SNP Shot: Genomic Insights

Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip congenital lipodystrophy, is a rare disorder characterized by a near-total absence of body fat (adipose tissue) and a strikingly muscular physique. Adipose tissue, found under the skin and around internal organs, serves to store energy and provide cushioning. CGL belongs to a group of related conditions called lipodystrophies, all marked by adipose tissue loss. This deficiency leads to fat storage in atypical locations like the liver and muscles, resulting in significant health complications.

The signs and symptoms of CGL are typically noticeable at birth or in early childhood. A key feature is insulin resistance, where the body's cells don't respond properly to insulin, a hormone crucial for regulating blood sugar (glucose) levels. Insulin resistance can progress to diabetes mellitus. Most individuals with CGL also have elevated levels of triglycerides in their blood (hypertriglyceridemia), potentially leading to small, yellow fat deposits under the skin (eruptive xanthomas) and pancreas inflammation (pancreatitis). Furthermore, CGL causes abnormal fat buildup in the liver (hepatic steatosis), which can enlarge the liver (hepatomegaly) and cause liver failure. Some individuals develop hypertrophic cardiomyopathy, a heart disease that can result in heart failure and dangerous irregular heartbeats (arrhythmias) that can be fatal.

Individuals with CGL have a distinct physical appearance. Due to the near absence of adipose tissue and muscle overgrowth, they appear very muscular. The lack of subcutaneous fat also makes veins appear more prominent. Common features include prominent brow ridges (orbital ridges), large hands and feet, and a protruding belly button (umbilicus). Affected females may experience clitoral enlargement (clitoromegaly), excessive hair growth (hirsutism), irregular menstruation, and ovarian cysts, potentially linked to hormonal imbalances. Many develop acanthosis nigricans, a skin condition associated with high insulin levels, causing skin folds and creases to become thick, dark, and velvety.

Researchers have identified four types of CGL, distinguished by their underlying genetic mutations. These types also exhibit some differences in their clinical presentations. For example, in addition to the general characteristics, some individuals with CGL type 1 develop bone cysts in their arms and legs after puberty. Type 2 can be associated with mild to moderate intellectual disability. Type 3 may result in poor growth and short stature, alongside other health issues. Type 4 is linked to muscle weakness, developmental delays, joint abnormalities, pyloric stenosis (narrowing of the lower stomach), and severe arrhythmias that can lead to sudden death.

Inheritance:

CGL is inherited in an autosomal recessive manner. This means that both copies of the relevant gene in each cell must carry a mutation for the condition to manifest. Individuals with autosomal recessive conditions inherit one mutated gene copy from each parent, who typically do not exhibit any signs or symptoms of the condition.