Pyruvate Dehydrogenase Lipoic Acid Synthetase Deficiency via the LIAS Gene

Pyruvate Dehydrogenase Lipoic Acid Synthetase Deficiency (PDHLD) appears to be an exceptionally rare disorder, with fewer than 5 cases reported to date (Mayr et al. 2011; Baker 2nd et al. 2013). Based on current knowledge, onset appears to be within the first few days of birth and begins with hypotonia and seizures. Other symptoms have included failure to thrive, feeding difficulties, sleep disturbances, severe psychomotor and developmental delays, acquired microcephaly and neurological symptoms. Biochemically, patients typically have greatly elevated lactate and glycine levels. PDHLD has been fatal in early childhood for the majority of molecularly confirmed patients. There is currently no known treatment for PDHLD (Mayr et al. 2011; Baker 2nd et al. 2013).

Current knowledge of PDHLD suggests that this is an autosomal recessive disorder, and LIAS is the only gene involved. To date, only missense variants and a small indel have been reported, and all affected patients have been homozygous for a familial variant (Mayr et al. 2011; Baker 2nd et al. 2013).

The LIAS gene encodes the pyruvate dehydrogenase lipoic acid synthetase enzyme, which is involved in the synthesis of lipoic acid within the mitochondria. Lipoic acid functions as a co-enzyme for three key mitochondrial dehydrogenase complexes in eukaryotes: the pyruvate dehydrogenase complex (PDHc), the α-ketoglutarate dehydrogenase complex (α-KGDH), and the branched chain ketoacid dehydrogenase complex (BCKDH). All three of these complexes are similar in structure and are comprised of three main subunits (E1, E2 and E3). Normally, lipoic acid is bound to the E2 subunits. PDHLD patients have been found to have greatly decreased levels of the PDHc E2 subunit, as well as decreased PDHc enzyme activity (Mayr et al. 2011). In addition to these three dehydrogenase complexes, lipoic acid is also used in the glycine cleavage system (GCS), explaining the hyperglycinemia observed in PDHLD patients (Mayr et al. 2011; Baker 2nd et al. 2013)

At this time, the sensitivity of this test is difficult to estimate due to the low number of cases reported in the literature.

To date, no large deletions or duplications have been described in the LIAS gene.

This test provides full coverage of all coding exons of the LIAS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).