PDH E₁β deficiency with novel mutations in two patients with Leigh syndrome

Abstract

Most cases of pyruvate dehydrogenase complex (PDHc) deficiency are attributable to mutations in the PDHA1 gene which encodes the E(1)α subunit, with few cases of mutations in the genes for E(3), E3BP (E(3) binding protein), E(2) and E(1)-phosphatase being reported. Only seven patients with deficiency of the E(1)β subunit have been described, with mutations in the PDHB gene in six of them. Clinically they presented with a non-specific encephalomyopathy. We report two patients with new mutations in PDHB and Leigh syndrome. Patient 1 was a boy with neonatal onset of hyperlactataemia, corpus callosum hypoplasia and a convulsive encephalopathy. After neurological deterioration, he died at age 5 months. Autopsy revealed the characteristic features of Leigh syndrome. Patient 2, also a boy, presented a milder clinical course. First symptoms were noticed at age 16 months with muscular hypotonia, lactic acidosis and recurrent episodes of somnolence and transient tetraparesis. MRI revealed bilateral signal hyperintensities in the globus pallidus, midbrain and crura cerebri. PDHc and E(1) activities were deficient in fibroblasts in patient 1; in patient 2 PDHc deficiency was found in skeletal muscle. Mutations in PDHA1 were excluded. Sequencing of PDHB revealed a homozygous point mutation (c.302T>C), causing a predicted amino acid change (p.M101T) in patient 1. Patient 2 is compound heterozygote for mutations c.301A>G (p.M101V) and c.313G>A (p.R105Q). All three mutations appear to destabilize the E(1) enzyme with a decrease of both E(1)α and E(1)β subunits in immunoblot analysis. To our knowledge, these patients with novel PDHB mutations are the first reported with Leigh syndrome.

Distinct Retinal Deficits in a Zebrafish Pyruvate Dehydrogenase-Deficient Mutant

“…A mutant defective in the E2 subunit of the same complex has been linked to the noa (no optokinetic response a) mutant, which was similarly identified in a screen for mutants affected in visual behavior (Brockerhoff et al, 1995(Brockerhoff et al, , 1998Taylor et al, 2004). Mutations in this complex cause Leigh's syndrome in humans (Quintana et al, 2009), a progressive neurometabolic disorder characteristic of focal, bilateral lesions in one or more areas of the CNS (Leigh, 1951;McKusick et al, 1986).…”

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

“…In females microcephaly, corpus callosum agenesis, facial dysmorphism, spasticity and infantile spasm are characteristic whereas in males basal ganglia and midbrain affection, ataxia, ptosis, choreoathetotic movements and peripheral neuropathy are more frequently found.PDHB n=17(Brown et al 2004;Okajima et al 2008;Quintana et al 2009;Imbard et al 2011): The phenotype is quite similar to PDHA1 deficiency. Typical clinical presentation includes encephalopathy, hypotonia, respiratory difficulties and lactic acidosis.…”

Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content

“…M101 is a highly conserved amino acid and p.M101V and p.M101T substitutions have been observed in other patients with reduced PDH activity in both, fibroblasts and skeletal muscle. 13 The second variant, paternally inherited, is a novel c.42 +1G4A substitution, affecting the first nucleotide of the first intron of the PDHB gene (Figure 2c). PCR amplification of a region comprising the first 500 bp of the PDHB cDNA resulted in double bands in patient 2.…”

“…19 The variants detected in PDH complex after exome sequencing would explain the clinical phenotype that has been previously described in patients with mutations in genes of this complex. 13 In these cases, the rise of mitochondria and the corresponding CoQ 10 concentration would try to compensate the lack of acetyl-CoA and also to contribute to NQO1 activity to prevent oxidative damage. These results indicate the importance of the balanced requirement for CoQ 10 and electron chain complexes, and also promote that early Encephalopathy, PDH mutations and unbalanced Q 10 C Asencio et al…”