such as metformin and fibrates, are often used to manage these conditions.
The most impactful therapeutic intervention is Leptin Replacement Therapy, using a synthetic form of the hormone called metreleptin. Since fat cells are the primary source of leptin, individuals with BSCL have extremely low levels, contributing to metabolic chaos. Metreleptin replacement helps regulate energy metabolism, improving insulin sensitivity and reducing hypertriglyceridemia and the amount of fat stored in the liver. Metreleptin is used as an adjunct to diet and other standard treatments, improving metabolic control and reducing the risk of long-term complications.