TY - JOUR
T1 - Multisystem progeroid syndrome with lipodystrophy, cardiomyopathy, and nephropathy due to an LMNA p.R349W variant
AU - Hussain, Iram
AU - Jin, Ruilin Raelene
AU - Baum, Howard B.A.
AU - Greenfield, Jerry R.
AU - Devery, Sophie
AU - Xing, Chao
AU - Hegele, Robert A.
AU - Carranza-Leon, Barbara G.
AU - Linton, Macrae F.
AU - Vuitch, Frank
AU - Wu, Kathy H.C.
AU - Precioso, Débora Rossi
AU - Oshima, Junko
AU - Agarwal, Anil K.
AU - Garg, Abhimanyu
N1 - Funding Information:
We thank Carmel Tovar for illustrations, Katie Tunison for assistance with immunoblotting and RNA sequencing experiments, Claudia Quittner for help with evaluation of patients, Nivedita Patni, MD, for performing the skin biopsy of patient 300.3 at the UT Southwestern Medical Center, Addenbrooke Molecular Genetics Lab for genotyping LMNA variant in 2 of the patients, and the patients and their families for participating in this study. This work was supported by the National Institutes of Health, (Grant R01-DK105448), Clinical and Translational Science Awards (Grants UL1RR024982, UL1TR001105, UL1TR000433, and R01-CA210916), and the Southwestern Medical Foundation.
Publisher Copyright:
© Endocrine Society 2020.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Background: Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome. Methods: We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations. Results: Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts. Conclusions: The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality.
AB - Background: Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome. Methods: We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations. Results: Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts. Conclusions: The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality.
KW - Cardiomyopathy
KW - Diabetes mellitus
KW - Focal segmental glomerulosclerosis
KW - Lamin A/C
KW - Lipodystrophy
KW - Progeroid syndrome
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U2 - 10.1210/jendso/bvaa104
DO - 10.1210/jendso/bvaa104
M3 - Article
C2 - 32939435
AN - SCOPUS:85096473704
SN - 2472-1972
VL - 4
JO - Journal of the Endocrine Society
JF - Journal of the Endocrine Society
IS - 10
ER -