Clinical spectrum of LMNA-associated type 2 familial partial lipodystrophy: a systematic review

Citation: Fernandez-Pombo, A.; Diaz-Lopez, E.J.; Castro, A.I.; Sanchez-Iglesias, S.; Cobelo-Gomez, S.; Prado-Moraña, T.; Araujo-Vilar, D. Clinical Spectrum of LMNA-Associated Type 2 Familial Partial Lipodystrophy: A Systematic Review. Cells 2023,12, 725. https:// doi.org/10.3390/cells12050725 Academic Editor: Thomas Dechat Received: 31 January 2023 Revised: 16 February 2023 Accepted: 17 February 2023 Published: 24 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cells Systematic Review Clinical Spectrum of LMNA-Associated Type 2 Familial Partial Lipodystrophy: A Systematic Review Antia Fernandez-Pombo 1,2 , Everardo Josue Diaz-Lopez 1,2 , Ana I. Castro 2,3, Sofia Sanchez-Iglesias 1, Silvia Cobelo-Gomez 1, Teresa Prado-Moraña 1,2 and David Araujo-Vilar 1,2,* 1UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain 2Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain 3CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), 28029 Madrid, Spain *Correspondence: [email protected]; Tel.: +34-981-951-611 Abstract: Type 2 familial partial lipodystrophy (FPLD2) is a laminopathic lipodystrophy due to pathogenic variants in the LMNA gene. Its rarity implies that it is not well-known. The aim of this review was to explore the published data regarding the clinical characterisation of this syndrome in order to better describe FPLD2. For this purpose, a systematic review through a search on PubMed until December 2022 was conducted and the references of the retrieved articles were also screened. A total of 113 articles were included. FPLD2 is characterised by the loss of fat starting around puberty in women, affecting limbs and trunk, and its accumulation in the face, neck and abdominal viscera. This adipose tissue dysfunction conditions the development of metabolic complications associated with insulin resistance, such as diabetes, dyslipidaemia, fatty liver disease, cardiovascular disease, and reproductive disorders. However, a great degree of phenotypical variability has been described. Therapeutic approaches are directed towards the associated comorbidities, and recent treatment modalities have been explored. A comprehensive comparison between FPLD2 and other FPLD subtypes can also be found in the present review. This review aimed to contribute towards augmenting knowledge of the natural history of FPLD2 by bringing together the main clinical research in this field. Keywords: LMNA; Dunnigan disease; type 2 familial partial lipodystrophy; laminopathies; FPLD2 1. Introduction The LMNA gene codifies for lamin A/C, which is an intermediate filament protein present in the nuclear lamina and an important determinant of nuclear and cellular architecture. The correct processing of the A-type lamins is essential for the prevention of several disorders [ 1 ]. In this regard, prelamin A is farnesylated, methylated and processed by zinc metalloprotease to form the mature lamin A (Figure 1). Thus, there are a number of diseases caused by pathogenic variants in the LMNA gene (familial partial lipodystrophy type 2 [FPLD2] or Dunnigan disease, HutchinsonGilford progeria syndrome, mandibuloacral dysplasia type A, Emery Dreifuss muscular dystrophy, Limb-Girdle muscular dystrophy or atypical progeroid syndrome, among others) or other genes that influence this lamin processing (such as ZMPSTE24 gene variants in mandibuloacral dysplasia type B or in restrictive dermopathy type 1) or in genes that influence its proper functioning on chromatin (such as BANF1 gene variants in Néstor-Guillermo progeria syndrome). These disorders are known as laminopathies, which mainly affect mesenchymal tissues (muscle, adipose tissue and bone), although some affect the nervous system (Figure 1) [1–3]. Cells 2023,12, 725. https://doi.org/10.3390/cells12050725 https://www.mdpi.com/journal/cells Cells 2023,12, 725 2 of 23 Cells 2023, 12, x FOR PEER REVIEW 2 of 22 mainly affect mesenchymal tissues (muscle, adipose tissue and bone), although some affect the nervous system (Figure 1) [1–3]. Figure 1. Lamin A processing pathway and laminopathies affecting mesenchymal tissues. Prelamin A is farnesylated, methylated and processed by ZMPSTE24, giving rise to the mature lamin A. Alterations in this lamin A processing pathway are responsible for several disorders known as laminopathies, which mainly affect mesenchymal tissues. In this figure, laminopathies are distributed according to the most characteristically affected mesenchymal tissue (adipose tissue in the case of type 2 familial partial lipodystrophy). MSC: mesenchymal stem cell. FPLD2 also belongs to a bigger family of FPLD syndromes that include a set of Mendelian disorders due to variants in different genes related to adipogenesis and lipogenesis and which share subcutaneous fat loss from the limbs and gluteal region, in addition to the variable regional accumulation of excess fat [4–6]. Due to adipose tissue dysfunction, ectopic fat accumulation and, consequently, insulin resistance, they also share several metabolic abnormalities and comorbidities. However, there is a great degree of phenotypical variability between the different FPLD disorders. To date, seven subtypes and another four unclassified variants of FPLD have been described, with FPLD2 and FPLD1 being the most frequent [7]. The extreme rarity of lipodystrophy syndromes such as FPLD2 implies that they are not well-known. In fact, the knowledge we currently have about the clinical characterisation of this disease, the associated comorbidities and its natural course is mainly based on studies limited to small samples. In addition, among the most fascinating traits of this Figure 1. Lamin A processing pathway and laminopathies affecting mesenchymal tissues. Prelamin A is farnesylated, methylated and processed by ZMPSTE24, giving rise to the mature lamin A. Alterations in this lamin A processing pathway are responsible for several disorders known as laminopathies, which mainly affect mesenchymal tissues. In this figure, laminopathies are distributed according to the most characteristically affected mesenchymal tissue (adipose tissue in the case of type 2 familial partial lipodystrophy). MSC: mesenchymal stem cell. FPLD2 also belongs to a bigger family of FPLD syndromes that include a set of Mendelian disorders due to variants in different genes related to adipogenesis and lipogenesis and which share subcutaneous fat loss from the limbs and gluteal region, in addition to the variable regional accumulation of excess fat [ 4 – 6 ]. Due to adipose tissue dysfunction, ectopic fat accumulation and, consequently, insulin resistance, they also share several metabolic abnormalities and comorbidities. However, there is a great degree of phenotypical variability between the different FPLD disorders. To date, seven subtypes and another four unclassified variants of FPLD have been described, with FPLD2 and FPLD1 being the most frequent [7]. The extreme rarity of lipodystrophy syndromes such as FPLD2 implies that they are not well-known. In fact, the knowledge we currently have about the clinical characterisation of this disease, the associated comorbidities and its natural course is mainly based on studies limited to small samples. In addition, among the most fascinating traits of this disorder, as in the rest of laminopathies, are its complex genotype-phenotype associations and its clinical heterogeneity [2]. Thus, this review aimed to collect and summarise the published data regarding the classical and atypical clinical features of Dunnigan disease and its associated comorbidities, Cells 2023,12, 725 3 of 23 as well as the differential diagnosis with other FPLD subtypes, in order to contribute to the understanding of this disorder. 2. Materials and Methods 2.1. Search Strategy To show the current knowledge about the clinical characteristics, organ abnormalities and associated comorbidities of FPLD2, a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol was conducted [ 8 ]. The protocol for this systematic review is also published in the Open Science Forum registries and can be accessed using the following: https://osf.io/d453h (accessed on 15 February 2023). For this purpose, a search on PubMed was performed using the terms “Dunnigan” OR “familial partial lipodystrophy” OR “FPLD”. The database was searched up to December 2022, without a time limitation and without language restrictions. The references of the retrieved articles were also screened to identify additional studies and expand our search (Figure 2). Cells 2023, 12, x FOR PEER REVIEW 3 of 22 disorder, as in the rest of laminopathies, are its complex genotype-phenotype associations and its clinical heterogeneity [2]. Thus, this review aimed to collect and summarise the published data regarding the classical and atypical clinical features of Dunnigan disease and its associated comorbidities, as well as the differential diagnosis with other FPLD subtypes, in order to contribute to the understanding of this disorder. 2. Materials and Methods 2.1. Search Strategy To show the current knowledge about the clinical characteristics, organ abnormalities and associated comorbidities of FPLD2, a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol was conducted [8]. The protocol for this systematic review is also published in the Open Science Forum registries and can be accessed using the following: https://osf.io/d453h (accessed on 15 February 2023). For this purpose, a search on PubMed was performed using the terms “Dunnigan” OR “familial partial lipodystrophy” OR “FPLD”. The database was searched up to December 2022, without a time limitation and without language restrictions. The references of the retrieved articles were also screened to identify additional studies and expand our search (Figure 2). Figure 2. Search strategy and flow diagram of articles. Figure 2. Search strategy and flow diagram of articles. 2.2. Study Selection A total of 788 articles were identified through this database search. Studies that report clinical and/or biochemical data on patients with FPLD2 were eligible for inclusion in the current review. The main exclusion criteria were (a) articles not fulfilling the topic of interest of this review; (b) review articles, meta-analyses, individual case reports, editorials or comments; and (c) studies not conducted on humans. Two authors independently reviewed the abstracts of the retrieved articles, applying the previously-mentioned inclusion and Cells 2023,12, 725 4 of 23 exclusion criteria and, subsequently reviewed the full text of the studies to determine their final inclusion. 2.3. Identification and Inclusion of Studies From the 788 articles initially found, 454 were excluded taking into account that they did not fulfil the topic of interest of this review, two were excluded because they were published errata and 66 were excluded because they were focused on other FPLD subtypes or laminopathies, other than Dunnigan disease. During the screening and eligibility processes, 79 review articles or meta-analyses, 71 individual case reports, eight letters to the editor and one comment were also excluded. In addition, a total of 6 studies were finally included after the screening of the references of the initial pool of retrieved articles. Thus, finally, 113 articles were included in the current review. The flow diagram regarding the research strategy can be seen in Figure 2. 3. Results 3.1. Prevalence Since the first report of Dunnigan disease in 1974 [ 9 ], several cases have been described over the years. Although it is difficult to speak of prevalence in a rare disorder, in 2017, taking into account database and literature searches, a prevalence of 1.7–2.8 cases per million was determined for partial lipodystrophy (both FPLD and acquired partial lipodystrophy) [10]. With the aim of evaluating the prevalence of missense variants in the LMNA gene exclusively, a DNA sequencing data extraction was performed from 60,706 unrelated individuals in the Exome Aggregation Consortium (ExAC) database. Allele frequencies ranged from 1-per-100,000 to 1-per-1,000 and were primarily heterozygous (only two were homozygous [p.S625C and p.R644C]) [11]. In a more recent analysis, looking for clinical and molecular lipodystrophy diagnostic codes, also using the ExAC database, a pathogenic variant carrier prevalence for autosomal dominant FPLD of ~1 in 7588 individuals was estimated. What is more striking is that additional pathogenic variants in the LMNA gene (such as the p.R482Q variant associated with FPLD2) were also found in patients with metabolic abnormalities in the lipodystrophy spectrum, but without a clinical diagnosis [ 12 ]. This only confirms that lipodystrophy syndromes such as Dunnigan disease are underdiagnosed and underestimated conditions, poorly understood by physicians outside the specialist treatment centre setting. Thus, there is definitely great difficulty in making a realistic estimate of a specific subgroup of rare and heterogeneous diseases, and only large and prolonged registries will make it possible to present a more objective picture of the real data. 3.2. Clinical Characteristics As for most FPLD subtypes (except for types 5, 6 and those associated with PCYT1A and MFN2 genes), the reported transmission of FPLD2 supports an autosomal dominant mode of inheritance [ 13 – 15 ]. However, this disorder can actually be considered a codominant disease, taking into account that homozygous cases have also been described [ 16 ]. It is classically characterised by the loss of fat from the trunk, buttocks and upper and lower limbs, in addition to fat accumulation in the face, neck and supraclavicular fossae, giving a Cushingoid appearance [ 13 , 15 , 17 , 18 ] (Figure 3). In this sense, in vivo morphofunctional assessment of fat depots in the neck area of FPLD2 patients by PET/CT analysis exhibited the absence of brown adipose tissue activity, therefore showing that failure in adipose tissue browning may be a contributor to disease [ 19 ]. Trunk lipoatrophy also contributes to the appearance of labial hypertrophy [15]. Lipomas are likewise a common characteristic of these patients, with a reported prevalence of 20%, even in lipoatrophic areas [ 20 ]. Along with this abnormal fat distribution, muscular hypertrophy and myalgias are also recurrent features in these patients [13,21–23]. Cells 2023,12, 725 5 of 23 Cells 2023, 12, x FOR PEER REVIEW 5 of 22 functional assessment of fat depots in the neck area of FPLD2 patients by PET/CT analysis exhibited the absence of brown adipose tissue activity, therefore showing that failure in adipose tissue browning may be a contributor to disease [19]. Trunk lipoatrophy also contributes to the appearance of labial hypertrophy [15]. Lipomas are likewise a common characteristic of these patients, with a reported prevalence of 20%, even in lipoatrophic areas [20]. Along with this abnormal fat distribution, muscular hypertrophy and myalgias are also recurrent features in these patients [13,21–23]. Figure 3. Clinical features of Dunnigan disease. While there is a loss of adipose tissue from the trunk, buttocks and limbs, fat excess in the face and neck and muscle hypertrophy is evident in women with FPLD2; in men, this characteristic phenotype is not so apparent. Other characteristic features of these patients are the presence of very prominent peripheral veins due to the lack of subcutaneous fat [24], the presence of signs of insulin resistance such as acanthosis nigricans and acrochordons [16,25,26], as well as signs of hyperandrogenism in affected women, such as hirsutism [13,23]. Although the onset of the phenotype has been described in some cases in childhood, with other signs and comorbidities occurring later in life [27], in most cases, in this specific FPLD subtype, lipodystrophy usually appears progressively around puberty in women, and later in men [13,14,23,28]. Patients sometimes admit to having several difficulties coming to terms with their appearance, relating to physical discomfort and psychological distress, especially in the case of women, which may lead them to consider the possibility of undergoing cosmetic surgery [14]. Clinical research has also revealed that the expression and severity of the phenotype may be markedly dependent on sex, with women being more affected. On the contrary, in men, the clinical diagnosis of FPLD can be more problematic, taking into account the less-apparent lipodystrophy phenotype in most cases and its later onset (Figure 3), leading to delays in the diagnosis [13,26]. In fact, men are usually diagnosed after their female relatives. Figure 3. Clinical features of Dunnigan disease. While there is a loss of adipose tissue from the trunk, buttocks and limbs, fat excess in the face and neck and muscle hypertrophy is evident in women with FPLD2; in men, this characteristic phenotype is not so apparent. Other characteristic features of these patients are the presence of very prominent peripheral veins due to the lack of subcutaneous fat [ 24 ], the presence of signs of insulin resistance such as acanthosis nigricans and acrochordons [ 16 , 25 , 26 ], as well as signs of hyperandrogenism in affected women, such as hirsutism [13,23]. Although the onset of the phenotype has been described in some cases in childhood, with other signs and comorbidities occurring later in life [ 27 ], in most cases, in this specific FPLD subtype, lipodystrophy usually appears progressively around puberty in women, and later in men [13,14,23,28]. Patients sometimes admit to having several difficulties coming to terms with their appearance, relating to physical discomfort and psychological distress, especially in the case of women, which may lead them to consider the possibility of undergoing cosmetic surgery [14]. Clinical research has also revealed that the expression and severity of the phenotype may be markedly dependent on sex, with women being more affected. On the contrary, in men, the clinical diagnosis of FPLD can be more problematic, taking into account the less-apparent lipodystrophy phenotype in most cases and its later onset (Figure 3), leading to delays in the diagnosis [ 13 , 26 ]. In fact, men are usually diagnosed after their female relatives. When comparing heterozygous and homozygous patients, more severe lipoatrophy was also found in the latter. Thus, in a recent study conducted on 65 patients carrying the monoallelic LMNA p.(Thr655Asnfs*49) variant and 13 carrying the same biallelic variant, while 54% of heterozygous subjects were diagnosed during family screening, 69% of homozygous patients were diagnosed due to medical complications, all of them presenting obvious clinical features of lipodystrophy [ 16 ]. In this sense, compound heterozygosity in the LMNA gene was also found to be associated with a relatively more severe FPLD2 phenotype [29]. It has also been reported that most FPLD2 patients with the previously described classic phenotype are those who harbour heterozygous missense variants affecting arginine at codon 482 in exon 8 of the LMNA gene, while those presenting with other LMNA variants are considered to have atypical FPLD2. Thus, patients with the p.(R644C), the p.(R582H) or Cells 2023,12, 725 6 of 23 the p.(R582C) variants in exon 11, patients with the p.(T528M) variant in exon 9, patients with the p.(D47N) variant in exon 1, or even patients with the p.(R471G) variant in exon 8 of the LMNA gene, were shown, in previous studies, to have a milder phenotype, with less severe loss of fat, occurring at an older age in some cases. In contrast, other cases with the p.(R349W) variant in exon 6 showed a more remarkable fat loss, even in the face [ 5 , 30 – 36 ]. Other distinctive features found in subjects with non-codon 482 FPLD2 were the absence of prominent labia majora, the lack of acanthosis nigricans and hirsutism [ 5 ] and the presence of frequent muscle signs such as myalgias or weakness [ 37 ]. In addition, other cases of FPLD2 with other heterozygous pathogenic variants, such as p.(R541P) or p.(K486E), were reported to have a more complex phenotype that may more closely resemble generalised lipodystrophy [ 38 ]. This clinical heterogeneity suggests the possible influence of other factors, such as environment, which might induce epigenetic changes or the presence of single nucleotide polymorphisms in LMNA that could modulate the clinical expressivity of this disorder. 3.3. Body Composition Throughout the literature, the body composition of patients with FPLD2 has mainly been evaluated through dual-energy X-ray absorptiometry (DXA) (Figure 4) or magnetic resonance imaging (MRI), although some isolated studies have used bioelectrical impedance analysis (BIA) for this purpose. These body composition techniques have been shown to help diagnosis by revealing even subclinical changes in fat deposition suggestive of lipodystrophy [ 37 , 39 ]. Through these techniques, the previously mentioned clinical findings of the near-total absence of adipose tissue in the limbs and truncal area (without reduction in intraabdominal and intrathoracic fat), along with an excess of adipose tissue in the face, neck, chin, axillae, and labia majora have been confirmed [ 4 , 30 , 40 – 42 ]. In addition, using the Dixon method of MRI, not only was quantified fat liver observed to be high in FPLD2 subjects, but pancreatic fat was also greater in this population. Furthermore, a positive relationship was demonstrated between these specific fat contents and metabolic parameters such as glycated haemoglobin (HbA1c) or triglycerides [41,43]. Although computed tomography and MRI remain the reference standards for assessing visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) distribution, these are expensive and limited techniques with certain operative contraindications. Thus, the determination of possible correlations between MRI data of truncal adiposity and simpler clinical measures, such as BIA-derived data in FPLD women, could be of use in the assessment of body composition in these subjects. In this sense, a significant correlation between mid-thigh fat percentage by MRI and BIA has been observed [ 44 ], and the measurement of total fat percentage most strongly correlated with both VAT and SAT [45]. Furthermore, in line with previously described clinical findings, women with atypical FPLD showed less severe loss of adipose tissue, evaluated via MRI, from the limbs and trunk, and particularly from the gluteal region and proximal thighs than women with typical FPLD [ 5 , 33 ]. Despite this loss of fat, periarticular adipose tissue was found to be preserved in the lower limbs of patients with Dunnigan disease [ 46 ]. In addition, several studies compared the body composition of FPLD2 subjects with other FPLD subtypes, such as that associated with pathogenic variants in the PPARG gene. In these studies, patients with FPLD3 showed higher limb fat, with preserved truncal fat mass and increased skinfold thickness in the thigh, calf, triceps, and biceps, along with higher levels of leptin than FPLD2 subjects [ 36 , 47 – 49 ]. Although FPLD3 patients are, therefore, considered to have milder lipodystrophy, it has been observed that they develop more severe metabolic complications [ 47 ], suggesting that the severity of these metabolic disturbances may not only be associated with the extent of fat loss. Cells 2023,12, 725 7 of 23 Cells 2023, 12, x FOR PEER REVIEW 7 of 22 Figure 4. Comparative body composition determined by Dual-Energy X-ray Absorptiometry. Comparative, colour-mapped, total body composition scans via whole-body Dual-Energy X-ray Absorptiometry of patients with FPLD2, FPLD3 and non-lipodystrophic subjects. Green represents an area of low-level % fat (0–25%), yellow an area of medium-level % fat (25–60%), and red an area of highlevel % fat (60–100%); (A) Less-pronounced fat loss can be observed in the woman with PPARGassociated FPLD in comparison with the women with FPLD2. Differences can be seen even when comparing different variants within exon 8 of the LMNA gene; (B) Differences in the distribution of adipose tissue are less evident in men with FPLD2 when compared with age and BMI-matched healthy or obese controls. Although computed tomography and MRI remain the reference standards for assessing visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) distribution, these are expensive and limited techniques with certain operative contraindications. Thus, the determination of possible correlations between MRI data of truncal adiposity and simpler clinical measures, such as BIA-derived data in FPLD women, could be of use in the assessment of body composition in these subjects. In this sense, a significant correlation between mid-thigh fat percentage by MRI and BIA has been observed [44], and the measurement of total fat percentage most strongly correlated with both VAT and SAT [45]. Furthermore, in line with previously described clinical findings, women with atypical FPLD showed less severe loss of adipose tissue, evaluated via MRI, from the limbs and trunk, and particularly from the gluteal region and proximal thighs than women with typical FPLD [5,33]. Despite this loss of fat, periarticular adipose tissue was found to be preserved in the lower limbs of patients with Dunnigan disease [46]. In addition, several studies compared the body composition of FPLD2 subjects with other FPLD subtypes, such as that associated with pathogenic variants in the PPARG gene. In these studies, patients with FPLD3 showed higher limb fat, with preserved truncal fat mass and increased skinfold thickness in the thigh, calf, triceps, and biceps, along with higher levels of leptin Figure 4. Comparative body composition determined by Dual-Energy X-ray Absorptiometry. Comparative, colour-mapped, total body composition scans via whole-body Dual-Energy X-ray Absorptiometry of patients with FPLD2, FPLD3 and non-lipodystrophic subjects. Green represents an area of low-level % fat (0–25%), yellow an area of medium-level % fat (25–60%), and red an area of high-level % fat (60–100%); ( A ) Less-pronounced fat loss can be observed in the woman with PPARG-associated FPLD in comparison with the women with FPLD2. Differences can be seen even when comparing different variants within exon 8 of the LMNA gene; ( B ) Differences in the distribution of adipose tissue are less evident in men with FPLD2 when compared with age and BMI-matched healthy or obese controls. On the other hand, several adipose tissue cut-offs and indexes have been proposed in the literature to help guide the diagnosis of Dunnigan disease. Thus, lower-limb fat measured by DXA in female children with FPLD2 was initially found to be below or equal to the 1st percentile for NHANES [ 28 ]. In a subsequent study, it was also determined that lower-limb fat percentage below the 1st percentile according to DXA may direct the diagnosis of FPLD2 in women (with a specificity of 0.995 and a sensitivity of 1.0), especially if there are concomitant metabolic complications, and, therefore, genetic testing should be carried out in these cases [ 50 ]. Fat Mass Ratio (FMR), defined as the ratio between the trunk and lower-limb fat mass through DXA, was likewise proposed. It showed a greater value for FPLD2 subjects in comparison with controls as well as improved accuracy for evaluating these patients with a cut-off point of 1.2 [ 51 ]. Another index proposed as an objective measurement capable of determining fat excess in these patients was the body adiposity index (BAI), calculated as (hip circumference/height1.5)-18. Thus, BAI was found to be lower in FPLD2 in comparison with age and BMI-matched healthy individuals and Cells 2023,12, 725 8 of 23 presented a more significant correlation with parameters such as total fat percentage and fat mass, as well as with leptin levels, than BMI [52]. DXA may provide not only quantitative but also qualitative information. In this sense, a method was recently described which may be useful in the diagnosis of lipodystrophy syndromes such as FPLD2 through the reconstruction of DXA images using a colour-coded representation that highlights only adipose tissue (“fat shadows”). This method was able to differentiate FPLD from control subjects with 85% sensitivity and 96% specificity. In addition, the identification of the “Dunnigan sign” (hypertrophy of mons pubis fat surrounded by subcutaneous lipoatrophy) is also helpful in recognising subjects with FLPD2, which can easily be acknowledged by this specific method [53]. As far as skeletal muscle is concerned, in comparison with healthy women matched for age and BMI, patients with FPLD2 showed greater volume in the thigh, calf and psoas muscles, as well as increased arm and leg muscle masses when measured via DXA. In addition, insulin sensitivity was shown to be negatively correlated to calf muscle volume [ 54 ]. However, in a recent study, despite this increased muscularity, FPLD2 subjects did not demonstrate increased muscle strength and even showed earlier fatigue on chest-press exercise. Furthermore, the increase in skeletal muscle was found to be likely due to reduced muscle protein degradation rather than to greater protein synthesis, with impaired mitochondrial function playing a relevant role in this dysfunction [55]. On the other hand, bone can also be assessed through body composition techniques such as DXA. Laminopathies such as Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, LMNA-associated atypical progeroid syndrome, Néstor-Guillermo progeria syndrome, restrictive dermopathy or lethal foetal akinesia are characterised by bone alterations, suggesting that lamin A/C could play an important role in the pathogeny of the loss of bone mass related to ageing [ 56 – 59 ]. However, in the case of FPLD2, no differences in bone mineral density evaluated via DXA were found compared to non-lipodystrophic obese women or women with FPLD1 [ 60 ]. Nevertheless, in another study, several patients with FPLD showed non-specific degenerative radiographic abnormalities such as osteoarthritis or calcific tendonitis and/or osteochondrosis [61]. 3.4. Comorbidities and Organ Abnormalities Most lipodystrophy syndromes such as FPLD2 are characterised by the presence of insulin resistance and, consequently, by a variable degree of metabolic dysfunction, with diabetes, dyslipidaemia, fatty liver disease, cardiovascular disease, and reproductive dysfunction. In fact, it is known that patients with different FPLD subtypes with similar truncal mass to subjects with non-FPLD obesity have worse metabolic profiles [ 62 ]. In addition to several clinical characteristics, Table 1shows the main reported comorbidities of FPLD2 as well as specific differential features and comorbidities of other FPLD syndromes for their differential diagnosis, taking into account the great similarities of these lipodystrophy syndromes [63–87]. It has been reported that comorbidities in Dunnigan disease develop after age 10, which is why it has been proposed that while clinical review and dietetic support are beneficial for children with this disorder, formal screening for organ abnormalities before the age of 10 may not be of benefit. However, this recommendation has to be taken with caution considering the anticipation phenomenon recently described for this population, with the occurrence of metabolic complications such as diabetes and hypertriglyceridaemia at an earlier age across generations [28,88,89]. Cells 2023,12, 725 9 of 23 Table 1. Clinical characteristics of FPLD2 and its differential diagnosis with other familial partial lipodystrophy syndromes. FPLD2 Main Characteristics [4–6,13–128] Differential Characteristics of other FPLD Syndromes [63–87] Gene LMNA Unknown (FPLD1), PPARG (FPLD3), PLIN1 (FPLD4), CIDEC (FPLD5), LIPE (FPLD6), CAV1 (FPLD7), AKT2,PCYT1A,ADRA2A,MFN2. Inheritance AD (homozygous cases have also been described). AR in FPLD5, FPLD6, PCYT1Aand MFN2-related FPLD Onset of phenotype Puberty in women, later in men. - Birth (FPLD7) - Childhood-adulthood (other FPLD). Abnormal fat distribution - Loss of fat in the limbs, trunk and gluteal region. - Accumulation of fat in the face, neck, chin, axillae, interscapular area, labia majora and abdominal viscera. - Less apparent in men. - Atypical FPLD2 (non-codon 482 FPLD2): milder phenotype. - FPLD1: accumulation of abdominal fat. - FPLD3: less severe loss of fat. - FPLD7: loss of fat in the face and upper body. Clinical features - Subcutaneous lipomas. - Muscular hypertrophy, mialgias. - Phlebomegaly. - Signs of insulin resistance (acanthosis nigricans, acrochordons). - Hyperandrogenism. - Hypertrophy of mons pubis, “Dunnigan sign”. - FPLD1: KöB index > 3.477. - FPLD3: less prominent musculature, no phlebomegaly. - FPLD6: multiple lipomatosis. - FPLD7: congenital cataracts, progeroid features. -PCYT1A-related FPLD: short stature, muscular atrophy. -MFN2-related FPLD: lipomatous masses. Analytical parameters - Lower plasma leptin and adiponectin levels than controls, with no standardised cut-offs. - Generally increased TNF-α, IL-1β, IL-6 and IL-10 levels. -MFN2-related FPLD: very low leptin levels. - FPLD6: elevated creatine kinase levels. Main comorbidities - Insulin resistance. - Type 2 diabetes mellitus. - Dyslipidaemia (high triglyceride levels, low HDL cholesterol). - Acute pancreatitis. - Hypertension. - Cardiovascular disease (cardiac hypertrophy, atrioventricular conduction defects, heart failure, early atherosclerosis, arrhythmias). - Liver disease (NAFLD, NASH). - Fertility problems. - PCOS. - Renal disease (proteinuria and progression to renal failure). - Anticipation phenomenon (diabetes, hypetriglyceridaemia). - FPLD3: earlier and more severe metabolic complications. Early hypertension. - FPLD6: auto-fluorescent drusen-like retinal deposits. Muscular dystrophy in some patients. -MFN2-related FPLD: peripheral axonal neuropathy. In order to demonstrate a comprehensive comparison between FPLD2 and other FPLD subtypes, references [63–87] , related to FPLD subtypes other than Dunnigan disease, have been added in addition to the retrieved articles from the database search and reference screening. AD: autosomal dominant; AR: autosomal recessive; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; PCOS: polycystic ovary syndrome. Cells 2023,12, 725 16 of 23 Data Availability Statement: No new data were created or analysed in this study. Data sharing is not applicable to this article. Acknowledgments: We are indebted to the patients of this study for their collaboration. Conflicts of Interest: D.A.-V. has received honoraria as scientific advisor from Amryt Pharma. The rest of the authors declare no conflict of interest. References 1. Broers, J.L.; Ramaekers, F.C.; Bonne, G.; Yaou, R.B.; Hutchison, C.J. Nuclear lamins: Laminopathies and their role in premature ageing. Physiol. Rev. 2006,86, 967–1008. [CrossRef] [PubMed] 2. Guillín-Amarelle, C.; Fernández-Pombo, A.; Sánchez-Iglesias, S.; Araújo-Vilar, D. Lipodystrophic laminopathies: Diagnostic clues. Nucleus 2018,9, 249–260. [CrossRef] [PubMed] 3. 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