MEGDEL syndrome
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MEGDEL syndrome is an inherited disorder that affects multiple body systems. It is named for several of its features: 3-methylglutaconic aciduria (MEG), deafness (D), encephalopathy (E), and Leigh-like disease (L).

  • genetic conditions

Frequency

MEGDEL syndrome is a rare disorder; its prevalence is unknown. At least 40 affected individuals have been mentioned in the medical literature.

Causes

MEGDEL syndrome is caused by mutations in the SERAC1 gene. The function of the protein produced from this gene is not completely understood, although research suggests that it is involved in altering (remodeling) certain fats called phospholipids, particularly a phospholipid known as phosphatidylglycerol. Another phospholipid called cardiolipin is made from phosphatidylglycerol. Cardiolipin is a component of the membrane that surrounds cellular structures called mitochondria, which convert the energy from food into a form that cells can use, and is important for the proper functioning of these structures.

SERAC1 gene mutations involved in MEGDEL syndrome lead to little or no SERAC1 protein function. As a result, phosphatidylglycerol remodeling is impaired, which likely alters the composition of cardiolipin. Researchers speculate that the abnormal cardiolipin affects mitochondrial function, reducing cellular energy production and leading to the neurological and hearing problems characteristic of MEGDEL syndrome. It is unclear how SERAC1 gene mutations lead to abnormal release of 3-methylglutaconic acid in the urine, although it is thought to be related to mitochondrial dysfunction.

Inheritance

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.

Other Names for This Condition

  • 3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy, and Leigh-like syndrome
  • 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
  • MEGDHEL syndrome
  • SERAC1 defect

This entry is adapted from https://medlineplus.gov/genetics/condition/megdel-syndrome

References

  1. Sarig O, Goldsher D, Nousbeck J, Fuchs-Telem D, Cohen-Katsenelson K, Iancu TC,Manov I, Saada A, Sprecher E, Mandel H. Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV withsensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novelmutations in SERAC1. Am J Med Genet A. 2013 Sep;161A(9):2204-15. doi:10.1002/ajmg.a.36059.
  2. Tort F, García-Silva MT, Ferrer-Cortès X, Navarro-Sastre A, Garcia-Villoria J,Coll MJ, Vidal E, Jiménez-Almazán J, Dopazo J, Briones P, Elpeleg O, Ribes A.Exome sequencing identifies a new mutation in SERAC1 in a patient with3-methylglutaconic aciduria. Mol Genet Metab. 2013 Sep-Oct;110(1-2):73-7. doi:10.1016/j.ymgme.2013.04.021.
  3. Wortmann S, Rodenburg RJ, Huizing M, Loupatty FJ, de Koning T, Kluijtmans LA, Engelke U, Wevers R, Smeitink JA, Morava E. Association of 3-methylglutaconicaciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome(MEGDEL association) in four patients with a disorder of the oxidativephosphorylation. Mol Genet Metab. 2006 May;88(1):47-52.
  4. Wortmann SB, de Brouwer APM, Wevers RA, Morava E. SERAC1 Deficiency. 2014 Apr 17 [updated 2020 Jul 23]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, BeanLJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA):University of Washington, Seattle; 1993-2020. Available fromhttp://www.ncbi.nlm.nih.gov/books/NBK195853/
  5. Wortmann SB, Duran M, Anikster Y, Barth PG, Sperl W, Zschocke J, Morava E,Wevers RA. Inborn errors of metabolism with 3-methylglutaconic aciduria asdiscriminative feature: proper classification and nomenclature. J Inherit MetabDis. 2013 Nov;36(6):923-8. doi: 10.1007/s10545-012-9580-0.Review.
  6. Wortmann SB, Vaz FM, Gardeitchik T, Vissers LE, Renkema GH,Schuurs-Hoeijmakers JH, Kulik W, Lammens M, Christin C, Kluijtmans LA, Rodenburg RJ, Nijtmans LG, Grünewald A, Klein C, Gerhold JM, Kozicz T, van Hasselt PM,Harakalova M, Kloosterman W, Barić I, Pronicka E, Ucar SK, Naess K, Singhal KK,Krumina Z, Gilissen C, van Bokhoven H, Veltman JA, Smeitink JA, Lefeber DJ,Spelbrink JN, Wevers RA, Morava E, de Brouwer AP. Mutations in the phospholipidremodeling gene SERAC1 impair mitochondrial function and intracellularcholesterol trafficking and cause dystonia and deafness. Nat Genet. 2012 Jun10;44(7):797-802. doi: 10.1038/ng.2325.
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