Discovery of a lipodystrophy gene: one answer, one hundred questions.

Lipodystrophy is a rare and heterogenous disorder characterized by absence or loss of adipose tissue from different parts of the body. Classification of the different lipodystrophy syndromes is based mainly on whether the disease is congenital/familial or acquired, and whether the fat loss is generalized or partial. Since the first patient with lipodystrophy was described 115 years ago (1) much has been learned about the clinical features of this condition. However, until recently, little was known about the etiology and pathogenesis of these syndromes. Two groups have now identified the gene mutations responsible for familial partial lipodystrophy. Surprisingly, all the mutations were found in lamin A/C, a gene on human chromosome 1q21‐22 encoding a nuclear envelope protein (2, 3). The gene for congenital generalized lipodystrophy was mapped to human chromosome 9q34 (4). While these findings provide some insight into the genetic causes of familial lipodystrophy, they also raise many new questions. In order to better understand these recent discoveries and their implications, it is helpful to review briefly what is known about lipodystrophies (5) and lamins (6‐9) and about their potential relationship. Lipodystrophies are divided into familial and acquired categories. Familial lipodystrophies can further be subdivided into two major groups: congenital generalized lipodystrophy (Berardinelli‐Seip syndrome) and familial partial lipodystrophy (Dunnigan variety) (Table 1). Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by almost complete absence of adipose tissue from birth. All metabolically active fat (subcutaneous, intra-abdominal, intrathoracic, bone marrow, parathyroid glands) is missing whereas mechanical fat (palms, soles, orbits, buccal region, tongue) is preserved. Familial partial lipodystrophy (FPLD) has an autosomal dominant inheritance, but the onset of symptoms occurs in puberty when patients start losing subcutaneous fat from the extremities, and typically accumulate fat in the neck and face. The rest of the metabolically active adipose tissue remains normal. The two main syndromes of acquired lipodystrophy are acquired generalized lipodystrophy (Lawrence syndrome) and acquired partial lipodystrophy (Barraquer‐ Simons syndrome). Acquired generalized lipodystrophy is characterized by an onset in childhood or adolescence. Patients lose subcutaneous fat from the extremities, the trunk, the neck and face as well as from palms and soles. Concomitant autoimmune disease is common in these patients. Acquired partial lipodystrophy begins also in childhood and affects primarily the face spreading then down to the neck, shoulders, upper extremities and trunk. There also is an association with autoimmune diseases, especially mesangiocapillary glomerulonephritis that typically develops years after the onset of the lipodystrophy. All the lipodystrophies share a characteristic phenotype of increased muscular appearance in the areas of fat loss. This may explain why women are more frequently diagnosed with the disease than men, who may not seek medical attention, as their findings may not be as noticeable. Metabolically, the lipodystrophy syndromes are accompanied by severe disturbances of glucose and lipid metabolism with the exception of acquired partial lipodystrophy, which only rarely shows metabolic complications. A hallmark of lipodystrophy is