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Familial partial lipodystrophy, Dunnigan variety, is transmitted as an autosomal dominant trait. Individuals, both males and females, of several generations can be affected. The chance of transmission from an affected parent to offspring is 1:2 or 50%. Most of the patients have been of European origin, however, patients of African-American and Indian origin have been noted . This lipodystrophy is characterized by gradual loss of subcutaneous fat (fat under the skin) from the upper and lower extremities during puberty with normal appearance at birth. The arms and legs appear very muscular. Veins under the skin appear prominent. Variable amount of fat is lost from the trunk. The loss of subcutaneous truncal fat is more evident anteriorly. In women, lack of fat in the buttocks (gluteal regions) is striking and they complain of "no-hips" or "flat hips". In many patients (mostly women), excess fat may accumulate in the face, and neck at puberty or thereafter. The patients may develop a double chin, excess supraclavicular fat (fat above the clavicle) and a round face (cushingoid appearance). Acanthosis nigricans (dark velvety pigmentation of the skin), hirsutism (increased body hair), menstrual abnormalities, and polycystic ovaries (enlarged ovaries) are observed infrequently. The patients usually have high levels of serum triglycerides that lead to recurrent episodes of acute pancreatitis and low levels of HDL cholesterol. Though fatty liver occasionally develops, cirrhosis has not yet been reported in these patients. The onset of glucose intolerance or diabetes mellitus usually occurs after age 20. Compared with affected men, women with FPLD are particularly predisposed to develop diabetes, high levels of triglycerides, low levels of HDL cholesterol and early onset coronary artery disease and other types of atherosclerotic vascular disease. Our recent data analysis suggests that women with FPLD who have had multiple pregnancies and those with increased accumulation of fat in the non-lipodystrophic regions such as chin may be more predisposed to develop diabetes mellitus. Whole-bodymagnetic resonance imaging reveals subcutaneous fat loss but increased intermuscular fat in the arms and legs and excess intraabdominal fat.
Genetic Basis
Lamin A/C (LMNA) mutations
Our group initially localized the gene for FPLD on the chromosome 1q21-22. Subsequently, many missense mutations (alterations) have been identified in the Lamin A/C ( LMNA ) gene in patients with FPLD. Lamin A/C is a component of the nuclear lamina which is located between chromatin and the inner nuclear membrane. It is likely that defective lamins A/C cause premature death of fat cells in the extremities. Lamin A/C gene has 12 exons which by alternative splicing in exon 10 encodes lamin A (full form) or C (short form). Three-fourths of the FPLD patients have mutations at the codon position 482 where arginine is replaced by glutamine, leucine or tryptophan on exon 8. Some patients with mutations in exon 11 have been observed to have less severe form of lipodystrophy than those with exon 8 mutations. Rare patients with FPLD reveal mutations in exon 1 and these patients develop cardiomyopathy (disease of heart muscles) which manifests as premature congestive heart failure and cardiac arrhythmias (rhythm disturbances), such as heart blocks and atrial fibrillation necessitating the use of cardiac pacemakers.
Interestingly, the same gene is mutated in patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy (diseases causing weakness of muscles), dilated cardiomyopathy (significant dysfunction of heart), mandibuloacral dysplasia, Hutchinson-Gilford Progeria syndrome (Premature aging syndrome) and Charcot-Marie-Tooth disease type 2 (a progressive disease causing nerve damage).
References
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