Clinical Guidance

Phenotypic severity is difficult to predict based on genotype and residual enzyme function . However, some correlations have been reported for individuals who have at least one (p.Gly229Cys) pathogenic variant:

• Normal intellectual functioning has been reported in individuals with early-onset disease with compound heterozygosity for the (p.Gly229Cys) pathogenic variant and an additional pathogenic allele.

• All individuals with an exclusively hepatic presentation have been homozygous for the (p.Gly229Cys) pathogenic variant .

Note: Individuals homozygous for the (p.Gly229Cys) pathogenic variant were initially thought to have a primarily hepatic presentation. Subsequently, individuals homozygous for (p.Gly229Cys) were found to have the early-onset neonatal neurologic presentation as well.

Source: GeneReviews — "Dihydrolipoamide Dehydrogenase Deficiency"

Diagnostic Criteria

Dihydrolipoamide dehydrogenase (DLD) functions as the E3 subunit of three mitochondrial enzyme complexes: branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, -ketoglutarate dehydrogenase (KGDH) complex, and pyruvate dehydrogenase (PDH) complex . 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.

Source: GeneReviews — "Dihydrolipoamide Dehydrogenase Deficiency"

Differential Diagnosis

Early-onset neurologic presentation Table 5. Genes of Interest in the Differential Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency

Management Guidelines

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 involved 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

Source: GeneReviews — "Dihydrolipoamide Dehydrogenase Deficiency"

Clinical Guidance

Avoid the following:

• Fasting

• Catabolic stressors

• Extremes of dietary intake until dietary tolerance/stressors are identified

• Liver-toxic medications

Source: GeneReviews — "Dihydrolipoamide Dehydrogenase Deficiency"

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.

Source: GeneReviews — "Dihydrolipoamide Dehydrogenase Deficiency"

Surveillance Guidelines

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) | • For rapidly growing infants, monitoring weekly or 2x weekly

• Routinely in older persons1

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

| • Physical exam /or US to assess size of liver

• Blood measurements of liver transaminases assessment of liver synthetic function

| At each visit

Neurologic

| Physical exam to evaluate for peripheral neuropathy EMG if clinically concerned4

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; US = ultrasound

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.

Source: GeneReviews — "Dihydrolipoamide Dehydrogenase Deficiency"