DLD

Dihydrolipoamide dehydrogenase (DLD) is a mitochondrial enzyme essential for energy metabolism, playing a key role in the pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and branched-chain α-ketoacid dehydrogenase complexes. 

Mutations in the DLD gene can lead to dihydrolipoamide dehydrogenase deficiency (DLDD), a rare metabolic disorder that disrupts mitochondrial function, resulting in lactic acidosis, neurological impairments, and multi-organ dysfunction.

What is Dihydrolipoamide Dehydrogenase (DLD)?

The DLD gene encodes dihydrolipoamide dehydrogenase (DLD), also known as E3, a key mitochondrial enzyme and flavoprotein (an enzyme containing flavin cofactors) essential for energy metabolism. DLD functions within three critical enzyme complexes:

• Pyruvate dehydrogenase complex (PDHC) – links glycolysis to the citric acid cycle.
• α-Ketoglutarate dehydrogenase complex (α-KGDHC) – a central component of the citric acid cycle.
• Branched-chain α-ketoacid dehydrogenase complex (BCKDH) – breaks down branched-chain amino acids.

DLD is also involved in the glycine cleavage system (GCS) and regulating oxidative stress.

DLD Deficiency (Dihydrolipoamide Dehydrogenase Deficiency, DLDD)

DLDD is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants in the DLD gene. It impairs mitochondrial function, leading to lactic acidosis, energy metabolism defects, and neurological, hepatic, or myopathic manifestations.

Clinical Presentations

The following clinical manifestations can occur with DLD deficiency:

Neurologic Form

Infantile-onset hypotonia, seizures, ataxia, developmental delay, and metabolic crises are often seen.

Hepatic Form

Episodes of acute liver failure, encephalopathy, coagulopathy, and metabolic acidosis occur, likely due to impaired cellular energy metabolism.

Myopathic Form

Muscle weakness, exercise intolerance, and elevated creatine kinase (CK), with some response to riboflavin, can all be seen in the myopathic form of DLD deficiency.

Diagnosis

Both biochemical and genetic testing are used for diagnosis of DLD deficiency.

• Biochemical Testing: elevated lactate, α-ketoglutarate, branched-chain ketoacids, and transaminases are key markers.
• Genetic Testing: genetic testing confirms biallelic pathogenic DLD variants. The c.685G>T (p.Gly229Cys) mutation is prevalent in Ashkenazi Jewish populations.
• Newborn Screening: may detect elevated citrulline, but sensitivity varies.

Management & Treatment

Managing DLD deficiency focuses on stabilizing metabolic crises, optimizing nutrition, and providing targeted pharmacologic support. 

During metabolic crises, immediate intervention includes IV glucose to prevent catabolism, bicarbonate therapy to correct acidosis, and temporary protein restriction to reduce metabolic burden, with gradual reintroduction once the crisis resolves. 

In severe cases, renal support, such as dialysis, may be necessary.

Dietary modifications are essential in long-term management, with controlled protein intake and amino acid-specific adjustments to prevent metabolic decompensation. 

Pharmacologic support includes dichloroacetate (DCA) to help manage lactic acidosis and riboflavin supplementation, particularly for patients with the myopathic form of the disease. Additional supportive care may be required for seizures, vision impairment, and cardiac dysfunction.

Preventive strategies focus on minimizing metabolic stress by avoiding fasting, catabolic triggers, and hepatotoxic medications. Early intervention and ongoing monitoring are essential to improve long-term outcomes for individuals with DLD deficiency.

Genetics & Family Screening

DLDD follows autosomal recessive inheritance. Carrier screening is recommended for families with a known history, especially in high-risk populations.

When is DLD Activity or Genetic Testing Relevant?

Testing for DLDD may be appropriate in the following clinical scenarios:

Suspected Mitochondrial Disorders

Individuals, especially infants or young children, exhibiting symptoms like lactic acidosis, developmental delays, seizures, muscle weakness, or feeding difficulties may be evaluated for DLD deficiency. 

Diagnostic approaches include measuring DLD activity in tissues such as muscle or fibroblasts and conducting genetic testing to identify mutations in the DLD gene.

Differential Diagnosis of Metabolic Disorders

DLD testing aids in distinguishing DLD deficiency from other metabolic disorders with overlapping symptoms.

Family Screening

For families with a known history of DLD deficiency, genetic testing can determine carrier status or assess the risk of having affected offspring.

It's important to note that DLD activity measurement isn't a standard test for the general population but is reserved for specific clinical scenarios.

Test Procedure and Interpretation

The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for DLD genetic testing are considered to be without mutations that can alter the activity of the DLD proteins.

Clinical Implications of Positive DLD Mutations

The clinical implications of a positive DLD mutation test result will vary by individual, although DLD mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of various neurological, metabolic, hepatic, and/or muscle symptoms.

Patients or practitioners with questions about the clinical implications of DLD mutations should seek further assessment with a genetic counselor or expert. 

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