Marfanoid–progeroid–lipodystrophy syndrome

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Marfanoid–progeroid–lipodystrophy syndrome
Protein FBN1 PDB 1apj.png
A mutation in the protein profibrillin, encoded by FBN1, is the cause of Marfanoid–progeroid–lipodystrophy syndrome.

Marfanoid–progeroid–lipodystrophy syndrome (MPL), also known as Marfan lipodystrophy syndrome (MFLS) or progeroid fibrillinopathy, is an extremely rare medical condition which manifests as a variety of symptoms including those usually associated with Marfan syndrome, an appearance resembling that seen in neonatal progeroid syndrome (NPS; also known as Wiedemann–Rautenstrauch syndrome), and severe partial lipodystrophy.[1][2][3][4][5] It is a genetic condition that is caused by mutations in the FBN1 gene, which encodes profibrillin, and affects the cleavage products of profibrillin, fibrillin-1, a fibrous structural protein, and asprosin, a glucogenic protein hormone.[1][6] As of 2016, fewer than 10 cases of the condition have been reported.[1] Lizzie Velasquez and Abby Solomon have become known publicly through the media for having the condition.[7][8]

In addition to severe lipodystrophy (loss of adipose tissue), individuals with MPL show a concomitant marked loss of lean tissue mass, which also contributes to their "skinny" appearance.[3] Based on visual inspection, it was originally thought that the lipodystrophy associated with MPL was generalized.[3] However, it appears in fact to be partial, being confined to the face, distal extremities, and the paravertebral and lateral regions of the buttocks.[3] Normal amounts of subcutaneous fat are found in the torso over the chest and abdomen.[3] As such, the breasts are normal in females with MPL.[1][2]

Individuals with MPL have an appearance of being prematurely aged, but this is not due to actual early aging and is instead due to their paucity of subcutaneous fat.[1] As such, MPL is not truly a form of progeria.[1]

In 2016, it was discovered that the partial lipodystrophy associated with MPL is caused by loss of the C-terminal domain cleavage product of profibrillin and novel glucogenic protein hormone, which has been named asprosin.[6][8] Due to asprosin deficiency, individuals with MPL eat less, and do not gain weight or develop symptoms of diabetes like insulin resistance.[8][3][9] MPL patients burn less energy than normal individuals, but also consume less, and their net energy balance is moderately reduced.[10] In contrast to MPL patients, whose asprosin is undetectable in the blood, individuals with obesity and diabetes have elevated levels of asprosin.[6] As such, FBN1 has been nicknamed the "thin gene", and drug development for targeted inhibition of asprosin signaling is considered to be an "unusually promising" potential therapeutic route in the treatment of obesity and diabetes.[8]


  1. ^ a b c d e f Passarge E, Robinson PN, Graul-Neumann LM (2016). "Marfanoid-progeroid-lipodystrophy syndrome: a newly recognized fibrillinopathy". Eur. J. Hum. Genet. 24 (9): 1244–7. doi:10.1038/ejhg.2016.6. PMID 26860060.
  2. ^ a b Graul-Neumann LM, Kienitz T, Robinson PN, Baasanjav S, Karow B, Gillessen-Kaesbach G, Fahsold R, Schmidt H, Hoffmann K, Passarge E (2010). "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene". Am. J. Med. Genet. A. 152A (11): 2749–55. doi:10.1002/ajmg.a.33690. PMID 20979188.
  3. ^ a b c d e f O'Neill B, Simha V, Kotha V, Garg A (2007). "Body fat distribution and metabolic variables in patients with neonatal progeroid syndrome". Am. J. Med. Genet. A. 143A (13): 1421–30. doi:10.1002/ajmg.a.31840. PMID 17523150.
  4. ^ Jacquinet A, Verloes A, Callewaert B, Coremans C, Coucke P, de Paepe A, Kornak U, Lebrun F, Lombet J, Piérard GE, Robinson PN, Symoens S, Van Maldergem L, Debray FG (2014). "Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene". Eur J Med Genet. 57 (5): 230–4. doi:10.1016/j.ejmg.2014.02.012. PMID 24613577.
  5. ^ Garg A, Xing C (2014). "De novo heterozygous FBN1 mutations in the extreme C-terminal region cause progeroid fibrillinopathy". Am. J. Med. Genet. A. 164A (5): 1341–5. doi:10.1002/ajmg.a.36449. PMID 24665001.
  6. ^ a b c Romere C, Duerrschmid C, Bournat J, Constable P, Jain M, Xia F, Saha PK, Del Solar M, Zhu B, York B, Sarkar P, Rendon DA, Gaber MW, LeMaire SA, Coselli JS, Milewicz DM, Sutton VR, Butte NF, Moore DD, Chopra AR (2016). "Asprosin, a Fasting-Induced Glucogenic Protein Hormone". Cell. 165 (3): 566–79. doi:10.1016/j.cell.2016.02.063. PMC 4852710. PMID 27087445.
  7. ^ Bordo, Sara (Director); Campo, Michael (Writer); Velasquez, Lizzie (Star) (2015). A Brave Heart: The Lizzie Velasquez Story. Event occurs at 45:50 to 50:36.
  8. ^ a b c d Kennedy, Pagan (25 Nov 2016). "The Thin Gene". The New York Times. Retrieved 22 May 2017.
  9. ^ "The girl who must eat every 15 minutes to stay alive". The Telegraph. 28 June 2010. Lizzie Velasquez weighs just four stone and has almost zero per cent body fat but she is not anorexic. [...] Despite consuming between 5,000 and 8,000 calories daily, the communications student, has never tipped over 4st 3lbs.
  10. ^ Duerrschmid C, He Y, Wang C, Li C, Bournat J, Romere C, Saha PK, Lee M, Phillips KJ, Jain M, Jia P, Zhao Z, Farias M, Wu Q, Milewicz DM, Sutton VR, Moore DM, Butte NF, Krashes MJ, Xu Y, and Chopra AR (2017) - "Asprosin Activates the Hypothalamic Hunger-Circuitry" - article under consideration for publication as of 8/30/2017.

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