3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
MEGDEL

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List of symptoms



Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Psychomotor retardation nervous 100 % 22683713 2013-11-14
Spasticity nervous 100 % 22683713 2013-11-14
Dystonia nervous 100 % 22683713 2013-11-14
Hearing loss nervous 100 % 22683713 2013-11-14
Developmental delay nervous 100 % 22683713 2013-11-14
Cerebellar atrophy nervous 100 % 22683713 2013-11-14
Cerebral atrophy nervous 100 % 22683713 2013-11-14
Basal ganglia pathology nervous 100 % 22683713 2013-11-14
3-methylglutaconic aciduria urinary 100 % 22683713 2013-11-14
Lactate accumulation circulatory 93 % 22683713 2013-11-14
Increased serum alanine circulatory 62 % 22683713 2013-11-14



List of references:


Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.
Saskia B Wortmann, Frédéric M Vaz, Thatjana Gardeitchik, Lisenka E L M Vissers, G Herma Renkema, Janneke H M Schuurs-Hoeijmakers, Wim Kulik, Martin Lammens, Christin Christin, Leo A J Kluijtmans, Richard J Rodenburg, Leo G J Nijtmans, Anne Grünewald, Christine Klein, Joachim M Gerhold, Tamas Kozicz, Peter M van Hasselt, Magdalena Harakalova, Wigard Kloosterman, Ivo Barić, Ewa Pronicka, Sema Kalkan Ucar, Karin Naess, Kapil K Singhal, Zita Krumina, Christian Gilissen, Hans van Bokhoven, Joris A Veltman, Jan A M Smeitink, Dirk J Lefeber, Johannes N Spelbrink, Ron A Wevers, Eva Morava, Arjan P M de Brouwer,

Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking.

Nature genetics - Jun 2012