Familial Partial Lipodystrophy Type Research Articles

Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C

Mutations in the LMNA gene result in diverse phenotypes including Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy with conduction system disease, Dunnigan type familial partial lipodystrophy, mandibulo acral dysplasia, Hutchinson Gilford progeria syndrome, restrictive dermopathy and autosomal recessive Charcot Marie Tooth type 2. The c.1930C > T (R644C) missense mutation has previously been reported in eight unrelated patients with variable features including left ventricular hypertrophy, limb girdle muscle weakness, dilated cardiomyopathy and atypical progeria. Here we report on the details of nine additional patients in eight families with this mutation. Patients 1 and 2 presented with lipodystrophy and insulin resistance, Patient 1 having in addition focal segmental glomerulosclerosis. Patient 3 presented with motor neuropathy, Patient 4 with arthrogryposis and dilated cardiomyopathy with left ventricular non-compaction, Patient 5 with severe scoliosis and contractures, Patient 6 with limb girdle weakness and Patient 7 with hepatic steatosis and insulin resistance. Patients 8 and 9 are brothers with proximal weakness and contractures. Nonpenetrance was observed frequently in first degree relatives. This report provides further evidence of the extreme phenotypic diversity and low penetrance associated with the R644C mutation. Possible explanations for these observations are discussed.

Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism

The lipodystrophies are characterized by loss of adipose tissue in some anatomical sites, frequently with fat accumulation in nonatrophic depots and ectopic sites such as liver and muscle. Molecularly characterized forms include Dunnigan-type familial partial lipodystrophy (FPLD), partial lipodystrophy with mandibuloacral dysplasia (MAD), Berardinelli-Seip congenital generalized lipodystrophy (CGL), and some cases with Barraquer-Simons acquired partial lipodystrophy (APL). The associated mutant gene products include 1) nuclear lamin A in FPLD type 2 and MAD type A; 2) nuclear lamin B2 in APL; 3) nuclear hormone receptor peroxisome proliferator-activated receptor gamma in FPLD type 3; 4) lipid biosynthetic enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2 in CGL type 1; 5) integral endoplasmic reticulum membrane protein seipin in CGL type 2; and 6) metalloproteinase ZMPSTE24 in MAD type B. An unresolved question is whether metabolic disturbances are secondary to adipose repartitioning or result from a direct effect of the mutant gene product. Careful analysis of clinical, biochemical, and imaging phenotypes, using an approach called "phenomics," reveals differences between genetically stratified subtypes that can be used to guide basic experiments and to improve our understanding of common clinical entities, such as metabolic syndrome or the partial lipodystrophy syndrome associated with human immunodeficiency virus infection.

141st ENMC International Workshop Inaugural Meeting of the EURO-Laminopathies Project Nuclear Envelope-linked Rare Human Diseases: From Molecular Pathophysiology towards Clinical Applications 10–12 March 2006, Naarden, The Netherlands

EURO-Laminopathies is a European Commissionfunded research project, including 13 scientific group leaders in the fields of human genetics, clinical research, structural biology, molecular cell biology, and pharmaceutical industry, and one administrative manager from eight countries (Austria, France, Germany, Italy Israel, Spain, Switzerland and the United Kingdom). The consortium held its kick-off meeting as an International ENMC Workshop in Naarden on the weekend of March 10–12, 2006. The EURO-Laminopathies project aims at understanding the molecular mechanisms of laminopathies, which are rare human diseases linked tomutations in genes encoding nuclear envelope proteins, such as A-type lamins (LMNA), proteins involved in the post-translational processing of A-type lamins (ZMPSTE24), and lamin-binding proteins (EMD, LBR, LAP2). Laminopathies are clinically manifested after birth, can affect different tissues andprogressively develop during childhood or adolescence, often leading to early death. Efficient therapies have been hampered by the lack

Peroxisome proliferator-activated receptor-ã and lipodystrophy

Lipodystrophies have long been regarded as rare, mostly genetic disorders of metabolism. However, HIV-associated lipodystrophy has emerged as a serious complication of highly active antiretroviral therapy. Peroxisome proliferator-activated receptor (PPAR)-γ is now known to be an important transcription factor involved in adipocyte differentiation and function. Consequently, PPARγ has emerged as an important pathophysiological mechanism in one of the hereditary lipodystrophies (familial partial lipodystrophy type 3) and in HIV-associated lipodystrophy. Furthermore, the potential of PPARγ agonists in lipodystrophies is under active investigation.

Effectiveness of Gastric Bypass Surgery in a Patient With Familial Partial Lipodystrophy

Familial partial lipodystrophy (FPL) is associated with loss of subcutaneous fat in the extremities but preservation, or increase, of fat in the face, neck, and trunk. Patients with FPL manifest marked insulin resistance and develop diabetes and hypertriglyceridemia that are often very difficult to manage with pharmacologic agents, the current standard of therapy for FPL. Roux-en-Y gastric bypass (RYGB), a surgical procedure that leads to marked weight loss in morbidly obese subjects, improves insulin sensitivity (1,2) and reverses (3) or prevents diabetes (4). This is the first report of RYGB in a patient with FPL that resulted in unanticipated dramatic improvement in the metabolic control of her lipodystrophy. The patient is a 55-year-old Caucasian woman with FPL who underwent a laparoscopic RYGB for treatment of severe gastroesophageal reflux disease and gastroparesis, failing standard medical therapy. She reported a history of truncal obesity and thin extremities throughout her life. She was diagnosed with FPL type 1 based on physical exam findings of distal loss of subcutaneous fat in her extremities with excess fat in her chin and face and marked abdominal obesity. Her medical problems included poorly controlled type 2 diabetes, hypertriglyceridemia with a history of recurrent pancreatitis, coronary artery disease, hypertension, depression, and asthma. Her family history was significant for early coronary artery disease in her mother. …

ALMNASplicing Mutation in Two Sisters with Severe Dunnigan-Type Familial Partial Lipodystrophy Type 2

To date, all cases of familial partial lipodystrophy type 2 (FPLD2; Mendelian Inheritance in Man 151660) result from missense mutations in LMNA, which encodes nuclear lamin A/C (Mendelian Inheritance in Man 150330). The objective of the study was to carry out mutational analysis of LMNA in two sisters with a particularly severe FPLD2 phenotype. This was a descriptive case report with molecular studies. The study was conducted at a referral center. We report two sisters of South Asian origin. The first presented with acanthosis nigricans at age 5 yr, diabetes with insulin resistance, hypertension and hypertriglyceridemia at age 13 yr, and partial lipodystrophy starting at puberty. Her sister and their mother had a similar metabolic profile and physical features, and their mother died of vascular disease at age 32 yr. There were no interventions. LMNA sequencing showed that the sisters were each heterozygous for a novel G>C mutation at the intron 8 consensus splice donor site, which was absent from the genomes of 300 healthy individuals. The retention of intron 8 in mRNA predicted a prematurely truncated lamin A isoform (516 instead of 664 amino acids) with 20 nonsense 3'-terminal residues. The mutant lamin A isoform failed to interact normally with emerin and failed to localize to the nuclear envelope. This is the first LMNA splicing mutation to be associated with FPLD2, and it causes a severe clinical and metabolic phenotype.

Peroxisomal proliferator activated receptor-γ deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3)

BackgroundFamilial partial lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition.MethodsWe present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol.ResultsThe mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable.ConclusionTaken together with previous studies of human PPARG mutations, these findings suggest that PPAR-γ deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.

Berardinelli seip syndrome

Lipodystrophy is a heterogeneous group of disorders characterized by loss of adipose tissue. Here, we report on clinical spectra of neuromuscular manifestations of Turkish patients with lipodystrophy. Seventy-four patients with lipodystrophy and 20 healthy controls were included. Peripheral sensorimotor neuropathy was a common finding (67.4%) in lipodystrophic patients with diabetes. Neuropathic foot ulcers were observed in 4 patients. Drop foot developed in 1 patient with congenital generalized lipodystrophy type 1. Muscle symptoms and hypertrophy were consistent findings in congenital generalized lipodystrophy (21/21) and familial partial lipodystrophy (25/34); on the other hand, overt myopathy with elevated creatine kinase activity was a distinctive characteristic of congenital generalized lipodystrophy type 4. Muscle biopsies revealed myopathic changes at different levels. Accumulation of triglycerides was observed which contributes to insulin resistance. All patients with congenital generalized lipodystrophy suffered from tight Achilles tendons at various levels. Scoliosis was observed in congenital generalized lipodystrophy type 4 (2/2) and familial partial lipodystrophy type 2 (2/17). Atlantoaxial instability was unique to congenital generalized lipodystrophy type 4 (2/2). Bone cysts were detected in congenital generalized lipodystrophy type 1 (7/10) and congenital generalized lipodystrophy type 2 (2/8). Our study suggests that lipodystrophies are associated with a wide spectrum of neuromuscular abnormalities.

Retinoid X Receptor Heterodimers in the Metabolic Syndrome

To the Editor: The excellent review of nuclear receptors by Shulman and Mangelsdorf (Aug. 11 issue)1 mentioned that the study of patients with mutations in PPARγ, the gene encoding peroxisome-proliferator–activated receptor γ (PPARγ), which is rare, can yield corroborating and new insights into the metabolic syndrome. However, it is important to acknowledge that all reported cases of the metabolic syndrome involving heterozygous germ-line loss-of-function PPARγ mutations2–5 concurrently have familial partial lipodystrophy type 3 (FPLD3). Given the role of PPARγ in adipogenesis, it seems reasonable that adipose tissue is repartitioned from peripheral to central stores in patients with . . .

Altered pre-lamin A processing is a common mechanism leading to lipodystrophy

Lipodystrophies are a heterogeneous group of human disorders characterized by the anomalous distribution of body fat associated with insulin resistance and altered lipid metabolism. The pathogenetic mechanism of inherited lipodystrophies is not yet clear; at the molecular level they have been linked to mutations of lamin A/C, peroxisome proliferator-activated receptor (PPARgamma) and other seemingly unrelated proteins. In this study, we examined lamin A/C processing in three laminopathies characterized by lipodystrophic phenotypes: Dunnigan type familial partial lipodystrophy, mandibuloacral dysplasia and atypical Werner's syndrome. We found that the lamin A precursor was specifically accumulated in lipodystrophy cells. Pre-lamin A was located at the nuclear envelope and co-localized with the adipocyte transcription factor sterol regulatory element binding protein 1 (SREBP1). Using co-immunoprecipitation experiments, we obtained the first demonstration of an in vivo interaction between SREBP1 and pre-lamin A. Binding of SREBP1 to the lamin A precursor was detected in patient fibroblasts as well as in control fibroblasts forced to accumulate pre-lamin A by farnesylation inhibitors. In contrast, SREBP1 did not interact in vivo with mature lamin A or C in cultured fibroblasts. To gain insights into the effect of pre-lamin A accumulation in adipose tissue, we inhibited lamin A precursor processing in 3T3-L1 pre-adipocytes. Our results show that pre-lamin A sequesters SREBP1 at the nuclear rim, thus decreasing the pool of active SREBP1 that normally activates PPARgamma and causing impairment of pre-adipocyte differentiation. This defect can be rescued by treatment with troglitazone, a known PPARgamma ligand activating the adipogenic program.

A new LMNA mutation causing limb girdle muscular dystrophy 1B

Sirs: We describe a family with adult-onset limb girdle muscular dystrophy 1B (LGMD1B) due to a new mutation in LMNA encoding for lamin A/C. Lamins A/C maintain nuclear shape and provide a structural support for chromosomes [7]. Mutations in LMNA cause a variety of diseases, now called laminopathies: autosomaldominant and autosomal-recessive Emery-Dreifuss muscular dystrophy (AD-EDMD and AR-EDMD) [1], limb girdle muscular dystrophy 1B (LGMD1B) [8], dilated cardiomyopathy (DCM) with conduction defect [3], familial partial lipodystrophy type Dunnigan (FPLP) [11], CharcotMarie-Tooth neuropathy 2B1 (CMT2B1) [10], and several progeria syndromes [2, 9].The molecular mechanisms leading to these different clinical phenotypes are not understood. It appears that different parts of the molecule play different roles in their interaction with other molecules and stability of the protein [4, 7]. The 48 year old female index patient was well until she was 35 years of age when she noticed difficulty in climbing stairs. The muscular weakness was slowly progressive and was accompanied by mild dyspnea. She denied any stiffness or rigidity of her back, elbows or ankles. The family history revealed that the father had died at a young age because of lung cancer but muscle weakness could not be recalled. Her mother was in good health. On physical examination manual muscle testing revealed a moderate limb-girdle weakness with the pelvic girdle being predominantly affected (hip-flexor paresis 3–4/5). There were no contractures (Fig. A and B). The 19 year old daughter had minimal limb girdle weakness without contractures. Cardiac examination was normal. The creatinkinase was 10-times above normal. Metabolically, there were no signs of insulin-resistance, hyperlipidemia or other abnormalities typical of lipodystrophy The muscle specimen showed signs of a mild dystrophy with a normal immunohistochemical analysis. Cardiac examination revealed permanent atrial fibrillation and AV-block III° after cardioversion. A pacemaker was implanted at age 49. Cardiac MRI was performed using a phased array cardiac surface coil. On CINE-MRI images wall motion abnormalities could be detected at the apex and inferoseptal wall of the left ventricle, as well as a delayed contrast enhancement in the same regions (Fig. C). The phenomenon of delayed myocardial enhancement on MRI was first used to detect areas of non-viable myocardium in chronic myocardial infarction [5]. To our knowledge, we are the first to describe this phenomenon in a patient with muscular dystrophy. For mutation analysis of LMNA all exons and the promoter region were amplified [3]. The analysis was confirmed by sequencing in both directions (Fig. D) and subsequently by restriction enzyme analysis (Fig. E). The identified missense mutation exchanges tryptophan at position 498 for cysteine (W498C). The mutation was found in the index patient and in both of her children. Her mother did not carry the mutation. LGMD1B is rare within the LMNA-associated neuromuscular disorders. Whereas only eight mutations have been found leading to LGMD1B the EDMD phenotype is caused by more than 40 mutations spread out over the entire gene [6, 12–14]. On the protein level, tryptophan 498 is located at the C-terminus of betastrand 6 within the globular domain of lamin A/C. At this position there is a conserved aromatic residue in lamins. The side chain of tryptophan 498 is located at the center of a cavity, surrounded by mainly hydrophobic side chains of different beta-strands that are not close in the lamin sequence but in tertiary structure. Interestingly, another mutation associated with the rare LGMD1B phenotype is also found in the globular domain of lamin A/C, Y481H [6]. Y481 is located on beta 5 in a cavity close to W498 (Fig. E). This might be coincidental but could also represent a mutational hotspot in LMNA for LGMD1B.

Köbberling type of familial partial lipodystrophy: an underrecognized syndrome.

The phenotypic expression of partial lipodystrophy is present in two familial syndromes: familial partial lipodystrophy type 1 (FPLD1), with fat loss from the extremities, and central obesity and FPLD type 2, with fat loss from the extremities, abdomen, and thorax. The latter disorder is associated with mutations in the LMNA gene. FPLD1 is thought to be rare. Here, we report 13 subjects with FPLD1, suggesting that this syndrome is more common than previously thought. Fasting glucose, plasma lipids, leptin, HbA(1c), and anthropomorphic measurements were evaluated in 13 subjects with clinical features of FPLD1 and are compared with two age-matched control groups, with and without diabetes. Only women with clinical features of FPLD1 have been identified. Although they lack extremity and gluteal subcutaneous fat, they do have truncal obesity. Skinfold thickness on the arm and leg was significantly less than that in control subjects. The ratio of skinfold thickness from abdomen to thigh was significantly higher in subjects, suggesting an easy method for identifying affected patients. FPLD1 subjects also had components of the metabolic syndrome, including hypertension, insulin resistance, and severe hypertriglyceridemia resulting in pancreatitis. Premature coronary artery disease was present in 31% of subjects. None of the subjects had coding mutations in the LMNA gene or in the gene coding for peroxisome proliferator-activated receptor (PPAR)-gamma. FPLD1 is more common than previously described, but the diagnosis is often missed. Early recognition and intensive treatment of hyperlipidemia and diabetes in FPLD1 is important for prevention of pancreatitis and early cardiovascular disease.