Congenital generalized lipodystrophy type 1

Other Names: Berardinelli-Seip congenital lipodystrophy type 1; BSCL1; AGPAT2-related Brunzell syndrome

Congenital generalized lipodystrophy (also known as Berardinelli–Seip lipodystrophy) is an extremely rare autosomal recessive condition, characterized by an extreme scarcity of fat in the subcutaneous tissues. It is a type of lipodystophy disorder where the magnitude of fat loss determines the severity of metabolic complications.

Epidemiology

Only 250 cases of the condition have been reported, and it is estimated that it occurs in 1 in 10 million people worldwide.

Cause

In individuals with Type 1 CGL, the disorder is caused by a mutation at the AGPAT2 gene encoding 1-acylglycerol-3-phosphate O-acyltransferase 2 and located at 9q34.3. This enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, which is important in the biosynthesis of fats. This enzyme is highly expressed in adipose tissue, so it can be concluded that when the enzyme is defective in CGL, lipids cannot be stored in the adipose tissue.

Inheritance

Autosomal recessive inheritance, a 25% chance

BSCL1 is inherited in an autosomal recessive manner.

Clinical characteristics

Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.

Signs and symptoms

Berardinelli-Seip congenital lipodystrophy (BSCL) should be suspected in individuals with one or more of the following major and/or minor findings. Major Criteria

• Lipoatrophy affecting the trunk, limbs, and face
• Acromegaloid features include gigantism, muscular hypertrophy, advanced bone age, prognathism, prominent orbital ridges, enlarged hands and feet, clitoromegaly, and enlarged external genitalia in males.
• Hepatomegaly
• Elevated serum concentration of triglycerides
• Insulin resistance

Minor Criteria

• Hypertrophic cardiomyopathy may be present in infancy or develop later in life.
• Psychomotor retardation or mild (IQ 50-70) to moderate (IQ 35-50) intellectual impairment
• Hirsutism
• Precocious puberty in females
• Bone cysts
• Phlebomegaly. Prominence of the veins of the lower and upper limbs is observed, in part because of the lack of subcutaneous fat.

Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Berardinelli-Seip congenital lipodystrophy (BSCL), the following clinical evaluations are recommended:

• Complete blood count
• Serum concentration of electrolytes, AST, alanine transaminase, urea, creatinine, insulin, C-peptide, triglycerides, and cholesterol
• Oral glucose tolerance test; when appropriate, clamp glucose homeostasis study
• Ultrasound of the liver to evaluate liver size and fatty content
• Echocardiogram to evaluate for cardiac hypertrophy
• Renal ultrasound examination to evaluate for kidney size
• Physical examination for orthopedic complications including reduced hip mobility and genu valgum
• Skeletal survey, especially of the long bones, to evaluate for bone cysts
• Bone age and assessment of sexual maturity rating/pubertal status
• Complete ophthalmologic examination, including slit lamp examination, to evaluate for ophthalmologic complications due to hyperlipemia and/or diabetes mellitus
• Assessment of cognitive ability with age-appropriate scales
• Consultation with a clinical geneticist and/or genetic counselor.

Genetic testing can also confirm the disease, as mutations in the AGPAT2 gene is indicative of CGL1, a mutation in the BSCL2 gene is indicative of CGL2, and mutations in the CAV1 and PTRF genes are indicative of CGL3 and CGL4 respectively.

Treatment

Metformin is the main drug used for treatment, as it is normally used for patients with hyperglycemia. Metformin reduces appetite and improves symptoms of hepatic steatosis and polycystic ovary syndrome. Leptin can also be used to reverse insulin resistance and hepatic steatosis, to cause reduced food intake, and decrease blood glucose levels.

Diet CGL patients have to maintain a strict diet for life, as their excess appetite will cause them to overeat. Carbohydrate intake should be restricted in these patients. To avoid chylomicronemia, CGL patients with hypertriglyceridemia need to have a diet very low in fat. CGL patients also need to avoid total proteins, trans fats, and eat high amounts of soluble fiber to avoid getting high levels of cholesterol in the blood.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• metreleptin (Brand name: Myalept)Adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.

NIH genetic and rare disease info

• NIH info on Congenital generalized lipodystrophy type 1

Congenital generalized lipodystrophy type 1 is a rare disease.

Congenital generalized lipodystrophy type 1 Resources
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