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: 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 therapyies; total protein intake 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 pregnancies 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.)

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 at the most reasonable cost 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.

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.

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.

Treatment of Manifestations

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

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.