Generalized Lipodystrophy and Genetic Testing

Generalized lipodystrophy (GL) is a rare, complex, and clinically heterogeneous disorder characterized by the widespread lack or loss of subcutaneous adipose tissue in most or all parts of the body, resulting in relative leptin deficiency.1,2

Types of GL There are 2 types of GL: congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, and acquired generalized lipodystrophy (AGL), also known as Lawrence syndrome. CGL is an autosomal recessive disorder characterized by a generalized lack of adipose tissue at birth or shortly thereafter (within the first year of life) and is accompanied by prominent muscularity and subcutaneous veins.1 In contrast to patients with CGL, patients with AGL are born with normal fat distribution but lose fat in a generalized fashion over time, typically starting in childhood or adolescence. Approximately 50% of patients with AGL present with panniculitis or autoimmune disease such as juvenile dermatomyositis during or prior to fat loss.1,3

Genetic testing

• Although CGL is an inherited disorder, genetic testing can rule in, but not rule out, CGL because not all defective genes associated with CGL have been identified.3

• There are only 4 known genes with mutations that cause CGL, and not all patients with CGL will have mutations in the 4 known genes.4 Genes in which the mutations are known to cause CGL are listed in the table below.5

Gene Lipodystropy type Genetic testing clinically available

AGPAT2 CGL1 Yes

BSCL2 CGL2 Yes

CAV1 CGL3 No

PTRF CGL4 No

• Genetic tests are only available in clinical laboratories for AGPAT2 and BSCL2, although some research laboratories perform genetic testing of all 4 known genes.3 GL Diagnosis The American Association of Clinical Endocrinologists (AACE) task force recommends considering a group of clinical characteristics that are supportive of GL.1 Identifying key clinical characteristics may lead to early detection of GL.

Core clinical characteristic for GL1

• Loss or absence of subcutaneous body fat in a generalized fashion

Supportive clinical characteristics for GL1

• Presence of diabetes with evidence of severe insulin • Evidence of hepatic steatosis or steatohepatitis resistance –– Hepatomegaly and/or elevated transaminases in –– Diabetes mellitus with requirement for high doses the absence of a known cause of liver disease of insulin (eg, requiring ≥200 U/day, ≥2 U/kg/day, (eg, viral hepatitis) may be consistent with or currently taking U-500 insulin) nonalcoholic fatty liver disease –– Ketosis-resistant diabetes –– Radiographic evidence of hepatic steatosis (eg, on ultrasound or computed tomography) • Other evidence of severe insulin resistance –– Acanthosis nigricans • Family history of similar physical appearance and/or –– PCOS or PCOS-like symptoms (hyperandro- history of fat loss genism, oligomenorrhea, and/or polycystic • Prominent muscularity and phlebomegaly (enlarged ovaries) veins) in the extremities

• Presence of hypertriglyceridemia • Disproportionate hyperphagia (cannot stop eating, –– Severe hypertriglyceridemia (≥500 mg/dL) waking up to eat, fighting for food) –– Triglyceride levels that are nonresponsive to therapy and/or modifications to diet (≥250 mg/dL) • Secondary hypogonadism in a male or primary/ secondary amenorrhea in a female patient –– History of pancreatitis associated with hypertriglyceridemia

Not all patients with the clinical characteristics listed in the table above will have GL.

Abbreviation: PCOS, polycystic ovary syndrome.

References: 1. Handelsman Y, Oral EA, Bloomgarden ZT, et al. The clinical approach to the detection of lipodystrophy – an AACE consensus statement. Endocr Pract. 2013;19(1):107-116. 2. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548-2556. doi:10.1210/ jc.2004- 0395. 3. Garg A. Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011;96(11):3313-3325. 4. Bristol Myers Squibb/AstraZeneca Briefing Document (Metreleptin Advisory Committee Meeting). December 11, 2013. Available at http://www.fda.gov/downloads/AdvisoryCommittees/Committees MeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM377929.pdf. Accessed February 26, 2014. 5. National Organization for Rare Disorders. The physician’s guide to lipodystrophy disorders. http://nordphysicianguides.org/Lipodystrophies/. Published 2012. Accessed February 6, 2014.