Lipodystrophic Laminopathies: From Dunnigan Disease to Progeroid Syndromes

Citation: Díaz-López, E.J.; Sánchez-Iglesias, S.; Castro, A.I.; Cobelo-Gómez, S.; Prado-Moraña, T.; Araújo-Vilar, D.; Fernandez-Pombo, A. Lipodystrophic Laminopathies: From Dunnigan Disease to Progeroid Syndromes. Int. J. Mol. Sci. 2024,25, 9324. https://doi.org/10.3390/ ijms25179324 Academic Editor: Pavel Hozák Received: 14 July 2024 Revised: 20 August 2024 Accepted: 26 August 2024 Published: 28 August 2024 Copyright: © 2024 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/). International Journal of Molecular Sciences Review Lipodystrophic Laminopathies: From Dunnigan Disease to Progeroid Syndromes Everardo JosuéDíaz-López 1,2 , Sofía Sánchez-Iglesias 1, Ana I. Castro 2,3, Silvia Cobelo-Gómez 1, Teresa Prado-Moraña 1,2, David Araújo-Vilar 1,2 and Antia Fernandez-Pombo 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; [email protected] (E.J.D.-L.); [email protected] (S.S.-I.); [email protected] (S.C.-G.); [email protected] (T.P.-M.); [email protected] (D.A.-V.) 2Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain; [email protected] 3CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), 28029 Madrid, Spain *Correspondence: [email protected] or [email protected] Abstract: Lipodystrophic laminopathies are a group of ultra-rare disorders characterised by the presence of pathogenic variants in the same gene (LMNA) and other related genes, along with an impaired adipose tissue pattern and other features that are specific of each of these disorders. The most fascinating traits include their complex genotype-phenotype associations and clinical heterogeneity, ranging from Dunnigan disease, in which the most relevant feature is precisely adipose tissue dysfunction and lipodystrophy, to the other laminopathies affecting adipose tissue, which are also characterised by the presence of signs of premature ageing (Hutchinson Gilford-progeria syndrome, LMNA-atypical progeroid syndrome, mandibuloacral dysplasia types A and B, NestorGuillermo progeria syndrome, LMNA-associated cardiocutaneous progeria). This raises several questions when it comes to understanding how variants in the same gene can lead to similar adipose tissue disturbances and, at the same time, to such heterogeneous phenotypes and variable degrees of metabolic abnormalities. The present review aims to gather the molecular basis of adipose tissue impairment in lipodystrophic laminopathies, their main clinical aspects and recent therapeutic strategies. In addition, it also summarises the key aspects for their differential diagnosis. Keywords: laminopathies; lipodystrophy; Dunnigan disease; FPLD; Hutchinson-Gilford progeria syndrome; mandibuloacral dysplasia; atypical progeroid syndrome; Nestor-Guillermo progeria syndrome; progeria; adipose tissue 1. Introduction Nuclear lamins are crucial nuclear envelope proteins that provide essential structural support and facilitate interactions between extranuclear structures and nucleoplasm components. The A-type nuclear lamins A and C are encoded by the LMNA gene [1,2]. Laminopathies are inherited diseases resulting from abnormalities in A-type lamins due to variants in the LMNA gene or in other genes involved in prelamin A processing [ 3 , 4 ]. These disorders have diverse clinical manifestations, which may include bone and cardiac abnormalities, lipodystrophy, dermopathy, neuropathy, metabolic abnormalities and premature ageing [ 5 ]. In particular, lipodystrophic laminopathies, characterised by selective loss of adipose tissue, represent a distinct subset of these conditions [6]. There are several diseases related to the LMNA gene presenting with adipose tissue dysfunction, such as Dunnigan disease or familial partial lipodystrophy type 2 (FPLD2), Hutchinson-Gilford progeria syndrome (HGPS), LMNA-associated atypical progeroid syndrome (APS) and mandibuloacral dysplasia type A (MADA) [ 7 ]. Among the progeroid syndromes, those associated with LMNA variants are particularly significant due to their Int. J. Mol. Sci. 2024,25, 9324. https://doi.org/10.3390/ijms25179324 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2024,25, 9324 2 of 25 resemblance to aspects of ageing and range from the mild acceleration observed in MADA to severe acceleration in HGPS [ 8 ]. In addition, variants in genes affecting lamin A/C processing and nuclear lamina structure, such as ZMPSTE24 (linked to mandibuloacral dysplasia type B [MADB]) and BANF1 (associated with Nestor-Guillermo progeria syndrome [NGPS]), can also result in accelerated ageing syndromes that share adipose tissue impairment [9]. These syndromes underscore the critical role of nuclear envelope proteins in human health and require an interdisciplinary clinical approach to improve diagnosis, monitoring and therapeutic development. This review aims to comprehensively examine lipodystrophic laminopathies, covering the genetic basis of adipose tissue disturbance as a common denominator of these disorders, their clinical manifestations and current therapeutic strategies, in order to improve understanding and guide future research and clinical practice. 2. Aetiopathogenesis of Adipose Tissue Impairment in Lipodystrophic Laminopathies The nuclear lamina is a dense fibrillar network located underneath the inner nuclear membrane. Major components of the nuclear lamina are members of the lamin family of type V intermediate filament proteins, which are important determinants of nuclear and cellular architecture and are significant regulators of stem cell differentiation [ 10 ]. The LMNA gene codifies for A-type lamins and LMNB1 and LMNB2 for lamins B1 and B2, respectively. In this sense, prelamin A is farnesylated, methylated and processed by ZMPSTE24 to form the mature lamina. The correct processing of the A-type lamins is essential for the prevention of laminopathies, which are, as previously mentioned, caused by variants in the LMNA gene (such as Dunnigan disease or several premature ageing syndromes), in other genes that influence lamina processing (such as ZMPSTE24 gene variants in MADB or in restrictive dermopathy) or in genes that influence its proper functioning on chromatin (such as BANF1 gene variants in NGPS). Thus, LMNA-related syndromes are considered to be primary laminopathies and the others secondary laminopathies [10–12]. Laminopathies mainly affect mesenchymal tissues (adipose tissue, muscle, bone) [ 10 ], although, due to their complex genotype-phenotype associations, not all of them share the same mesenchymal tissue abnormalities. Thus, adipose tissue is affected specifically in the primary lipodystrophic laminopathies Dunnigan disease, HGPS, LMNA-atypical progeroid syndrome (APS) and MADA, and in the secondary lipodystrophic laminopathies MADB and NGPS [ 11 ]. This raises several questions when it comes to understanding how variants in the same gene can lead to similar adipose tissue disturbances and, at the same time, to such heterogeneous phenotypes. Thus, the precise mechanisms linking nuclear envelope abnormalities to lipodystrophy remain unknown. However, various theories have been discussed over the years and different pathogenetic mechanisms leading to improper fat distribution in lamin Alinked lipodystrophies have been proposed [ 10 , 13 – 25 ]. One such theory is that regulated structural reorganisation of A-type lamins is needed during mesenchymal stem cell differentiation or quiescence. If these rearrangements in the organisation of the lamina are hindered by mutant lamins or their abscence, they could ultimately lead to adipose tissue or muscle impairment [ 20 ]. Another theory refers to gene expression and an alteration in transcription factors such as the sterol regulatory element-binding protein 1c (SREBP-1c), which, when sequestered by prelamin A, is not able to properly activate the peroxisome proliferator-activated receptor gamma (PPARG) [ 18 ], which is essential in the adipogenesis process. On the other hand, variants in the LMNA gene may prevent the correct maturation of prelamin A, generating aberrant electrical charges that alter the interaction with several peptides, such as SREBP-1c itself [ 26 ], precluding adipogenesis through the previously mentioned reduction of PPARG activation [ 27 ]. Other factors could intervene in this inactivation of PPARG, such as the barrier-to-autointegration factor (BAF) [ 28 ] or the retinoblastoma protein (pRb) [ 29 ], whose subnuclear localisation and degradation by the proteasome also depend on A-type lamins. pRB promotes adipogenesis, and its phosphorylated form is reduced in lipoatrophic areas in patients with Dunnigan disease [ 30 ]. Int. J. Mol. Sci. 2024,25, 9324 3 of 25 Furthermore, the accumulation of prelamin A alters the nuclear envelope and chromatin organisation, generating oxidative stress, the accumulation of reactive oxygen species [ 30 , 31 ] and a premature ageing phenotype [ 14 , 30 ]. As for the reason why mutant lamin A is unable to complete its maturation, the altered electrical charges previously mentioned were considered responsible by preventing the correct coupling of ZMPSTE24 with prelamin A [32]. Another mechanism proposed to explain the alteration in adipogenesis and premature ageing is the alteration in autophagic flux, which seemed to be reduced [ 33 , 34 ]. Early activation of autophagy in laminopathic adipocyte precursors followed by autophagic flux impairment has also been related to impaired white adipocyte turnover and failure of adipose tissue browning and, therefore, to fat loss and improper accumulation in these syndromes [ 23 ]. However, the reason why some areas of the body can be affected and not others, with lamins being ubiquitous proteins, is not completely clear. This could be explained due to the differential expression of different variants of lamins, originated by alternative splicing, establishing different relationships and exerting different functions, depending on the cell type [35]. Nevertheless, the clinical heterogeneity of these disorders also suggests the possible influence of other factors that may even induce epigenetic changes. Thus, one of the hypotheses being raised is that variability in the clinical expressivity of these disorders could be triggered by certain epigenetic marks. Moreover, some studies suggest that the mechanisms responsible for the loss of adipose tissue may be related to certain microRNAs (miRNAs) and histone modifications. In this sense, miRNAs are small, non-coding RNA molecules that play a crucial role in the post-transcriptional regulation of gene expression, usually by mRNA cleavage, mRNA destabilisation or translational repression. They have been shown to be involved in important epigenetic mechanisms such as histone modifications, which are relevant for chromatin formation and the maintenance of the nuclear lamina [ 21 , 36 , 37 ]. Specifically, the role of dynamic chromatin remodelling on adipogenesis has recently been reported and, more precisely, how pathogenic variants in the LMNA gene can modulate certain epigenetic marks such as the anti-adipogenic miRNA miR-335 in adipocyte progenitors, altering the processes of adipocyte differentiation [21]. 3. Dunnigan Disease Dunnigan disease, also known as FPLD2 (MIM#151660), is characterised by the loss of adipose tissue from the trunk, buttocks and upper and lower limbs mainly from puberty, associated with an accumulation of fat in the face, neck, supraclavicular fossae and labia majora/pubic area [ 38 – 41 ]. Most of the subjects with this phenotype harbour heterozygous missense variants affecting arginine at codon 482 in exon 8 of the LMNA gene. However, variants in other exons have also been reported and are shown to promote atypical FPLD2, with a variable pattern and severity of fat loss [ 42 – 51 ] (Figures 1and 2). There is also a tendency towards the formation of subcutaneous lipomas (found in 20% of cases), which can guide the diagnosis in subjects with a concordant phenotype [ 30 ] and, along with this reported abnormal pattern of fat distribution, muscular hypertrophy and myalgias are also recurrent features [ 52 – 54 ]. Identification of the “Dunnigan sign” (hypertrophy of mons pubis fat surrounded by subcutaneous lipoatrophy) is likewise helpful in diagnosing women with this disorder. Due to their lack of subcutaneous fat, these patients tend to show very prominent peripheral veins [ 55 ]. Signs of hyperandrogenism, such as hirsutism, can be seen in affected women [ 52 , 56 ], as well as the presence of signs of insulin resistance, including acrochordons and acanthosis nigricans [ 57 – 59 ] (Figure 1). The clinical diagnosis of this disorder is not difficult in women for trained physicians considering that the expression and severity of the previously mentioned phenotype may be markedly dependent on sex, with women being more affected. On the contrary, men typically show a less-apparent lipodystrophy phenotype and a later onset [41,42]. Int. J. Mol. Sci. 2024,25, 9324 4 of 25 Int. J. Mol. Sci. 2024, 25, x FOR PEER REVIEW 4 of 26 mentioned phenotype may be markedly dependent on sex, with women being more affected. On the contrary, men typically show a less-apparent lipodystrophy phenotype and a later onset [41,42]. Figure 1. Phenotypic features of patients with lipodystrophic laminopathies. (A) 48-year-old woman with Dunnigan disease and classic phenotype due to the p.(Arg482Trp) variant in exon 8 of the LMNA gene (FPLD2 #1); (B) 62-year-old woman with Dunnigan disease and atypical phenotype due to the p.(Thr528Met) variant in exon 9 of the LMNA gene (FPLD2 #2); (C) Classic FPLD2 is usually characterised by the accumulation of fat in the face and neck, giving a Cushingoid appearance; (D) Signs of insulin resistance such as acanthosis nigricans are common features in FPLD2; (E) The presence of subcutaneous lipomas and a concordant phenotype can guide the diagnosis in patients with FPLD2, as is the case of this subject, who developed lipomas within 3 months of follow-up; (F) 7-year-old boy with Hutchinson-Gilford progeria syndrome diagnosed at birth due to the 1822G > A, p.(G608S) variant in the LMNA gene (HGPS #1), showing the following phenotypical characteristics: generalised lipodystrophy, generalised alopecia, leucomelanodermal macules affecting the entire body, prominent cranial venous tree (H), bulging eyes due to the absence of retroorbital fat, small and sharp nose, small ears of normal implantation, dental malposition and absence of teeth, micrognathia and nasal voice. He presented a distended abdomen, with a reducible umbilical hernia and no hepatosplenomegaly. He showed marked veins in the lower limbs. Apparently normal clavicles, nail dysplasia and coxa valga could also be observed. Regarding comorbidities, he presented recurrent infections, bronchial asthma, subclinical hypothyroidism, myopia and, at the age of 5, he was hospitalised due to an occlusive dissection of the left internal carotid artery; (G) 16-year-old woman with Hutchinson-Gilford progeria syndrome AB CD E FGH I J KL M Figure 1. Phenotypic features of patients with lipodystrophic laminopathies. (A) 48-year-old woman with Dunnigan disease and classic phenotype due to the p.(Arg482Trp) variant in exon 8 of the LMNA gene (FPLD2 #1); (B) 62-year-old woman with Dunnigan disease and atypical phenotype due to the p.(Thr528Met) variant in exon 9 of the LMNA gene (FPLD2 #2); (C) Classic FPLD2 is usually characterised by the accumulation of fat in the face and neck, giving a Cushingoid appearance; (D) Signs of insulin resistance such as acanthosis nigricans are common features in FPLD2; (E) The presence of subcutaneous lipomas and a concordant phenotype can guide the diagnosis in patients with FPLD2, as is the case of this subject, who developed lipomas within 3 months of follow-up; (F) 7-year-old boy with Hutchinson-Gilford progeria syndrome diagnosed at birth due to the 1822G > A, p.(G608S) variant in the LMNA gene (HGPS #1), showing the following phenotypical characteristics: generalised lipodystrophy, generalised alopecia, leucomelanodermal macules affecting the entire body, prominent cranial venous tree (H), bulging eyes due to the absence of retroorbital fat, small and sharp nose, small ears of normal implantation, dental malposition and absence of teeth, micrognathia and nasal voice. He presented a distended abdomen, with a reducible umbilical hernia and no hepatosplenomegaly. He showed marked veins in the lower limbs. Apparently normal clavicles, nail dysplasia and coxa valga could also be observed. Regarding comorbidities, he presented recurrent infections, bronchial asthma, subclinical hypothyroidism, myopia and, at the age of 5, he was hospitalised due to an occlusive dissection of the left internal carotid artery; (G) 16-year-old woman with Hutchinson-Gilford progeria syndrome diagnosed at birth due to the c.1824C > T, p.(G608G) variant in the LMNA gene (HGPS #2), showing the following phenotypical characteristics: generalised lipodystrophy, cutaneous sclerosis, generalised alopecia, small and sharp nose, small mouth with dental crowding and micrognathia (I). She presented apparently normal clavicles, dysplastic nails, joint stiffness and coxa valga. Regarding comorbidities, she only showed mild aortic insufficiency. However, at the age of 16 she presented an acute myocardial infarction; (K) 17-year-old man with LMNA-atypical progeroid syndrome diagnosed Int. J. Mol. Sci. 2024,25, 9324 5 of 25 at 6 months of age due to the heterozygous c.29C > T, p.(Thr10Ile) variant in the LMNA gene, showing the following phenotypic characteristics: generalised lipodystrophy affecting palms and soles (J,L), with thin skin, leucomelanodermal macular lesions (M) and a progeroid facies with proptotic eyeballs as a consequence of the probable absence of retro-orbital fat, a pointed nasal pyramid, high-pitched voice and slight crowding of teeth. Hepatomegaly and splenomegaly were palpable. He had joint contractures affecting the upper and lower limbs and metatarsophalangeal stiffness. He presented pseudodislocation of the ankle joint which conditions talus-valgus feet. There was no resorption of the distal phalanges and he had normal nails. He had mild scoliosis, normal clavicles and no mandibular hypoplasia. He presented phlebomegaly in the limbs (L). Regarding comorbidities, he was diagnosed with diabetes mellitus, hypertriglyceridaemia, dilated cardiomyopathy with moderate pulmonary hypertension, for which he underwent a heart transplant, and he developed central nervous system lymphoma following the immunosuppressive therapy received. The images included here are of patients from our Lipodystrophy Unit (UETeM reference centre) and have not previously been published elsewhere. Int. J. Mol. Sci. 2024, 25, x FOR PEER REVIEW 8 of 26 Figure 2. Body composition determined by Dual-Energy X-Ray Absorptiometry of patients with lipodystrophic laminopathies and a non-lipodystrophic subject. Colour mapped, total body composition scans via whole-body Dual-Energy X-Ray Absorptiometry of (A) a 42-year-old nonlypodystrophic woman, showing normal fat distribution; (B) a 48-year-old woman with classical FPLD2 (FPLD2 #1) and loss of fat in the upper and lower limbs and its accumulation in the face, neck and pubic area; (C) a 62-year-old woman with atypical FPLD2 (FPLD2 #2) showing loss of fat in the upper and lower limbs and less accumulation in the face and neck; (D) a 7-year-old boy with Hutchinson-Gilford progeria syndrome (HGPS #1), presenting with severe generalised lipodystrophy, including palms and soles as well as muscle atrophy; (E) a 16-year-old woman with Hutchinson-Gilford progeria syndrome (HGPS #2), presenting with severe generalised lipodystrophy, including palms and soles, and muscle atrophy; (F) a 17-year-old man with LMNAatypical progeroid syndrome, showing generalised lipodystrophy, with preserved adipose tissue in the palms, loss of fat in the soles and muscle mass atrophy. 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%). These are original data from patients of our Lipodystrophy Unit (UETeM reference centre) and have not previously been published elsewhere. FPLD2: familial partial lipodystrophy type 2; HGPS: Hutchinson-Gilford progeria syndrome; APS: LMNA-atypical progeroid syndrome; BMI: body mass index; FM: fat mass; FFM: fat-free mass. 4. Hutchinson-Gilford Progeria Syndrome With an estimated prevalence of one case per 20 million inhabitants (www.progeriaresearch.org; accessed on 7 July 2024), HGPS (#MIM176670) is considered to be one of the most severe laminopathies, originating from the aberrant splicing of the LMNA gene and the consequent expression of an abnormal lamin A protein, called progerin [118,119]. Patients are healthy at birth with the phenotype usually becoming evident at 18–24 months of age, including a broad range of clinical features [120–122] (Figures 1 and 2): low body weight, with severe generalised lipodystrophy while preserving intraabdominal fat, along with muscular atrophy, growth retardation and short stature, early alopecia with prominent scalp veins, loss of skin elasticity and skin hypo/hyperpigmentation, beaked nose, micrognathia, high-arched palate, mandibular osteolysis, dental crowding, high-pitched voice, sensorineural hearing loss, nail Figure 2. Body composition determined by Dual-Energy X-Ray Absorptiometry of patients with lipodystrophic laminopathies and a non-lipodystrophic subject. Colour mapped, total body composition scans via whole-body Dual-Energy X-Ray Absorptiometry of (A) a 42-year-old nonlypodystrophic woman, showing normal fat distribution; (B) a 48-year-old woman with classical FPLD2 (FPLD2 #1) and loss of fat in the upper and lower limbs and its accumulation in the face, neck and pubic area; (C) a 62-year-old woman with atypical FPLD2 (FPLD2 #2) showing loss of fat in the upper and lower limbs and less accumulation in the face and neck; (D) a 7-year-old boy with Hutchinson-Gilford progeria syndrome (HGPS #1), presenting with severe generalised lipodystrophy, including palms and soles as well as muscle atrophy; (E) a 16-year-old woman with HutchinsonGilford progeria syndrome (HGPS #2), presenting with severe generalised lipodystrophy, including palms and soles, and muscle atrophy; (F) a 17-year-old man with LMNA-atypical progeroid syndrome, showing generalised lipodystrophy, with preserved adipose tissue in the palms, loss of fat in the soles and muscle mass atrophy. 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%). These are original data from patients of our Lipodystrophy Unit (UETeM reference centre) and have not previously been published elsewhere. FPLD2: familial partial lipodystrophy type 2; HGPS: Hutchinson-Gilford progeria syndrome; APS: LMNA-atypical progeroid syndrome; BMI: body mass index; FM: fat mass; FFM: fat-free mass. Int. J. Mol. Sci. 2024,25, 9324 6 of 25 Dunnigan disease can become a serious disorder with potentially lethal associated comorbidities and metabolic complications. Although these comorbidities usually develop after the age of 10, an anticipation phenomenon has been described, with the occurrence of metabolic disturbances at an earlier age across generations [ 60 – 62 ]. In this sense, the response of maladaptive adipose tissue acquires a dysfunctional pattern of adipocytokine production. These adipocytokines, synthesised both by adipocytes and by other inflammatory cells, interfere with insulin signalling pathways, generating resistance to its action [ 63 ]. Ectopic fat accumulation, mainly in the liver and muscle, also plays a relevant role in the aetiopathogenesis of insulin resistance. This can lead to a variable degree of metabolic complications, including non-ketotic diabetes, with a prevalence ranging from 28% to 51% [ 58 , 64 – 68 ], or dyslipidaemia, which is fundamentally characterised by high triglyceride levels, also related to acute pancreatitis in some of these subjects [ 69 ], and low high-density lipoprotein cholesterol [ 46 , 58 , 61 , 70 – 73 ]. Hypertension has also been described with a prevalence of up to 41% [ 46 , 59 , 74 ]. Kidney alterations including proteinuria and renal failure have likewise been reported [ 75 ]. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, ultimately leading to cirrhosis, are other frequent organ abnormalities due to ectopic lipid storage in the liver [ 58 , 76 ]. An increased prevalence of cardiac manifestations, such as cardiac hypertrophy [ 56 , 77 ], atrioventricular conduction defects, heart failure due to ventricular dilatation [ 78 , 79 ], early atherosclerosis [ 80 – 82 ] and arrhythmias [ 78 , 79 , 83 ], has also been described in this population. Polycystic ovary syndrome, fertility problems and a higher rate of miscarriages and stillbirths can likewise be observed [84–87]. Furthermore, it should be taken into account that Dunnigan disease, in addition to belonging to the laminopathy family due to the involvement of the LMNA gene in its aetiopathogenesis, also belongs to the FPLD group of syndromes, which comprises a total of nine FPLD subtypes and another three unclassified variants of FPLD [ 88 – 110 ]. This set of disorders shares most of the previously mentioned phenotypic characteristics and comorbidities and, therefore, attention should be paid to certain peculiarities of each specific disease that may help to perform a correct differential diagnosis. The main differential characteristics of Dunnigan disease and the other 11 FPLD subtypes can be seen in Table 1. There is currently no cure for this disorder and fat loss is generally not recovered. However, the morbidity and mortality of this condition could be improved with early intervention and, therefore, its treatment should be fundamentally oriented towards the control of the metabolic complications previously described. Apart from diet, along with physical activity (after an adequate cardiological assessment and avoiding vigorous exercise) and standard treatments mainly aimed at the control of diabetes and dyslipidaemia, several drugs have been specifically tested in this population. Metreleptin, a human recombinant leptin, has been approved by the European Medicines Agency (EMA) for the treatment of FPLD subjects > 12 years of age who have not responded to standard therapies (glycated haemoglobin [HbA1c] > 8% and/or triglycerides > 500 mg/dL) (https://www.ema.europa.eu/en/medicines/human/EPAR/myalepta, accessed on 7 July 2024). However, its response in partial lipodystrophy is considered to be less robust than in generalised forms. In this sense, while metreleptin has been proven to reduce serum triglyceride levels regardless of patients’ leptin levels, the reduction in HbA1c was found to be inconsistent [ 111 – 113 ]. It also seems to improve hepatic steatosis [ 114 ], although more studies in this field and in this specific population are needed. On the other hand, new drugs focused on hepatic lipid metabolism have also been investigated in recent years with promising results, as is the case of volanesorsen, an antisense inhibitor of apolipoprotein C-III. Its efficacy and safety have been evaluated in a 52-week phase II/III study, showing an 88% decrease in triglycerides and a significant reduction in hepatic fat fraction in 40 patients with FPLD [ 115 ]. Less robust results have been observed for gemcabene calcium, a monocalcium salt of a dialkyl ether dicarboxylic acid, the efficacy and safety of which has been evaluated in five women with FPLD (two with the LMNA R482Q variant), showing a median change in serum triglycerides of − 19.6% [ 116 ]. Vupanorsen, an Int. J. Mol. Sci. 2024,25, 9324 7 of 25 inhibitor of ANGPTL3, has also been studied in a small number of patients with FPLD (two of them with Dunnigan disease) showing a reduction of triglyceride fasting levels of 59.9%, as well as in other lipoproteins [ 117 ]. In addition, a phase II study regarding the effectiveness of obeticholic acid in reducing hepatic triglyceride levels in patients with Dunnigan disease and hepatic steatosis has recently been completed (ClinicalTrials. gov Identifier: NCT02430077). Table 1. Differential features of Dunnigan disease in comparison with other familial partial lipodystrophy syndromes. Dunnigan Disease [30,38–87] Other FPLD Subtypes [88–110] Molecular characteristics Nuclear lamina alteration Variants in LMNA gene - Classic FPLD2: R482W and R482Q variants in exon 8 - Atypical FPLD2: non-codon 482 variants - Unknown: FPLD1. - Adipogenesis dysregulation: FPLD3 (PPARG gene), FPLD9 (PLAAT3 gene). - Lipid droplet impairment or lipolysis dysregulation: FPLD4 (PLIN1 gene), FPLD5 (CIDEC gene), FPLD6 (LIPE gene), FPLD8 (ADRA2A gene). - Insulin signal transduction alteration: AKT2-related FPLD. - Caveolar function alteration: FPLD7 (CAV1 gene). - Dysregulation of phosphatidylcholine biosynthesis: PCYT1A-related FPLD. - Mitochondrial dysfunction: MFN2-related FPLD. Type of inheritance Autosomal dominant/Semi-dominant inheritance - Polygenic: FPLD1, FPLD7. - Autosomal dominant: FPLD3, FPLD4, FPLD7, FPLD8 and AKT2-related FPLD. - Autosomal recessive: FPLD5, FPLD6, FPLD9, PCYT1Aand MFN2-related FPLD. Onset of fat loss Puberty in women, later in men - Birth: FPLD7 - Childhood: FPLD1, FPLD4, FPLD5, PCYT1Aand MFN2-related FPLD - Adolescence: FPLD3, FPLD8 and MFN2-related FPLD - Adulthood: FPLD3, FPLD4, FPLD6, AKT2and MFN2-related FPLD Abnormal fat pattern - Loss of fat in the limbs, trunk and gluteal region. - Accumulation of fat in the face, neck, chin, axillae, interscapular area and abdominal viscera. - Hypertrophy of mons pubis fat surrounded by subcutaneous lipoatrophy (“Dunnigan sign”). - Subcutaneous lipomas (20%) - FPLD3: less severe loss of fat. - FPLD6 and MFN2-related FPLD: multiple lipomatous masses. - FPLD7: loss of fat in the face and upper body. - FPLD9: adipose tissue loss varies from partial to generalised. Adipokine Disturbance - Leptin levels ranging from low to normal values. - Lower adiponectin levels in comparison with healthy controls MFN2-related FPLD: very low leptin concentrations. Clinical features - Muscular hypertrophy - Myalgias - Phlebomegaly - Hirsutism in women - Acanthosis nigricans and acrochordons - FPLD1: KöB index > 3.477 - FPLD3: less prominent musculature, phlebomegaly - FPLD6: muscular dystrophy -PCYT1A-related FPLD: short stature, muscular atrophy. Organ abnormalities and comorbidities Metabolic abnormalities - Non-ketotic diabetes - Hypertriglyceridaemia, low HDL cholesterol Heart abnormalities - Cardiac hypertrophy - Atrioventricular conduction defects - Heart failure - Early atherosclerosis - Arrhythmias Liver abnormalities - NAFLD - NASH - Cirrhosis Kidney abnormalities - Proteinuria - Chronic renal failure Reproductive abnormalities - Polycystic ovary syndrome - Fertility problems - Miscarriages and stillbirths Others - Hypertension - Acute pancreatitis - FPLD3: earlier and more severe metabolic complications - FPLD5: diabetes with ketosis. - FPLD6: auto-fluorescent drusen-like retinal deposits. Increased CK levels. - FPLD7: congenital cataracts. - FPLD9: neurological abnormalities (demyelinating neuropathy, intellectual disability). -MFN2-related FPLD: peripheral axonal neuropathy. FPLD: familial partial lipodystrophy; HDL: high-density lipoprotein; CK: creatine kinase; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis. 4. Hutchinson-Gilford Progeria Syndrome With an estimated prevalence of one case per 20 million inhabitants (www.progeriaresearch. org; accessed on 7 July 2024), HGPS (#MIM176670) is considered to be one of the most severe laminopathies, originating from the aberrant splicing of the LMNA gene and the consequent expression of an abnormal lamin A protein, called progerin [ 118 , 119 ]. Patients are healthy at birth with the phenotype usually becoming evident at 18–24 months of age, including a broad range of clinical features [ 120 – 122 ] (Figures 1and 2): low body weight, with severe generalised lipodystrophy while preserving intraabdominal fat, along with muscular atrophy, growth retardation and short stature, early alopecia with prominent scalp veins, loss of skin Int. J. Mol. Sci. 2024,25, 9324 8 of 25 elasticity and skin hypo/hyperpigmentation, beaked nose, micrognathia, high-arched palate, mandibular osteolysis, dental crowding, high-pitched voice, sensorineural hearing loss, nail dystrophy, joint stiffness, short club-shaped distal phalanges (acroosteolysis) and osteopenia. Patients with HGPS do not show intellectual impairment [119]. The most significant abnormalities in HGPS, which ultimately lead to death at around the age of 14 [123], are cardiovascular complications (myocardial ischemia, infarction and stroke) [ 124 ]. Patients can suffer insulin resistance with some showing elevated levels of serum triglycerides, total cholesterol and low-density lipoprotein cholesterol with reduced levels of high-density lipoprotein cholesterol [ 122 , 125 ]. However, interestingly, metabolic derangements are mild and HGPS patients rarely develop dyslipidaemia or increased C-reactive protein, two characteristics often observed in cardiovascular disease in the general population [ 124 , 126 ]. This leads to the suspicion that the mechanisms leading to the development of these cardiovascular complications in this group of patients differ from the normal ageing population. Thus, beyond atherosclerosis, there is evidence of intimal thickening and an increase in arterial stiffness leading to many measurable changes in the vasculature of these patients [ 122 , 127 ]. They also present vascular walls with a dramatically thickened fibrotic matrix with a depletion of medial smooth muscle cells that is replaced by collagen, with secondary maladaptive vascular remodelling, probably due in part to the extreme sensitivity of these cells to progerin expression [122,127–130]. Even though there is currently no cure for this disorder, in recent years, a number of therapies have shown promise in preclinical stages for its treatment and, in 2020, lonafarnib became the first (and only) ever U.S. Food and Drug Administration (FDA) and EMA approved treatment for this condition. This drug is a farnesyltransferase inhibitor, which works by inhibiting the processing of prelamin A to progerin [ 131 – 133 ], the administration of which has been shown to improve some of the symptoms of the disease (such as rate of weight gain, pulse-wave velocity, carotid artery wall echodensity, skeletal rigidity, cardiovascular stiffness, bone density and sensorineural hearing) and also a decreased mortality rate [ 132 , 134 , 135 ]. In combination with lonafarnib, the rapamycin analog everolimus is also currently being tested in an ongoing phase I/II clinical trial (ClinicalTrials.gov Identifier: NCT02579044). Likewise, particularly remarkable is the addition of progerinin as a new candidate specifically developed for progeria, the safety, tolerability, pharmacokinetics and pharmacodynamic profile of which is being studied in another phase I clinical trial (ClinicalTrials.gov Identifier: NCT04512963). Furthermore, a potential genetic therapeutic strategy employing antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to block the pathogenic splicing of mutant transcripts has shown a significant reduction of progerin transcripts in the aorta, a 61.6% increase in lifespan and rescue of vascular smooth muscle cell loss in large arteries in transgenic mouse models of HGPS [ 136 ]. CRISPR/Cas9 gene editing also seems a promising strategy for the treatment of genetic diseases, including HGPS [137]. 5. LMNA-Atypical Progeroid Syndrome This syndrome, due to different missense LMNA variants (such as P4R, E111K, D136H, E159K, C588R, R349W or T10I) is characterised by a marked phenotypic heterogeneity, with evidence of both partial and generalised lipodystrophy (Figure 2). While the accumulation of farnesylated prelamin A has been demonstrated in some cases, in other cases the pathogenesis of clinical manifestations was not related to this accumulation [138–140]. The onset of the phenotype occurs later than in HGPS and MAD, during childhood or early adulthood, [ 139 , 141 , 142 ] and life expectancy is likewise longer [ 143 ]. Patients with APS usually share several progeroid features (Figure 1), including short stature, partial alopecia, early greying of hair, mottled skin pigmentation, sclerodermiform lesions, beaked nose, high-arched palate, micrognatia, abnormal teeth implantation with dental crowding, high-pitched voice, sensorineural hearing impairment, joint stiffness and osteoporosis [ 138 , 139 , 144 ]. However, although they have overlapping features when compared with HGPS and MAD patients, acroosteolysis and clavicular resorption/hypoplasia are Int. J. Mol. Sci. 2024,25, 9324 9 of 25 usually absent or mild in this specific disorder [ 139 ]. On the other hand, this syndrome is frequently associated with metabolic abnormalities and cardiovascular complications, including valvular disease, rhythm disturbances, coronary artery disease and cardiomyopathy. Proteinuric nephropathy is also present in the majority of cases [139,142,144,145]. In 2018, Hussain I et al. proposed the designation of a distinctive syndrome due to heterozygous LMNA p.T10I variants, called generalised lipodystrophy-associated progeroid syndrome, considering the unique and relatively homogeneous clinical features of this disorder in comparison with the previously reported APS. These specific characteristics were early childhood onset of generalised lipodystrophy along with other progeroid features, more severe metabolic complications and a notable need for cardiac transplantation [ 140 ]. Another recurrent variant is the previously mentioned R349W, which leads to a multisystem progeroid syndrome with lipodystrophy characterised by a loss of fat in the limbs and face and its accumulation in the dorsocervical region, along with the shared progeroid features described [ 141 , 142 ]. On the other hand, the missense LMNA variant p.(Thr528Met) was identified in heterozygosity in subjects with FPLD2, in a compound heterozygous state in subjects with APS and severe partial lipodystrophy and, recently, in homozygosity in subjects with homogeneous APS clinical features with major musculoskeletal involvement [146]. Regarding the availability of specific therapies, it should be noted that metreleptin has been successfully used in some isolated cases for the treatment of associated comorbidities [147]. 6. Other LMNA-Associated Lipodystrophies 6.1. LMNA-Associated Generalised Lipodystrophy Only one case with the p.(Arg582His) variant in exon 11 of the LMNA gene in a homozygous fashion and near-total fat loss has been reported. However, adipose tissue was found to be preserved in the retroorbital area, mons pubis and the genital region. This homozygous variant was also associated with an earlier onset of metabolic complications in comparison to heterozygous cases [ 148 ]. Another family of four with the p.(Arg582Cys) variant in exon 11 of the LMNA gene in the homozygous and heterozygous states has been described. All members showed extremely distinct features including a severe generalised lipodystrophic phenotype and metabolic abnormalities leading to death at a young age [ 47 ]. Finally, although the pathogenic p.(Arg571Ser) variant in the LMNA gene has been previously associated with cardiomyopathy and neuropathy without lipodystrophy [ 149 , 150 ], in 2017, another two cases harbouring generalised loss of fat were also described. The onset of the phenotype in these cases occurred after birth and in early childhood with both subjects developing severe metabolic abnormalities and dying at an early age [151]. 6.2. LMNA-Associated Cardiocutaneous Progeria Only one patient has been reported with this specific syndrome due to the p.(Asp300Gly) variant in the LMNA gene developing an unspecified pattern of fat loss around the third decade of life. Cardiac and cutaneous manifestations along with a prematurely aged appearance were also described for this patient. In addition, it should be noted that this disorder may also be related to a greater incidence of malignancy, an unprecedented finding in LMNA-linked progeria disorders [152]. 7. Mandibuloacral Dysplasia Patients with MAD present with a range of clinical manifestations. Facial features typically include prominent scalp veins, ocular proptosis, beak-like nose, dental crowding and progressive osteolysis affecting the mandible, terminal phalanges and clavicles. Skeletal abnormalities include acroosteolysis, prominent interphalangeal joints and dystrophic nails [ 153 ]. Cutaneous manifestations in MAD include thin, wrinkled skin with mottled hyperpigmentation and atrophy in the acral regions, along with visible veins and tendons due to the absence of subcutaneous fat [ 154 ]. Although skeletal and cardiac Int. J. Mol. Sci. 2024,25, 9324 16 of 25 Acknowledgments: We are indebted to the patients of this study for their collaboration. Conflicts of Interest: D.A.-V. has received fees from Amryt Pharmaceuticals and Regeneron Pharmaceuticals for scientific advice, travel, conference registration and research grants. 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