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GRACILE syndrome(FLNMS)

MedGen UID:
400428
Concept ID:
C1864002
Disease or Syndrome
Synonyms: Fellman syndrome; Finnish lactic acidosis with hepatic hemosiderosis; Finnish lethal neonatal metabolic syndrome; FLNMS; Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactic acidosis and Early death
SNOMED CT: Growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death (703388005); Fellman syndrome (703388005); Finnish lethal neonatal metabolic syndrome (703388005); GRACILE syndrome (703388005); Finnish lactic acidosis with hepatic hemosiderosis (703388005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): BCS1L (2q35)
 
OMIM®: 603358
Orphanet: ORPHA53693

Definition

GRACILE syndrome is a severe disorder that begins before birth. GRACILE stands for the condition's characteristic features: growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death.\n\nIn GRACILE syndrome, growth before birth is slow (intrauterine growth retardation). Affected newborns are smaller than average and have an inability to grow and gain weight at the expected rate (failure to thrive). A characteristic of GRACILE syndrome is excess iron in the liver, which likely begins before birth. Iron levels may begin to improve after birth, although they typically remain elevated. Within the first day of life, infants with GRACILE syndrome have a buildup of a chemical called lactic acid in the body (lactic acidosis). They also have kidney problems that lead to an excess of molecules called amino acids in the urine (aminoaciduria). Babies with GRACILE syndrome have cholestasis, which is a reduced ability to produce and release a digestive fluid called bile. Cholestasis leads to irreversible liver disease (cirrhosis) in the first few months of life.\n\nBecause of the severe health problems caused by GRACILE syndrome, infants with this condition do not survive for more than a few months, and about half die within a few days of birth. [from MedlinePlus Genetics]

Clinical features

From HPO
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Intrauterine growth retardation
MedGen UID:
473406
Concept ID:
C1386048
Pathologic Function
Cholestasis
MedGen UID:
925
Concept ID:
C0008370
Disease or Syndrome
Impairment of bile flow due to obstruction in bile ducts.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Increased serum iron
MedGen UID:
57739
Concept ID:
C0151900
Finding
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Increased serum ferritin
MedGen UID:
69130
Concept ID:
C0241013
Finding
Increased concentration of ferritin in the blood circulation.
Chronic lactic acidosis
MedGen UID:
374224
Concept ID:
C1839437
Finding
A chronic form of lactic acidemia.
Increased serum pyruvate
MedGen UID:
376596
Concept ID:
C1849488
Finding
An increased concentration of pyruvate in the blood.

Recent clinical studies

Etiology

Kasapkara ÇS, Tümer L, Ezgü FS, Küçükçongar A, Hasanoğlu A
Ren Fail 2014 Jul;36(6):953-4. Epub 2014 Mar 24 doi: 10.3109/0886022X.2014.900422. PMID: 24655110
Ezgu F, Senaca S, Gunduz M, Tumer L, Hasanoglu A, Tiras U, Unsal R, Bakkaloglu SA
Gene 2013 Oct 10;528(2):364-6. Epub 2013 Jul 26 doi: 10.1016/j.gene.2013.07.007. PMID: 23892085
Dimauro S, Garone C
Semin Fetal Neonatal Med 2011 Aug;16(4):181-9. Epub 2011 May 28 doi: 10.1016/j.siny.2011.04.010. PMID: 21620786
Fellman V, Visapää I, Vujic M, Wennerholm UB, Peltonen L
Acta Obstet Gynecol Scand 2002 May;81(5):398-402. doi: 10.1034/j.1600-0412.2001.810504.x. PMID: 12027811

Diagnosis

Baker RA, Priestley JRC, Wilstermann AM, Reese KJ, Mark PR
Am J Med Genet A 2019 Mar;179(3):373-380. Epub 2018 Dec 24 doi: 10.1002/ajmg.a.61019. PMID: 30582773
Akduman H, Eminoglu T, Okulu E, Erdeve O, Atasay B, Arsan S
Genet Couns 2016;27(4):509-512. PMID: 30226971
Kasapkara ÇS, Tümer L, Ezgü FS, Küçükçongar A, Hasanoğlu A
Ren Fail 2014 Jul;36(6):953-4. Epub 2014 Mar 24 doi: 10.3109/0886022X.2014.900422. PMID: 24655110
Fellman V, Lemmelä S, Sajantila A, Pihko H, Järvelä I
J Hum Genet 2008;53(6):554-558. Epub 2008 Apr 2 doi: 10.1007/s10038-008-0284-0. PMID: 18386115
Fellman V
Blood Cells Mol Dis 2002 Nov-Dec;29(3):444-50. doi: 10.1006/bcmd.2002.0582. PMID: 12547234

Prognosis

Akduman H, Eminoglu T, Okulu E, Erdeve O, Atasay B, Arsan S
Genet Couns 2016;27(4):509-512. PMID: 30226971
Kasapkara ÇS, Tümer L, Ezgü FS, Küçükçongar A, Hasanoğlu A
Ren Fail 2014 Jul;36(6):953-4. Epub 2014 Mar 24 doi: 10.3109/0886022X.2014.900422. PMID: 24655110
Ezgu F, Senaca S, Gunduz M, Tumer L, Hasanoglu A, Tiras U, Unsal R, Bakkaloglu SA
Gene 2013 Oct 10;528(2):364-6. Epub 2013 Jul 26 doi: 10.1016/j.gene.2013.07.007. PMID: 23892085
Morán M, Marín-Buera L, Gil-Borlado MC, Rivera H, Blázquez A, Seneca S, Vázquez-López M, Arenas J, Martín MA, Ugalde C
Hum Mutat 2010 Aug;31(8):930-41. doi: 10.1002/humu.21294. PMID: 20518024

Clinical prediction guides

Baker RA, Priestley JRC, Wilstermann AM, Reese KJ, Mark PR
Am J Med Genet A 2019 Mar;179(3):373-380. Epub 2018 Dec 24 doi: 10.1002/ajmg.a.61019. PMID: 30582773
Tegelberg S, Tomašić N, Kallijärvi J, Purhonen J, Elmér E, Lindberg E, Nord DG, Soller M, Lesko N, Wedell A, Bruhn H, Freyer C, Stranneheim H, Wibom R, Nennesmo I, Wredenberg A, Eklund EA, Fellman V
Orphanet J Rare Dis 2017 Apr 20;12(1):73. doi: 10.1186/s13023-017-0624-2. PMID: 28427446Free PMC Article
Morán M, Marín-Buera L, Gil-Borlado MC, Rivera H, Blázquez A, Seneca S, Vázquez-López M, Arenas J, Martín MA, Ugalde C
Hum Mutat 2010 Aug;31(8):930-41. doi: 10.1002/humu.21294. PMID: 20518024

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