Cristina Guillín-Amarelle

Type 1 familial partial lipodystrophy: understanding the Köbberling syndrome

Familial partial lipodystrophy are Mendelian disorders involving abnormal body fat distribution and insulin resistance. The current classification includes the Köbberling syndrome (type 1 familial partial lipodystrophy), characterized by fat loss in the lower limbs and abnormal fat accumulation in other areas. Type 1 familial partial lipodystrophy appears to be heritable, but little is known about it, including putative contributing mutations. We aimed to characterize this syndrome better by evaluating a group of women with phenotypic features of type 1 familial partial lipodystrophy. This is a case-controlled study in which 98 women with type 1 familial partial lipodystrophy that lacked classical mutations known to cause familial partial lipodystrophy were compared with 60 women without lipodystrophy and 25 patients with type 2 familial partial lipodystrophy (Dunnigan disease). Clinical course, body composition by dual-energy X-ray absorptiometry, HbA1c, lipid profile, insulin, leptin and family history were evaluated in all of the participants. Analyses of receiver-operating characteristic curve were performed for type 1 familial partial lipodystrophy diagnosis, comparing different truncal/limbs ratios. Among patients with type 1 familial partial lipodystrophy, 68 % developed recognizable lipodystrophy before adolescence, and most displayed an autosomal-dominant pattern (86 %). Women with type 1 familial partial lipodystrophy had less lower-limb adipose tissue than women without lipodystrophy, but significantly more than patients with Dunnigan disease. Moreover, metabolic disturbances occurred more frequently in the type 1 familial partial lipodystrophy group (81 %) than in the non-lipodystrophic group (30 %, p<0.05). The severity of metabolic disturbances was inversely proportional to the percentage of fat in the lower extremities and directly proportional to the amount of visceral adipose tissue. Metabolic profiles were worse in type 1 familial partial lipodystrophy than in Dunnigan disease. According to the receiver-operating characteristic curve analysis, the best ratio was subscapular/calf skinfolds (KöB index), with a cut-off value of 3.477 (sensitivity: 89 %; specificity: 84 %). Type 1 familial partial lipodystrophy was an early-onset, autosomal-dominant lipodystrophy, characterized by fat loss in the lower limbs and abnormal fat accumulation in the abdominal visceral region, associated to insulin resistance and metabolic disorders. A KöB index >3.477 is highly suggestive of this syndrome.

Síndromes lipodistróficos infrecuentes

Cristina Guillı́n-Amarelle , Sofı́a Sánchez-Iglesias b y David Araújo-Vilar * a Servicio de Endocrinoloxı́a e Nutrición, Complexo Hospitalario Universitario de Santiago de Compostela, Departamento de Medicina, Instituto de Investigaciones Sanitarias de Santiago-Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña, España b Grupo de Patoloxı́a Molecular-UETeM, CIMUS, Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña, España

Lipodystrophic laminopathies: Diagnostic clues

ABSTRACT The nuclear lamina is a complex reticular structure that covers the inner face of the nucleus membrane in metazoan cells. It is mainly formed by intermediate filaments called lamins, and exerts essential functions to maintain the cellular viability. Lamin A/C provides mechanical steadiness to the nucleus and regulates genetic machinery. Laminopathies are tissue-specific or systemic disorders caused by variants in LMNA gene (primary laminopathies) or in other genes encoding proteins which are playing some role in prelamin A maturation or in lamin A/C function (secondary laminopathies). Those disorders in which adipose tissue is affected are called laminopathic lipodystrophies and include type 2 familial partial lipodystrophy and certain premature aging syndromes. This work summarizes the main clinical features of these syndromes, their associated comorbidities and the clues for the differential diagnosis with other lipodystrophic disorders.

Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia’s encephalopathy

Celia’s encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.

Skipped BSCL2 Transcript in Celia's Encephalopathy (PELD): New Insights on Fatty Acids Involvement, Senescence and Adipogenesis.

Objective PELD (Progressive Encephalopathy with or without Lipodystrophy or Celia’s Encephalopathy) is a fatal and rare neurodegenerative syndrome associated with the BSCL2 mutation c.985C>T, that results in an aberrant transcript without the exon 7 (Celia seipin). The aim of this study was to evaluate both the process of cellular senescence and the effect of unsaturated fatty acids on preadipocytes from a homozygous c.985C>T patient. Also, the role of aberrant seipin isoform on adipogenesis was studied in adipose-derived human mesenchymal stem cells. Material and methods Cellular senescence was evaluated using β-galactosidase staining of preadipocytes obtained from a homozygous c.985C>T patient. Moreover, these cells were cultured during 24 hours with Intralipid, a soybean oil-based commercial lipid emulsion. The expression of the different BSCL2 transcripts was measured by qPCR. Adipose-derived human mesenchymal stem cells were differentiated to a fat lineage using StemPRO adipogenesis kit, and the expression of BSCL2 transcripts and several adipogenesis-related genes was measured by qPCR. Results the treatment of preadipocytes with unsaturated fatty acids significantly reduced the expression of the BSCL2 transcript without exon 7 by 34 to 63%. On the other hand, at least in preadipocytes, this mutation does not disturb cellular senescence rate. Finally, during adipocyte differentiation of adipose-derived human mesenchymal stem cells, the expression of adipogenic genes (PPARG, LPIN1, and LPL) increased significantly over 14 days, and noteworthy is that the BSCL2 transcript without exon 7 was differentially expressed by 332 to 723% when compared to day 0, suggesting an underlying role in adipogenesis. Conclusions our results suggest that Celia seipin is probably playing an underestimated role in adipocyte maturation, but not in senescence, and its expression can be modified by exogenous factors as fatty acids.

Bone mineral density in familial partial lipodystrophy

Type 1 and type 2 familial partial lipodystrophies (FPLD) are characterized by the loss or increase in subcutaneous fat in certain body regions, as well as metabolic disorders. Higher muscle volume and mass have also been described. However, so far, possible bone involvement has not been studied. The aim of this study was to evaluate bone mineral density (BMD) in patients with type 1 and type 2 FPLD.

Inflammatory myopathy in the context of an unusual overlapping laminopathy

Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.

Morbid Obesity and Psychiatric Disorders Hiding a Sex Aneuploidy: A Case of Late Diagnosis of 48,XXYY Syndrome

48,XXYY syndrome is a rare sex chromosomal aneuploidy, with a prevalence of 1:18,000 - 1:50,000 males. Despite it being considered as a variant of Klinefelter syndrome, it is now known to be a distinct entity, differing from the latter due to a greater degree of severity and prevalence of psychiatric disorders and mental deficiency. We present the case of a 37-year-old man with psychiatric disease who attended our department due to morbid obesity, identified as a 48,XXYY genotype. Clinical evaluation and cytogenetic analysis is presented.

Imágenes en pediatríaAcantosis nigricans en los síndromes de resistencia grave a la insulinaAcantosis nigricans in severe insulin resistance syndromes

B f n d p Berardinelli-Seip. La lipodistrofia parcial familiar tipo 2 es una enfermedad autosómica dominante caracterizada por la pérdida de grasa en extremidades y nalgas, y acúmulo en cara y sotabarba. La acantosis nigricans (AN) es un signo cutáneo de resistencia a la insulina (RI), que se manifiesta como un oscurecimiento y engrosamiento de la piel. La mayor prevalencia de obesidad entre niños y adolescentes ha hecho que este signo se pueda observar más frecuentemente y debe ser diferenciado de otros cuadros infrecuentes de RI grave no asociados con la obesidad. Los síndromes de Donohue, Rabson-Mendenhall y RI tipo A son trastornos debidos a mutaciones en el receptor de la insulina. El síndrome de Donohue se manifiesta desde el nacimiento con AN, facies de duende, pubertad precoz, escaso panículo adiposo, hipertricosis, retraso del desarrollo e hipoglucemias. El síndrome de RabsonMendenhall1 (fig. 1) se caracteriza por retraso del desarrollo, AN, apiñamiento dental e hipertrofia gingival (fig. 2) y macropene/clitoromegalia. El síndrome de RI tipo A suele

Acantosis nigricans en los síndromes de resistencia grave a la insulina

B f n d p Berardinelli-Seip. La lipodistrofia parcial familiar tipo 2 es una enfermedad autosómica dominante caracterizada por la pérdida de grasa en extremidades y nalgas, y acúmulo en cara y sotabarba. La acantosis nigricans (AN) es un signo cutáneo de resistencia a la insulina (RI), que se manifiesta como un oscurecimiento y engrosamiento de la piel. La mayor prevalencia de obesidad entre niños y adolescentes ha hecho que este signo se pueda observar más frecuentemente y debe ser diferenciado de otros cuadros infrecuentes de RI grave no asociados con la obesidad. Los síndromes de Donohue, Rabson-Mendenhall y RI tipo A son trastornos debidos a mutaciones en el receptor de la insulina. El síndrome de Donohue se manifiesta desde el nacimiento con AN, facies de duende, pubertad precoz, escaso panículo adiposo, hipertricosis, retraso del desarrollo e hipoglucemias. El síndrome de RabsonMendenhall1 (fig. 1) se caracteriza por retraso del desarrollo, AN, apiñamiento dental e hipertrofia gingival (fig. 2) y macropene/clitoromegalia. El síndrome de RI tipo A suele