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Dihydrolipoamide Dehydrogenase Deficiency via the DLD Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
DLD 81406 81406,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9321DLD81406 81406,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

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).

Clinical Sensitivity - Sequencing with CNV PGxome

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.

Testing Strategy

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).

Indications for Test

Candidates for this test are patients with biochemical, enzymatic test results and/or clinical features consistent with dihydrolipoamide dehydrogenase (DLD) deficiency/maple syrup urine disease (MSUD) type III. Testing is also indicated for family members of patients with known DLD mutations. We will also sequence the DLD gene to determine carrier status.


Official Gene Symbol OMIM ID
DLD 238331
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Dihydrolipoamide dehydrogenase deficiency AR 246900


  • Brassier A. et al. 2013. Molecular Genetics and Metabolism. 109: 28-32. PubMed ID: 23478190
  • Cameron J.M. et al. 2006. American Journal of Medical Genetics. Part A. 140: 1542-52. PubMed ID: 16770810
  • Carrozzo R. et al. 2014. Mitochondrion. 18: 49-57. PubMed ID: 25251739
  • Elpeleg O.N. et al. 1997. Human Mutation. 10: 256-7. PubMed ID: 9298831
  • Grafakou O. et al. 2003. European Journal of Pediatrics. 162: 714-8. PubMed ID: 12925875
  • Hong Y.S. et al. 1996. Human Molecular Genetics. 5: 1925–30. PubMed ID: 8968745
  • Hong Y.S. et al. 1997. Biochimica Et Biophysica Acta. 1362: 160-8. PubMed ID: 9540846
  • Human Gene Mutation Database (Bio-base).
  • Liu TC et al. 1993. Proceedings of the National Academy of Sciences. 90: 5186–90. PubMed ID: 8506365
  • Odièvre M.H. et al. 2005. Human Mutation. 25: 323-4. PubMed ID: 15712224
  • Quinonez S.C. et al. 2013. Pediatric Neurology. 48: 67-72. PubMed ID: 23290025
  • Quinonez, S.C. and Thoene, J.G. 2014. Dihydrolipoamide Dehydrogenase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 25032271
  • Quintana E. et al. 2010. Journal of Inherited Metabolic Disease. 33 Suppl 3: S315-9. PubMed ID: 20652410
  • Robinson B.H. 2014. Lactic Acidemia: Disorders of Pyruvate Carboxylase and Pyruvate Dehydrogenase. Online Metabolic & Molecular Bases of Inherited Disease, New York, NY: McGraw-Hill.
  • Scott S.A. et al. 2010. Human Mutation. 31: 1240-50. PubMed ID: 20672374
  • Shaag A. et al. 1999. American Journal of Medical Genetics. 82: 177-82. PubMed ID: 9934985
  • Shany E. et al. 1999. Biochemical and Biophysical Research Communications. 262: 163-6. PubMed ID: 10448086


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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