scholarly journals UNUSUAL PRESENTATIONS OF LMNA-ASSOCIATED LIPODYSTROPHY WITH COMPLEX PHENOTYPES AND GENERALIZED FAT LOSS: WHEN THE GENETIC DIAGNOSIS UNCOVERS NOVEL FEATURES

2020 ◽  
Vol 6 (2) ◽  
pp. e79-e85
Author(s):  
Natalia Xavier S. de Andrade ◽  
Suleyman Cem Adiyaman ◽  
Berna Demir Yuksel ◽  
Carla T. Ferrari ◽  
Abdelwahab Jalal Eldin ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Pathogenic Variant ◽  
The Body ◽  
Muscle Disease ◽  
Partial Lipodystrophy ◽  
Fat Loss ◽  
Pathogenic Variants ◽  
Complex Phenotypes ◽  
Familial Partial Lipodystrophy

Objective: Lipodystrophy represents a group of rare diseases characterized by loss of body fat. While patients with generalized lipodystrophy exhibit near-total lack of fat, partial lipodystrophy is associated with selective fat loss affecting certain parts of the body. Although classical familial partial lipodystrophy (FPLD) is a well-described entity, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants. Methods: We have encountered 2 unique cases with complex phenotypes, generalized fat loss, and very low leptin levels that made the distinction between generalized versus partial lipodystrophy quite challenging. Results: We present a 61-year-old female with generalized fat loss, harboring the heterozygous pathogenic variant p.R541P (c.1622G>C) on the LMNA gene. The discovery of the pathogenic variant led to correct clinical diagnosis of her muscle disease, identification of significant heart disease, and a recommendation for the implantation of a defibrillator. She was able to start metreleptin based on her generalized fat loss pattern and demonstration of the genetic variant. Secondly, we report a 40-year-old Turkish female with generalized fat loss associated with a novel heterozygous LMNA pathogenic variant p.K486E (c.1456A>G), who developed systemic B cell follicular lymphoma. Conclusion: Clinicians need to recognize that the presence of an LMNA variant does not universally lead to FPLD type 2, but may lead to a phenotype that is more complex and may resemble more closely generalized lipo-dystrophy. Additionally, providers should recognize the multisystem features of laminopathies and should screen for these features in affected patients, especially if the variant is not at the known hotspot for FPLD type 2.

scholarly journals Case Report: An Atypical Form of Familial Partial Lipodystrophy Type 2 Due to Mutation in the Rod Domain of Lamin A/C

2021 ◽  
Vol 12 ◽  
Author(s):  
Carolina Cecchetti ◽  
M. Rosaria D’Apice ◽  
Elena Morini ◽  
Giuseppe Novelli ◽  
Carmine Pizzi ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Coiled Coil ◽  
Missense Variant ◽  
Lamin A ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Atypical Form ◽  
Amino Terminal ◽  
Familial Partial Lipodystrophy

PurposeFamilial partial lipodystrophy type 2 (FPLD2) patients generally develop a wide variety of severe metabolic complications. However, they are not usually affected by primary cardiomyopathy and conduction system disturbances, although a few cases of FPLD2 and cardiomyopathy have been reported in the literature. These were all due to amino-terminal heterozygous lamin A/C mutations, which are considered as new forms of overlapping syndromes.Methods and ResultsHere we report the identification of a female patient with FPLD2 due to a heterozygous missense variant c.604G>A in the exon 3 of the LMNA gene, leading to amino acid substitution (p.Glu202Lys) in the central alpha-helical rod domain of lamin A/C with a high propensity to form coiled-coil dimers. The patient’s cardiac evaluations that followed the genetic diagnosis revealed cardiac rhythm disturbances which were promptly treated pharmacologically.ConclusionsThis report supports the idea that there are “atypical forms” of FPLD2 with cardiomyopathy, especially when a pathogenic variant affects the lamin A/C head or alpha-helical rod domain. It also highlights how increased understanding of the genotype-phenotype correlation could help clinicians to schedule personalized monitoring of the lipodystrophic patient, in order to prevent uncommon but possible devastating manifestations, including arrhythmias and sudden death.

LMNA-associated partial lipodystrophy: anticipation of metabolic complications

2017 ◽  
Vol 54 (6) ◽  
pp. 413-416 ◽  
Author(s):  
Isabelle Jeru ◽  
Camille Vatier ◽  
Marie-Christine Vantyghem ◽  
Olivier Lascols ◽  
Corinne Vigouroux
Keyword(s):  
First Generation ◽  
Genetic Diagnosis ◽  
Diagnostic Procedures ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Mean Delay ◽  
Familial Partial Lipodystrophy ◽  
Similar Body ◽  
Early Occurrence

BackgroundType-2 familial partial lipodystrophy (FPLD2) is a rare autosomal dominant lipodystrophic disorder due to mutations inLMNAencoding lamin A/C, a key epigenetic regulator. FPLD2 severity is determined by the occurrence of metabolic complications, especially diabetes and hypertriglyceridaemia. We evaluated the disease history and severity over generations.MethodsThis retrospective study of the largest cohort of patients with FPLD2 reported to date investigates 85 patients from 24 families comprising three generations (G1: n=39; G2: n=41; G3: n=5).ResultsLipodystrophy appears with the same characteristics and at the same age in first generation (G1;18.6±1.5 years) and second generation (G2;15.9±0.8 years). Despite similar body mass index (23.7±0.6 vs 23.8±0.6 kg/m2), the mean delay between the onset of lipodystrophy and diabetes was far shorter in G2 (10.5±2.4 years) than in G1 (29.0±3.5 years) (p=0.0002). The same is true for the delay preceding hypertriglyceridaemia (G2: 4.5±1.4; G1: 19.3±3.2 years) (p=0.002), revealing an anticipation phenomenon. Observations in G3, and analysis within each family of disease history and diagnostic procedures, confirmed this result.ConclusionsThis study is a rare example of anticipation unrelated to a trinucleotide expansion. Discovery of this early occurrence of metabolic complications in young generations underlines the utility of presymptomatic genetic diagnosis, with careful metabolic screening and preventive lifestyle in all at-risk individuals.

scholarly journals Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to R482 and N466 Variants in the LMNA Gene

2021 ◽  
Vol 10 (6) ◽  
pp. 1259
Author(s):  
David Araújo-Vilar ◽  
Sofía Sánchez-Iglesias ◽  
Ana I. Castro ◽  
Silvia Cobelo-Gómez ◽  
Álvaro Hermida-Ameijeiras ◽  
...  
Keyword(s):  
Body Composition ◽  
Skinfold Thickness ◽  
Pathogenic Variant ◽  
The Other ◽  
Metabolic Abnormalities ◽  
Lmna Gene ◽  
Partial Lipodystrophy ◽  
Variable Expressivity ◽  
Familial Partial Lipodystrophy

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.

scholarly journals SAT-622 Heterogeneity of Familial Partial Lipodystrophy Type 2 from a Genotype-Phenotype Perspective

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Maria Cristina Foss de Freitas ◽  
Abdelwahab Jalal Eldin ◽  
Baris Akinci ◽  
Callie Corsa ◽  
Ormond A MacDougald ◽  
...  
Keyword(s):  
Body Composition ◽  
Hepatic Steatosis ◽  
Clinical Manifestation ◽  
Fat Free Mass ◽  
Partial Lipodystrophy ◽  
Pathogenic Variants ◽  
Number Of Patients ◽  
Familial Partial Lipodystrophy ◽  
Total Fat

Abstract Phenotypic heterogeneity is a well-known feature of Familial Partial Lipodystrophy Type 2 (FPLD2) which is caused by pathogenic variants in the LMNA gene. Clinical diagnosis can be challenging in some cases. Likewise, trained physicians can report differences in body composition and clinical manifestation of FPLD2, highlighting the importance of accurate phenotyping. In this study, we aimed to identify phenotype-genotype correlations in a cohort of systematically evaluated patients with FPLD2. We retrospectively evaluated 43 patients diagnosed with FPLD2 (age 50.3±16.1 years, 79.1% women). Per pathogenic variants, patients were divided into two groups; 24 with R482Q (RQ: 55 ± 3.2 years, 70.8% women) and 19 with non-R482Q (Non-RQ: 46 ± 3.2 years, 84.2% women). Non-RQ group consisted of several pathogenic LMNA variants in exons 1, and 5 through 11. Also, DEXA parameters were studied in a subgroup of 19 patients with available assessments (in 11 RQ and 8 non-RQ patients) that were matched for age, sex and BMI. Patients in the RQ group were older when they were first diagnosed with lipodystrophy (48.6 ± 3.2 years and 37.4 ± 3.1 years, p = 0.03). Although the prevalence of diabetes, hepatic steatosis and other co-morbidities associated with metabolic control were similar in both groups at the time of the study, patients with RQ pathogenic variants were diagnosed later in life with diabetes (46.0 ± 4.2 years vs. 35 ± 3.5 years, p = 0.03) and hepatic steatosis (45.3 ± 6.9 years vs. 30.1 ± 3.7 years, p < 0.01. Although more pancreatitis episodes were reported in the RQ group (13 ± 3 vs. 2 ± 1, p = 0.02), the number of patients with a history of pancreatitis was similar across the groups suggesting the occurrence of recurrent pancreatitis episodes in selected patients with RQ pathogenic variant. Pain was a common complaint among the patients, but it was less severe in the RQ group (4.2±2.1 vs 2.3±2.0, p=0.05). In terms of body composition, patients with RQ pathogenic variants had greater bone mass (legs: 879 ± 59.3 g vs. 703.5 ± 33.7 g, p= 0.01; trunk 914.2 ± 65.5 g vs. 674.1 ± 28.0 g, p = 0.005, total body: 2643.7 ± 158.9 g vs. 2140.6 ± 78.4 g, p = 0.005) and higher fat mass in the legs (19 vs. 14%, p = 0.02). Similarly, patients with RQ pathogenic variants had less lean percentage (76 vs. 81%, p = 0.009), and accordingly, less fat-free mass percentage (80 vs. 85%, p = 0.02) in the legs. Total fat-free mass of the RQ group was also lower (66 vs. 76%, p = 0.0009). Genotype-phenotype characterization is important not only for understanding the natural history and clinical manifestation of the disease but also for establishing more accurate and precise diagnostic criteria or therapeutic approaches. Our data suggest more fat preservation in LMNA R482Q carriers, presumably leading to a later diagnosis of lipodystrophy and metabolic abnormalities. More studies are needed to confirm the differences observed in body composition.

scholarly journals Prevalent ALMS1 Pathogenic Variants in Spanish Alström Patients

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 282
Author(s):  
Brais Bea-Mascato ◽  
Carlos Solarat ◽  
Irene Perea-Romero ◽  
Teresa Jaijo ◽  
Fiona Blanco-Kelly ◽  
...  
Keyword(s):  
High Frequency ◽  
Haplotype Analysis ◽  
Genetic Diagnosis ◽  
Allelic Frequency ◽  
Structural Protein ◽  
Alström Syndrome ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Alstrom Syndrome

Alström syndrome (ALMS) is an ultrarare disease with an estimated prevalence lower than 1 in 1,000,000. It is associated with disease-causing mutations in the Alström syndrome 1 (ALMS1) gene, which codifies for a structural protein of the basal body and centrosomes. The symptomatology involves nystagmus, type 2 diabetes mellitus (T2D), obesity, dilated cardiomyopathy (DCM), neurodegenerative disorders and multiorgan fibrosis. We refined the clinical and genetic diagnosis data of 12 patients from 11 families, all of them from Spain. We also studied the allelic frequency of the different variants present in this cohort and performed a haplotype analysis for the most prevalent allele. The genetic analysis revealed 2 novel homozygous variants located in the exon 8, p.(Glu929Ter) and p.(His1808GlufsTer20) in 2 unrelated patients. These 2 novel variants were classified as pathogenic after an in silico experiment (computer analysis). On the other hand, 2 alleles were detected at a high frequency in our cohort: p.(Tyr1714Ter) (25%) and p.(Ser3872TyrfsTer19) (16.7%). The segregation analysis showed that the pathogenic variant p.(Tyr1714Ter) in 3 families is linked to a rare missense polymorphism, p.(Asn1787Asp). In conclusion, 2 novel pathological mutations have been discovered in homozygosis, as well as a probable founder effect in 3 unrelated families.

scholarly journals Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1947
Author(s):  
Alice-Anaïs Varlet ◽  
Emmanuèle Helfer ◽  
Catherine Badens
Keyword(s):  
Mechanical Properties ◽  
Signaling Pathways ◽  
Metabolic Disorders ◽  
Lamin A ◽  
Partial Lipodystrophy ◽  
Familial Partial Lipodystrophy ◽  
Atherosclerotic Cardiovascular Diseases ◽  
Almost All ◽  
Type V

Laminopathies are rare and heterogeneous diseases affecting one to almost all tissues, as in Progeria, and sharing certain features such as metabolic disorders and a predisposition to atherosclerotic cardiovascular diseases. These two features are the main characteristics of the adipose tissue-specific laminopathy called familial partial lipodystrophy type 2 (FPLD2). The only gene that is involved in FPLD2 physiopathology is the LMNA gene, with at least 20 mutations that are considered pathogenic. LMNA encodes the type V intermediate filament lamin A/C, which is incorporated into the lamina meshwork lining the inner membrane of the nuclear envelope. Lamin A/C is involved in the regulation of cellular mechanical properties through the control of nuclear rigidity and deformability, gene modulation and chromatin organization. While recent studies have described new potential signaling pathways dependent on lamin A/C and associated with FPLD2 physiopathology, the whole picture of how the syndrome develops remains unknown. In this review, we summarize the signaling pathways involving lamin A/C that are associated with the progression of FPLD2. We also explore the links between alterations of the cellular mechanical properties and FPLD2 physiopathology. Finally, we introduce potential tools based on the exploration of cellular mechanical properties that could be redirected for FPLD2 diagnosis.

scholarly journals Geographical Variation in the profile of RET Variants in Patients with Medullary Thyroid Cancer: A Comprehensive Review

2021 ◽  
Author(s):  
Rui M. B. Maciel ◽  
Ana Luiza Maia
Keyword(s):  
Haplotype Analysis ◽  
Medullary Thyroid Cancer ◽  
Genetic Diagnosis ◽  
Epidemiological Data ◽  
Global Perspective ◽  
Causative Role ◽  
Medullary Thyroid ◽  
Pathogenic Variants

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98%, 50% and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants have been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

Sign in / Sign up

Export Citation Format

Share Document