A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation

Hussain, Iram; Patni, Nivedita; Ueda, Masako; Sorkina, Ekaterina; Valério, Cynthia Melissa; Cochran, Elaine; Brown, Rebecca; Peeden, Joseph N.; Tikhonovich, Yulia V.; Tiulpakov, Anatoly; Stender, Sarah; Klouda, Elisabeth; Tayeh, Marwan K.; Innis, Jeffrey W.; Meyer, Anders R.L.; Lal, Priti; Godoy-Matos, Amélio F.; Teles, Milena Gurgel; Adams‐Huet, Beverley; Rader, Daniel J.; Hegele, Robert A.; Oral, Elif A.; Garg, Abhimanyu

doi:10.1210/jc.2017-02078

Cited by 49 publications

(45 citation statements)

References 36 publications

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“…Lipodystrophy-associated progeroid syndromes due to different LMNA pathogenic variants have been described with cardiomyopathy which could be worsened by a concomitant diabetes, as noted in Patient 1 [15]. It is striking to note that coronary arteries were not significantly stenotic in this patient.…”

Section: Discussionmentioning

confidence: 57%

“…Cardiomyopathic features have been reported in a few patients with typical FPLD2 carrying the most frequent p.(Arg482Trp) or p.(Arg482Gln) LMNA pathogenic variants affecting the immunoglobulin-like C-terminal domain of A-type lamins [13]. Most forms of mixed laminopathy phenotypes with lipodystrophy and cardiomyopathy have been described in patients with non p.Arg482 LMNA pathogenic variants affecting different protein domains [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Mosbah

Vatier

Boccara

et al. 2020

Cells

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Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects.A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing.

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Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Mosbah

Vatier

Boccara

et al. 2020

Cells

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“…The phenotypic differences among patients with LMNA mutations are suggested to correlate with the underlying mutation. Perhaps the most illustrious example is the fairly universal generalized lipodystrophy and metabolic changes in those with T101 mutations . Other mutations, however, do not yet have as well‐defined features.…”

Section: Discussionmentioning

confidence: 99%

“…Perhaps the most illustrious example is the fairly universal generalized lipodystrophy and metabolic changes in those with T101 mutations. 13 Other mutations, however, do not yet have as welldefined features. The P4R mutation has been suggested to have a novel phenotype without the aforementioned metabolic abnormalities described in APS, as four out of seven reported cases did not have metabolic abnormalities; however, the patients without metabolic abnormalities were fairly young (mean age 20 years, range 11-27 years).…”

Section: Discussionmentioning

confidence: 99%

Diffuse, mottled hyperpigmentation and mutations in LMNA gene in a 5‐year‐old boy, his mother, and his grandmother: Atypical progeroid syndrome

Schultz

Miller

Maguiness

2019

Pediatric Dermatology

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We present a multigenerational family with a phenotypic spectrum of skin dyspigmentation, lipodystrophy, bony anomalies, and progeroid facies. All were found to be heterozygous for a c.11C>G (p.Pro4Arg) (P4R) mutation in the lamin A/C gene consistent with atypical progeroid syndrome. Various phenotypic associations have been reported with specific mutations in atypical progeroid syndrome, but the strength of each phenotype‐genotype relationship is unknown. This report adds to the literature of patients with atypical progeroid syndrome and highlights an unusual diagnosis that may present to dermatologists.

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“…In addition to these four major groups of CGL, patients with GL associated with Lamin A/C (LMNA) p.T10I (26), and biallelic peroxisome proliferator activated receptor gamma (PPARG) (27) pathogenic variants have been reported. Patients with biallelic loss-of-function pathogenic variants in phosphate cytidylyltransferase 1 alpha (PCYT1A) gene were reported to have a severe PL phenotype (28), and potentially can be classified in the CGL category.…”

Section: Congenital Generalized Lipodystrophymentioning

confidence: 99%

Current Diagnosis, Treatment and Clinical Challenges in the Management of Lipodystrophy Syndromes in Children and Young People

Özen

Akıncı

Oral

2020

Jcrpe

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Lipodystrophy is a heterogeneous group of disorders characterized by lack of body fat in characteristic patterns, which can be genetic or acquired. Lipodystrophy is associated with insulin resistance that can develop in childhood and adolescence, and usually leads to severe metabolic complications. Diabetes mellitus, hypertriglyceridemia, and hepatic steatosis ordinarily develop in these patients, and most girls suffer from menstrual abnormalities. Severe complications develop at a relatively young age, which include episodes of acute pancreatitis, renal failure, cirrhosis, and complex cardiovascular diseases, and all of these are associated with serious morbidity. Treatment of lipodystrophy consists of medical nutritional therapy, exercise, and the use of anti-hyperglycemic and lipid-lowering agents. New treatment modalities, such as metreleptin replacement, promise much in the treatment of metabolic abnormalities secondary to lipodystrophy. Current challenges in the management of lipodystrophy in children and adolescents include, but are not limited to: (1) establishing specialized centers with experience in providing care for lipodystrophy presenting in childhood and adolescence; (2) optimizing algorithms that can provide some guidance for the use of standard and novel therapies to ensure adequate metabolic control and to prevent complications; (3) educating patients and their parents about lipodystrophy management; (4) improving patient adherence to chronic therapies; (5) reducing barriers to access to novel treatments; and (5) improving the quality of life of these patients and their families.

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A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation

Cited by 49 publications

References 36 publications

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Diffuse, mottled hyperpigmentation and mutations in LMNA gene in a 5‐year‐old boy, his mother, and his grandmother: Atypical progeroid syndrome

Current Diagnosis, Treatment and Clinical Challenges in the Management of Lipodystrophy Syndromes in Children and Young People

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