Dihydrolipoamide Dehydrogenase Deficiency via the DLD Gene

Dihydrolipoamide dehydrogenase (DLD) deficiency, sometimes referred to as maple syrup urine disease (MSUD) type 3, is a disorder caused by defects in the dihydrolipoamide dehydrogenase enzyme. The phenotypic spectrum of DLD deficiency is broad and includes an early-onset neurological form, a mainly hepatic form, and a myopathic form, each described below (Quinonez and Thoene 2014). It should be noted, however, that clinical presentation occurs along a continuum and it may be difficult to differentiate between the different forms.

The initial presentation of the early-onset form of DLD deficiency is generally a lethargic, hypotonic infant with lactic acidosis. Some patients also display a Leigh syndrome phenotype (Quinonez et al. 2013; Carrozzo et al. 2014), and others may exhibit visual impairment (Quinonez and Thoene 2014). The first metabolic decompensation in these infants is often fatal, and others may not survive subsequent metabolic decompensations that occur during the early years of life. Surviving individuals often have growth defects and neurological difficulties, such as seizures, ataxia, spasticity, and intellectual disability (Elpeleg et al. 1997; Quinonez and Thoene 2014). Those with neonatal onset of DLD deficiency generally have a poor prognosis (Carrozzo et al. 2014).

In individuals with the hepatic form of the disease, onset ranges from early in life to as late as the third decade. Symptoms include nausea and emesis, which is followed by signs of liver injury (such as elevated transaminases) and potentially increased liver glycogen content and fibrosis or necrosis. These individuals also suffer from acute metabolic episodes that are often associated with lactic acidosis, hypoglycemia, hyperammonemia and hepatomegaly. Liver failure may occur and can be fatal. These patients do not tend to have neurological symptoms, though they do often experience recurrent attacks of hepatopathy, which are often precipitated by an event such as illness or an extreme dietary change (Brassier et al. 2013; Quinonez and Thoene 2014).

Thus far, few patients with the myopathic form of DLD deficiency have been reported. One individual presented in infancy with photophobia and ptosis, exercise induced fatigability, generalized muscle weakness and cramps, lactic acidosis and elevated plasma creatine kinase (Quintana et al. 2010). A second patient was reported in the second decade of life, presenting with muscle weakness and pain, intermittent lactic acidosis, ketoacidosis, and elevation of creatine kinase (Carrozzo et al. 2014).

These patients may be identified by biochemical testing, which may reveal lactic acidosis, elevated α-ketoglutarate, branched chain keto-acids and branched chain amino acids in the urine, as well as allo-isoleucine in the plasma. Such biochemical signs may be intermittent or absent during testing (Quinonez and Thoene 2014). It should also be noted that the levels of branched chain amino acids are not as high as observed in classical maple syrup urine disease (Robinson 2014).

Dihydrolipoamide dehydrogenase (DLD) deficiency is an autosomal recessive disorder caused by pathogenic variants in the DLD gene, which is located on chromosome 7 at 7q31.1. To date, approximately 20 pathogenic variants in the DLD gene have been reported, with the variants being a mix of missense, splicing, small insertion and small deletions (Liu et al. 1993; Hong et al. 1996; Grafakou et al. 2003; Human Gene Mutation Database). Two specific variants (p.Gly229Cys and p.Tyr35*) are common in the Ashkenazi Jewish population (Elpeleg et al. 1997; Shaag et al. 1999; Scott et al. 2010).

The DLD gene encodes the dihydrolipoamide dehydrogenase, which is the E3 subunit of three mitochondrial enzyme complexes: the branched chain α-ketoacid dehydrogenase (BCKDH) complex, the α-ketoglutarate dehydrogenase (aKGDH) complex, and the pyruvate dehydrogenase (PDH) complex (Quinonez and Thoene 2014; Robinson 2014).

Although the sensitivity of this test is difficult to estimate due to the low number of cases reported in the literature, it appears to be high as nearly all reported patients have been found to have two causative DLD variants that are detectable via direct sequencing (Liu et al. 1993; Hong et al. 1996; Elpeleg et al. 1997; Hong et al. 1997; Shaag et al. 1999; Grafakou et al. 2003; Odièvre et al. 2005; Cameron et al. 2006; Quintana et al. 2010; Quinonez and Theone al. 2014; Shany et al 1999).

To date, no large deletions or duplications have been reported in the DLD gene.

This test provides full coverage of all coding exons of the DLD 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).