Familial partial lipodystrophy

Overview

Familial Partial Lipodystrophy (FPL) is a rare genetic disorder characterized by the abnormal distribution of body fat. Individuals with FPL typically lose subcutaneous fat in the limbs, buttocks, and trunk while accumulating excess fat in other areas such as the face, neck, or abdomen. This abnormal fat distribution is often accompanied by severe metabolic disturbances, including insulin resistance, diabetes, hypertriglyceridemia, and fatty liver disease. Symptoms usually begin during adolescence or early adulthood and progress over time.

Causes

FPL is caused by mutations in various genes involved in fat metabolism and adipocyte function. The most common forms are:

• FPL type 2 (Dunnigan-type): Caused by mutations in the LMNA gene, which encodes lamin A/C, a protein important for nuclear structure and function.

• Other types: Can result from mutations in genes such as PPARG, AKT2, PLIN1, and CIDEC.

The disorder is typically inherited in an autosomal dominant manner, meaning only one copy of the altered gene is sufficient to cause the condition.

Symptoms

The clinical features of FPL can vary depending on the genetic subtype but commonly include:

• Loss of fat: Thinning of the limbs, buttocks, and trunk, often giving a muscular appearance.

• Fat accumulation: Increased fat around the face, neck, chin (double chin), and visceral areas (abdomen).

• Insulin resistance: Leading to type 2 diabetes mellitus or glucose intolerance.

• Dyslipidemia: Elevated triglycerides and low HDL cholesterol levels.

• Fatty liver: Non-alcoholic fatty liver disease (NAFLD) or steatohepatitis.

• Polycystic ovary syndrome (PCOS)-like features: In women, irregular menstruation, hirsutism, and infertility.

• Acanthosis nigricans: Dark, velvety patches of skin, typically in body folds.

Diagnosis

Diagnosis of FPL is based on clinical features, family history, imaging studies, and genetic testing. Common diagnostic steps include:

• Clinical evaluation: Assessment of fat distribution and metabolic symptoms.

• Family history: Identification of similar symptoms in relatives supports a genetic cause.

• Imaging studies: MRI or DEXA scans to evaluate fat distribution.

• Laboratory tests: To detect insulin resistance, elevated triglycerides, liver enzymes, and glucose levels.

• Genetic testing: Confirms the diagnosis and identifies the specific gene mutation.

Treatment

There is no cure for FPL, so treatment focuses on managing the metabolic complications and preventing long-term damage. Key components include:

• Diet and exercise: Lifestyle modification to improve insulin sensitivity and lipid control.

• Medications:

  • Metformin or insulin sensitizers for diabetes management.

  • Statins or fibrates to control high cholesterol and triglycerides.

  • Leptin replacement therapy (metreleptin) in selected cases with leptin deficiency.

• Liver monitoring: Regular screening for fatty liver and liver function.

• Hormonal therapy: In women with PCOS-like features, hormonal treatments may be used to regulate cycles and reduce symptoms.

• Genetic counseling: For affected individuals and their families.

Prognosis

The prognosis of Familial Partial Lipodystrophy depends on the severity of metabolic complications and how well they are managed. With proper treatment and monitoring, many individuals can maintain a reasonable quality of life. However, poorly controlled diabetes, pancreatitis from hypertriglyceridemia, and progressive liver disease can significantly impact health. Early diagnosis and aggressive management of metabolic risk factors are key to improving long-term outcomes.