Dihydrolipoamide Dehydrogenase Deficiency

Clinical characteristics.

The phenotypes of dihydrolipoamide dehydrogenase (DLD) deficiency are an overlapping continuum that ranges from early-onset neurologic manifestations to adult-onset liver involvement and, rarely, a myopathic presentation. Early-onset DLD deficiency typically manifests in infancy as hypotonia 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 affected individuals 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. Individuals with the myopathic presentation may experience muscle cramps, weakness, and an elevated creatine kinase.

Diagnosis/testing.

The diagnosis of dihydrolipoamide dehydrogenase deficiency (DLD) is established in a proband with suggestive clinical and supportive laboratory findings and/or by identification of biallelic pathogenic variants in DLD.

Management.

Treatment of manifestations:

• Routine daily treatment for those with the early-onset neurologic presentation: protein intake at approximately recommended dietary allowance (RDA); if there is evidence of significant hyperleucinosis, protein intake should consist of branched-chain amino acid (BCAA)-free powder formula with 2-3 g/kg/day natural protein; ketogenic/high-fat diet; dichloroacetate (DCA) supplementation (50-75 mg/kg/day); feeding therapy and consideration of gastrostomy tube for persistent feeding issues; standard treatment for developmental delay / intellectual disability, cardiac dysfunction, and vision impairment / optic atrophy.
• Acute inpatient treatment for those with early-onset neurologic presentation: address any precipitating factors (infection, fasting, medications); D₁₀ (half or full-normal saline) with age-appropriate electrolytes; consideration of bicarbonate therapy for those with severe metabolic acidosis; withholding of protein for a maximum of 24 hours; consideration of renal replacement therapies; total protein intake at RDA; if there is evidence of significant hyperleucinosis, protein intake should be adjusted to provide 2-3.5 g/kg/day as BCAA-free amino acids; isoleucine and valine supplements; maintain serum osmolality within the normal reference range; levocarnitine (IV or PO) 50-100 mg/kg/day divided three times per day; continuation of DCA; standard therapy for seizures.
• For hepatic presentation: removal or treatment of precipitating factors; dextrose-containing IV fluids (6-8 mg/kg/min) with age-appropriate electrolytes and/or frequent feedings; consider correction of metabolic acidosis using sodium bicarbonate; consideration of DCA and/or dialysis; consideration of fresh frozen plasma for coagulopathy.
• For the myopathic presentation: At least one affected individual with severe exercise intolerance responded well to riboflavin supplementation (220 mg/day).

Prevention of primary manifestations: No compelling evidence exists for the prevention of acute episodes, despite multiple attempted dietary strategies and medications. Provide protein intake at or around recommended dietary allowance and titrate based on growth and plasma amino acid values; supplementation with levocarnitine, if deficient.

Prevention of secondary complications: DCA has been associated with the development of peripheral neuropathy; thus, individuals receiving this medication require close monitoring.

Surveillance: Measurement of growth parameters and evaluation of nutritional status and safety of oral intake at each visit; full amino acid profile (from plasma or filter paper) weekly or twice weekly in rapidly growing infants and routinely in older individuals; at least monthly visit with a metabolic specialist in infancy; assessment of developmental milestones at each visit or as needed; physical examination and/or ultrasound to assess liver size, measurement of liver transaminases and liver synthetic function, and assessment for peripheral neuropathy at each visit; echocardiogram at least annually or based on clinical status; ophthalmologic evaluation as clinically indicated.

Agents/circumstances to avoid: Fasting, catabolic stressors, and extremes of dietary intake until dietary tolerance/stressors are identified; liver-toxic medications.

Evaluation of relatives at risk: Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of DLD deficiency and to avoid risk factors that may precipitate an acute event. For at-risk newborn sibs when molecular genetic prenatal testing was not performed: in parallel with NBS either test for the familial DLD pathogenic variants or measure plasma lactate, plasma amino acids, and urine organic acids.

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 a pregnancy at increased risk are possible if the DLD pathogenic variants in the family are known.

Suggestive Findings

The diagnosis of dihydrolipoamide dehydrogenase (DLD) deficiency should be suspected in individuals with the following clinical and supportive laboratory findings.

Clinical findings

• 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.
  • Neurologic impairment presents in those who survive the first year of life.
• Hepatic. Recurrent liver injury/failure frequently preceded by nausea and emesis
  • Age of onset ranges from the neonatal period to the third decade.
  • Individuals with the hepatic form typically have normal intellect with no residual neurologic deficit between acute metabolic episodes unless neurologic damage has occurred.
• Myopathic. Muscle cramps, weakness, and an elevated creatine kinase
  While muscle involvement is the main feature in previously reported individuals, additional findings include intermittent acidosis and hepatic involvement [Quintana et al 2010, Carrozzo et al 2014].

Supportive laboratory findings

• Newborn screening (NBS). Citrulline is elevated on NBS dried blood spot [Haviv et al 2014, Quinonez et al 2014].
  Note: (1) 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; (2) 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; (3) DLD deficiency is not listed as a condition on the differential diagnosis for an increased citrulline on the ACMG ACT Sheet and is not currently reported on most NBS panels.
• Abnormal laboratory findings typically associated with the neurologic presentation:
  • 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
  • Hypoglycemia. <40 mg/dL (<2.2 mmol/L)
  • Other metabolic abnormalities listed in Table 1
• Laboratory findings typically associated with the hepatic presentation:
  • Elevated lactate level (>2.2 µmol/L)
  • Isolated elevated transaminases to fulminant hepatic failure
  • Absence of other metabolic abnormalities (See Table 1.)
• Laboratory findings typically associated with the myopathic presentation:
  • Normal-to-elevated serum creatinine kinase (CK) level, up to 20 times the normal range during acute episodes (<192 U/L) [Carrozzo et al 2014]
  • Occasionally elevated transaminases, lactate, and other metabolic abnormalities (See Table 1.)

Table 1.

Metabolic Abnormalities in DLD Deficiency by Presentation

Establishing the Diagnosis

The diagnosis of dihydrolipoamide dehydrogenase deficiency (DLD) is established in a proband with suggestive clinical and supportive laboratory findings (see Table 1) AND/OR by identification of biallelic pathogenic variants in DLD (see Table 2).

Note: The presence of decreased DLD enzymatic activity in fibroblasts, lymphocytes, or liver tissue can also be used to establish the diagnosis but is not recommended as a first-line test, given the general availability of molecular genetic testing.

When laboratory findings suggest the diagnosis of DLD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of DLD is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants.

• Targeted analysis for the c.685G>T (p.Gly229Cys) pathogenic variant may be considered first in individuals of Ashkenazi Jewish ancestry.
• Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.
• If only one or no variant is detected by the sequencing method used, the gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications may be considered.

A multigene panel that includes DLD and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 2.

Molecular Genetic Testing Used in Dihydrolipoamide Dehydrogenase Deficiency

Clinical Description

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

Early-Onset Neurologic Presentation

The most frequent clinical finding 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. Typically, seizures are generalized tonic-clonic and occur during episodes of metabolic decompensation and not during periods when affected individuals are metabolically stable [Quinonez et al 2013]. Medication-refractory epilepsy has been seen in one affected individual with neurologic impairment secondary to metabolic decompensation [Author, personal observation]. Of note, normal intellectual functioning has been reported in individuals with certain genotypes (see Genotype-Phenotype Correlations).

Table 3.

Features of the Early-Onset Neurologic Phenotype

Metabolic phenotype. 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).

• Some affected individuals have experienced worsening of clinical status with high-fat diets [Brassier et al 2013], while others have achieved metabolic control with ketogenic diets (see Management).
• Some individuals with DLD deficiency have features of Leigh syndrome [Quinonez et al 2013]. Leigh syndrome consists of characteristic clinical findings and brain pathology.
  The diagnostic criteria for Leigh syndrome include: (1) progressive neurologic disease with motor and intellectual developmental delay; (2) signs and features of brain stem or basal ganglia disease; (3) elevated lactate levels in the blood or cerebrospinal fluid; and (4) one or more of three features:
  • Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T₂-weighted MRI)
  • Typical neuropathologic changes at postmortem examination
  • Typical neuropathology in a similarly affected sib

Liver abnormalities. Hepatomegaly and liver dysfunction/failure (elevated transaminases, synthetic failure) can occur during acute episodes and occasionally are the cause of death.

• Between acute episodes both liver size and transaminase levels can return to normal.
• Liver biopsies have shown increased glycogen content and mild fibrosis or fatty, acute necrosis with a Reye syndrome-like appearance.

Cardiac dysfunction. Hypertrophic cardiomyopathy was reported in two affected individuals and "myocardial dysfunction" in one.

Hyperammonemia (≤250 µmol/L) is sometimes observed at the time of initial presentation, although this is typically associated with various degrees of hepatic injury/failure [Quinonez et al 2013, Bravo-Alonso et al 2019].

Vision impairment/optic atrophy can occur, with progression to full blindness reported.

Hepatic Presentation

Affected individuals 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 [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 affected individuals, including those who presented later in life. The hepatic manifestations of these individuals are typically only present during acute episodes, while other findings (muscle cramps, behavioral disturbances, and vision loss) have been reported when affected individuals are clinically well.

Table 4.

Features of the Hepatic Phenotype

Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes (see Management) affected individuals 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 individuals 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 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), and differentiation of the two types can be difficult, especially in neonates. To date, the only affected individual 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. Therefore, the absence of hypotonia and neurologic deficit and the presence of hepatic signs are useful discriminating features.

Genotype-Phenotype Correlations

Phenotypic severity is difficult to predict based on genotype and residual enzyme function [Quinonez et al 2013]. However, some correlations have been reported for individuals who have at least one c.685G>T (p.Gly229Cys) pathogenic variant:

• 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.
• All individuals with an exclusively hepatic presentation have been homozygous for the c.685G>T (p.Gly229Cys) pathogenic variant [Brassier et al 2013].
  Note: Individuals homozygous for the c.685G>T (p.Gly229Cys) pathogenic variant were initially thought to have a primarily hepatic presentation. Subsequently, individuals homozygous for c.685G>T (p.Gly229Cys) were found to have the early-onset neonatal neurologic presentation as well.

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.

DLD deficiency may also be referred to as lipoamide dehydrogenase deficiency.

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 [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 are unknown; DLD deficiency is likely very rare.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with dihydrolipoamide dehydrogenase (DLD) deficiency, the evaluations summarized in the following tables (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6.

Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in an Ill Neonate

Table 7.

Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in a Stabilized Neonate/Infant

Table 8.

Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in an Older Child or Adult

Treatment of Manifestations

Early-Onset Neurologic Presentation

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, if they survive the initial episode, experience various degrees of chronic neurologic impairment.

Table 9.

Routine Daily Treatment in Individuals with Early-Onset Neonatal Dihydrolipoamide Dehydrogenase Deficiency

Additional therapies used with limited success include the following:

• Thiamine
• Coenzyme Q₁₀
• Lipoic acid
• Riboflavin (though effective in one person with the myopathic form of DLD deficiency)
• Biotin

Table 10.

Acute Inpatient Treatment in Individuals with Early-Onset Neonatal Dihydrolipoamide Dehydrogenase Deficiency

Hepatic Presentation

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

Table 11.

Acute Treatment in Individuals with Acute Liver Injury or Failure Due to Dihydrolipoamide Dehydrogenase Deficiency

Limited data exist for chronic management of individuals with the primarily hepatic presentation. Between episodes, affected individuals 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 all forms of DLD deficiency.

• Provide protein intake at or around recommended dietary allowance and titrate based on growth and plasma amino acid values. See Maple Syrup Urine Disease for the recommended intake and target levels of leucine, isoleucine, and valine.
• Supplement with levocarnitine if deficient.

Prevention of Secondary Complications

Dichloroacetate has been associated with the development of peripheral neuropathy; thus, individuals receiving this medication require close monitoring.

Surveillance

Table 12.

Recommended Surveillance for Individuals with Dihydrolipoamide Dehydrogenase Deficiency

Agents/Circumstances to Avoid

Avoid the following:

• Fasting
• Catabolic stressors
• Extremes of dietary intake until dietary tolerance/stressors are identified
• Liver-toxic medications

Evaluation of Relatives at Risk

Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of DLD deficiency and to avoid risk factors that may precipitate an acute event. For at-risk newborn sibs when molecular genetic prenatal testing was not performed: in parallel with newborn screening, either test for the familial DLD pathogenic variants or measure plasma lactate, plasma amino acids, and urine organic acids.

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 EU Clinical Trials Register 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.

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., presumed to be carriers of one DLD pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a DLD pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If each parent is known to be heterozygous for a DLD pathogenic variant, each sib of an affected individual has at conception 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.
• 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 pathogenic variant in DLD.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a DLD pathogenic variant.

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/preimplantation genetic 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. 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 from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular 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 person 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 generation [Vaubel et al 2011, Ambrus & Adam-Vizi 2013].

Mechanism of disease causation. DLD deficiency is caused by biallelic pathogenic variants in DLD that result in decreased function or loss of function.

Table 13.

Notable DLD Pathogenic Variants

Revision History

• 30 September 2021 (sq) Revision: in Treatment of Manifestations: protein intake and hyperleucinosis
• 9 July 2020 (ma) Comprehensive update posted live
• 17 July 2014 (me) Review posted live
• 21 February 2014 (sq) Original submission

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