Multiple Symmetric Lipomatosis Patients Research Articles

Multiple Symmetric Lipomatosis: A Cross-Sectional Study to Investigate Clinical Features and Patients’ Quality of Life

Within the subcutaneous adipose tissue diseases, multiple symmetric lipomatosis (MSL) (syn.: Launois Bensaude Syndrome, Morbus Madelung, benign symmetric lipomatosis) is rare. The pathogenesis of MSL remains unclear. We investigated the largest German cohort of MSL patients to obtain anamnestic data and quality of life with a standard questionnaire. Twenty-nine patients with confirmed MSL were included and filled in a questionnaire designed for this study. The questionnaire assessed common anamnestic factors, such as quality of life (EQ-5D-3L) and subjective treatment goals and success (“Patient-Benefit-Index-Lymphedema”, PBI-L). The gender distribution of the patients involved in the study was m/f: 1/4 (male: n = 6 (21%); female n = 23 (79%)). While the exact pathophysiology of MSL remains unclear, a subset of patients’ positive family history suggests a strong genetic factor, sometimes compatible with autosomal dominant inheritance. Patients with MSL showed lower health states (EQ VAS Score: m = 51, sd = 24, range = 0–90) than the German norm population (m = 77). Around two thirds (68%) of patients reported relevant benefits of therapy (liposuction/lipectomy). In our cohort about one third of the patients reported a positive family history for MSL-like features. Additionally, at least in some patients, a strong genetic factor, compatible with autosomal dominant inheritance, seems a possible major driver of MSL development. Alcohol consumption and MSL development has to be regarded as a controversial issue. Patients suffering from MSL have a clear decrease in quality of life and a marked wish for treatment.

Cbl Proto-Oncogene B (CBLB) c.197A>T Mutation Induces Mild Metabolic Dysfunction in Partial Type I Multiple Symmetric Lipomatosis (MSL).

BackgroundMultiple symmetric lipomatosis (MSL) is a rare disease showing chronic progression of multiple, symmetrical, and non-encapsulated subcutaneous lipoma. The cause of the disease remains unknown.Patients and MethodsThis study reported and summarized 13 sporadic cases of Type I MSL patients in terms of histopathology and cellular and molecular biology and assessed the CBLB c.197A>T mutation in the IRS1-PI3K-Akt pathway.ResultsThe clinical data showed that these 13 Type I patients were all male with a mean age of 57.0 ± 6.6 years old and consumed alcohol heavily. The laboratory tests revealed that most of the patients had hyperuricemia, diabetes, hyperinsulinemia, or insulin resistance; however, their blood lipid levels were close to a normal range. The imaging data exhibited lipomas that only occurred subcutaneously but not viscerally, ie, Types Ia (15.4%), Ib (30.8%), and Ic (53.8%). The molecular analyses of adipocytes of isoprenaline stimulated human adipose tissue-derived mesenchymal stromal cells (hADSCs) isolated from the adipose tissue lipoma-like masses (ATLLM) demonstrated that these adipocytes did not express UCP-1. The Cbl proto-oncogene B (CBLB), an E3 ubiquitin-protein ligase, was associated with insulin resistance and obesity and was mutated (ie, CBLB c.197A>T) in four MSL patients after the whole genome and Sanger sequencing of the blood samples. Furthermore, the CBLB c.197A>T mutation induced hADSC resistance to insulin by inactivation of the IRS-1-PI3K-AKT pathway.ConclusionThis study analyzed clinical, histopathological, and cellular and molecular biological characterizations of 13 Type I MSL patients and identified the CBLB c.197A>T heterozygous mutation that could be responsible for MSL metabolic dysfunction or even MSL development.

Total and regional body composition and energy expenditure in multiple symmetric lipomatosis

The aim of the present study was to investigate possible alterations in body composition and resting energy expenditure (REE) in type 1 multiple symmetric lipomatosis (MSL). Thirteen men aged from 40 to 78 years affected by type I MSL were compared with 13 healthy control subjects. Fat mass (FM) and fat-free mass (FFM) were determined by DEXA using both standard analysis and specifically for the lipomatous region. REE was measured by indirect calorimetry. FM was higher in MSL subjects at proximal arm level, but significantly lower at distal leg level than in controls (left 1.63+/-0.55 vs. 2.26+/-0.49 kg, P<0.05; right 1.63+/-0.53 vs. 2.40+/-0.54 kg, P<0.01). Arm FFM was similar in the two groups, while distal leg FFM was significantly lower in MSL cases (left: 7.8+/-1.3 vs. 8.7+/-0.8 kg, P<0.05; right: 8.0+/-1.5 vs. 9.2+/-0.9 kg, P<0.05). FFM strongly correlated with REE (r:0.86;P<0.001). REE, expressed as an absolute value and adjusted for FFM (1830+/-215 vs. 1675+/-120 kcal, P<0.05) was higher in MSL patients. In conclusion, MSL patients had a marked FFM and FM atrophy in the lower segments of the legs and an altered energy expenditure (hypermetabolism).

Multiple symmetric lipomatosis: Korean experience.

Multiple symmetric lipomatosis (MSL) is a rare disorder that is characterized by abnormal adipose tissue growth mainly at the neck, abdominal wall, back, shoulder girdle, and arms. A suggested mechanism for accumulation of adipose tissue is a defect in the lipolytic pathway of fat cell. To evaluate the clinical, morphologic, and biochemical findings in Korean patients. A total of 32 patients with MSL were evaluated retrospectively. Ten patients were seen at our hospital. The remaining 22 patients from literature were reviewed. Biochemical analyses and neurologic studies were performed. All cases were a sporadic form of MSL. The age of onset ranged from 26 to 70 years (mean of 49.4 years). The male-to-female ratio was 31:1. All but two patients were alcoholics with a daily intake of more than 80 g of alcohol for at least 10 years. In metabolic studies of 17 patients, a Fredrickson type IIb or IV hyperlipoproteinemia was found in three patients. High-density lipoprotein cholesterol values were higher in three patients. A glucose tolerance test was abnormal in five patients. A high prevalence of neurologic abnormalities was observed. Clinical signs of peripheral neuropathy were present in 11 of 13 patients. Central nervous system involvement was found clinically in 3 of 13 patients. The surgical removal of the fatty tissue and abstinence from alcohol are essential for relieving the patients from functional impairment. Not only metabolic studies of lipid abnormalities but also a complete neurologic examination were required in order to improve the quality of life in MSL patients.

Multiple Symmetric Lipomatosis

BACKGROUND Multiple symmetric lipomatosis (MSL) is a rare disorder that is characterized by abnormal adipose tissue growth mainly at the neck, abdominal wall, back, shoulder girdle, and arms. A suggested mechanism for accumulation of adipose tissue is a defect in the lipolytic pathway of fat cell. OBJECTIVE To evaluate the clinical, morphologic, and biochemical findings in Korean patients. METHOD A total of 32 patients with MSL were evaluated retrospectively. Ten patients were seen at our hospital. The remaining 22 patients from literature were reviewed. Biochemical analyses and neurologic studies were performed. RESULTS All cases were a sporadic form of MSL. The age of onset ranged from 26 to 70 years (mean of 49.4 years). The male-to-female ratio was 31:1. All but two patients were alcoholics with a daily intake of more than 80 g of alcohol for at least 10 years. In metabolic studies of 17 patients, a Fredrickson type IIb or IV hyperlipoproteinemia was found in three patients. High-density lipoprotein cholesterol values were higher in three patients. A glucose tolerance test was abnormal in five patients. A high prevalence of neurologic abnormalities was observed. Clinical signs of peripheral neuropathy were present in 11 of 13 patients. Central nervous system involvement was found clinically in 3 of 13 patients. CONCLUSION The surgical removal of the fatty tissue and abstinence from alcohol are essential for relieving the patients from functional impairment. Not only metabolic studies of lipid abnormalities but also a complete neurologic examination were required in order to improve the quality of life in MSL patients.

Multiple symmetric lipomatosis: clinical aspects and outcome in a long-term longitudinal study.

Multiple symmetric lipomatosis (MSL) is a rare disease characterized by the growth of uncapsulated masses of adipose tissue. MSL is associated with high ethanol intake and complicated by somatic and autonomic neuropathy and by the infiltration of the adipose tissue at the mediastinal level. To date, the disease is considered as slowly progressive, but long-term longitudinal data are still lacking. In this study, a long-term follow-up of a large series of MSL patients is presented. We studied 31 patients with MSL (30 males and one female) first evaluated at our institution from 1973 to 1992. All patients were followed until 1998-1999 or until death, with a mean follow-up of 14.5+/-5.0 y (range 4-26 y). Both at baseline and during follow-up, the location and the size of the subcutaneous lipomatous fat depots, the presence and the extension of deeply localized lipomatous tissue, and the presence and the severity of both somatic and autonomic neuropathy were evaluated. Eight MSL patients died during follow-up (25.8% of patients). A sudden death was proved to be the cause of death in three patients. All these three patients had severe autonomic neuropathy and none had coronary disease, acute myocardial infarction or other cardiac abnormalities. No signs or symptoms of coronary heart disease were present in the whole series. In addition to this high fatality rate, a substantial morbidity related to the occupation of the mediastinal space by the lipomatus tissue and to somatic neuropathy was also observed. MSL is associated with a significant morbidity and mortality. Therefore, the definition of 'benign symmetric lipomatosis', still adopted by several authors, cannot be justified.

Multiple symmetric lipomatosis may be the consequence of defective noradrenergic modulation of proliferation and differentiation of brown fat cells.

Multiple symmetric lipomatosis (MSL) is an inherited disorder in which enlarging and unencapsulated lipomas symmetrically develop in the subcutaneous tissue of the neck, shoulders, mammary, and truncal regions. In some cases, it is associated with mitochondrial DNA abnormalities. The pathogenesis of MSL is completely unknown, although the fat deposits may be due to a neoplastic-like proliferation of functionally defective brown adipocytes. It has recently been demonstrated that the beta(3)-adrenergic receptor is the functionally relevant adrenergic receptor subtype in brown adipocytes and that its stimulation by noradrenaline (NA) modulates the expression of genes, such as uncoupling protein (UCP)-1 and inducible nitric oxide synthase (iNOS), involved in fat cell proliferation and differentiation. Furthermore, Trp64Arg mutation of the beta(3)-adrenoceptor has been implicated in lower NA activity in adipose tissues. The aim of this study was to investigate the molecular and functional characteristics of MSL adipocytes and to analyse the effects of nitric oxide (NO) on the proliferation/differentiation of MSL adipocytes in culture, and the relevance of putative noradrenergic deficit in the development of lipomas in MSL patients. Cultured MSL adipocytes were able to synthesize UCP-1 (the selective marker of brown adipocytes), but unlike that of normally functioning brown fat cells, the expression of the UCP-1 gene was not significantly induced by NA. NA is also defective in inducing iNOS gene expression, thus leading to reduced NO production and a consequent reduction in the anti-proliferative, adipogenic (mitochondrial biogenesis) effects of NA on MSL cells. Furthermore, the transcriptional peroxisome proliferator-activated receptor gamma co-activator-1 (PGC-1), which plays a key role in the sympathetic-stimulated mitochondrial biogenesis of brown adipocytes, is expressed but not induced by NA in MSL cells, as it is in brown adipocytes. The study did not find any association between beta(3)-adrenoceptor gene polymorphism and noradrenergic signalling defects in MSL subjects with or without mitochondrial DNA mutations.

Multiple symmetric lipomatosis: an updated clinical report.

A systematic survey of 19 male patients with multiple symmetric lipomatosis (MSL) gives evidence for newly delineated and clinically relevant features of the disease. Signs and symptoms of a hitherto unrecognized severe peripheral and autonomic neuropathy were observed in all patients. A mediastinal location of lipomatous tissue was identified by computed tomography in five patients, with clinical evidence of a space-occupying syndrome in four of them. A further deep location of lipomatous tissue below the trapezius muscle, independent of the involvement of the overlying subcutaneous adipose tissue, was demonstrated in seven patients. Alcohol-related abnormalities in liver function tests were present in 10 of 19 patients. The disease is characterized by peculiar metabolic abnormalities, such as marked increase in adipose tissue lipoprotein lipase activity, a plasma hyperalphalipoproteinemia and a specific defect of the adrenergic-stimulated lipolysis in lipomatous tissue. Finally, a red blood cell macrocytosis or overt macrocytic anemia and abnormalities in liver function tests were found in MSL patients, related to elevated alcohol intake. An 8-year follow-up of nine MSL patients demonstrated that peripheral neuropathies and space-occupying mediastinal syndromes represent the most incapacitating, sometimes rapidly progressive, complication of MSL.

Metabolic abnormalities in multiple symmetric lipomatosis: elevated lipoprotein lipase activity in adipose tissue with hyperalphalipoproteinemia.

Lipoprotein lipase activity in lipomatous tissue, post-heparin lipoprotein lipase activity in plasma, and the composition and concentration of serum lipoproteins were studied in 15 patients with Multiple Symmetric Lipomatosis (MSL). Extremely elevated lipoprotein lipase activity in adipose tissue was found in MSL patients. Total and hepatic post-heparin plasma lipolytic activity was normal, while a moderate but statistically significant increase of extrahepatic lipolytic activity was present. An abnormal composition of serum lipoproteins, characterized by a significant increase in high density lipoproteins, namely HDL2 subfraction, and apoprotein A-I, was demonstrated. A concomitant decrease in and abnormal composition of low density lipoproteins were found. This lipoprotein pattern is consistent with a newly recognized type of hyperalphalipoproteinemia. Significant correlations were found between serum HDL2 cholesterol values and lipoprotein lipase activity in adipose tissue (as well as between serum VLDL-triglyceride and HDL2 cholesterol values). These observations confirm the role of adipose tissue lipoprotein lipase in triglyceride-rich lipoprotein catabolism. The elevated levels of lipoprotein lipase activity in adipose tissue, in addition to a previously demonstrated decrease in adrenergic-stimulated lipid mobilization, could account for both the abnormal fat accumulation in lipomatous fat cell and for hyperalphalipoproteinemia in MSL patients. The occurrence of MSL in two brothers suggests an inherited enzymatic defect, indicating MSL as a "triglyceride storage disease in adipose tissue".

Multiple symmetric lipomatosis: a defect in adrenergic-stimulated lipolysis.

The cellularity of normal and lipomatous adipose tissue and its response to different lipolytic agents have been studied in a group of 10 patients with multiple symmetric lipomatosis (MSL). In MSL patients, fat cells from lipomatous tissue are smaller than normal, uninvolved adipocytes. Fat cells from lipomata show minimal variations in size following conspicuous increase of lipomatous masses. These findings suggest that the growth of lipomata can be attributed to the neoformation of adipocytes rather than to an enlargement in the single fat cells. The incidence of reduced glucose tolerance and of hyperlipoproteinemia is similar in MSL patients and in controls. A significant reduction in plasma free fatty acids was observed in MSL patients after a 24-h fast as well as after noradrenaline infusion. A specific insensitivity of lipomatous tissue to the lipolytic effect of noradrenaline and isoprenaline was observed in vitro, as indicated by glycerol release in the medium, whereas response to theophylline and to dibutyryl cyclic AMP was retained. The lipolytic response to catecholamines was retained. The lipolytic response to catecholamines was normal in the nonlipomatous adipose tissue of MSL patients. In basal conditions ATP concentrations were similar in normal and in lipomatous adipose tissue. However, incubation with noradrenaline induced a significant fall in intracellular ATP levels in normal tissue, whereas no variations were observed in lipomatous tissue. Theophylline, instead, induced a prompt and significant decrease in intracellular ATP levels in lipomatous tissue. These observations indicate that the block in catecholamine-stimulated lipolysis in lipomatous tissue of MSL patients can be localized at a level preceding the formation of cyclic AMP.