Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations

Abstract

Coenzyme Q(10) (CoQ(10)) is a vital lipophilic molecule that transfers electrons from mitochondrial respiratory chain complexes I and II to complex III. Deficiency of CoQ(10) has been associated with diverse clinical phenotypes, but, in most patients, the molecular cause is unknown. The first defect in a CoQ(10) biosynthetic gene, COQ2, was identified in a child with encephalomyopathy and nephrotic syndrome and in a younger sibling with only nephropathy. Here, we describe an infant with severe Leigh syndrome, nephrotic syndrome, and CoQ(10) deficiency in muscle and fibroblasts and compound heterozygous mutations in the PDSS2 gene, which encodes a subunit of decaprenyl diphosphate synthase, the first enzyme of the CoQ(10) biosynthetic pathway. Biochemical assays with radiolabeled substrates indicated a severe defect in decaprenyl diphosphate synthase in the patient's fibroblasts. This is the first description of pathogenic mutations in PDSS2 and confirms the molecular and clinical heterogeneity of primary CoQ(10) deficiency.

Figure  1.

CoQ₁₀ biosynthetic pathway. Isopentenyl diphosphates derived from the mevalonate pathway generate geranylgeranyl diphosphate. Additional isopentenyl diphosphates are added by decaprenyl diphosphate synthase, which, in humans is a heterotetramer composed of two prenyl diphosphate synthase subunit 1 and two prenyl diphosphate synthase subunit 2 molecules. PHB is derived from the amino acids tyrosine or phenylalanine. After PHB and decaprenyl diphosphate are produced, at least seven enzymes catalyze condensation, methylation, decarboxylation, and hydroxylation reactions to synthesize CoQ₁₀.^,

Figure  2.

A, At age 5 mo, the child was severely hypotonic. B, T₂-weighted MR image of the brain at age 3 mo, showing bilateral increased signal intensities at the putamen and globus pallidus, as well as increased white matter signal in the parieto-occipital regions and atrophy in the occipital lobe and peri-insular region. C, EEG during right-sided focal status epilepticus, showing continuous high-voltage 2-hz sharp waves over the entire right hemisphere. D, Gomori trichrome stain, demonstrating several muscle fibers with abnormal subsarcolemmal mitochondrial aggregates (500×). E, COX stain, showing a similar pattern of increased subsarcolemmal stain (400×).