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Infrequent Lipodystrophies: Challenges in Pathogenesis, Diagnosis and Treatment
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Infrequent Lipodystrophies: Challenges in Pathogenesis, Diagnosis and Treatment

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 41333

Special Issue Editor

Dr. David Araújo-Vilar

E-Mail Website
Guest Editor
UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela, 15703 Santiago de Compostela, Spain
Interests: infrequent lipodystrophies; adipose tissue; laminopathies; seipinopathies; neurodegeneration; diabetes mellitus; transgenic mice; insulin resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lipodystrophies are a heterogeneous set of clinical entities, which, with the exception of that associated with AIDS, have a very low prevalence. On the other hand, its etiology is diverse, and may be congenital or acquired. Among the familiar subtypes, more than 30 causal genes have been described to date; and among the acquired forms, some have been related to autoimmune processes. Therefore, they are disorders with complex and different pathogenetic mechanisms, and in many cases little or nothing known. Added to all this is a great phenotypic variability that, associated with its low prevalence, makes diagnosis a challenge for physicians, including pediatricians and endocrinologists. Lipodystrophies have no cure today, and the therapeutic approach is focused on controlling the metabolic, hepatic, and reproductive comorbidities that are often associated with these disorders.

This Special Issue welcomes articles either highlighting recent developments in or providing new experimental (in vitro or animal model) or clinical (human) data related to pathogenesis, diagnosis and treatment of infrequent lipodystrophies. We would appreciate it if the authors provided a brief section in their manuscript indicating the novelty of their findings or, in the case of review articles, provided personal views on a particular topic.

Dr. David Araújo-Vilar
Guest Editor

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Keywords

  • Novel Genes
  • Pathogenetic Mechanisms
  • Animal Models
  • Diagnosis Criteria
  • Therapeutical Approaches

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Published Papers (7 papers)

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Research

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15 pages, 2974 KiB  
Article
Variable Expressivity and Allelic Heterogeneity in Type 2 Familial Partial Lipodystrophy: The p.(Thr528Met) LMNA Variant
by David Araújo-Vilar, Antía Fernández-Pombo, Berta Victoria, Adrián Mosquera-Orgueira, Silvia Cobelo-Gómez, Ana Castro-Pais, Álvaro Hermida-Ameijeiras, Lourdes Loidi and Sofía Sánchez-Iglesias
J. Clin. Med. 2021, 10(7), 1497; https://doi.org/10.3390/jcm10071497 - 3 Apr 2021
Cited by 9 | Viewed by 3371
Abstract
Type 2 familial partial lipodystrophy, or Dunnigan disease, is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution. This rare condition results from variants principally affecting exons 8 and 11 of the LMNA gene. In this study, five FPLD2-diagnosed patients carrying the [...] Read more.
Type 2 familial partial lipodystrophy, or Dunnigan disease, is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution. This rare condition results from variants principally affecting exons 8 and 11 of the LMNA gene. In this study, five FPLD2-diagnosed patients carrying the c.1583C>T, p.(Thr528Met) variant in exon 9 of the LMNA gene and with obvious clinical heterogeneity were evaluated. Specific polymorphisms in LMNA and in PPARG were also detected. Exhaustive clinical course, physical examination, biochemical features and family history were recorded, along with the assessment of anthropometric features and body composition by dual-energy X-ray absorptiometry. Preadipocytes obtained from a T528M patient were treated with the classic adipose differentiation medium with pioglitazone. Various adipogenes were evaluated by real-time PCR, and immunofluorescence was used to study intracellular localization of emerin, lamin A and its precursors. As demonstrated with Oil red O staining, the preadipocytes of the T528M patient failed to differentiate, the expression of various adipogenic genes was reduced in the lipodystrophic patient and immunofluorescence studies showed an accumulation of farnesylated prelamin A in T528M cells. We conclude that the T528M variant in LMNA could lead to FPLD2, as the adipogenic machinery is compromised. Full article
(This article belongs to the Special Issue Infrequent Lipodystrophies: Challenges in Pathogenesis, Diagnosis and Treatment)
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9 pages, 271 KiB  
Article
Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to R482 and N466 Variants in the LMNA Gene
by David Araújo-Vilar, Sofía Sánchez-Iglesias, Ana I. Castro, Silvia Cobelo-Gómez, Álvaro Hermida-Ameijeiras, Gemma Rodríguez-Carnero, Felipe F. Casanueva and Antía Fernández-Pombo
J. Clin. Med. 2021, 10(6), 1259; https://doi.org/10.3390/jcm10061259 - 18 Mar 2021
Cited by 4 | Viewed by 3132
Abstract
Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the “atypical” disease. The aim of this study was to investigate the [...] Read more.
Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the “atypical” disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with the R482 variant. Clinical, metabolic, and body composition data were compared between both groups. The thigh skinfold thickness was significantly decreased in the R482 group in comparison with the N466 group (4.2 ± 1.8 and 5.6 ± 2.0 mm, respectively, p = 0.002), with no other differences in body composition. Patients with the N466 variant showed higher triglyceride levels (177.5 [56–1937] vs. 130.0 [55–505] mg/dL, p = 0.029) and acute pancreatitis was only present in these subjects (20%). Other classic metabolic abnormalities related with the disease were present regardless of the pathogenic variant. Thus, although FPLD2 patients with the R482 and N466 variants share most of the classic characteristics, some phenotypic and metabolic differences suggest possible heterogeneity even within exon 8 of the LMNA gene. Full article
(This article belongs to the Special Issue Infrequent Lipodystrophies: Challenges in Pathogenesis, Diagnosis and Treatment)
12 pages, 1537 KiB  
Article
Partial Lipodystrophy and LMNA p.R545H Variant
by Silvia Magno, Giovanni Ceccarini, Andrea Barison, Iacopo Fabiani, Alessandro Giacomina, Donatella Gilio, Caterina Pelosini, Anna Rubegni, Michele Emdin, Gian Luca Gatti, Filippo Maria Santorelli, Maria Rita Sessa and Ferruccio Santini
J. Clin. Med. 2021, 10(5), 1142; https://doi.org/10.3390/jcm10051142 - 9 Mar 2021
Cited by 3 | Viewed by 4945
Abstract
Laminopathies are disorders caused by LMNA gene mutations, which selectively affect different tissues and organ systems, and present with heterogeneous clinical and pathological traits. The molecular mechanisms behind these clinical differences and tissue specificity have not been fully clarified. We herein examine the [...] Read more.
Laminopathies are disorders caused by LMNA gene mutations, which selectively affect different tissues and organ systems, and present with heterogeneous clinical and pathological traits. The molecular mechanisms behind these clinical differences and tissue specificity have not been fully clarified. We herein examine the case of a patient carrying a heterozygous LMNA c.1634G>A (p.R545H) variant with a mild, transient myopathy, who was referred to our center for the suspicion of lipodystrophy. At physical examination, an abnormal distribution of subcutaneous fat was noticed, with fat accumulation in the anterior regions of the neck, resembling the fat distribution pattern of familial partial lipodystrophy type 2 (FPLD2). The R545H missense variant has been found at very low allelic frequency in public databases, and in silico analysis showed that this amino acid substitution is predicted to have a damaging role. Other patients carrying the heterozygous LMNA p.R545H allele have shown a marked clinical heterogeneity in terms of phenotypic body fat distribution and severity of organ system involvement. These findings indicate that the LMNA p.R545H heterozygous variant exhibits incomplete penetrance and highly variable expressivity. We hypothesized that additional genetic factors, epigenetic mechanisms, or environmental triggers might explain the variable expressivity of phenotypes among various patients. Full article
(This article belongs to the Special Issue Infrequent Lipodystrophies: Challenges in Pathogenesis, Diagnosis and Treatment)
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10 pages, 1372 KiB  
Article
Bscl2 Deficiency Does Not Directly Impair the Innate Immune Response in a Murine Model of Generalized Lipodystrophy
by Ahlima Roumane, George D. Mcilroy, Arda Balci, Weiping Han, Mirela Delibegović, Massimiliano Baldassarre, Philip Newsholme and Justin J. Rochford
J. Clin. Med. 2021, 10(3), 441; https://doi.org/10.3390/jcm10030441 - 23 Jan 2021
Cited by 5 | Viewed by 3265
Abstract
Congenital Generalized Lipodystrophy type 2 (CGL2) is the most severe form of lipodystrophy and is caused by mutations in the BSCL2 gene. Affected patients exhibit a near complete lack of adipose tissue and suffer severe metabolic disease. A recent study identified infection as [...] Read more.
Congenital Generalized Lipodystrophy type 2 (CGL2) is the most severe form of lipodystrophy and is caused by mutations in the BSCL2 gene. Affected patients exhibit a near complete lack of adipose tissue and suffer severe metabolic disease. A recent study identified infection as a major cause of death in CGL2 patients, leading us to examine whether Bscl2 loss could directly affect the innate immune response. We generated a novel mouse model selectively lacking Bscl2 in the myeloid lineage (LysM-B2KO) and also examined the function of bone-marrow-derived macrophages (BMDM) isolated from global Bscl2 knockout (SKO) mice. LysM-B2KO mice failed to develop lipodystrophy and metabolic disease, providing a model to study the direct role of Bscl2 in myeloid lineage cells. Lipopolysaccharide-mediated stimulation of inflammatory cytokines was not impaired in LysM-B2KO mice or in BMDM isolated from either LysM-B2KO or SKO mice. Additionally, intracellular fate and clearance of bacteria in SKO BMDM challenged with Staphylococcus aureus was indistinguishable from that in BMDM isolated from littermate controls. Overall, our findings reveal that selective Bscl2 deficiency in macrophages does not critically impact the innate immune response to infection. Instead, an increased susceptibility to infection in CGL2 patients is likely to result from severe metabolic disease. Full article
(This article belongs to the Special Issue Infrequent Lipodystrophies: Challenges in Pathogenesis, Diagnosis and Treatment)
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Review

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14 pages, 648 KiB  
Review
Lipodystrophy as a Late Effect after Stem Cell Transplantation
by Daniel Tews, Ansgar Schulz, Christian Denzer, Julia von Schnurbein, Giovanni Ceccarini, Klaus-Michael Debatin and Martin Wabitsch
J. Clin. Med. 2021, 10(8), 1559; https://doi.org/10.3390/jcm10081559 - 8 Apr 2021
Cited by 12 | Viewed by 3201
Abstract
Survivors of childhood cancer are at high risk of developing metabolic diseases in adulthood. Recently, several patients developing partial lipodystrophy following hematopoietic stem cell transplantation (HSCT) have been described. In this review, we summarize the cases described so far and discuss potential underlying [...] Read more.
Survivors of childhood cancer are at high risk of developing metabolic diseases in adulthood. Recently, several patients developing partial lipodystrophy following hematopoietic stem cell transplantation (HSCT) have been described. In this review, we summarize the cases described so far and discuss potential underlying mechanisms of the disease. The findings suggest that HSCT-associated lipodystrophies may be seen as a novel form of acquired lipodystrophy. Full article
(This article belongs to the Special Issue Infrequent Lipodystrophies: Challenges in Pathogenesis, Diagnosis and Treatment)
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22 pages, 673 KiB  
Review
Celia’s Encephalopathy (BSCL2-Gene-Related): Current Understanding
by Sofía Sánchez-Iglesias, Antía Fernández-Pombo, Silvia Cobelo-Gómez, Álvaro Hermida-Ameijeiras, Helena Alarcón-Martínez, Rosario Domingo-Jiménez, Alejandro Iván Ruíz Riquelme, Jesús R. Requena and David Araújo-Vilar
J. Clin. Med. 2021, 10(7), 1435; https://doi.org/10.3390/jcm10071435 - 1 Apr 2021
Cited by 11 | Viewed by 4346
Abstract
Seipin, encoded by the BSCL2 gene, is a protein that in humans is expressed mainly in the central nervous system. Uniquely, certain variants in BSCL2 can cause both generalized congenital lipodystrophy type 2, upper and/or lower motor neuron diseases, or progressive encephalopathy, with [...] Read more.
Seipin, encoded by the BSCL2 gene, is a protein that in humans is expressed mainly in the central nervous system. Uniquely, certain variants in BSCL2 can cause both generalized congenital lipodystrophy type 2, upper and/or lower motor neuron diseases, or progressive encephalopathy, with a poor prognosis during childhood. The latter, Celia’s encephalopathy, which may or may not be associated with generalized lipodystrophy, is caused by the c.985C >T variant. This cytosine to thymine transition creates a cryptic splicing zone that leads to intronization of exon 7, resulting in an aberrant form of seipin, Celia seipin. It has been proposed that the accumulation of this protein, both in the endoplasmic reticulum and in the nucleus of neurons, might be the pathogenetic mechanism of this neurodegenerative condition. In recent years, other variants in BSCL2 associated with generalized lipodystrophy and progressive epileptic encephalopathy have been reported. Interestingly, most of these variants could also lead to the loss of exon 7. In this review, we analyzed the molecular bases of Celia’s encephalopathy and its pathogenic mechanisms, the clinical features of the different variants, and a therapeutic approach in order to slow down the progression of this fatal neurological disorder. Full article
(This article belongs to the Special Issue Infrequent Lipodystrophies: Challenges in Pathogenesis, Diagnosis and Treatment)
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Graphical abstract

15 pages, 1115 KiB  
Review
Rare Forms of Lipomatosis: Dercum’s Disease and Roch-Leri Mesosomatous Lipomatosis
by Madleen Lemaitre, Sebastien Aubert, Benjamin Chevalier, Arnaud Jannin, Julien Bourry, Gaetan Prévost, Herve Lefebvre and Marie-Christine Vantyghem
J. Clin. Med. 2021, 10(6), 1292; https://doi.org/10.3390/jcm10061292 - 21 Mar 2021
Cited by 10 | Viewed by 18004
Abstract
In contrast to obesity, which is very frequent, lipomatosis and lipodystrophy syndromes are rare diseases of adipose tissue. Lipodystrophy syndromes are characterized by metabolic abnormalities associated with partial or generalized lipoatrophy. Lipomatosis is defined by the presence of several body lipomas without lipoatrophy. [...] Read more.
In contrast to obesity, which is very frequent, lipomatosis and lipodystrophy syndromes are rare diseases of adipose tissue. Lipodystrophy syndromes are characterized by metabolic abnormalities associated with partial or generalized lipoatrophy. Lipomatosis is defined by the presence of several body lipomas without lipoatrophy. Dercum’s disease (DD) and Roch-Leri mesosomatous lipomatosis (RLML) are rare and poorly characterized forms of lipomatosis. They have raised little clinical interest despite the non-negligible consequences of DD on quality of life. The main clinical presentation of these diseases includes multiple lipomas, which are painful in DD (in contrast to RLML). The two diseases are frequently associated with obesity and metabolic syndrome, with hypertension, diabetes, or dyslipidemia. The long-term course of the diseases remains poorly described. DD affects mainly women, whereas RLML mostly affects men. In both diseases lipomas are found on the back and thighs, as well as on the abdomen in DD and the forearms in RLML. The painful lipomas tend to recur after surgery in DD (in contrast to RLML). Most cases are sporadic. No specific treatment has been identified, as the pathophysiology remains unknown. Nevertheless, low-grade fat inflammation and specific abnormalities such as hyperbasophilia deserve further investigation. The aim of this review is to analyze the available literature on the topic. Full article
(This article belongs to the Special Issue Infrequent Lipodystrophies: Challenges in Pathogenesis, Diagnosis and Treatment)
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