Heterogeneity and high prevalence of bone manifestations, and bone mineral density in congenital generalized lipodystrophy subtypes 1 and 2.

Introduction: Congenital Generalized Lipodystrophy (CGL) is a rare autosomal recessive disease caused by mutations in genes responsible for the formation and development of adipocytes. Bone abnormalities are described. However, there is a scarcity of data. Objective: To describe bone characteristics in a large CGL1 and 2 case series. Methods: Cross-sectional study that assessed bone radiological features of CGL patients of a reference hospital in Fortaleza (CE), Brazil. Patients underwent clinical and bone mineral metabolism evaluation, radiographs of the axial and appendicular skeleton and bone mineral density (BMD) assessment by DEXA (dual energy X-ray absorptiometry). Results: Nineteen patients were included, fourteen were CGL1 and 5, CGL2. Median age was 20 years (8-42) and 58% were women. Median BMI and percentage of body fat were, respectively, 21 Kg/m² (16-24), and 10.5% (7.6-15). The median leptin concentration was 1 ng/mL (0.1-3.3). Diabetes mellitus and dyslipidemia were present in 79% and 63% of patients, respectively. Median calcium and phosphate were normal in almost all patients (95%). Median parathyroid hormone and 25-OH-vitamin D were 23 pg/mL (7-75) and 28 ng/mL (18-43). Osteolytic lesions, osteosclerosis and pseudo-osteopoikylosis, were present in 74%, 42% and 32% of patients, respectively. Lytic lesions were found predominantly in the extremities of long bones, bilaterally and symmetrically, spine was spared. Osteosclerosis was present in axial and appendicular skeleton. Pseudo-osteopoikilosis was found symmetrically in epiphyses of femur and humerus, in addition to the pelvis. BMD Z-score greater than +2.5 SD was observed in 13 patients (68.4%). BMD was higher in CGL1 compared to CGL2 in lumbar spine and total body in adults. No associations were found between high BMD and HOMA-IR (p=0.686), DM (p=0.750), osteosclerosis (p=0.127) or pseudo-osteopoikilosis (p=0.342), and, between pain and bone lesions. Fractures were found in 3 patients. Conclusion: Bone manifestations are prevalent, heterogeneous, and silent in CGL1 and CGL2. Osteolytic lesions are the most common, followed by osteosclerosis and pseudo-osteopoikilosis. Bone mass is high in most cases. There was no pain complaint related to bone lesions. Thus, systematic assessment of bone manifestations in CGL is essential. Studies are needed to better understand its pathogenesis and clinical consequences.

Across-species benefits of adrenalectomy on congenital generalized lipoatrophic diabetes: a review.

Two adrenalectomies py -45erformed fourteen years apart notoriously alleviated insulin resistance in a female teenager with Congenital Generalized Lipoatrophy (CGL, 1988) and in a murine model of CGL (2002). Following a successful therapeutic trial with anti-glucocorticoids, we performed the first surgical procedure on an 18-year-old girl. Before surgery, the anti-glucocorticoid therapy produced a rapid and striking drop in fasting serum insulin levels (from over 400 to 7.0 mU/L) and a slower -but impressive- fall in fasting serum triglycerides from 7,400 to 220-230 mg/dL. In contrast, fasting serum glucose levels dropped more slowly, from 225-290 to 121-138 mg/dL. Two weeks following total adrenalectomy, the fasting serum glucose level was 98 mg/dL, with a corresponding serum insulin level of 10 mU/L. During an Oral Glucose Tolerance Test, the 2-hour serum glucose was 210 mg/dL, and serum insulin values during the test did not exceed 53 mU/L. In 2002, the A-ZIP/F1 hypoleptinemic mouse had its adrenal glands removed. Even though this CGL model does not respond well to leptin replacement, an infusion of recombinant leptin reduced the characteristic hypercorticosteronemia of this murine model of CGL. Adrenalectomy in this transgenic mouse improved insulin sensitivity in the liver and muscle. In summary, adrenalectomy -in both a human and a mouse case of CGL- limited adipose tissue exposure to corticosteroid action and led to a notorious metabolic improvement. On a broader scenario, given that leptin restrains the adrenal axis, the reduced leptin activity of the leptin resistance displayed by obese subjects should lead to adrenal axis overactivity. This overactivity should result in elevated serum levels of free cortisol, free fatty acids, and glycerol. In this manner, leptin resistance should lead to peripheral (adipose tissue, liver, and muscle) insulin resistance and islet beta-cell apoptosis, paving the way to Type 2 diabetes.

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.

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.

Bone Mineral Density in Congenital Generalized Lipodystrophy: The Role of Bone Marrow Tissue, Adipokines, and Insulin Resistance.

Congenital Generalized Lipodystrophy (CGL) is a rare syndrome characterized by the almost total absence of subcutaneous adipose tissue due to the inability of storing lipid in adipocytes. Patients present generalized lack of subcutaneous fat and normal to low weight. They evolve with severe metabolic disorders, non-alcoholic fatty liver disease, early cardiac abnormalities, and infectious complications. Although low body weight is a known risk factor for osteoporosis, it has been reported that type 1 and 2 CGL have a tendency of high bone mineral density (BMD). In this review, we discuss the role of bone marrow tissue, adipokines, and insulin resistance in the setting of the normal to high BMD of CGL patients. Data bases from Pubmed and LILACS were searched, and 113 articles published until 10 April 2021 were obtained. Of these, 76 were excluded for not covering the review topic. A manual search for additional literature was performed using the bibliographies of the studies located. The elucidation of the mechanisms responsible for the increase in BMD in this unique model of insulin resistance may contribute to the understanding of the interrelationships between bone, muscle, and adipose tissue in a pathophysiological and therapeutic perspective.

Generalized lipoatrophy syndromes.

Generalized lipodystrophy (GL) syndromes are a group of rare heterogenous disorders, characterized by total subcutaneous fat loss. The frequency of GL is currently assessed as approximately 0,23 cases per million of the population, in Europe - as 0,96 cases per million of the population. They can be congenital (CGL) or acquired (AGL) depending on the etiology and the time of the onset of fat loss. Both CGL and AGL are often associated with different metabolic complications, such as hypertriglyceridemia, insulin resistance and lipoatrophic diabetes mellitus, metabolically associated FLD, arterial hypertension, proteinuria, reproductive system disorders. In this review we aimed to summarize the information on all forms of generalized lipodystrophy, especially the ones of genetic etiology, their clinical manifestations and complications, the perspectives for diagnostics, treatment and further research.

Misdiagnosis of Paget's Disease of Bone in a Congenital Generalized Lipodystrophy Patient: Case Report.

Paget's disease of bone (PDB) is a common skeleton disorder in which the diagnosis is suggested by radiological analyses. Congenital generalized lipodystrophy (CGL) is a rare, but a radiologic differential diagnosis of Paget's disease. Patients present total or almost total lack of subcutaneous adipose tissue, leptin deficiency, and precocious ectopic lipid accumulation, which lead to intense insulin resistance, poorly controlled diabetes mellitus, and hypertriglyceridemia. CGL subtypes 1 and 2 present sclerosis and osteolytic lesions that can resemble "pagetic" lesions. The clinical correlation is, therefore, essential. We report a CGL patient with bone lesions in which the radiographic findings led to a misdiagnosis of PDB. This case report brings awareness to CGL, a life-threating condition. Its early recognition is essential to avoid clinical complications and premature death. Therefore, it is important to consider CGL as PDB's differential diagnosis, especially in countries with high prevalence of this rare disease, such as Brazil.

Approach to Diagnosing a Pediatric Patient With Severe Insulin Resistance in Low- or Middle-income Countries.

Diabetes mellitus (DM) in children is most often caused by impaired insulin secretion (type 1 DM). In some children, the underlying mechanism for DM is increased insulin resistance, which can have different underlying causes. While the majority of these children require insulin dosages less than 2.0 U/kg/day to achieve normoglycemia, higher insulin requirements indicate severe insulin resistance. Considering the therapeutic challenges in patients with severe insulin resistance, early diagnosis of the underlying cause is essential in order to consider targeted therapies and to prevent diabetic complications. Although rare, several disorders can attribute to severe insulin resistance in pediatric patients. Most of these disorders are diagnosed through advanced diagnostic tests, which are not commonly available in low- or middle-income countries. Based on a case of DM with severe insulin resistance in a Surinamese adolescent who was later confirmed to have autosomal recessive congenital generalized lipodystrophy, type 1 (Berardinelli-Seip syndrome), we provide a systematic approach to the differential diagnosis and work-up. We show that a thorough review of medical history and physical examination generally provide sufficient information to diagnose a child with insulin-resistant DM correctly, and, therefore, our approach is especially applicable to low- or middle-income countries.

Targeted massively parallel sequencing for congenital generalized lipodystrophy.

OBJECTIVE: Our aim is to establish genetic diagnosis of congenital generalized lipodystrophy (CGL) using targeted massively parallel sequencing (MPS), also known as next-generation sequencing (NGS). METHODS: Nine unrelated individuals with a clinical diagnosis of CGL were recruited. We used a customized panel to capture genes related to genetic lipodystrophies. DNA libraries were generated, sequenced using the Illumina MiSeq, and bioinformatics analysis was performed. RESULTS: An accurate genetic diagnosis was stated for all nine patients. Four had pathogenic variants in AGPAT2 and three in BSCL2. Three large homozygous deletions in AGPAT2 were identified by copy-number variant analysis. CONCLUSION: Although we have found allelic variants in only 2 genes related to CGL, the panel was able to identify different variants including deletions that would have been missed by Sanger sequencing. We believe that MPS is a valuable tool for the genetic diagnosis of multi-genes related diseases, including CGL.

Targeted massively parallel sequencing for congenital generalized lipodystrophy

ABSTRACT Objective: Our aim is to establish genetic diagnosis of congenital generalized lipodystrophy (CGL) using targeted massively parallel sequencing (MPS), also known as next-generation sequencing (NGS). Subjects and methods: Nine unrelated individuals with a clinical diagnosis of CGL were recruited. We used a customized panel to capture genes related to genetic lipodystrophies. DNA libraries were generated, sequenced using the Illumina MiSeq, and bioinformatics analysis was performed. Results: An accurate genetic diagnosis was stated for all nine patients. Four had pathogenic variants in AGPAT2 and three in BSCL2. Three large homozygous deletions in AGPAT2 were identified by copy-number variant analysis. Conclusions: Although we have found allelic variants in only 2 genes related to CGL, the panel was able to identify different variants including deletions that would have been missed by Sanger sequencing. We believe that MPS is a valuable tool for the genetic diagnosis of multi-genes related diseases, including CGL.

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.

Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease.

Berardinelli-Seip congenital lipoatrophy (BSCL) is characterized by near total fat atrophy, associated with the progressive development of metabolic complications. BSCL type 1 (BSCL1) is caused by mutations in AGPAT2, encoding 1-acylglycerol-3phosphate-O-acyltransferase ß (recently renamed lysophosphatidic acid acyltransferase beta), which catalyzes the transformation of lysophosphatidic acid in phosphatidic acid, the precursor of glycerophospholipids and triglycerides. BSCL1 is an autosomal recessive disease due to AGPAT2 pathogenic variants leading to a depletion of triglycerides inside the adipose organ, and to a defective signaling of key elements involved in proper adipogenesis. We herein investigated the characteristics of two AGPAT2 variants in Caucasian Italian patients with Berardinelli-Seip congenital lipoatrophy. The first patient exhibited a novel homozygous nonsense c.430 C > T AGPAT2 mutation (p.Gln144*) predicting the synthesis of a truncated enzyme of approximately half of the proper size. The second patient harbored a homozygous AGPAT2 missense variant (p.Arg159Cys), never described previously in BSCL1 patients: the segregation of the disease with the mutation in the pedigree of the family and the in silico analysis are compatible with a causative role of the p.Arg159Cys variant. We remark that BSCL1 can be clinically very heterogeneous at presentation and that the associated complications, occurring in the natural history of the disease, reduce life-expectancy. We point to the necessity for medical treatments capable of reducing the risk of cardiovascular death. In BSCL1 patients, the assessment of cardiovascular disease with conventional diagnostic means maybe particularly challenging.

Seipin-linked congenital generalized lipodystrophy type 2: a rare case with multiple lytic and pseudo-osteopoikilosis lesions.

Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome (BSCL), is a part of lipodystrophic syndromes that constitute a heterogeneous group of genetic or acquired generalized or partial body fat loss disorders. It is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. CGL is classified as type 1-4, depending on the gene involved, and bone lytic lesion is found frequently in type 1 especially in long bones, but reported to be rare in type 2. Here we report an active lifestyle 25-year-old woman with type 2 CGL showing multiple bone lytic and pseudo-osteopoikilosis lesions in hands and feet. Radiograph bone survey showed no apparent abnormality in pelvic bone or axial skeletons. Bone marrow was completely absent and extra-skeletal general fat loss was also evident in whole-body magnetic resonance imaging sparing the orbital, axial, sole, and palmar regions. Radiographic bone survey is important even for type 2 CGL to find the change of bones to provide direction of preventing excessive overload or activity.

The long-term management of congenital generalized lipodystrophy (Berardinelli-Seip syndrome): the clinical manifestations of Japanese siblings for approximately 20 years.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease that is characterized by loss of subcutaneous and visceral adipose tissues, and associated with dysregulation of glycolipid metabolism. In the present study, we reported the clinical manifestations and treatments of Japanese siblings with CGL caused by BSCL2 gene mutations with a clinical course of approximately 20 yr. Comprehensive management with metreleptin therapy, dietary control with additional medication, and psychosocial counseling in line with the patients' stages of growth and development were important in achieving long-term metabolic control of this condition.

Berardinelli-Seip syndrome and progressive myoclonus epilepsy.

Berardinelli-Seip syndrome, or congenital generalized lipodystrophy type 2 (CGL2), is characterized by a lack of subcutaneous adipose tissue and precocious metabolic syndrome with insulin resistance, resulting in diabetes, dyslipidaemia, hepatic steatosis, cardiomyopathy, and acanthosis nigricans. Most reported mutations are associated with mild, non-progressive neurological impairment. We describe the clinical and EEG data of a patient with progressive myoclonus epilepsy (PME), CGL2, and progressive neurological impairment, carrying a homozygous BSCL2 nonsense mutation. The patient had epilepsy onset at the age of two, characterized by monthly generalized tonic-clonic seizures. By the age of three, he presented with drug-resistant ongoing myoclonic absence seizures, photosensitivity, progressive neurological degeneration, and moderate cognitive delay. Molecular analysis of the BSCL2 gene yielded a homozygous c.(1076dupC) p.(Glu360*) mutation. Application of a vagus nerve stimulator led to temporary improvement in seizure frequency, general neurological condition, and EEG background activity. Specific BSCL2 mutations may lead to a peculiar CGL2 phenotype characterized by PME and progressive neurodegeneration. Application of a vagus nerve stimulator, rarely used for PMEs, may prove beneficial, if only temporarily, for both seizure frequency and general neurological condition.

Retinopathy and Uveitis in Congenital Generalized Lipodystrophy with Hypertriglyceridemia and Uncontrolled Diabetes (Berardinelli-Seip Syndrome).

Congenital lipodystrophy syndromes are characterized by a paucity of adipose tissue and are associated with metabolic abnormalities including insulin resistance, diabetes mellitus, and severe hypertriglyceridemia. Herein, we present a case of proliferative diabetic retinopathy with an attack of anterior uveitis in a young female with congenital generalized lipodystrophy - Berardinelli-Seip syndrome. To the best of our knowledge, this is the first description of ocular involvement in Berardinelli-Seip syndrome.

Further delineation of AGPAT2 and BSCL2 related congenital generalized lipodystrophy in young infants.

BACKGROUND AND OBJECTIVES: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder with two major subtypes, which are caused by AGPAT2 and BSCL2 mutations. Our aim was to further investigate the genetic features and clinical characteristics of infant patients with CGL. PATIENTS AND METHODS: Three male infants and two female infants aged from one month to three months and unrelated with each other were involved in this study. Both whole-exome and Sanger sequencing were conducted, and variants were compared with in-house and public databases. RESULTS: The five infants with CGL displayed generalized lipodystrophy, skeletal muscle hypertrophy, hepatomegaly, hypertriglyceridemia, hyperinsulinemia, and liver dysfunction. Four patients (#2-5) showed more severe hypertriglyceridemia than Patient #1. A compound heterozygosity for novel frameshift mutations c.622_626delTCCTC and c.513delC in AGPAT2 was identified in Patient #1. Seven mutations in BSCL2 were found among Patients #2-5, in which splice site mutation c.404+1G > T, nonsense mutation c.402C > G, and frameshift mutation c.759_760delGA were novel. After medical treatment, metabolic parameters for all patients were under control. At the time of writing, they are seven to seventeen months old with much improved physical and cognitive development. CONCLUSIONS: Two novel mutations in AGPAT2 and three novel mutations in BSCL2 were identified from five unrelated infant patients diagnosed with CGL1 and CGL2.

A Patient with Berardinelli-Seip Syndrome, Novel AGPAT2 Splicesite Mutation and Concomitant Development of Non-diabetic Polyneuropathy

Primary polyneuropathy in the context of Seip-Berardinelli type 1 seipinopathy, or congenital generalized lipodystrophy type 1 (CGL1) has not been previously reported. We report the case history of a 27 year old female CGL1 patient presenting with an unusual additional development of non-diabetic peripheral neuropathy and learning disabilities in early adolescence. Whole exome sequencing (WES) of the patient genome identified a novel variant, homozygous for a 52 bp intronic deletion in the AGPAT2 locus, coding for 1-acylglycerol-3-phosphate O-acyltransferase 2, which is uniquely associated with CGL1 seipinopathies, with no molecular evidence for dual diagnosis. Functional studies using RNA isolated from patient peripheral blood leucocytes showed abnormal RNA splicing resulting in the loss of 25 amino acids from the patient AGPAT2 protein coding sequence. Stability and transcription levels for the misspliced AGPAT2 mRNA in our patient nonetheless remained normal. Any AGPAT2 protein produced in our patient is therefore likely to be dysfunctional. However, formal linkage of this deletion to the neuropathy observed remains to be shown. The classical clinical presentation of a patient with AGPAT2-associated lipodystrophy shows normal cognition and no development of polyneuropathy. Cognitive disabilities and polyneuropathy are features associated exclusively with clinical CGL type 2 arising from seipin (BSCL2) gene mutations. This case study suggests that in some genetic contexts, AGPAT2 mutations can also produce phenotypes with primary polyneuropathy.

Genetics of Lipodystrophy.

Lipodystrophy disorders are characterized by selective loss of fat tissue with metabolic complications including insulin resistance, hypertriglyceridemia, and nonalcoholic liver disease. These complications can be life-threatening, affect quality of life, and result in increased health care costs. Genetic discoveries have been particularly helpful in understanding the pathophysiology of these diseases, and have shown that mutations affect pathways involved in adipocyte differentiation and survival, lipid droplet formation, and lipid synthesis. In addition, genetic testing can identify patients whose phenotypes are not clearly apparent, but who may still be affected by severe metabolic complications.