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

Iram Hussain, Nivedita Patni, Masako Ueda, Ekaterina Sorkina, Cynthia M. Valerio, Elaine Cochran, Rebecca J. Brown, Joseph Peeden, Yulia Tikhonovich, Anatoly Tiulpakov, Sarah R.S. Stender, Elisabeth Klouda, Marwan K. Tayeh, Jeffrey W. Innis, Anders Meyer, Priti Lal, Amelio F. Godoy-Matos, Milena G. Teles, Beverley Adams-Huet, Daniel J. Rader & 3 others Robert A. Hegele, Elif A. Oral, Abhimanyu Garg

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome.

Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS.

Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications.

Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.

Original languageEnglish (US)
Pages (from-to)1005-1014
Number of pages10
JournalThe Journal of clinical endocrinology and metabolism
Volume103
Issue number3
DOIs
StatePublished - Mar 1 2018

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Congenital Generalized Lipodystrophy
Lamin Type A
Mutation
Transplants
Progeria
Medical problems
Leptin
Hypertriglyceridemia
HDL Cholesterol
Skin
Cardiomyopathies
Triglycerides
Genes
Insulin
Acanthosis Nigricans
Skin Pigmentation
Hepatomegaly
Contracture
Serum

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation. / Hussain, Iram; Patni, Nivedita; Ueda, Masako; Sorkina, Ekaterina; Valerio, Cynthia M.; Cochran, Elaine; Brown, Rebecca J.; Peeden, Joseph; Tikhonovich, Yulia; Tiulpakov, Anatoly; Stender, Sarah R.S.; Klouda, Elisabeth; Tayeh, Marwan K.; Innis, Jeffrey W.; Meyer, Anders; Lal, Priti; Godoy-Matos, Amelio F.; Teles, Milena G.; Adams-Huet, Beverley; Rader, Daniel J.; Hegele, Robert A.; Oral, Elif A.; Garg, Abhimanyu.

In: The Journal of clinical endocrinology and metabolism, Vol. 103, No. 3, 01.03.2018, p. 1005-1014.

Research output: Contribution to journalArticle

Hussain, I, Patni, N, Ueda, M, Sorkina, E, Valerio, CM, Cochran, E, Brown, RJ, Peeden, J, Tikhonovich, Y, Tiulpakov, A, Stender, SRS, Klouda, E, Tayeh, MK, Innis, JW, Meyer, A, Lal, P, Godoy-Matos, AF, Teles, MG, Adams-Huet, B, Rader, DJ, Hegele, RA, Oral, EA & Garg, A 2018, 'A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation', The Journal of clinical endocrinology and metabolism, vol. 103, no. 3, pp. 1005-1014. https://doi.org/10.1210/jc.2017-02078
Hussain, Iram ; Patni, Nivedita ; Ueda, Masako ; Sorkina, Ekaterina ; Valerio, Cynthia M. ; Cochran, Elaine ; Brown, Rebecca J. ; Peeden, Joseph ; Tikhonovich, Yulia ; Tiulpakov, Anatoly ; Stender, Sarah R.S. ; Klouda, Elisabeth ; Tayeh, Marwan K. ; Innis, Jeffrey W. ; Meyer, Anders ; Lal, Priti ; Godoy-Matos, Amelio F. ; Teles, Milena G. ; Adams-Huet, Beverley ; Rader, Daniel J. ; Hegele, Robert A. ; Oral, Elif A. ; Garg, Abhimanyu. / A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation. In: The Journal of clinical endocrinology and metabolism. 2018 ; Vol. 103, No. 3. pp. 1005-1014.
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abstract = "Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome.Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS.Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications.Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.",
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T1 - A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation

AU - Hussain, Iram

AU - Patni, Nivedita

AU - Ueda, Masako

AU - Sorkina, Ekaterina

AU - Valerio, Cynthia M.

AU - Cochran, Elaine

AU - Brown, Rebecca J.

AU - Peeden, Joseph

AU - Tikhonovich, Yulia

AU - Tiulpakov, Anatoly

AU - Stender, Sarah R.S.

AU - Klouda, Elisabeth

AU - Tayeh, Marwan K.

AU - Innis, Jeffrey W.

AU - Meyer, Anders

AU - Lal, Priti

AU - Godoy-Matos, Amelio F.

AU - Teles, Milena G.

AU - Adams-Huet, Beverley

AU - Rader, Daniel J.

AU - Hegele, Robert A.

AU - Oral, Elif A.

AU - Garg, Abhimanyu

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome.Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS.Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications.Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.

AB - Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome.Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS.Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications.Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.

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