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Dihydrolipoamide Dehydrogenase Deficiency

Synonyms: DLD Deficiency, E3 Deficiency, Lipoamide Dehydrogenase Deficiency

, MD and , MD.

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Summary

Clinical characteristics.

The phenotypes of dihydrolipoamide dehydrogenase (DLD) deficiency are an overlapping continuum that ranges from early-onset neurologic manifestations to adult-onset isolated liver involvement. Early-onset DLD deficiency typically manifests as a hypotonic infant with lactic acidosis. Affected infants frequently do not survive their initial metabolic decompensation, or die within the first few years of life during a recurrent metabolic decompensation. Children who live beyond the first two to three years frequently exhibit growth deficiencies and residual neurologic deficits (intellectual disability, spasticity, ataxia, and seizures). In contrast, isolated liver involvement can present as early as the neonatal period and as late as the third decade. Evidence of liver injury/failure is preceded by nausea and emesis and frequently associated with encephalopathy and/or coagulopathy. Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes patients frequently return to baseline with no residual neurologic deficit or intellectual disability. Liver failure can result in death, even in those with late-onset disease.

Diagnosis/testing.

The diagnosis of DLD deficiency is suspected in a proband with a characteristic clinical history and biochemical evidence of defective function of three mitochondrial enzyme complexes (branched chain alpha-ketoacid dehydrogenase [BCKDH] complex, α-ketoglutarate dehydrogenase [αKGDH] complex, and pyruvate dehydrogenase [PDH] complex). These may manifest as lactic acidosis, elevated α-ketoglutarate in the urine, the presence of branched chain keto-acids in the urine, elevated plasma levels of branched chain amino acids (leucine, isoleucine, and valine), and the presence of allo-isoleucine in plasma. Of note, these biochemical changes may be absent or intermittent. The diagnosis is confirmed by the presence of biallelic pathogenic variants in DLD.

Management.

Treatment of manifestations: Management of DLD deficiency is difficult due to the various metabolic pathways involved. Management of the early-onset neurologic presentation relies on empiric treatment of the three isolated enzyme complex deficiencies (none of which appear to significantly alter the natural history of the disease):

  • BCKDH complex deficiency: dietary leucine restriction, BCAA-free medical foods, judicious supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring;
  • αKGDH complex: very rare, no recommendations available;
  • PDH complex: ketogenic diet (due to defective carbohydrate oxidation), trial of dichloroacetate (DCA), and thiamine supplementation.

Management of the primarily hepatic presentation typically involves supportive therapy during times of acute liver injury or failure, including nutritional support, IV glucose for hypoglycemia, correction of metabolic acidosis, correction of coagulopathy, and avoidance of liver-toxic medications.

Prevention of primary manifestations: No compelling evidence exists for the prevention of acute episodes, despite multiple attempted dietary strategies and medications.

Surveillance: Routine monitoring of growth and development; plasma amino acid levels (to guide dietary management). For those receiving DCA, monitoring for the development of peripheral neuropathy.

Agents/circumstances to avoid: Fasting, catabolic stressors, liver-toxic medications.

Evaluation of relatives at risk: If the DLD pathogenic variants in an affected proband are known, at-risk sibs should undergo molecular genetic testing prenatally or as soon as possible after birth so that those who have inherited both pathogenic variants can receive appropriate interventions and avoid risk factors that may precipitate an acute event.

Genetic counseling.

DLD deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the DLD pathogenic variants in the family are known.

Diagnosis

Dihydrolipoamide dehydrogenase (DLD) functions as the E3 subunit of three mitochondrial enzyme complexes: branched chain alpha-ketoacid dehydrogenase (BCKDH) complex, α-ketoglutarate dehydrogenase (αKGDH) complex, and pyruvate dehydrogenase (PDH) complex [Chuang et al 2014]. Of note, although DLD also functions as the L protein of the glycine cleavage system, pathogenic variants of DLD do not appear to date to impair the function of this system in vivo.

The phenotypic spectrum of DLD deficiency includes an early-onset neurologic presentation, a primarily hepatic presentation, and a mild myopathic presentation (seen in one patient).

No formal diagnostic criteria have been established for dihydrolipoamide dehydrogenase (DLD) deficiency.

The diagnosis of dihydrolipoamide dehydrogenase (DLD) deficiency is suspected in individuals with the following presentations:

  • Neurologic (early-onset hypotonia, lethargy, and emesis)
    • In untreated infants, manifestations progress to deepening encephalopathy (lethargy, tone abnormalities, feeding difficulties, decreased level of alertness, and occasionally seizures) and eventual death.
    • Those who survive the first years of life frequently display neurologic impairment.
    • Abnormal laboratory findings typically associated with the neurologic presentation include the following:
      • Metabolic acidosis. Arterial pH <7.35 or venous pH <7.32 and serum bicarbonate <22 mmol/L in children and adults or <17 mmol/L in neonates
      • Elevated plasma concentration of lactate: >2.2 mmol/L
      • Hypoglycemia: <40 mg/dL (<2.2 mmol/L)
  • Hepatic (recurrent liver injury/failure frequently preceded by nausea and emesis)
    • Liver injury can range from isolated elevated transaminases to fulminant hepatic failure and death.
    • Age of onset ranges from the neonatal period to the third decade [Barak et al 1998, Brassier et al 2013].
    • Patients with the hepatic form typically have normal intellect with no residual neurologic deficit between acute metabolic episodes unless neurologic damage has occurred.
  • Myopathic. The one patient with this mild phenotype exhibited ptosis, weakness, and elevated plasma creatine kinase and lactate levels [Quintana et al 2010].
  • Elevated citrulline on newborn screening (NBS) dried blood spot. Two symptomatic infants with DLD deficiency had an elevated citrulline level on dried blood spot testing [Haviv et al 2014]. Note that newborn screening has failed to identify asymptomatic individuals with DLD deficiency when either dried blood spot citrulline or leucine is used as a primary screening analyte.

The diagnosis of dihydrolipoamide dehydrogenase deficiency is established in a proband with the following:

  • A clinical history consistent with DLD deficiency (see preceding section)
  • Biochemical evidence of defective BCKDH, αKGDH, or PDH function:
    • Lactic acidosis (plasma lactate >2.2 mmol/L and arterial pH <7.35)
    • Elevated urine α-ketoglutarate levels (see Table 1)
    • Presence of branched chain keto-acids in urine
    • Elevated branched chain amino acids (leucine, isoleucine, and valine) in plasma and the presence of allo-isoleucine in plasma (see Table 1)
      Note: Individuals with an early-onset or hepatic presentation only occasionally have biochemical evidence of dysfunctional branched chain amino acid (BCAA) metabolism (i.e., elevations of allo-isoleucine and branched chain ketoacids; see Table 1), making leucine an unreliable marker for screening.
  • The presence of either biallelic pathogenic variants in DLD (see Table 2) or decreased DLD enzymatic activity in fibroblasts, lymphocytes, or liver tissue if molecular genetic testing is not available or is not definitive

Table 1.

Metabolic Abnormalities in DLD Deficiency by Presentation

MetabolitePresentationNormal
NeurologicHepatic
Plasma lactateElevatedElevated<2.2 µmol/L
Urine α-ketoglutarate 1Normal to elevatedTypically normalNeonates: 4-524 mmol/mol creatinine
Children: 36-117 mmol/mol creatinine
Adults: 4-74 mmol/mol creatinine
Urine branched chain keto-acids 1Absent to elevatedTypically absentNeonates 2: <7 mmol/mol creatinine
All other ages: not detectable
Plasma leucine 3Normal to elevatedTypically normalInfants: 46-147 µmol/L
Children: 30-246 µmol/L
Adolescents-adults: 86-206 µmol/L
Plasma isoleucine 3Normal to elevatedTypically normalInfants: 12-77 µmol/L
Children: 6-122 µmol/L
Adolescents-adults: 34-106 µmol
Plasma valine 3Normal to elevatedTypically normalInfants: 79-217 µmol/L
Children: 132-480 µmol/L
Adolescents-adults: 155-343 µmol
Plasma allo-isoleucineNormal to elevatedTypically normal<5 µmol/L 4
1.
2.

2-oxoisocaproate and 2-oxo-3-methylvalerate; 2-oxoisovalerate detectable only in premature infants

3.
4.

Table 2.

Summary of Molecular Genetic Testing Used in Dihydrolipoamide Dehydrogenase Deficiency

Gene 1Test MethodProportion of Probands with Pathogenic Variants Detectable by This Method
DLDSequence analysis 239/40 (98%) 3
Deletion/duplication analysis 4Unknown 5
Targeted analysis for pathogenic variants 6See footnote 7
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.
4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

No deletions or duplications involving DLD have been reported to cause dihydrolipoamide dehydrogenase deficiency.

6.

Variant panels may differ by laboratory.

7.

The c.685G>T (p.Gly229Cys) pathogenic variant is common in Ashkenazi Jews (see Prevalence).

Clinical Characteristics

Clinical Description

As part of three mitochondrial enzyme complexes (branched chain alpha-ketoacid dehydrogenase complex, α-ketoglutarate dehydrogenase complex, and pyruvate dehydrogenase complex), dihydrolipoamide dehydrogenase (DLD) functions as the E3 subunit responsible for the reoxidation of the reduced lipoyl moiety of the E2 subunit.

Persons with dihydrolipoamide dehydrogenase (DLD) deficiency exhibit variable phenotypic and biochemical consequences based on the three affected enzyme complexes. Although the spectrum of disease ranges from early-onset neurologic manifestations to isolated adult-onset liver involvement, it is a continuum and differentiation between the two major presentations can occasionally be difficult.

Early-onset neurologic presentation. The most frequent clinical picture in early-onset DLD deficiency is that of a hypotonic infant with lactic acidosis (Table 3). Affected infants frequently do not survive their initial metabolic decompensation or die within the first one to two years of life during a recurrent metabolic decompensation. Children who live beyond the first two to three years frequently exhibit growth deficiencies and residual neurologic deficits including intellectual disability, spasticity (hypertonia and/or hyperreflexia), ataxia, and seizures. Of note, normal intellectual functioning has been reported in individuals with early-onset disease with compound heterozygosity for the c.685G>T (p.Gly229Cys) pathogenic variant and an additional pathogenic allele [Shaag et al 1999].

Hepatomegaly and liver dysfunction/failure (elevated transaminases, synthetic failure) occur in individuals with an early-onset neurologic picture and can occasionally be a cause of death (Table 3).

Similar to other inborn errors of metabolism, DLD deficiency is associated with recurrent episodes of metabolic decompensation typically triggered by illness/fever, surgery, fasting, or diet (high in fats and/or protein). Owing to the variability in each individual’s biochemical phenotype, some patients have experienced worsening of clinical status with high-fat diets [Robinson et al 1981, Hong et al 1997, Brassier et al 2013], while others have achieved metabolic control with ketogenic diets (see Management) [Cerna et al 2001, Grafakou et al 2003].

Liver biopsies have shown increased glycogen content and mild fibrosis or fatty, acute necrosis with a Reye syndrome-like appearance [Grafakou et al 2003, Cameron et al 2006]. Between acute episodes both liver size and transaminase levels can return to normal [Sansaricq et al 2006].

Other findings of the early-onset neurologic presentation include the following:

Table 3.

Features of the Early-Onset Neurologic Phenotype

Disease FeaturesFrequency 1%
Clinical presentation 2Hypotonia16/2370
Developmental delay12/2352
Emesis12/2352
Hepatomegaly9/2339
Lethargy8/2335
Seizures7/2330
Spasticity (hypertonia and/or hyperreflexia)7/2330
Leigh syndrome phenotype6/2326
Failure to thrive6/2326
Microcephaly5/2322
Vision impairment4/2317
Ataxia3/2313
Cardiac involvement3/2313
Laboratory abnormalitiesMetabolic acidosis 321/2391
Elevated plasma lactate 418/2378
Elevated urine α-ketoglutarate 413/2357
Hypoglycemia 511/2348
Elevated plasma BCAA 410/2343
Elevated transaminases9/2339
Elevated urine branched chain keto-acids 47/2330
Hepatic failure4/2317
Elevated plasma allo-isoleucine 44/2317
Low free plasma carnitine 63/2313
Hyperammonemia 72/238

Only patients biochemically confirmed to have DLD deficiency included

BCAA = branched chain amino acids

1.
2.

Later physical examination and neurologic findings are likely underrepresented as children with an early-onset presentation frequently die in their first year(s) of life.

3.

Arterial pH <7.35 or venous pH <7.32; serum bicarbonate <22 mmol/L in infants, children, and adults; or <17 mmol/L in neonates

4.

See Table 1.

5.

Glucose <40 mg/dL

6.

Carnitine (free) <38±22 [Millington 2002]

7.

Ammonia >100 µmol/L in neonates or >60 µmol/L in infants, children, and adults

Hepatic presentation. Patients with a primarily hepatic presentation can develop signs and symptoms as early as the neonatal period and as late as the third decade of life [Barak et al 1998, Brassier et al 2013]. Evidence of liver injury/failure (Table 4) is preceded by nausea and emesis and frequently associated with encephalopathy and/or coagulopathy. Liver failure as a cause of death has been reported in multiple patients, including those who presented later in life [Elpeleg et al 1997a, Shaag et al 1999].

Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes (see Management) patients may return to baseline with normal transaminases, coagulation parameters, mental status, and no residual neurologic deficit or intellectual disability.

Affected individuals frequently experience lifelong recurrent attacks of hepatopathy that decrease with age. Attacks are often precipitated by catabolism, intercurrent illness/fever, and dietary extremes. These patients additionally are more susceptible to hepatotropic viruses (e.g., Epstein-Barr virus) and medications (e.g., acetaminophen) [Brassier et al 2013, Quinonez et al 2013].

Liver biopsy electron microscopy has shown the presence of lipid droplets [Brassier et al 2013].

Table 4.

Clinical Features of the Hepatic Phenotype

Disease FeaturesFrequency 1%
Clinical presentationNausea/emesis13/13100
Hepatomegaly9/1369
Hepatic encephalopathy7/1354
Muscle cramps3/1323
Behavioral disturbances1/138
Vision loss1/138
Laboratory abnormalitiesElevated transaminases13/13100
Coagulopathy11/1385
Elevated lactate 210/1377
Hyperammonemia 38/1362
Hypoglycemia 45/1338
Elevated urine α-ketoglutarate 22/1315
Low carnitine 51/138
Elevated plasma BCAA 21/138

Only patients biochemically confirmed to have DLD deficiency included

BCAA = branched chain amino acids

1.
2.

See Table 1.

3.

Ammonia >100 µmol/L in neonates or >60 µmol/L in infants, children, and adults

4.

Glucose <40 mg/dL

5.

Carnitine (free) <38±22 [Millington 2002]

Although Table 3 and Table 4 reveal features common to both the early-onset neurologic presentation and the hepatic presentation (i.e., elevated transaminases, hepatomegaly, and lactate elevations), differentiation of the two types can be difficult especially in neonates [Hong et al 2003, Cameron et al 2006]. To date, the only patient with a hepatic phenotype who displayed hypotonia or residual neurologic deficiencies had experienced a severe episode associated with deep coma and residual vision loss and behavioral disturbances [Elpeleg et al 1990]. Therefore, the absence of hypotonia and neurologic deficit and the presence of hepatic signs are useful discriminating features.

Myopathic presentation. One patient has been described with a mild phenotype consisting primarily of myopathic symptoms [Quintana et al 2010]. The patient exhibited ptosis, weakness, and an elevated creatine kinase and lactate.

Genotype-Phenotype Correlations

Phenotypic severity is difficult to predict based on genotype and residual enzyme function [Shany et al 1999, Quinonez et al 2013].

Individuals homozygous for the c.685G>T (p.Gly229Cys) pathogenic variant, which is common in the Ashkenazi Jewish population, were initially thought to have a milder, primarily hepatic presentation. Subsequently, individuals homozygous for c.685G>T (p.Gly229Cys) were found to have the early-onset neonatal neurologic presentation as well [Hong et al 2003, Sansaricq et al 2006]. Conversely, all individuals with an exclusively hepatic presentation have been homozygous for the c.685G>T (p.Gly229Cys) pathogenic variant [Shaag et al 1999, Brassier et al 2013].

Newborn screening (NBS) has recently identified two symptomatic infants with DLD deficiency who had an elevated citrulline level on dried blood spot (DBS) testing [Haviv et al 2014]. Both of these infants as well as all subsequently identified children in the initial report were homozygous for the c.685G>T (p.Gly229Cys) pathogenic variant or compound heterozygous for that allele and another pathogenic variant. An elevated citrulline level has also been seen in a patient without the c.685G>T (p.Gly229Cys) allele [Authors, personal observation]. Note: The exact mechanism of hypercitrullinemia in these infants has yet to be identified; aspartate depletion through decreased oxaloacetate production has been suggested [Haviv et al 2014].

Nomenclature

DLD deficiency is occasionally referred to as maple syrup urine disease (MSUD) type 3 as it functions as the E3 subunit of BCKDH. Note that MSUD type 1 is caused by biallelic pathogenic variants in BCKDHA (E1α) or BCKDHB (E1β) and MSUD type 2 is caused by biallelic pathogenic variants in DBT (E2). See Maple Syrup Urine Disease.

Prevalence

In the Ashkenazi Jewish population, the carrier frequency of the c.685G>T (p.Gly229Cys) pathogenic variant is estimated to be between 1:94 and 1:110 with an estimated disease frequency of 1:35,000 to 1:48,000 [Shaag et al 1999, Scott et al 2010]. This is likely an underestimate of disease, as additional pathogenic variants account for DLD deficiency in this population as well [Shaag et al 1999].

The incidence and carrier frequency in other populations is unknown and likely very rare.

Differential Diagnosis

Pyruvate dehydrogenase complex (PDHC) deficiency most commonly presents with neurologic impairment, hypotonia, structural brain abnormalities, and lactic acidosis with a normal lactate:pyruvate ratio [Patel et al 2012]. While the clinical findings and preliminary laboratory values are similar, individuals with DLD deficiency frequently also display biochemical evidence of: (a) defective α-ketoglutarate dehydrogenase with elevated urine α-ketoglutarate; and (b) branched chain alpha-ketoacid dehydrogenase complex dysfunction with elevated plasma branched chain amino acids and urine branched chain ketoacids.

Maple syrup urine disease (MSUD) types 1 and 2. Signs in individuals with classic MSUD by age:

  • 12 to 24 hours. A maple syrup odor in cerumen, elevated plasma concentrations of branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) and allo-isoleucine, and a generalized disturbance of plasma amino acid concentration ratios
  • Two to three days. Ketonuria, irritability, and poor feeding
  • Four to five days. Deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling"
  • Seven to ten days. Possible coma and central respiratory failure

Individuals with DLD deficiency (which may be referred to as MSUD type 3; see Nomenclature) can typically be differentiated from MSUD types 1 and 2 by the presence of severe lactic acidosis, α-ketoglutarate excretion in the urine, and liver involvement. The maple syrup odor frequently seen in patients with MSUD types 1 and 2 is not typically found in individuals with DLD deficiency.

Isolated α-ketoglutarate dehydrogenase deficiency has been reported in two sets of consanguineous siblings with choreoathetoid movements, hypotonia, developmental delay, and lactic acidosis. All patients exhibited isolated elevations of α-ketoglutarate in the urine [Kohlschütter et al 1982, Guffon et al 1993].

Elevated citrulline on newborn screening dried blood spot has been identified in two symptomatic patients with DLD deficiency [Haviv et al 2014]. As recommended by the American College of Medical Genetics (see ACMG ACT Sheet / ACMG Algorithm), other causes of an elevated citrulline on dried blood spot including citrullinemia type I, argininosuccinic acidemia, citrullinemia type II (citrin deficiency), and pyruvate carboxylase deficiency should be investigated.

Defects in lipoic acid metabolism have recently been identified as a cause of neonatal lactic acidosis and a biochemical phenotype similar to DLD deficiency. Lipoic acid is the essential cofactor attached to the E2 subunits of BCKDH, αKGDH, and PDH as well as to the H protein of the glycine cleavage system (see Glycine Encephalopathy). Pathogenic variants have been identified in multiple genes encoding enzymes involved in lipoic acid metabolism: NUF1, BOLA3, LIAS, IBA57, and LIPT1 [Cameron et al 2011, Mayr et al 2011, Navarro-Sastre et al 2011, Ajit Bolar et al 2013, Haack et al 2013, Soreze et al 2013, Tort et al 2014]. Unlike children with DLD deficiency, children with defects in lipoic acid metabolism (except LIPT1 deficiency) have elevated glycine in body fluids.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with dihydrolipoamide dehydrogenase (DLD) deficiency, the following evaluations are recommended:

  • In the acute setting, measurement/evaluation of:
    • Blood acid-base status
    • Plasma/serum concentration of lactate, glucose, and ammonia
    • Plasma amino acids
    • Plasma total and free carnitine
    • Urine organic acids
    • Liver function and transaminases (ALT/AST)
    • Liver size via physical examination and/or ultrasonography
    • Cardiac size via echocardiography
    • Consultation with a clinical geneticist and/or genetic counselor
  • After metabolic stability has been achieved:
    • Clinical assessment of physical growth and development status
    • Formal ophthalmologic evaluation if concern for vision loss
    • Brain MRI if clinical concern for Leigh-like syndrome or other structural brain damage
    • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Consensus recommendations for the management of DLD deficiency do not currently exist. Theoretical difficulties exist for the management of these patients based on the various metabolic pathways affected by the three affected enzyme complexes. In practice, these difficulties have been experienced and make empiric treatment recommendations challenging.

DLD pathogenic variants cause variable deficiency in three enzymatic pathways. The treatment for individual enzyme complex deficiencies warrants consideration:

  • Branched chain α-ketoacid dehydrogenase (BCKDH) complex. Management consists primarily of dietary leucine restriction, BCAA-free medical foods, judicious supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring (see MSUD).
  • Alpha-ketoglutarate dehydrogenase (αKGDH) complex. Due to the rarity of this isolated deficiency, limited information is available for the management of these patients.
  • Pyruvate dehydrogenase (PDH) complex. Due to defective carbohydrate oxidation, ketogenic diets have become part of regular management in these patients. Additionally, dichloroacetate (DCA) and thiamine supplementation are frequently tried [Patel et al 2012].

Early-Onset Neurologic Presentation

Review of treatment strategies. The multiple strategies that have been attempted in children with an early-onset neurologic presentation do not appear to significantly alter the natural history of disease. Even with treatment, children often die in the neonatal/infantile period or experience various degrees of chronic neurologic impairment if they survive the initial episode. The individual treatment strategies typically address deficiency of one abnormal enzymatic complex.

Protein/BCAA-restriction. Based on decreased BCKDH activity, restriction of protein to recommended dietary allowances (RDA) has been attempted with questionable results. Three of the six reported patients experienced laboratory and/or clinical improvement with the use of protein restriction alone or in combination with medication therapy [Craigen 1996, Elpeleg et al 1997b, Grafakou et al 2003].

Ketogenic/high-fat diet. Ketogenic/high-fat diets are frequently employed in PDH deficiency [Patel et al 2012] and as a result have been attempted in DLD deficiency. A total of seven patients reported to date have been tried on a ketogenic/high-fat diet:

  • Five had no clinical or biochemical benefit. Of note, two of the five experienced clinical worsening with an increase in acidosis and hypoglycemia [Robinson et al 1981, Craigen 1996].
  • Two improved clinically. One was treated with lipid infusions (instead of high-dextrose infusions) during acute episodes [Hong et al 1997, Cerna et al 2001].

Carbohydrate tolerance. Patients with PDH deficiency classically present with lactate elevations due to defective carbohydrate oxidation. Although dextrose infusions may theoretically cause further lactate elevations during acute episodes, provision of dextrose-containing IV fluids is essential for the majority of acutely decompensated patients. Only one patient experienced worsening acidosis with increased dextrose concentrations in the TPN [Cerna et al 2001]. Not surprisingly, this patient is one of the two who benefitted from a ketogenic/high-fat diet.

Dichloroacetate (DCA). Through its ability to stimulate PDH activity by inhibiting PDH kinase, DCA has long been used to safely treat patients with congenital lactic acidosis, mitochondrial disorders, and PDH deficiency [Stacpoole et al 2008, Patel et al 2012]. A total of five patients have been tried on DCA with four experiencing at least transient decreases in lactic acid elevations [Craigen 1996, Elpeleg et al 1997b, Cerna et al 2001].

Additional therapies used with limited success include:

  • Thiamine
  • Coenzyme Q10
  • Lipoic acid
  • Riboflavin
  • Biotin

Empiric recommendations for acute management (based on the above review)

Goals of therapy should be the correction of metabolic acidosis, promotion of an anabolic/metabolically stable state, maintenance of normoglycemia, and treatment of precipitating factors that may be present. This is typically achieved by the following:

  • Metabolic acidosis should be treated with sodium bicarbonate if bicarbonate is ≤14 mEq/L and/or blood pH <7.2.
  • Promotion of an anabolic state:
    • Maintain serum glucose concentration in the normal range. D10 (half or full-normal saline) with age-appropriate electrolytes should be started at maintenance rate and adjusted based on the presence or absence of increased intracranial pressure or hypoglycemia.
      • Elevation of plasma leucine and increased intracranial pressure are a potential complication of DLD deficiency. Similar to the management of classic MSUD link, overhydration and quickly infused boluses of fluids should be avoided if possible.
      • If provision of dextrose-containing fluids worsens metabolic acidosis, consider decreasing the infusion rate and providing the majority of calories in the form of intralipid.
    • Intralipids can be added to provide additional calories with cautious monitoring for acidemia.
  • Protein should initially be withheld for a maximum of 24 hours to avoid worsening of catabolism. Protein should then be reintroduced gradually.
    • Branched-chain amino acids should be introduced slowly and followed closely with frequent plasma amino acid evaluations.
    • Goal levels/ratios should be similar to those listed in MSUD.
  • Levocarnitine (IV or PO) 50 - 100 mg/kg/d divided three times per day should be given during the acute period.
  • Dichloroacetate (DCA) can be considered and continued if lactate decreases with its introduction.
  • Any precipitating factors (infection, fasting, medications) should be treated/discontinued as soon as possible.
  • If lactic acidosis/encephalopathy persists, dialysis can be considered as it has been successful in DLD deficiency and classic MSUD [Schaefer et al 1999, Quinonez et al 2013].

Hepatic Presentation

Management of patients with the primarily hepatic presentation typically involves supportive therapy during times of acute liver injury or failure, including the following:

  • Nutritional support in the form of dextrose-containing IV fluids (6-8 mg/kg/min) with age-appropriate electrolytes and/or frequent feedings [Elpeleg et al 1990, Shaag et al 1999, Brassier et al 2013]
  • Correction of metabolic acidosis with sodium bicarbonate
  • Correction of any coagulopathy with fresh frozen plasma
  • Consideration of DCA treatment for lactic acidosis during acute episodes and for chronic management [Aptowitzer et al 1997, Shaag et al 1999]
  • Use of dialysis to treat persistent lactic acidosis and encephalopathy (successfully in 1 patient) [Elpeleg et al 1990]
  • Avoidance of liver-toxic medications

Episodes of catabolic stress (e.g., intercurrent illness, surgical procedures, pregnancy) require the assistance/care of a biochemical geneticist.

Limited data exist for chronic management of individuals with the primarily hepatic presentation. Between episodes, patients typically return to baseline and do not require treatment beyond the avoidance of fasting, catabolic stressors, and liver-toxic medications.

Prevention of Primary Manifestations

No compelling evidence exists for the prevention of acute episodes, despite multiple attempted dietary strategies and medications. The frequency of acute episodes decreases with age in most patients with DLD deficiency.

Although no specific therapy exists to prevent the neurologic dysfunction and/or the hepatic manifestations of DLD deficiency, avoidance of precipitating factors is recommended. As such, empiric recommendations include the following:

  • Provide protein intake at or around RDA and titrate based on growth and plasma amino acid values. See MSUD for the recommended intake and target levels of leucine, isoleucine, and valine.
  • Supplement with levocarnitine if deficient.
  • Avoid fasting, catabolic states, and extremes of dietary intake until dietary tolerance/stressors are identified.
  • Avoid liver-toxic medications.

Prevention of Secondary Complications

Age-appropriate immunizations including the influenza vaccine should be provided.

Dichloroacetate (DCA) has been associated with the development of peripheral neuropathy; thus, patients receiving this medication require close monitoring [Shaag et al 1999, Stacpoole et al 2008].

Surveillance

A patient’s primary care physician and biochemical geneticist should follow growth and development regularly. Developmental delays should be identified and treated as early as possible.

Plasma amino acid levels should be regularly followed to guide dietary management by the biochemical geneticist in conjunction with a qualified metabolic nutritionist.

Complications of DLD deficiency including hepatomegaly, cardiomyopathy, and CNS changes require regular surveillance if present.

Patients receiving dichloroacetate (DCA) need to be monitored for the development of peripheral neuropathy [Shaag et al 1999, Stacpoole et al 2008].

Agents/Circumstances to Avoid

Avoid the following:

  • Fasting
  • Catabolic stressors
  • Liver-toxic medications

Evaluation of Relatives at Risk

If the DLD pathogenic variants in an affected relative are known, at-risk sibs should undergo molecular genetic testing as soon as possible after birth so that those who have inherited both pathogenic variants can receive appropriate treatment and avoid risk factors that may precipitate an acute event. In some instances, families choose to perform prenatal testing so that treatment can begin shortly after birth for those who have inherited both pathogenic variants.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Dihydrolipoamide dehydrogenase (DLD) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with DLD deficiency are obligate heterozygotes (carriers) for a DLD pathogenic variant.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the DLD pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once both DLD pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantion genetic diagnosis for DLD deficiency are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Dihydrolipoamide Dehydrogenase Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
DLD7q31​.1Dihydrolipoyl dehydrogenase, mitochondrialDLD databaseDLDDLD

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Dihydrolipoamide Dehydrogenase Deficiency (View All in OMIM)

238331DIHYDROLIPOAMIDE DEHYDROGENASE; DLD
246900none found

Molecular Genetic Pathogenesis

Dihydrolipoamide dehydrogenase (DLD) functions as the E3 subunit in three mitochondrial enzyme complexes (BCKDH, αKGDH, PDH) and the L protein of the glycine cleavage system.

As the E3 subunit, it catalyzes the oxidative regeneration of the lipoic acid covalently bound to the E2 subunit, generating NADH in the process. DLD loss-of-function pathogenic variants lead to variable dysfunction of BCKDH, αKGDH, and PDH. The decreased activity of these three enzyme complexes leads to the often severe and variable phenotype seen in DLD deficiency.

To date no patient with DLD deficiency has presented with biochemical evidence of glycine cleavage system dysfunction (see Glycine Encephalopathy).

Additionally, multiple DLD pathogenic variants have been associated with elevated reactive oxygen species (ROS) generation [Vaubel et al 2011, Ambrus & Adam-Vizi 2013].

Gene structure. DLD comprises 14 exons and is approximately 30 kb long. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Variant types include missense, nonsense, small deletions, small insertions, and splice site variants [Quinonez et al 2013].

The c.685G>T (p.Gly229Cys) pathogenic variant is common in the Ashkenazi Jewish population. Carrier frequency is estimated at between 1:94 and 1:110 [Shaag et al 1999, Scott et al 2010].

Table 5.

DLD Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.685G>T 1p.Gly229CysNM_000108​.4
NP_000099​.2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Normal gene product. The normal gene product is dihydrolipoamide dehydrogenase, a 50-kd protein composed of 509 amino acids.

Abnormal gene product. Pathogenic variants cause the dihydrolipoamide dehydrogenase enzyme to be inactive or absent.

References

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Chapter Notes

Revision History

  • 17 July 2014 (me) Review posted live
  • 21 February 2014 (sq) Original submission
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