Pyruvate dehydrogenase E2 deficiency: a potentially treatable cause of episodic dystonia. Eur J Paediatr Neurol

Ferguson Smith Centre for Clinical Genetics, Yorkhill Hospital, Dalnair Street, Glasgow, G3 8SJ, UK.
European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society (Impact Factor: 2.3). 12/2009; 14(4):349-53. DOI: 10.1016/j.ejpn.2009.11.001
Source: PubMed


The association of progressive episodic dystonia and learning disability with distinctive neuroimaging findings may lead to consideration of atypical Pantothenate Kinase Associated Neurodegeneration (PKAN) and investigations directed towards that diagnosis. Recent reports indicate that deficiency of dihydrolipoamide acetyltransferase, the E2 component of the pyruvate dehydrogenase complex, may present similarly, and that this disorder should also be considered in the differential diagnosis. We describe two sisters with early onset episodic dystonia and pyruvate dehydrogenase deficiency caused by defects in the E2 subunit. Both have neuroimaging features similar to previously described patients and have mutations in the DLAT gene. As this condition is potentially treatable with a ketogenic diet, the possibility of this diagnosis should be considered in similar cases.

31 Reads
  • Source
    • "(Wexler et al., 1997; McWilliam et al., 2010; Barnerias et al., 2010 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ketogenic diet is a nonpharmacologic treatment for childhood epilepsy not amenable to drugs. At the present time, two works based on national research, one in Germany and one in the United States provide international guidelines to ensure a correct management of the ketogenic diet. Our Italian collaborative study group was set up in order to formulate a consensus statement regarding the clinical management of the ketogenic diet, patient selection, pre-ketogenic diet, counseling, setting and enforcement of dietary induction of ketosis, follow-up management, and eventual discontinuation of the diet.
    Epilepsia 04/2011; 52 Suppl 2(s2):83-9. DOI:10.1111/j.1528-1167.2011.03010.x · 4.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A technique has been devised and tested which allows separate training of neural network (NN) modules, each operating on a portion of the problem domain. A method for linking together the NN modules has been devised and shown to yield successful operation on the full problem domain. Methods in the graph theory literature known as connection matrix and reachability matrix were used to assist in both (i) decomposing the problem into subtasks and (ii) determining how to connect the NN modules that learn to perform the subtasks. The problem context used is a lattice of concept types underlying a knowledge base system
    Neural Networks, 1992. IJCNN., International Joint Conference on; 07/1992
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pyruvate dehydrogenase complex (PDHc) deficiencies are an important cause of primary lactic acidosis. Most cases result from mutations in the X-linked gene for the pyruvate dehydrogenase E1α subunit (PDHA1) while a few cases result from mutations in genes for E1β (PDHB), E2 (DLAT), E3 (DLD) and E3BP (PDHX) subunits or PDH-phosphatase (PDP1). To report molecular characterization of 82 PDHc-deficient patients and analyze structural effects of novel missense mutations in PDHA1. PDHA1 variations were investigated first, by exon sequencing using a long range PCR product, gene dosage assay and cDNA analysis. Mutation scanning in PDHX, PDHB, DLAT and DLD cDNAs was further performed in unsolved cases. Novel missense mutations in PDHA1 were located on the tridimensional model of human E1 protein to predict their possible functional consequences. PDHA1 mutations were found in 30 girls and 35 boys. Three large rearrangements, including two contiguous gene deletion syndrome were identified. Novel missense, frameshift and splicing mutations were also delineated and a nonsense mutation in a mosaic male. Mutations p.Glu75Ala, p.Arg88Ser, p.Arg119Trp, p.Gly144Asp, p.Pro217Arg, p.Arg235Gly, p.Tyr243Cys, p.Tyr243Ser, p.Arg245Gly, p.Pro250Leu, p.Gly278Arg, p.Met282Val, p.Gly298Glu in PDHA1 were predicted to impair active site channel conformation or subunit interactions. Six out of the seven patients with PDHB mutations displayed the recurrent p.Met101Val mutation; 9 patients harbored PDHX mutations and one patient DLD mutations. We provide an efficient stepwise strategy for mutation screening in PDHc genes and expand the growing list of PDHA1 mutations analyzed at the structural level.
    Molecular Genetics and Metabolism 08/2011; 104(4):507-16. DOI:10.1016/j.ymgme.2011.08.008 · 2.63 Impact Factor
Show more