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: 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.
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