Towards the genetic defect in MEGDEL syndrome: Four novel patients

Recently we defined MEGDEL syndrome as 3-MEthylGlutaconic aciduria type IV with sensori-neural Deafness, Encephalopathy, and Leigh-like syndrome. In addition to the four original patients, we found four new patients with the same distinctive phenotype in Pakistan, Croatia, Turkey and the Netherlands. In all eight patients (four girls, four boys) 3-methylglutaconic aciduria type I, II, III, V and ATP-ase deficiency were excluded. The children presented with characteristic association of 3-methylglutaconic aciduria (25–196 mmol/mol creatinine), sensori-neural deafness and neuro-radiological evidence of Leigh disease. They also had neonatal hypotonia, recurrent lactic acidemia and hypoglycemia, severe recurrent infections, feeding difficulties, failure to thrive, developmental delay, and progressive spasticity with extrapyramidal symptoms. One showed liver involvement. Muscle biopsy revealed OXPHOS dysfunction in six patients. Homozygosity mapping was performed in three unrelated children from consanguineous families. The largest overlapping homozygous region was 4.6 Mb on chromosome 2 and contained promising candidate genes, which we are now analyzing. In another patient we found a complex chromosome aberration, also overlapping with the described region on chromosome 2. Although MEGDEL may be genetically heterogeneous further patients from a consanguineous background may help to unravel its genetic basis.