Analysis of disease characteristics of a large patient cohort with congenital generalized lipodystrophy from the Middle East and North Africa.

BACKGROUND: Congenital generalized lipodystrophy (CGL) is a rare inherited disease characterized by a near-total absence of adipose tissue and is associated with organ system abnormalities and severe metabolic complications. Here, we have analyzed the disease characteristics of the largest CGL cohort from the Middle East and North Africa (MENA) who have not received lipodystrophy-specific treatment. METHODS: CGL was diagnosed clinically by treating physicians through physical assessment and supported by genetic analysis, fat loss patterns, family history, and the presence of parental consanguinity. Data were obtained at the time of patient diagnosis and during leptin-replacement naïve follow-up visits as permitted by available medical records. RESULTS: Data from 43 patients with CGL (37 females, 86%) were collected from centers located in eight countries. The mean (median, range) age at diagnosis was 5.1 (1.0, at birth-37) years. Genetic analysis of the overall cohort showed that CGL1 (n = 14, 33%) and CGL2 (n = 18, 42%) were the predominant CGL subtypes followed by CGL4 (n = 10, 23%); a genetic diagnosis was unavailable for one patient (2%). There was a high prevalence of parental consanguinity (93%) and family history (67%) of lipodystrophy, with 64% (n = 25/39) and 51% (n = 20/39) of patients presenting with acromegaloid features and acanthosis nigricans, respectively. Eighty-one percent (n = 35/43) of patients had at least one organ abnormality; the most frequently affected organs were the liver (70%, n = 30/43), the cardiovascular system (37%, n = 16/43) and the spleen (33%, n = 14/43). Thirteen out of 28 (46%) patients had HbA1c > 5.7% and 20/33 (61%) had triglyceride levels > 2.26 mmol/L (200 mg/dl). Generally, patients diagnosed in adolescence or later had a greater severity of metabolic disease versus those diagnosed during childhood; however, metabolic and organ system abnormalities were observed in a subset of patients diagnosed before or at 1 year of age. CONCLUSIONS: This analysis suggests that in addition to the early onset of fat loss, family history and high consanguinity enable the identification of young patients with CGL in the MENA region. In patients with CGL who have not received lipodystrophy-specific treatment, severe metabolic disease and organ abnormalities can develop by late childhood and worsen with age.

Natural history and comorbidities of generalised and partial lipodystrophy syndromes in Spain.

The rarity of lipodystrophies implies that they are not well-known, leading to delays in diagnosis/misdiagnosis. The aim of this study was to assess the natural course and comorbidities of generalised and partial lipodystrophy in Spain to contribute to their understanding. Thus, a total of 140 patients were evaluated (77.1% with partial lipodystrophy and 22.9% with generalised lipodystrophy). Clinical data were collected in a longitudinal setting with a median follow-up of 4.7 (0.5-17.6) years. Anthropometry and body composition studies were carried out and analytical parameters were also recorded. The estimated prevalence of all lipodystrophies in Spain, excluding Köbberling syndrome, was 2.78 cases/million. The onset of phenotype occurred during childhood in generalised lipodystrophy and during adolescence-adulthood in partial lipodystrophy, with the delay in diagnosis being considerable for both cohorts. There are specific clinical findings that should be highlighted as useful features to take into account when making the differential diagnosis of these disorders. Patients with generalised lipodystrophy were found to develop their first metabolic abnormalities sooner and a different lipid profile has also been observed. Mean time to death was 83.8 ± 2.5 years, being shorter among patients with generalised lipodystrophy. These results provide an initial point of comparison for ongoing prospective studies such as the ECLip Registry study.

Comorbidities and Survival in Patients With Lipodystrophy: An International Chart Review Study.

CONTEXT: Limited natural history data are available in patients with non-HIV-related lipodystrophy syndromes who never received disease-specific therapies, making interpretation of benefits of therapies in lipodystrophy syndromes challenging. OBJECTIVE: We assessed the natural history of non-HIV-related generalized lipodystrophy (GL) and partial lipodystrophy (PL) in patients who have never received leptin or other lipodystrophy-specific therapies. DESIGN/SETTING/PATIENTS: We conducted an international chart review of 230 patients with confirmed GL or PL at five treatment centers who never received leptin or other lipodystrophy-specific therapies. Patients were observed from birth to loss to follow-up, death, or date of chart abstraction. OUTCOME MEASURES: Lifetime prevalence of diabetes/insulin resistance and select organ abnormalities, time to diabetes/insulin resistance, first organ abnormality, disease progression, and mortality were described. RESULTS: Diabetes/insulin resistance was identified in 58.3% of patients. Liver abnormalities were the most common organ abnormality (71.7%), followed by kidney (40.4%), heart (30.4%), and pancreatitis (13.0%). Kaplan-Meier estimates of mean (SE) time to first organ abnormality were 7.7 years (0.9) in GL and 16.1 years (1.5) in PL (P < 0.001). Mean time to diabetes/insulin resistance was 12.7 years (1.2) in GL and 19.1 years (1.7) in PL (P = 0.131). Mean time to disease progression was 7.6 years (0.8) and comparable between GL and PL subgroups (P = 0.393). Mean time to death was 51.2 years (3.5) in GL and 66.6 years (1.0) in PL (P < 0.001). CONCLUSIONS: This large-scale study provides comprehensive, long-term data across multiple countries on the natural history of non-HIV-related lipodystrophy.

Lipodystrophies, dyslipidaemias and atherosclerotic cardiovascular disease.

Lipodystrophies are rare, heterogeneous, genetic or acquired, disorders characterised by varying degrees of body fat loss and associated metabolic complications, including insulin resistance, dyslipidaemias, hepatic steatosis and predisposition to atherosclerotic cardiovascular disease (ASCVD). The four main types of lipodystrophy, excluding antiretroviral therapy-induced lipodystrophy in HIV-infected patients, are congenital generalised lipodystrophy (CGL), familial partial lipodystrophy (FPLD), acquired generalised lipodystrophy (AGL) and acquired partial lipodystrophy (APL). This paper reviews the literature related to the prevalence of dyslipidaemias and ASCVD in patients with lipodystrophies. Patients with CGL, AGL and FPLD have increased prevalence of dyslipidaemia but those with APL do not. Patients with CGL as well as AGL present in childhood, and have severe dyslipidaemias (mainly hypertriglyceridaemia) and early onset diabetes mellitus as a consequence of extreme fat loss. However, only a few patients with CGL and AGL have been reported to develop coronary heart disease. In contrast, data from some small cohorts of FPLD patients reveal increased prevalence of ASCVD especially among women. Patients with APL have a relatively low prevalence of hypertriglyceridaemia and diabetes mellitus. Overall, patients with lipodystrophies appear to be at high risk of ASCVD due to increased prevalence of dyslipidaemia and diabetes and efforts should be made to manage these metabolic complications aggressively to prevent ASCVD.

Nurses' knowledge about Berardinelli-Seip Congenital Lipodystrophy.

Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare autosomal recessive disease characterized by the almost complete absence of adipose tissue. Due to a strong founder effect that resulted in a higher prevalence of BSCL in Rio Grande do Norte (RN), a state in northeastern Brazil, it has been essential that health professionals develop knowledge about this disease. Nurses are often the first point of contact with patients during health care assistance. The purpose of this study was to investigate the knowledge of these professionals about BSCL in two main hospitals in RN state. A questionnaire was applied to 199 nurses working in the Hospital Regional Mariano Coelho-HRMC (Regional Hospital Mariano Coelho), in Currais Novos-RN, and in the Hospital Universitário Onofre Lopes-HUOL (University Hospital Onofre Lopes), in Natal-RN. This study showed that most nursing professionals do not know about the disease, although they have already received patients with BSCL in those hospitals. The nurses from HRMC and HUOL lacked knowledge of BSCL and the healthcare of these patients requires immediate improvement. Significant efforts are required to close the gap between current and needed practice patterns.

Early commitment of cardiovascular autonomic modulation in Brazilian patients with congenital generalized lipodystrophy.

BACKGROUND: Metabolic abnormalities in congenital generalized lipodystrophy (CGL) are associated with microvascular complications. However, the evaluation of different types of neuropathy in these patients, including the commitment of cardiovascular autonomic modulation, is scarce. The objective of the present study was to determine the prevalence of cardiovascular autonomic neuropathy (CAN) in patients with CGL compared with individuals with type 1 diabetes and healthy subjects. METHODS: Ten patients with CGL, 20 patients with type 1 diabetes and 20 healthy subjects were included in the study. Controls were paired 1:2 for age, gender, BMI and pubertal stage. Heart rate variability (HRV) was analyzed using cardiovascular autonomic reflex tests, including postural hypotension test, Valsalva (VAL), respiratory (E/I) and orthostatic (30/15) coefficients, and spectral analysis of the HRV, determining very low (VLF), low (LF) and high (HF) frequencies components. The diagnosis of CAN was defined as the presence of at least two altered tests. RESULTS: CAN was detected in 40% of the CGL patients, 5% in type 1 diabetes patients and was absent in healthy individuals (p < 0.05). We observed a significant reduction in the E/I, VLF, LF and HF in CGL cases vs. type 1 diabetes and healthy individuals and lower levels of 30/15 and VAL in CGL vs. healthy individuals. A significant positive correlation was observed between leptin and 30/15 coefficient (r = 0.396; p = 0.036) after adjusting for insulin resistance and triglycerides. Autonomic cardiovascular tests were associated with HbA1c, HOMA-IR, triglycerides and albumin/creatinine ratio in CGL cases. CONCLUSIONS: We observed a high prevalence of CAN in young patients with CGL, suggesting that insulin resistance, hypertriglyceridemia and hypoleptinemia, may have been involved in early CAN development. Additional studies are needed to evaluate the role of leptinemia in the physiopathogenesis of the condition.

Identification of a novel nonsense mutation and a missense substitution in the AGPAT2 gene causing congenital generalized lipodystrophy type 1.

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disease characterized by the generalized scant of adipose tissue. CGL type 1 is caused by mutations in gene encoding 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2). A clinical and molecular genetic investigation was performed in affected and unaffected members of two families with CGL type 1. The AGPAT2 coding region was sequenced in index cases of the two families. The presence of the identified mutations in relevant parents was tested. We identified a novel nonsense mutation (c.685G>T, p.Glu229*) and a missense substitution (c.514G>A, p.Glu172Lys). The unaffected parents in both families were heterozygous carrier of the relevant mutation. The results expand genotype-phenotype spectrum in CGL1 and will have applications in prenatal and early diagnosis of the disease. This is the first report of Persian families identified with AGPAT2 mutations.

Childhood acquired lipodystrophy: a retrospective study.

OBJECTIVE: We sought to describe the clinical characteristics and complications of children with acquired lipodystrophy (LD). METHODS: We conducted a retrospective chart review at a tertiary, academic children's hospital of children clinically given a diagnosis of acquired LD between January 1997 and December 2004. RESULTS: During the study period, 23 patients were identified. Their mean age at diagnosis was 9.74 +/- 3.98 years. Of patients, 61% were girls. The length of the follow-up was 4.8 +/- 3.5 years from the time of LD diagnosis. Of patients, 30% had evidence of localized disease (7 of 23), 26% (6 of 23) had localized partial disease, and 44% (10 of 23) had generalized LD. The most common underlying diagnosis was dermatomyositis (78%), alone or in association with other autoimmune diseases (juvenile rheumatoid arthritis 17%). Panniculitis with autoimmunity was noted in 17% of the patients. More than half of the patients had at least one complication attributable to LD such as acanthosis nigricans (22%), hyperpigmentation (22%), hepatomegaly (13%), hypertension (13%), protuberant abdomen (9%), and hyperlipidemia (4%). The only predictor for development of complications was the age of diagnosis of LD, with younger age being associated with increased risk (7 vs 12 years, P = .04). LIMITATIONS: Limitations were inherent to the retrospective design. CONCLUSIONS: Childhood acquired LD is seen more frequently in the context of autoimmunity. Affected children should be monitored for the development of complications, particularly if given a diagnosis of LD at a younger age.