Mutations within the low density lipoprotein (LDL)-receptor gene result in familial hypercholesterolemia, an autosomal dominant inherited disease. Clinical homozygous affected subjects die of premature coronary artery disease as early as in early childhood. We identified a girl at the age of five yr with clinical homozygous familial hypercholesterolemia presenting with achilles tendon xanthomas and arcus lipoides. Her total cholesterol reached up to 1050 mg/dL. Molecular characterization of the LDL-receptor gene revealed a homozygous p.W577R mutation. Despite intensive treatment interventions with the combination of diet, statins, colestipol, and LDL-apheresis, the patient developed symptomatic coronary artery disease at the age of 16 yr. Subsequently, orthotopic liver transplantation was performed to cure the defective LDL-receptor gene. Clinical follow-up for almost nine yr post-transplantation revealed excellent liver function, normal liver enzymes, normal LDL-cholesterol, and regression of both tendon xanthomas and symptomatic coronary artery disease. In conclusion, liver transplantation can effectively reduce LDL-cholesterol in a familial hypercholesterolemia recipient with subsequent regression of xanthomas and atherosclerosis. Timing is extremely important in these exceptional cases to exclude the demand for heart transplantation due to severe coronary artery disease. In addition, the identification of the LDL-receptor as etiology of clinical homozygous hypercholesterolemia is a prerequisite once liver transplantation is considered as therapeutic option.

Mutation of a zinc-binding amino acid of PPARgamma leads to an altered protein-DNA binding pattern, resulting in a partial loss of function, which in turn is associated with partial lipodystrophy.

Purpose: Familial partial lipodystrophy caused by mutations in the PPARG gene is characterised by altered distribution of subcutaneous fat, muscular hypertrophy and symptoms of metabolic syndrome. PPARG encodes peroxisome proliferatoractivated receptor (PPAR)c, a nuclear hormone receptor playing a crucial role in lipid and glucose metabolism and in several other cellular regulatory processes. Methods: PPARG was screened for mutations by direct sequencing in two patients with lipodystrophy, one unaffected family member and 124 controls. Body composition was examined in affected patients, and they were investigated for abnormalities in laboratory results. Functional analysis of the mutant protein was assessed by determining transcriptional activity and possible interference with the wild-type protein.Results: In two patients with familial partial lipodystrophy, we identified a nucleotide substitution in the PPARG gene. This mutation results in the substitution of aspartate by asparagine at residue 424 (D424N) in the ligand-binding domain of PPARc. The unaffected family member and all 124 controls did not carry this mutation. D424N PPARc had a significantly lower ability than wild-type PPARc to activate a PPARc-stimulated reporter gene, but did not exert a negative effect on the wildtype protein. Partial activation of D424N PPARc was achieved in the presence of the agonist rosiglitazone. Conclusion: We report a new PPARG mutation, D424N, which is located in the ligand-binding domain of the protein and leads to familial partial lipodystrophy. D424N PPARc exhibited a loss of function, which was partially restored by adding the PPARc agonist rosiglitazone, suggesting possible treatment potential of this agent.A utosomal dominant familial partial lipodystrophy is a rare disease, characterised by loss of subcutaneous fat, mainly from the extremities, and accumulation of subcutaneous fat in the face and neck area. Affected people also have insulin resistance, diabetes mellitus, hypertriglyceridaemia, hepatic steatosis, and arterial hypertension.