A study of congenital generalized lipodystrophy (CGL) caused by BSCL2 gene mutation.

Congenital generalized lipodystrophy (CGL) is an extremely rare genetic disease mainly characterized by absence of whole-body adipose tissue and metabolic dysfunctions such as insulin resistance, diabetes mellitus, hypertriglyceridemia, hepatic steatosis, and acanthosis nigricans. In this study, we reported a novel case of a young woman patient with CGL. The patient came to the hospital for early-onset lipodystrophy and diabetes. She was 19-year-old with a height of 160 cm, a weight of 46 kg, BMI of 17.9 kg/m2, and a serum leptin level of 0.14 µg/L. Genomic DNA was extracted from blood samples of the patient and her family members, including her mother, father and brother. Genetic analysis revealed compound heterozygous mutations of the BSCL2 gene (c.560A>G and c.565G>T) in the patient. Her father carried a heterozygous mutation (c.565G>T), and her mother carried a heterozygous mutation (c.560A>G) in the BSCL2 gene. The mutant p.Y187C plasmid was transfected into HEK293T cells. The protein expression of SEIPIN and its interaction with glycerol-3-phosphate acyltransferase (GPAT3) were observed to be reduced. In addition, based on primary cultured skin fibroblasts from the patient, SEIPIN protein was decreased, and lipid droplets were much smaller when fatty acid was stimulated compared with those observed from healthy subject controls. However, histone deacetylase inhibitors (HDACis) was found capable of rescuing SEIPIN protein in fibroblasts of the patient. In addition, we further summarized and discussed gene mutations of BSCL2 reported in the current literature. Collectively, these findings have expanded the clinical phenotype and pathogenic gene spectrum of CGL, which might help clinicians to achieve better management of lipodystrophy.

Type 2 congenital generalized lipodystrophy with a heterozygous missense NOTCH2 mutation.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease with a prevalence of less than one in ten million. To our knowledge, ~500 cases, including 95% of BSCL2, have been reported in the literatures, but no types of CGL with NOTCH2 gene mutation has been described.

Endoplasmic reticulum stress and muscle dysfunction in congenital lipodystrophies.

Lipodystrophy syndromes are a group of rare diseases related to the pathological impairment of adipose tissue and metabolic comorbidities, including dyslipidemia, diabetes, insulin resistance, hypoleptinemia, and hypoadiponectinemia. They can be categorized as partial or generalized according to the degree of fat loss, and inherited or acquired disorders, if they are associated with genetic mutations or are related to autoimmunity, respectively. Some types of lipodystrophies have been associated with changes in both redox and endoplasmic reticulum (ER) homeostasis as well as muscle dysfunction (MD). Although ER stress (ERS) has been related to muscle dysfunction (MD) in many diseases, there is no data concerning its role in lipodystrophies' muscle physiopathology. Here we focused on congenital lipodystrophies associated with ERS and MD. We also described recent advances in our understanding of the relationships among ERS, MD, and genetic lipodystrophies, highlighting the adiponectin-protective roles.

Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit.

Various clinical differences have been observed between patients with the FBN1 gene mutation and those with the classical Marfan phenotype. Although FBN1 knockout (KO) or dominant-negative mutant mice are widely used as an animal model for Marfan syndrome (MFS), these mice cannot recapitulate the genotype/phenotype relationship of Marfanoid-progeroid-lipodystrophy (MPL) syndrome, which is caused by a mutation in the C-terminus of fibrillin-1, the penultimate exon of the FBN1 gene. Here, we describe the generation of a rabbit MPL model with C-terminal truncation of fibrillin-1 using a CRISPR/Cas9 system. FBN1 heterozygous (FBN1 Het) rabbits faithfully recapitulated the phenotypes of MFS, including muscle wasting and impaired connective tissue, ocular syndrome and aortic dilation. Moreover, skin symptoms, lipodystrophy, growth retardation and dysglycemia were also seen in these FBN1 Het rabbits, and have not been reported in other animal models. In conclusion, this novel rabbit model mimics the histopathological changes and functional defects of MPL syndrome, and could become a valuable model for studies of pathogenesis and drug screening for MPL syndrome.

Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent de novo mutation in the POLD1 gene.

Segmental progeroid syndromes with lipodystrophy are extremely rare, heterogeneous, and complex multi-system disorders that are characterized by phenotypic features of premature aging affecting various tissues and organs. In this study, we present a "sporadic/isolated" Japanese woman who was ultimately diagnosed with mandibular hypoplasia, deafness, progeroid features, and progressive lipodystrophy (MDPL) syndrome (MIM #615381) using whole exome sequencing analysis. She had been suspected as having atypical Werner syndrome and/or progeroid syndrome based on observations spanning a 30-year period; however, repeated genetic testing by Sanger sequencing did not identify any causative mutation related to various subtypes of congenital partial lipodystrophy (CPLD) and/or mandibular dysplasia with lipodystrophy (MAD). Recently, MDPL syndrome has been described as a new entity showing progressive lipodystrophy. Furthermore, polymerase delta 1 (POLD1) gene mutations on chromosome 19 have been identified in patients with MDPL syndrome. To date, 21 cases with POLD1-related MDPL syndrome have been reported worldwide, albeit almost entirely of European origin. Here, we identified a de novo mutation in exon 15 (p.Ser605del) of the POLD1 gene in a Japanese case by whole exome sequencing. To the best of our knowledge, this is the first identified case of MDPL syndrome in Japan. Our results provide further evidence that mutations in POLD1 are responsible for MDPL syndrome and serve as a common genetic determinant across different ethnicities.

Novel subtype of congenital partial lipodystrophy with mandibular hypoplasia, sensorineural deafness and short stature of unknown genetic origin.

The unique clinical manifestations of congenital partial lipodystrophy are herein reported due to its rarity.

Serum concentrations of fibroblast growth factor 21 are elevated in patients with congenital or acquired lipodystrophy.

OBJECTIVE: Patients with lipodystrophy (LD) suffer from loss of subcutaneous adipose tissue accompanied by dysregulation of several adipocyte-secreted factors. However, regulation of adipocyte-expressed fibroblast growth factor (FGF) 21 which acts in an insulin-mimetic, lipid-lowering, and anti-atherogenic manner has not been investigated in non-human immunodeficiency virus (HIV) LD. MATERIAL AND METHODS: Circulating serum FGF21 levels were quantified in 37 patients with non-HIV LD and 37 controls matched for age, gender, and body mass index. Moreover, FGF21 plasma levels and mRNA expression were measured in LD mice and control animals. Additionally, serum FGF21 levels were assessed in 10 LD patients before and during metreleptin therapy. RESULTS: Median FGF21 serum concentrations were significantly higher in LD patients (381.2ng/l) as compared to the control group (231.2ng/l; p=0.023). There was an independent and positive association between circulating FGF21 and serum triglycerides (TG), as well as fibrate treatment, in multiple linear regression analysis. LD mice showed significantly upregulated FGF21 plasma levels (4.5-fold), as well as mRNA expression in various adipose tissue depots and liver as compared to controls (p<0.05). Metreleptin treatment did not significantly alter circulating FGF21 levels in human subjects. CONCLUSIONS: Serum concentrations of FGF21 are elevated in patients with non-HIV LD with adipose tissue and liver being potential sources of increased production. TG and fibrate treatment are independent positive predictors of circulating FGF21.

[Genetics of congenital lipodystrophies]. / Génétique des lipodystrophies congénitales.

Congenital lipodystrophies are heterogeneous genetic diseases, leading to the loss of adipose tissue. This loss of adipose tissue can be generalized or partial, thus defining different phenotypes. These lipodystrophies have a major metabolic impact, secondary to lipotoxicity. This lipotoxicity is responsible for insulin resistance, dyslipidemia and hepatic steatosis. The severity of the metabolic impact correlates with the severity of the loss of adipose tissue. Mutations in 15 predisposition genes are currently described; BSCL2 and AGPT2 genes are the major genes in the generalized forms. On the contrary, LMNA and PPARG gene mutations are recovered in partial lipodystrophies forms. These different genes encode for proteins involved in adipocyte physiology, altering adipocyte differentiation, triglycerides synthesis and lysis or playing a major role in the lipid droplet formation. Congenital lipodystrophies treatment is based on the management of metabolic comorbidities but recombinant leptin therapy appears to have promising results. These different points have been recently discussed during the 2015 Endocrine Society Congress, notably by S. O'Rahilly and are highlighted in this review.

Enfermedades raras: Síndrome de Berardinelli - Seip. Presentación de un caso / Rare diseases: Syndrome Berardinelli - Seip Case report

El síndrome de Berardinelli - Seip es una lipodistrofia generalizada congénita con niveles elevados de hormona delcrecimiento y de lípidos séricos. Se trata de un trastorno autosómico recesivo extremadamente raro, con unaprevalencia estimada de menos de un caso por cada 1.000.000 personas. Fue descrita inicialmente por Berardinellien 1954. En 1963 Seip y Trygstad descubren la seipina, cuya mutación produce el síndrome. No se conoce laetiología, pero se sabe que es ocasionada en parte por la incapacidad de ciertos adipocitos para mantener laacumulación de grasa. Los factores asociados con el síndrome incluyen: tendencia a desarrollar resistencia a lainsulina, diabetes e hipertrigliceridemia. El diagnóstico de la enfermedad es principalmente clínico. El tratamientose basa en el control de las enfermedades asociadas.

Berardinelli - Seip syndrome is a generalized congenital lipodystrophy with elevated levels of serum lipids andgrowth hormone. It is an extremely rare autosomal recessive disorder with a prevalence of less than one case per1.000.000. It was initially described by Berardinelli in 1954. Seip and Trygstad discovered seipine, a proteine whichmutation produces syndrome. Unknown etiology, it is caused in part by the inability of fat cells for fataccumulation. Factors associated with the syndrome include: insuline resistence, diabetes, and hypertriglyceridemia. The diagnosis of this disease is mainly clinical. Treatment consists in controlling comorbidities.

Congenital lipodystrophies and dyslipidemias.

Lipodystrophies are rare acquired and genetic disorders characterized by the selective loss of adipose tissue. One key metabolic feature of patients with congenital inherited lipodystrophy is hypertriglyceridemia. The precise mechanisms by which the lack of adipose tissue causes dyslipidemia remain largely unknown. In recent years, new insights have arisen from data obtained in vitro in adipocytes, yeast, drosophila, and very recently in several genetically modified mouse models of generalized lipodystrophy. A common metabolic pathway involving accelerated lipolysis and defective energy storage seems to contribute to the dyslipidemia associated with congenital generalized lipodystrophy syndromes, although the pathophysiological changes may vary with the nature of the mutation involved. Therapeutic management of dyslipidemia in patients with lipodystrophy is primarily based on specific approaches using recombinant leptin therapy. Preclinical studies suggest a potential efficacy of thiazolidinediones that remains to be assessed in dedicated clinical trials.

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease.

Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.

Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene.

We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann-Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid-progeroid-lipodystrophy syndrome) and frameshift mutations at the 3' end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes.

Human congenital perilipin deficiency and insulin resistance.

Lipid droplets (LDs) can form in all eukaryotic cells, but white adipocytes are uniquely adapted to store energy as neutral lipid within a large unilocular LD. Non-esterified fatty acids can then be released from the LD store by lipases for use in oxidative tissues. Perilipin was the first mammalian LD protein to be identified in adipocytes where it plays a key role in co-ordinating access of lipases to the core triacylglycerol. We recently identified the first human loss-of-function mutations in PLIN1 in patients with a novel form of familial partial lipodystrophy, severe insulin resistance, diabetes, dyslipidaemia and fatty liver. Adipose tissue samples from affected patients revealed remarkably similar features to those previously observed in samples from obese insulin resistant patients, namely macrophage infiltration and fibrosis. Cellular mechanistic studies suggest that the mutations lead to increased basal lipolysis, which is likely to be a major factor in the subsequent inflammatory response. Perilipin is almost exclusively expressed in white adipocytes, so the serious metabolic sequelae observed in these patients suggest that primary defects in adipose tissue can lead to all the typical features seen in patients with the metabolic syndrome. They also suggest that lipolytic inhibitors may be therapeutically useful in these patients.

Focal congenital lipoatrophy and vascular malformation: a mild form of inverse Klippel-Trenaunay syndrome?

A 2 year-and seven month-old male boy with vascular malformation and localized soft tissue hypotrophy is reported. Such presentation could represent the mildest end of the spectrum of 'inverse' Klippel-Trenaunay syndrome, a recently proposed disorder presenting with tissue hypotrophy as opposed to partial or complete limb overgrowth of classic Klippel-Trenaunay syndrome.

Lipodistrofía congénita de Berardinelli-Seip / Lipodystrophy Berardinelli-Seip congenital

El síndrome de Berardinelli-Seip es una lipodistrofia generalizada congénita, de herencia autosómica recesiva, que se caracteriza por la disminución o ausencia de la grasa subcutánea. Predispone al desarrollo de resistencia a la insulina, diabetes, hipertrigliceridemia y esteatosis hepática, y también cursa con ateroesclerosis de inicio precoz. Además, los pacientes afectados presentan facie tosca, hipertrofia muscular, acromegalia y acantosis nigricans. Se presenta una paciente de sexo femenino, de 3 años de edad, con peso y talla inadecuados para la edad y antecedente de cuadros intermitentes de hipoglicemia desde el nacimiento y hepatomegalia desde los 4 meses de edad. En el examen físico se observa cara triangular con red venosa evidente, escaso tejido celular subcutáneo e hipermuscularidad. Se realiza una biopsia de piel, la cual es compatible con lipodistrofia y ultrasonido abdominal que demuestra hepatoesplenomegalia y daño hepático crónico (confirmado con biopsia de hígado).

The Berardinelli-Seip syndrome is an autosomal recessive, congenital generalized lipodystrophy, characterized by a decrease or absence of subcutaneous fat with a predisposition to develop insulin resistant diabetes, hypertriglyceridemia and early onset hepatic steatosis and atherosclerosis. Affected patients present a grotesque facie, muscle hypertrophy, acromegally and acanthosis nigricans. We present a three-year-old female patient, with low weight and height and a history of intermittent hypoglycemia since birth and hepatomegaly from 4 months of life. Her physical examination showed triangular face, collateral vascular network, lipoatrophy and muscle hypertrophy. Skin biopsy was consistent with lipodystrophy and abdominal ultrasound reported hepatosplenomegaly and chronic liver damage confirmed by liver biopsy.

Pregnancy in a woman with congenital generalized lipodystrophy: leptin's vital role in reproduction.

BACKGROUND: Congenital generalized lipodystrophy is a rare disorder characterized by scant adipose tissue, profound leptin deficiency, and severe insulin resistance, resulting in multiple metabolic derangements, including hyperandrogenism, anovulation, and impaired fecundity. CASE: A young woman with congenital generalized lipodystrophy receiving leptin therapy experienced menarche, conceived spontaneously, and delivered a liveborn male neonate. CONCLUSION: Adipose tissue is important to normal female reproductive function. Leptin in particular appears to play a key role in adipose-mediated regulation of fertility.

Pathology of congenital generalized lipodystrophy in Agpat2-/- mice.

Congenital generalized lipodystrophy (CGL) comprises a heterogeneous group of rare diseases associated with partial or total loss of adipose tissue. Of these, autosomal recessive Berardinelli-Seip congenital lipodystrophy (BSCL) is characterized by the absence of metabolically active subcutaneous and visceral adipose tissues. Metabolic abnormalities associated with lipodystrophy include insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes. One form of BSCL has been linked to genetic mutations affecting the lipid biosynthetic enzyme 1-acyl-sn-glycerol 3-phosphate O-acyltransferase 2 (AGPAT2), which is highly expressed in adipose tissue. Precisely how AGPAT2 deficiency causes lipodystrophy remains unresolved, but possible mechanisms include impaired lipogenesis (triglyceride synthesis and storage), blocked adipogenesis (differentiation of preadipocytes to adipocytes), or apoptosis/necrosis of adipocytes. Agpat2(-/-) mice share important pathophysiologic features of CGL previously reported in humans. However, the small white adipose tissue (WAT) depots consisting largely of amoeboid adipocytes with microvesiculated basophilic cytoplasm showed that adipogenesis with deficient lipogenesis was present in all usual locations. Although well-defined lobules of brown adipose tissue (BAT) were present, massive necrosis resulted in early ablation of BAT. Although necrotic or apoptotic adipocytes were not detected in WAT of 10-day-old Agpat2(-/-), the absence of adipocytes in aged mice indicates that these cells must undergo necrosis/apoptosis at some point. Another significant finding in aged lipodystrophic mice was massive pancreatic islet hypertrophy in the face of chronic hyperglycemia, which suggests that glucotoxicity is insufficient by itself to cause ß-cell loss and that adipocyte-derived factors help regulate total ß-cell mass.

An autosomal recessive syndrome of joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy.

CONTEXT: Genetic lipodystrophies are rare disorders characterized by partial or complete loss of adipose tissue and predisposition to insulin resistance and its complications such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, and polycystic ovarian syndrome. OBJECTIVE: The objective of the study was to report a novel autosomal recessive lipodystrophy syndrome. RESULTS: We report the detailed phenotype of two males and one female patient, 26-34 yr old, belonging to two pedigrees with an autosomal recessive syndrome presenting with childhood-onset lipodystrophy, muscle atrophy, severe joint contractures, erythematous skin lesions, and microcytic anemia. Other variable clinical features include hypergammaglobulinemia, hepatosplenomegaly, generalized seizures, and basal ganglia calcification. None of the patients had diabetes mellitus or acanthosis nigricans. Two had mild hypertriglyceridemia and all had low levels of high-density lipoprotein cholesterol. Skin biopsy of an erythematous nodular skin lesion from one of the patients revealed evidence of panniculitis. The lipodystrophy initially affected the upper body but later became generalized involving abdomen and lower extremities as well. CONCLUSIONS: We conclude that these patients represent a novel autoinflammatory syndrome resulting in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. The molecular genetic basis of this disorder remains to be elucidated.