Dihydrolipoamide Dehydrogenase Deficiency
Summary
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.
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 2013]. The E3 subunit is responsible for the reoxidation of the reduced lipoyl moiety of the E2 subunit. Although DLD also functions as the L protein of the glycine cleavage system, pathogenic variants in DLD do not appear 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 primarily myopathic presentation.
No formal clinical diagnostic criteria have been established for dihydrolipoamide dehydrogenase (DLD) deficiency.
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 kinaseWhile 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
Metabolite | Presentation | Normal | ||
---|---|---|---|---|
Neurologic | Hepatic | Myopathic | ||
Plasma lactate | ↑ | ↑ | Normal to ↑ | <2.2 µmol/L |
Urine α-ketoglutarate | Normal to ↑ | Typically normal | Normal to ↑ |
|
Urine branched-chain ketoacids | Absent to ↑ | Typically absent | Absent to ↑ |
|
Plasma leucine | Normal to ↑ | Typically normal | Normal to ↑ |
|
Plasma isoleucine | Normal to ↑ | Typically normal | Normal to ↑ |
|
Plasma valine | Normal to ↑ | Typically normal | Normal to ↑ |
|
Plasma allo-isoleucine | Normal to ↑ | Typically normal | Normal to ↑ | <5 µmol/L |
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.
Table 2.
Molecular Genetic Testing Used in Dihydrolipoamide Dehydrogenase Deficiency
Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
---|---|---|
DLD | Sequence analysis 3 | 42/43 (98%) 4 |
Gene-targeted deletion/duplication analysis 5 | Unknown 6 | |
Targeted analysis for pathogenic variants 7 | See footnote 8. |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants.
- 3.
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.
- 4.
Quintana et al [2010], Brassier et al [2013], Quinonez et al [2013], Carrozzo et al [2014], Haviv et al [2014], Bravo-Alonso et al [2019]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
No deletions or duplications involving DLD have been reported to cause dihydrolipoamide dehydrogenase deficiency.
- 7.
Variant panels may differ by laboratory.
- 8.
The c.685G>T (p.Gly229Cys) pathogenic variant is common in Ashkenazi Jews (see Prevalence).
Clinical Characteristics
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
Disease Features | Frequency 1 | % | |
---|---|---|---|
Clinical presentation 2 | Hypotonia | 16/25 | 64 |
Developmental delay | 12/25 | 48 | |
Emesis | 12/25 | 48 | |
Hepatomegaly | 10/25 | 40 | |
Lethargy | 8/25 | 32 | |
Seizures | 7/25 | 28 | |
Spasticity (hypertonia &/or hyperreflexia) | 7/25 | 28 | |
Leigh syndrome phenotype | 6/25 | 24 | |
Failure to thrive | 6/25 | 24 | |
Microcephaly | 5/25 | 20 | |
Vision impairment | 4/25 | 16 | |
Ataxia | 3/25 | 12 | |
Cardiac involvement | 3/25 | 12 | |
Laboratory abnormalities | Metabolic acidosis 3 | 22/25 | 88 |
↑ plasma lactate 4 | 18/25 | 72 | |
↑ urine α-ketoglutarate 4 | 13/25 | 52 | |
Hypoglycemia 5 | 12/25 | 48 | |
↑ plasma BCAA 4 | 10/25 | 40 | |
↑ transaminases | 11/25 | 44 | |
↑ urine branched-chain ketoacids 4 | 7/25 | 28 | |
Hepatic failure | 5/25 | 20 | |
↑ plasma allo-isoleucine 4 | 4/25 | 16 | |
Low free plasma carnitine 6 | 3/25 | 12 | |
Hyperammonemia 7 | 4/25 | 16 |
Includes only individuals biochemically confirmed to have DLD deficiency
BCAA = branched-chain amino acids
- 1.
Quinonez et al [2013], Bravo-Alonso et al [2019]
- 2.
Later physical examination and neurologic findings are likely underrepresented, as children with an early-onset presentation frequently die in the 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
- 7.
Ammonia >100 µmol/L in neonates or >60 µmol/L in infants, children, and adults
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
Disease Features | Frequency 1 | % | |
---|---|---|---|
Clinical presentation | Nausea/emesis | 13/13 | 100 |
Hepatomegaly | 9/13 | 69 | |
Hepatic encephalopathy | 7/13 | 54 | |
Muscle cramps | 3/13 | 23 | |
Behavioral disturbances | 1/13 | 8 | |
Optic atrophy | 1/13 | 8 | |
Laboratory abnormalities | ↑ transaminases | 13/13 | 100 |
Coagulopathy | 11/13 | 85 | |
↑ lactate 2 | 10/13 | 77 | |
Hyperammonemia 3 | 8/13 | 62 | |
Hypoglycemia 4 | 5/13 | 38 | |
↑ urine α-ketoglutarate 2 | 2/13 | 15 | |
Low carnitine 5 | 1/13 | 8 | |
↑ plasma BCAA 2 | 1/13 | 8 |
Includes only individuals biochemically confirmed to have DLD deficiency
BCAA = branched-chain amino acids
- 1.
Brassier et al [2013]
- 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
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.
Myopathic Presentation
Two individuals have been described with a phenotype consisting of primarily myopathic symptoms [Quintana et al 2010, Carrozzo et al 2014]. One of these people additionally exhibited ptosis, weakness, and elevated creatine kinase and lactate [Quintana et al 2010]. The other also experienced early episodes of hypotonia, lethargy, acidosis, and lactic acid elevations without CK elevations. In adolescence this individual developed myalgias, weakness, fatigue, significant hyperCKemia and transaminitis with significant improvement of all signs and symptoms with riboflavin supplementation [Carrozzo et al 2014].
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.
Differential Diagnosis
Early-onset neurologic presentation
Table 5.
Genes of Interest in the Differential Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency
Gene(s) | Disorder | MOI | Features of Differential Diagnosis Disorder | Distinguishing Features |
---|---|---|---|---|
BCKDHA BCKDHB DBT | Maple syrup urine disease (MSUD) types 1 & 2 | AR | Age 12-24 hrs. Maple syrup odor in cerumen, ↑ plasma concentrations of BCAAs 2 & allo-isoleucine, & generalized disturbance of plasma amino acid concentration ratios Age 2-3 days. Ketonuria, irritability, & poor feeding Age 4-5 days. Deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, & stereotyped movements (e.g., "fencing" & "bicycling") Age 7-10 days. Possible coma & central respiratory failure |
|
BOLA3 IBA57 LIAS LIPT1 NFU1 | Defects in lipoic acid metabolism (OMIM 605711, 614299, 614462, 615330, 616299) | AR | Neonatal lactic acidosis & a biochemical phenotype similar to DLD deficiency 3 | Unlike DLD deficiency, children w/defects in lipoic acid metabolism (except LIPT1 deficiency) have ↑ glycine in body fluids. |
DLAT LIAS PDHA1 PDHB PDHX PDP1 | Pyruvate dehydrogenase complex (PDHC) deficiency (OMIM PS312170) | AR XL 4 | Most commonly presents w/neurologic impairment, hypotonia, structural brain abnormalities, & lactic acidosis w/a normal lactate:pyruvate ratio 1 | While clinical findings & preliminary lab values are similar, DLD deficiency is often also assoc w/: (a) defective αKGDH w/↑ urine α-ketoglutarate & (b) BCKDH complex dysfunction w/↑ plasma BCAAs & urine branched-chain ketoacids. |
αKGDH = α-ketoglutarate dehydrogenase; AR = autosomal recessive; BCAA = branched-chain amino acid; BCKDH = branched-chain α-ketoacid dehydrogenase; DD = developmental delay; DLD = dihydrolipoamide dehydrogenase; MOI = mode of inheritance; PDH = pyruvate dehydrogenase; XL = X-linked
- 1.
Patel et al [2012]
- 2.
Leucine, isoleucine, and valine
- 3.
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) [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].
- 4.
PDHC deficiency is inherited in an autosomal recessive manner with the exception of pyruvate dehydrogenase E1-alpha deficiency (caused by mutation of PDHA1). See OMIM 312170.
Isolated α-ketoglutarate dehydrogenase deficiency (OMIM 203740) has been reported in two sets of consanguineous sibs with choreoathetoid movements, hypotonia, developmental delay, and lactic acidosis. All affected individuals exhibited isolated elevations of α-ketoglutarate in the urine.
Elevated citrulline on newborn screening dried blood spot has been identified in three symptomatic individuals with DLD deficiency [Haviv et al 2014, Quinonez 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, argininosuccinate lyase deficiency, citrullinemia type II (citrin deficiency), and pyruvate carboxylase deficiency should be investigated.
Isolated liver involvement has a broad differential and an underlying cause is not identified in up to 50% of cases. NBAS deficiency (OMIM 616483) and other inborn errors of metabolism, including fatty acid oxidation disorders (e.g., very long chain acyl-CoA dehydrogenase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, and short-chain acyl-CoA dehydrogenase deficiency), mitochondrial disorders, and disorders of the carnitine cycle (e.g., systemic primary carnitine deficiency and carnitine palmitoyltransferase II deficiency) should be considered [Haack et al 2015]. A comprehensive biochemical workup followed by genetic testing if indicated will appropriately evaluate for the various genetic conditions in the differential diagnosis.
Management
Consensus recommendations for the management of DLD deficiency do not currently exist. Theoretic difficulties exist for the management of affected individuals 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.
When dihydrolipoamide dehydrogenase (DLD) deficiency is suspected during the diagnostic evaluation, treatment should be initiated immediately.
Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.
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
System/Concern | Evaluation | Comment |
---|---|---|
Metabolic decompensation | Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietitian 1 | Transfer to a specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended) |
STAT blood gas (arterial or venous), ammonia, lactic acid, CK, & glucose | Urgent labs to be obtained if an acute metabolic crisis is suspected | |
Plasma free & total carnitine, plasma amino acids, & urine organic acids | To be obtained during a period of acute metabolic decompensation, if possible | |
Hepatic | Measure liver transaminases (AST, ALT) & assess liver synthetic function. | |
Assessment of liver size | Via physical exam &/or ultrasonography | |
Neurologic | Evaluate for seizures | Consider EEG if concerned. |
Cardiac | Echocardiogram | To assess for cardiac dysfunction & hypertrophy |
Table 7.
Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in a Stabilized Neonate/Infant
System/Concern | Evaluation | Comment |
---|---|---|
Constitutional | Assessment of growth parameters | |
Neurologic | Neurologic eval | Consider:
|
Eyes | Ophthalmologic eval | If concerns for vision loss |
Miscellaneous/ Other | Consultation w/psychologist &/or social worker | To ensure understanding of diagnosis & assessment of parental coping skills & resources |
Table 8.
Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in an Older Child or Adult
System/Concern | Evaluation | Comment |
---|---|---|
Hepatic | Measurement of liver transaminases (AST, ALT) & assessment of liver synthetic function | |
Eyes | Ophthalmologic eval | If concerns for vision loss or ptosis |
Metabolic |
| Laboratory studies should be obtained urgently if an acute metabolic crisis is suspected or routinely as part of baseline testing for those w/hepatic or myopathic forms. |
Neurologic | Assessment for muscular weakness | If myopathic form is suspected |
Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling |
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
Principle/Manifestation | Treatment | Consideration/Other |
---|---|---|
Protein/BCAA restriction 1, 2, 3 | BCAA-free powder formula | Leucine tolerance for neonates: 65-85 mg/kg/day |
Natural protein as a source of essential & nonessential amino acids: 2-3 g/kg/day |
| |
Defective carbohydrate oxidation | Ketogenic/high-fat diet 5 | Of 7 individuals treated:
|
Inhibition of PDH kinase activity | DCA supplementation (50-75 mg/kg/day) |
|
Poor weight gain / Failure to thrive | Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. | Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia |
Developmental delay / Intellectual disability | Standard treatment per developmental pediatrician / neurodevelopmental team | Incl PT, OT, & speech therapy as indicated |
Cardiac dysfunction | Standard treatment per cardiologist | |
Vision impairment / Optic atrophy | Standard treatment per ophthalmologist |
BCAA = branched-chain amino acids; DCA = dichloroacetate; OT = occupational therapy; PDH = pyruvate dehydrogenase; PT = physical therapy
- 1.
Recommendations are based on decreased branched-chain α-ketoacid dehydrogenase (BCKDH) complex activity.
- 2.
Restriction of protein to recommended dietary allowances has been attempted with questionable results.
- 3.
Three of the six reported individuals experienced laboratory and/or clinical improvement with the use of protein restriction alone or in combination with medication therapy.
- 4.
For rapidly growing infants, monitoring weekly or twice weekly is recommended.
- 5.
Ketogenic/high-fat diets are frequently employed in individuals who have pyruvate dehydrogenase (PDH) complex deficiency [Patel et al 2012].
- 6.
One was treated with lipid infusions (instead of high-dextrose infusions) during acute episodes [Hong et al 1997, Cerna et al 2001].
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
Manifestation/Concern | Treatment | Consideration/Other |
---|---|---|
Underlying precipitating factors | Any precipitating factors (infection, fasting, medications) should be treated/discontinued as soon as possible. | |
Metabolic acidosis |
|
|
Promotion of an anabolic state | D10 (half or full-normal saline) w/age-appropriate electrolytes should be started at maintenance rate & adjusted based on presence or absence of ↑ intracranial pressure or hypoglycemia. |
|
Correction of ↑ leucine concentration 3 |
| BCAAs should be introduced slowly & followed closely w/frequent plasma amino acid evaluations; see also MSUD. |
Consider renal replacement therapies in clinical settings w/appropriate resources & expertise | When hemodialysis is used it must be coupled w/effective nutritional mgmt to constrain the catabolic response & prevent recurrent clinical intoxication. 4 | |
Total protein intake (enteral + parenteral): 2-3.5 g/kg/day as BCAA-free amino acids | For individuals of any age who can tolerate enteral feeding (even if intubated), continuous nasogastric delivery (30-60 mL/hr) of a BCAA-free formula (0.7-1.2 kcal/mL) supplemented w/1% liquid solutions of isoleucine & valine can meet protein goals while providing additional calories. | |
Isoleucine & valine supplements (enteral + parenteral): 20-120 mg/kg/day each; titrate to plasma concentrations of 400-800 µmol/L | For parenteral administration, isoleucine & valine are each prepared as separate 1% solutions in normal saline. | |
Maintain serum osmolality w/in normal reference range (i.e., 275-300 mOsm/kg H2O). 5 | Establish euvolemia using isotonic sodium chloride solutions. | Overhydration & quickly infused boluses of fluids should be avoided if possible. |
Measure serum osmolality & electrolytes every 6-12 hrs. | Prevent serum osmolality from decreasing >5 mOsm/kg H2O per day (0.20 mOsm/kg H2O per hr). | |
Hypoglycemia |
|
|
Hyperammonemia |
| Although IV sodium benzoate + sodium phenylacetate have been used in such circumstances, their utility in DLD deficiency is doubtful, as most hyperammonemia is accompanied/caused by liver dysfunction, which is responsible for metabolism of nitrogen scavenger medications as well. |
Carnitine deficiency | Levocarnitine (IV or PO) 50-100 mg/kg/day divided three times per day should be given during the acute period. | |
Lactic acidosis | DCA can be considered & continued. |
|
Seizures | Standardized treatment w/AEDs by experienced neurologist |
|
AEDs = antiepileptic drugs; BCAAs = branched-chain amino acids; DCA = dichloroacetate; IV = intravenous; MSUD = maple syrup urine disease; PO = orally
- 1.
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 individuals. Only one affected individual experienced worsening acidosis with increased dextrose concentrations in the TPN.
- 2.
Note that bicarbonate therapy alone is not sufficient to correct the metabolic acidosis. Correction of metabolic acidosis relies on reversing the catabolic state by providing calorie support from glucose and interlipids.
- 3.
See also Maple Syrup Urine Disease, Management.
- 4.
Dialysis without simultaneous management of the underlying disturbance of protein turnover is analogous to treating diabetic ketoacidosis with invasive removal of glucose and ketones rather than insulin infusion. In both conditions, effective treatment depends not only on lowering concentrations of pathologic metabolites, but also on controlling the underlying metabolic derangement.
- 5.
To help avoid increased intracranial pressure
- 6.
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.
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
Principle/Manifestation | Treatment | Consideration/Other |
---|---|---|
Underlying precipitating factors | Any precipitating factors (infection, fasting, medications) should be treated/discontinued as soon as possible. | Avoidance of liver-toxic medications (See Agents/Circumstances to Avoid.) |
Nutritional support | Dextrose-containing IV fluids (6-8 mg/kg/min) w/age-appropriate electrolytes &/or frequent feedings | |
Metabolic acidosis | Consider correction using sodium bicarbonate (see Table 10). | |
Lactic acidosis | DCA can be considered. | If lactate decreases w/its introduction |
Consideration of dialysis | If persistent lactic acidosis & encephalopathy 2 | |
Coagulopathy | Fresh frozen plasma |
DCA = dichloroacetate; IV = intravenous
- 1.
Brassier et al [2013]
- 2.
Successful in one affected individual
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.
Myopathic Presentation
At least one affected individual with severe exercise intolerance responded well to riboflavin supplementation (220 mg/day), with resolution of symptoms [Carrozzo et al 2014].
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
System/Concern | Evaluation | Frequency/Comment |
---|---|---|
Feeding | Measurement of growth parameters & eval of nutritional status & safety of oral intake | At each visit |
Control of plasma amino acid levels | Full amino acid profile (either from plasma or filter paper) |
|
Visit w/metabolic specialist | At least monthly in infancy | |
Delayed acquisition of developmental milestones | Monitor developmental milestones. 2, 3 | At each visit or as needed |
Hepatomegaly |
| At each visit |
Neurologic | Physical exam to evaluate for peripheral neuropathy & EMG if clinically concerned 4 | |
Musculoskeletal | Physical medicine, OT/PT assessment of mobility, self-help skills | |
Cardiomyopathy | Echocardiogram | At least annually or based on clinical status |
Eyes | Ophthalmologic eval | As clinically indicated |
OT = occupational therapy; PT = physical therapy
- 1.
The frequency of amino acid monitoring varies by age, metabolic stability, compliance, and regional clinical practice and should be guided by a biochemical geneticist in conjunction with a qualified metabolic nutritionist.
- 2.
The Denver Developmental Screening Test II or a comparable tool is useful for monitoring development of infants and young children.
- 3.
School-age children, adolescents, and adults should have neurocognitive testing if indicated by school performance or behavioral problems.
- 4.
In individuals receiving dichloroacetate.
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.