APS patients have a few overlapping but some distinct clinical features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of clinical manifestations in APS patients seems not to be related to accumulation of mutant farnesylated prelamin A.
We conclude that these patients represent a novel autoinflammatory syndrome resulting in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. The molecular genetic basis of this disorder remains to be elucidated.
Metreleptin replacement therapy is equally effective in FPLD patients with both SH and MH in reducing serum and hepatic triglyceride levels, but did not improve hyperglycemia.
Familial partial lipodystrophy, Dunnigan variety (FPLD) is a well-recognized autosomal dominant disorder due to heterozygous missense mutations in lamin A/C (LMNA) gene. Most of the FPLD patients harbor mutations in the C-terminal of the lamin A/C and do not develop cardiomyopathy. On the other hand, affected subjects from three FPLD pedigrees with heterozygous R28W, R60G and R62G LMNA mutations in the amino-terminal had associated cardiomyopathy presenting as premature onset of congestive heart failure, dilated cardiomyopathy and conduction system disturbances. We report three new FPLD pedigrees presenting with cardiomyopathy associated with heterozygous LMNA mutations in the amino-terminal region. Two of them had previously reported R60G and R62G mutations and one has a novel D192V mutation. Affected subjects belonging to the pedigree with heterozygous R62G mutation had atrial fibrillation and required pacemaker implantation. The affected subjects from the other pedigrees with R60G and D192V mutation developed severe cardiomyopathy requiring defibrillator implantation and cardiac transplantation before 30 years of age in some and premature death in the fourth decade in others. Thus, our report provides further evidence of association of a multisystem dystrophy syndrome in FPLD patients harboring amino-terminal mutations in LMNA. Increased understanding of the genotype-phenotype association might help devise clinical strategies aimed at preventing devastating manifestations of cardiomyopathy including heart failure, arrhythmias and sudden death. Furthermore, the underlying molecular mechanisms by which these amino-terminal mutations cause lipodystrophy as well as cardiomyopathy remain to be understood.
Objective
Hepatic steatosis is a common complication in patients with lipodystrophies and can lead to cirrhosis. There is no proven effective therapy for hepatic steatosis, but cholic acid (CA), a farnesoid × receptor agonist, has previously been shown to reduce hepatic triglyceride (TG) content in mice and serum triglycerides in humans. Our objective was to assess clinical efficacy and tolerability of CA therapy in patients with lipodystrophy and hepatic steatosis.
Design
A randomized, double-blind, placebo-controlled, crossover study.
Methods
Eighteen patients with genetic or autoimmune lipodystrophies, and elevated hepatic TG content participated in the study. The intervention was CA (15 mg/kg/day) compared with placebo for a period of 6 months each. Hepatic TG content, the primary outcome variable, was measured with 1H magnetic resonance spectroscopy at baseline and at 3 and 6 months during each study period. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and TG were secondary end-points of the study.
Results
Compared to placebo, CA did not reduce hepatic TG content [median (interquartile range) 14.8% (9.4-19.0%) vs. 15.9% (10.5-26.5%), respectively; p = 0.42] or serum TG [340 mg/dL (233 – 433 mg/dL) vs. 390 mg/dL (233 – 595 mg/dL) respectively; p=0.45]. CA therapy also did not change AST, ALT or GGT levels. Two patients developed diarrhea and excessive flatus while taking CA and these symptoms resolved after reducing the dose of CA.
Conclusion
CA was well tolerated but did not reduce hepatic TG content in patients with lipodystrophy.
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