Leigh Syndrome in a Girl With a Novel DLD Mutation Causing E3 Deficiency

Abstract

We present the biochemical and molecular diagnosis of dihydrolipoamide dehydrogenase (DLD) deficiency (also known as E3 deficiency) and Leigh syndrome in a 14 year-old girl with previous history of learning disability and episodic encephalopathy and ketoacidosis. The diagnosis was suggested by biochemical laboratory values from plasma amino acids and urine organic acids, which were obtained during an acute episode of encephalopathy, lactic ketoacidosis and liver failure all precipitated by infectious mononucleosis. DLD deficiency was confirmed via enzymatic and molecular analyses. E3 activity from cultured skin fibroblasts ranged between 9% and 29% of the mean. Molecular analysis showed compound heterozygosity for novel and previously reported pathogenic mutations; p.I353T and p.G136del, respectively. The patient was managed using a combination of dietary augmentation as well as continuous renal replacement therapy given her severe and persistent lactic acidosis. Her acute decompensation resulted in brain MRI changes involving the posterior aspect of the putamina, lateral and medial thalami, substantia nigra, lateral geniculate bodies and splenium of the corpus callosum. Additional affected regions included the cortex and subcortical white matter of the right and left occipital lobes and the peri-rolandic region. We review the literature of molecularly confirmed patients with DLD deficiency and note that Leigh syndrome is common in reported patients. This case provides further evidence of the heterogeneous presentation of DLD deficiency as our patient presented with her most severe decompensation at an age much more advanced than in previously reported patients.

Leigh syndrome: One disorder, more than 75 monogenic causes

“…Patients with PDHc deficiency due to mutations in these genes present with a recognizable metabolic profile that reflects additional deficiency of aketoglutarate dehydrogenase and branched-chain a-keto acid dehydrogenase. [65][66][67] PDHc deficiency due to mutations in genes associated with TPP availability (TPK1, SLC19A3, and SLC25A19) can be missed because of the presence of TPP in routine PDHc enzymatic assays, but may be identifiable when measuring PDHc activity in the absence of TPP. 68,69 Mutations in the thiamine transporter SLC19A3 are well known to cause biotin/thiamineresponsive basal ganglia disease (BTBGD; MIM 607483), which phenocopies LS as a progressive encephalopathy with similar neuroimaging and episodic decline.…”

Molecular dynamics study of the structural basis of dysfunction and the modulation of reactive oxygen species generation by pathogenic mutants of human dihydrolipoamide dehydrogenase

“…Clinical complications generally appear at the neonatal age and often lead to premature death [32,[34][35][36][37][38][39][40][41][42][43][44]. Pathogenic mutations of LADH reside mostly either in the cofactor-binding sites, or in the disulfide active center or in the dimerization surface [27,32].…”

The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders

“…In most patients loss of function mutations have been identified. Lactate is constantly elevated with a normal lactate to pyruvate ratio.DLD n=28(Quinonez and Thoene 1993;Quintana et al 2010;Brassier et al 2013;Quinonez et al 2013;Haviv et al 2014):The presentation of E3 deficiency can range from early onset neurologic manifestation to adulthood onset with isolated liver involvement and normal intellectual development. A mild myopathic presentation was described in one patient.…”