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.

Metabolic and other morbid complications in congenital generalized lipodystrophy type 4.

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

A subtype of laminopathies: Generalized lipodystrophy-associated progeroid syndrome caused by LMNA gene c.29C>T mutation.

The term laminopathies refers to a group of congenital diseases characterized by accelerated degeneration of human tissues. Mutations in LMNA, LMNB, ZMPSTE24, and other genes lead to structural and functional abnormalities associated with lamins. One subtype of laminopathy is the generalized lipodystrophy-associated progeroid syndrome (GLPS), which occurs in patients with heterozygous mutations of the LMNA gene c.29C>T(p.T10I). This paper reports the first case of GLPS in China and compares the clinical features of other GLPS patients with literature reports. A 16-year-old male patient was treated for diabetic ketoacidosis, presenting with premature aging appearance, systemic lipodystrophy, severe fatty liver, and decreased bone density. After peripheral blood DNA extraction and second-generation sequencing, a heterozygous mutation of exon 1 of the LMNA gene c.29C>T(p.T10I) was detected. This case of GLPS may provide a diagnostic and therapeutic basis for potential patients.

Delayed Presentation of Berardinelli-Siep Lipodystrophy in an Adolescent Female.

Berardinelli-Siep syndrome (BSS) is a form of congenital generalized lipodystrophy that disrupts the pathways of lipid metabolism. It presents with physical exam findings, including muscular hypertrophy and lipoatrophy as well as serious metabolic consequences such as diabetes mellitus, hypertriglyceridemia, acute pancreatitis, hepatomegaly, and hepatic steatosis. Diagnosis generally occurs soon after birth or in childhood. The case presented is significant for a delayed diagnosis of suspected BSS Type 1 which is rather uncommon in a developed country. Due to the detrimental complications of BSS, such as hypertrophic cardiomyopathy, pancreatitis, and liver disease, early diagnosis and intervention are crucial. Pediatric providers must be knowledgeable about physical features of BSS and common presentations such as new onset diabetes, hypertriglyceridemia, or pancreatitis throughout early childhood and adolescence in order to avoid delayed diagnoses.

Metreleptin Treatment in a Boy with Congenital Generalized Lipodystrophy due to Homozygous c.465_468delGACT (p.T156Rfs*8) Mutation in the BSCL2 Gene: Results From the First-year

Congenital generalized lipodystrophy (CGL) is a rare, autosomal recessive disorder characterized by an almost complete absence of body fat. In CGL, patients may have hyperphagia due to leptin deficiency. Recombinant human leptin (metreleptin) has been suggested as an effective treatment option. We present successful treatment with metreleptin in a boy with CGL and results from the first year of follow-up. An eight-month-old boy presented with excessive hair growth and a muscular appearance. On examination he had hypertrichosis, decreased subcutaneous adipose tissue over the whole body and hepatomegaly. Laboratory investigations revealed hypertriglyceridemia, hyperinsulinemia, elevated liver transaminases and low leptin levels. Molecular genetic analysis detected a homozygous, c.465_468delGACT (p.T156Rfs*8) mutation in the BSCL2 gene. A diagnosis of CGL type 2 was considered. Despite dietary intervention, exercise, and treatment with additional omega-3 and metformin, the hypertriglyceridemia, hyperinsulinemia, and elevated liver transaminase levels worsened. Metreleptin treatment was started and after one year hyperphagia had disappeared, and there was dramatic improvement in levels of insulin, hemoglobin A1c, triglycerides and liver transaminases. Hepatosteatosis was lessened and hepatosplenomegaly was much improved. Metreleptin appears to be an effective treatment option in children with CGL that remarkably improved metabolic complications in the presented case. Initiation of metreleptin treatment in the early period may decrease mortality and morbidity, and increase the quality of life in children with CGL.

Characterization and Clinical Association of Autoantibodies Against Perilipin 1 in Patients With Acquired Generalized Lipodystrophy.

Acquired generalized lipodystrophy (AGL) is a rare condition characterized by massive loss of adipose tissue through the body, causing severe metabolic complications. Autoimmune destruction of adipocytes is strongly suspected based on the frequent association of AGL with autoimmune disorders. In 2018, autoantibodies against perilipin 1 (PLIN1) were identified in three patients with autoimmune-associated AGL. However, the pathogenic mechanism and clinical impact of anti-PLIN1 remain unsolved. The prevalence of anti-PLIN1 autoantibodies in an AGL cohort of 40 patients was 50% (20 of 40). Among positive patients, 10 had the autoimmune variety and 10 had panniculitis-associated AGL. The IgG isotype was predominant, although some IgM antibodies were detected. Epitope-mapping studies did not identify a single, major epitope. Instead, autoantibodies typically bound to several different peptides, among which the central (233-405) domain was detected in all antibody-positive patients, for both IgG and IgM autoantibodies. In-depth epitope mapping indicated that anti-PLIN1 autoantibodies predominantly recognize the αß-hydrolase domain containing 5 (ABHD5) binding site (383-405). Autoantibodies dose-dependently blocked the binding of PLIN1 to ABHD5 and caused a dislocation of ABHD5 toward the cytosol, leading to an increase in lipolysis and lipase activities. Finally, anti-PLIN1 titers significantly correlated with the amount of fat loss, metabolic control impairment, and severity of liver injury. Our data strongly support that anti-PLIN1 autoantibodies are a diagnostic biomarker and a cause of lipodystrophy in patients with AGL.

Unusual magnetic resonance imaging findings of cystic bone lesions in congenital generalized lipodystrophy.

Cystic bone lesions are the hallmark of skeletal abnormalities in patients with congenital generalized lipodystrophy (CGL). However, their pathophysiology is still unclear and theories about their origin remain largely speculative. This article reports on a patient with CGL and cystic bone lesions, some of them with unusual magnetic resonance imaging (MRI) findings that include elevated signal intensity on T1-weighted images and fluid-fluid levels, the latter evolving to a more "classic" cystic appearance on follow-up. Even though similar findings were first described almost 30 years ago, little attention was given to them back then; furthermore, other than the present report, no other study has performed sequential exams to follow their evolution in serial MRI. The authors conduct a review of the literature, hypothesizing that these remarkable findings may reflect an intermediate stage in the process of cystification of the abnormal bone marrow, incapable to perform adipose conversion, lending factual support to the modern theories about this issue.

Lipodystrophy for the Diabetologist-What to Look For.

PURPOSE OF REVIEW: Genetic or acquired lipodystrophies are characterized by selective loss of body fat along with predisposition towards metabolic complications of insulin resistance, such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, polycystic ovarian syndrome, and acanthosis nigricans. In this review, we discuss the various subtypes and when to suspect and how to diagnose lipodystrophy. RECENT FINDINGS: The four major subtypes are autosomal recessive, congenital generalized lipodystrophy (CGL); acquired generalized lipodystrophy (AGL), mostly an autoimmune disorder; autosomal dominant or recessive familial partial lipodystrophy (FPLD); and acquired partial lipodystrophy (APL), an autoimmune disorder. Diagnosis of lipodystrophy is mainly based upon physical examination findings of loss of body fat and can be supported by body composition analysis by skinfold measurements, dual-energy x-ray absorptiometry, and whole-body magnetic resonance imaging. Confirmatory genetic testing is helpful in the proband and at-risk family members with suspected genetic lipodystrophies. The treatment is directed towards the specific comorbidities and metabolic complications, and there is no treatment to reverse body fat loss. Metreleptin should be considered as the first-line therapy for metabolic complications in patients with generalized lipodystrophy and for prevention of comorbidities in children. Metformin and insulin therapy are the best options for treating hyperglycemia and fibrates and/or fish oil for hypertriglyceridemia. Lipodystrophy should be suspected in lean and muscular subjects presenting with diabetes mellitus, hypertriglyceridemia, non-alcoholic fatty liver disease, polycystic ovarian syndrome, or amenorrhea. Diabetologists should be aware of lipodystrophies and consider genetic varieties as an important subtype of monogenic diabetes.

Face-sparing Congenital Generalized Lipodystrophy Type 1 Associated With Nonclassical Congenital Adrenal Hyperplasia.

CONTEXT: Congenital generalized lipodystrophy, type 1 (CGL1), due to biallelic pathogenic variants in AGPAT2, is characterized by the near total loss of body fat from the face, trunk, and extremities. Patients develop premature diabetes, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. However, sparing of the facial fat and precocious pubertal development has not been previously reported in CGL1. CASE DESCRIPTION: We report a 21-year-old woman of European descent with CGL1 who had sparing of the facial fat and premature thelarche at birth with premature pubarche and menstrual bleeding at age 3 years. Her serum 17-OH progesterone level rose to 1000 ng/dL (30.26 nmol/L) after cosyntropin stimulation test, suggestive of nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. Hydrocortisone replacement therapy from age 3.5 to 10 years resulted in cessation of menstruation and growth of pubic hair, and a reduction of breast size. Sanger and whole-exome sequencing revealed compound heterozygous variants c.493-1G>C; p.(Leu165_Gln196del), and c.del366_588+534; p.(Leu123Cysfs*55) in AGPAT2 plus c.806G>C; p.(Ser269Thr) and c.844G>T; p.(Val282Leu) in CYP21A2. She developed diabetes at age 13 requiring high-dose insulin and had 7 episodes of acute pancreatitis due to extreme hypertriglyceridemia in the next 5 years. Metreleptin therapy was initiated at age 18 and after 3 years, she had remission of diabetes and hypertriglyceridemia; however, menstrual irregularity and severe hirsutism did not improve. CONCLUSION: Concomitant NCAH in this CGL1 patient was associated with precocious pubertal development and sparing of facial fat. Metreleptin therapy drastically improved her hyperglycemia and hyperlipidemia but not menstrual irregularity and hirsutism.

Berardinelli Seip Syndrome: A rare case report.

Berardinelli Seip Congenital Lipodystrophy (BSCL) or Congenital Generalized Lipodystrophy (CGL) is one of the four subgroups of lipodystrophy syndrome which is characterized by varying degrees of loss of adipose mass in the body. It is an extremely rare autosomal recessive disorder and commonly reported clinical presentations include muscular hypertrophy, gigantism, hepatomegaly, impaired glucose tolerance, acanthosis nigricans, hypertriglyceridaemia, cardiomyopathy, intellectual impairment, bone cysts and phlebomegaly. We present a case of a 4.5 years old male child born to consanguineous parents, presented with pneumonia. There was history of recurrent diarrhea and chest infection in the past. He had acromegaly like features, hirsutism, firm hepatomegaly, a well defined bone cyst in proximal right femur, pancytopenias with normal bone marrow biopsy report, hypertriglyceridemia and selective IgA deficiency. This is the first case of BSCL, reported in Pakistan with a bone cyst and IgA deficiency. Such patients need to be identified and monitored for complications like diabetes mellitus and hypertrophic cardiomyopathy.

Berardinelli-Seip Congenital Lipodystrophy - A Case Report and Review of Literature.

Berardinelli-Seip Congenital Lipodystrophy (BSCL), also known as congenital generalised lipodystrophy, is a genetic disorder where there is an absolute deficiency of adipose tissue. It affects the development of adipocytes and ultimately leads to an inability to store fat in adipocytes. It is extremely rare. Most of the cases reported are from Africa and North America. Only a handful of cases have been reported in the world. The aim of this case report is to highlight the significance of this rare metabolic disorder, which should be considered whilst managing young patients with severe insulin resistance. We present a case of a young Asian child with an increasing need for insulin for his diabetes. He was previously managed on the lines of type 1 diabetes mellitus and his insulin requirements kept on increasing. Diagnosis on the basis of genetic studies was not possible due to the non-availability of the test in Pakistan. BSCL is an infrequent condition leading to several cardiometabolic complications. Timely diagnosis can lead to better management and prevention of complications. Keywords: Insulin resistance, Lipodystrophy, Acanthosis nigricans, Hypertriglyceridemia, Genetic disease.

Severe aortic stenosis during leptin replacement therapy in a patient with generalized lipodystrophy-associated progeroid syndrome due to an LMNA variant: A case report.

Leptin replacement therapy (LRT) has drastically improved the prognosis of patients with lipodystrophy, but pro-inflammatory properties of leptin could become evident in the long term. Here, we report a 30-year-old Japanese woman with generalized lipodystrophy-associated progeroid syndrome due to a heterozygous LMNA variant (c.29C > T; p.T10I), who was diagnosed with severe aortic stenosis (AS) after more than a decade of LRT, which required transcatheter aortic valve implantation. Given her marked hypoadiponectinemia and the LMNA variant, our patient might have been susceptible to progeria-associated disorders, including aortic stenosis, which could have been exaggerated by the prolonged 'imbalanced adipokines' caused by LRT between pro-inflammatory leptin and anti-inflammatory adiponectin. Thus, long-term LRT could be associated with AS in patients with the LMNA variant to cause generalized lipodystrophy-associated progeroid syndrome and hypoadiponectinemia.

Successful treatment of severe hypertriglyceridemia with icosapent ethyl in a case of congenital generalized lipodystrophy type 4.

OBJECTIVES: Congenital generalized lipodystrophy type 4 (CGL4) is a rare autosomal recessive condition with high rates of morbidity and mortality. It is a multisystem condition associated with ventricular tachyarrhythmia, congenital myopathy, hepatitis, and metabolic profile of severe hypertriglyceridemia and insulin resistance. Metreleptin is the first line treatment, however it is unavailable in several countries. Herein, we describe a unique presentation and treatment of CGL4. CASE PRESENTATION: A 16-year-old female presented with insulin resistant diabetes, and was later found to have myopathy, hypertriglyceridemia, nonalcoholic fatty liver disease, ventricular arrhythmias, and genetic confirmation of CGL4 due to homozygous change in CAVIN1 gene. She had severe hypertriglyceridemia, frequently >17 mmol/L, requiring several hospital admissions. To better control hypertriglyceridemia, in context of known congenital myopathy, we opted for treatment with icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA), which reduces synthesis and enhances clearance of triglycerides. On this treatment, she was able to maintain stable triglyceride levels of 4 mmol/L. CONCLUSIONS: We present the first case report of a patient with CGL4, successfully treated for hypertriglyceridemia, with icosapent ethyl.

The neonatal onset diabetes mellitus of Chinese neonate with congenital generalized lipodystrophy 2: a case report.

BACKGROUND: Congenital generalized lipodystrophy (CGL) is a clinically heterogeneous disorder characterized by near total absence of adipose tissue along with metabolic complications. Diabetes mellitus developed from CGL usually present between ages 15 and 20 years, and there are few reports in neonate. CASE PRESENTATION: In this report, we described a rare clinical presentation of CGL in a 12-day-old Chinese female neonates with hyperglycemia, hyperlipidemia, and subsequently appeared diabetes, hepatomegaly and fatty liver. The two clinical-exome sequencing identified heterozygous null mutations (c.793C > T and c.565G > T) in BSCL2 gene which was inherited from father and mother respectively. To date, it was the firstly reported CGL patient with neonatal onset diabetes. The neonate was treated with antibiotic, insulin and deeply hydrolyzed formula milk to significantly decrease FBG and serum trigylcerides levels.  CONCLUSIONS: Our case report analyzes the causes of early onset diabetes may relate with the locus of BSCL2 gene mutations and infection induction. It also suggests the importance of early identification, genetic analysis, and symptomatic treatment in the CGL, which are essential for improving the prognosis of children.

Leptin Attenuates Cardiac Hypertrophy in Patients With Generalized Lipodystrophy.

CONTEXT: Lipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia. OBJECTIVE: Determine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy. METHODS: Open-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance. RESULTS: In GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ±â€…3.0, 6.5 ±â€…1.6, 6.5 ±â€…1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8 ±â€…1.7, 9.1 ±â€…1.3, 8.3 ±â€…1.7 mm, P < .01), and LV mass (140.7 ±â€…45.9, 128.7 ±â€…37.9, 110.9 ±â€…29.1 g, P < .01), and increased septal e' velocity (8.6 ±â€…1.7, 10.0 ±â€…2.1, 10.7 ±â€…2.4 cm/s, P < .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD. CONCLUSION: Metreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.

A Rare Case Of Berardinelli Seip Syndrome.

Berardinelli Seip Syndrome is a rare disorder associated with loss of adipose tissue leading to a myriad of findings owing to derangements of carbohydrate and lipid metabolism. There is no cure and the management comprising low fat diet, metformin and leptin replacement is aimed at preventing complications. We report this syndrome in a male child from Afghanistan.

Focus on progressive myoclonic epilepsy in Berardinelli-Seip syndrome.

INTRODUCTION: Berardinelli-Seip syndrome or congenital generalized lipodystrophy type 2 is a rare genetic disorder characterized by selective loss of subcutaneous adipose tissue associated with peripheral insulin resistance and its complications. Nonprogressive mental retardation, dystonia, ataxia, and pyramidal signs are commonly present, whereas epilepsy has only occasionally been observed. CASE REPORT: We report the case of two sisters, 11 and 18 years old respectively, with an overlapping clinical phenotype compatible with Berardinelli-Seip syndrome and progressive myoclonic epilepsy. Molecular analysis identified an autosomal recessive c.1048C > t;(p(Arg350*)) pathogenic mutation of exon 8 of the BSCL2 gene, which was present in a homozygous state in both patients. CONCLUSIONS: Our paper contributes to further delineate a complex phenotype associated with BSCL2 mutation, underlining how seipin has a central and partially still unknown role that goes beyond adipose tissue metabolism, with a prominent involvement in central nervous system pathology.

Cardiac Alterations in Patients with Familial Lipodystrophy.

Familial lipodystrophy is a rare genetic condition in which individuals have, besides metabolic changes and body fat deposits, a type of cardiomyopathy that has not been well studied. Many of the patients develop cardiovascular changes, the most commonly reported in the literature being the expression of a type of hypertrophic cardiomyopathy. This article, presented as a bibliographic review, reviews the clinical and cardiovascular imaging aspects in this scenario of cardiomyopathy in a rare metabolic disease, based on the latest scientific evidence published in the area. Despite the frequent association of congenital lipodystrophy and ventricular hypertrophy described in the literature, the pathophysiological mechanisms of this cardiomyopathy have not yet been definitively elucidated, and new information on cardiac morphological aspects is emerging in the aegis of recent and advanced imaging methods, such as cardiac magnetic resonance.