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GRACILE syndrome

Reviewed March 2014

What is GRACILE syndrome?

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.

In 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.

Because 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.

How common is GRACILE syndrome?

GRACILE syndrome is found almost exclusively in Finland, where it is estimated to affect 1 in 47,000 infants. At least 32 affected infants have been described in the medical literature.

What genes are related to GRACILE syndrome?

GRACILE syndrome is caused by a mutation in the BCS1L gene. The protein produced from this gene is found in cell structures called mitochondria, which convert the energy from food into a form that cells can use. In mitochondria, the BCS1L protein plays a role in oxidative phosphorylation, which is a multistep process through which cells derive much of their energy. The BCS1L protein is critical for the formation of a group of proteins known as complex III, which is one of several protein complexes involved in oxidative phosphorylation.

The genetic change involved in GRACILE syndrome alters the BCS1L protein, and the abnormal protein is broken down more quickly than the normal protein. What little protein remains is able to help form some complete complex III, although the amount is severely reduced, particularly in the liver and kidneys. As a result, complex III activity and oxidative phosphorylation are decreased in these organs in people with GRACILE syndrome. Without energy, these organs become damaged, leading to many of the features of GRACILE syndrome. It is not clear why a change in the BCS1L gene leads to iron accumulation in people with this condition.

Related Gene(s)

Changes in this gene are associated with GRACILE syndrome.

  • BCS1L

How do people inherit GRACILE syndrome?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of GRACILE syndrome?

These resources address the diagnosis or management of GRACILE syndrome and may include treatment providers.

  • Genetic Testing Registry: GRACILE syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1864002)
  • MedlinePlus Encyclopedia: Aminoaciduria (http://www.nlm.nih.gov/medlineplus/ency/article/003366.htm)
  • MedlinePlus Encyclopedia: Cholestasis (http://www.nlm.nih.gov/medlineplus/ency/article/000215.htm)

You might also find information on the diagnosis or management of GRACILE syndrome in Educational resources (http://ghr.nlm.nih.gov/condition/gracile-syndrome/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/gracile-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about GRACILE syndrome?

You may find the following resources about GRACILE syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for GRACILE syndrome?

  • Fellman syndrome
  • Finnish lactic acidosis with hepatic hemosiderosis
  • Finnish lethal neonatal metabolic syndrome
  • growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about GRACILE syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/gard).

What glossary definitions help with understanding GRACILE syndrome?

acidosis ; acids ; aciduria ; autosomal ; autosomal recessive ; bile ; cell ; cirrhosis ; digestive ; failure to thrive ; gene ; hepatic ; inherited ; intrauterine growth retardation ; iron ; kidney ; lactic acid ; lactic acidosis ; mitochondria ; mutation ; neonatal ; oxidative phosphorylation ; phosphorylation ; protein ; recessive ; syndrome

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Fellman V. The GRACILE syndrome, a neonatal lethal metabolic disorder with iron overload. Blood Cells Mol Dis. 2002 Nov-Dec;29(3):444-50. (http://www.ncbi.nlm.nih.gov/pubmed/12547234?dopt=Abstract)
  • Kotarsky H, Karikoski R, Mörgelin M, Marjavaara S, Bergman P, Zhang DL, Smet J, van Coster R, Fellman V. Characterization of complex III deficiency and liver dysfunction in GRACILE syndrome caused by a BCS1L mutation. Mitochondrion. 2010 Aug;10(5):497-509. doi: 10.1016/j.mito.2010.05.009. Epub 2010 May 23. (http://www.ncbi.nlm.nih.gov/pubmed/20580947?dopt=Abstract)
  • Visapää I, Fellman V, Vesa J, Dasvarma A, Hutton JL, Kumar V, Payne GS, Makarow M, Van Coster R, Taylor RW, Turnbull DM, Suomalainen A, Peltonen L. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet. 2002 Oct;71(4):863-76. Epub 2002 Sep 5. (http://www.ncbi.nlm.nih.gov/pubmed/12215968?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: March 2014
Published: January 27, 2015