ABSTRACT
Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 µM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.
Subject(s)
Alkyl and Aryl Transferases/genetics , Ataxia/diagnosis , Ataxia/genetics , Mitochondria, Muscle/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Muscle Weakness/diagnosis , Muscle Weakness/genetics , Point Mutation , Ubiquinone/analogs & derivatives , Ubiquinone/deficiency , Acidosis, Lactic/blood , Acidosis, Lactic/genetics , Acidosis, Lactic/pathology , Alkyl and Aryl Transferases/deficiency , Ataxia/blood , Ataxia/pathology , Consanguinity , Fatal Outcome , Female , Gene Expression , Hepatic Insufficiency/blood , Hepatic Insufficiency/genetics , Hepatic Insufficiency/pathology , Humans , Infant, Newborn , Intellectual Disability/blood , Intellectual Disability/genetics , Intellectual Disability/pathology , Mitochondria, Muscle/enzymology , Mitochondria, Muscle/pathology , Mitochondrial Diseases/blood , Mitochondrial Diseases/pathology , Muscle Weakness/blood , Muscle Weakness/pathology , Muscle, Skeletal/enzymology , Muscle, Skeletal/pathology , Proteinuria/blood , Proteinuria/genetics , Proteinuria/pathology , Renal Aminoacidurias/blood , Renal Aminoacidurias/genetics , Renal Aminoacidurias/pathology , Sequence Analysis, DNA , Ubiquinone/blood , Ubiquinone/geneticsABSTRACT
We present a patient affected by Dravet syndrome. Thorough analysis of genes that might be involved in the pathogenesis of such phenotype with both conventional and next generation sequencing resulted negative, therefore she was investigated by a-GCH that showed the presence of an unbalanced translocation resulting in a der(4)t(4;8)(p16.3,p23.3). This was an unconventional translocation, different from the recurrent translocation affiliated with WHS and did not involve LETM1.