Dihydrolipoamide dehydrogenase deficiency

Other Names: Pyruvate dehydrogenase E3 deficiency; DLD deficiency; E3-deficient maple syrup urine disease; E3 deficiency; Maple syrup urine disease, type III

Dihydrolipoamide dehydrogenase (DLD) deficiency is a very rare condition that can vary in age of onset, symptoms and severity. The condition may be characterized by early-onset lactic acidosis and delayed development (most commonly); later-onset neurological dysfunction; or adult-onset isolated liver disease.

Epidemiology

Dihydrolipoamide dehydrogenase deficiency occurs in an estimated 1 in 35,000 to 48,000 individuals of Ashkenazi Jewish descent. This population typically has liver disease as the primary symptom. In other populations, the prevalence of dihydrolipoamide dehydrogenase deficiency is unknown, but the condition is likely rare.

Cause

Mutations in the DLD gene cause dihydrolipoamide dehydrogenase deficiency. This gene provides instructions for making an enzyme called dihydrolipoamide dehydrogenase (DLD). DLD is one component of three different groups of enzymes that work together (enzyme complexes): branched-chain alpha-keto acid dehydrogenase (BCKD), pyruvate dehydrogenase (PDH), and alpha (α)-ketoglutarate dehydrogenase (αKGDH). The BCKD enzyme complex is involved in the breakdown of three protein building blocks (amino acids) commonly found in protein-rich foods: leucine, isoleucine, and valine. Breakdown of these amino acids produces molecules that can be used for energy. The PDH and αKGDH enzyme complexes are involved in other reactions in the pathways that convert the energy from food into a form that cells can use.

Mutations in the DLD gene impair the function of the DLD enzyme, which prevents the three enzyme complexes from functioning properly. As a result, molecules that are normally broken down and their byproducts build up in the body, damaging tissues and leading to lactic acidosis and other chemical imbalances. In addition, the production of cellular energy is diminished. The brain is especially affected by the buildup of molecules and the lack of cellular energy, resulting in the neurological problems associated with dihydrolipoamide dehydrogenase deficiency. Liver problems are likely also related to decreased energy production in cells. The degree of impairment of each complex contributes to the variability in the features of this condition.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

The signs and symptoms of dihydrolipoamide dehydrogenase (DLD) deficiency can vary widely among affected people. Early-onset DLD deficiency typically appears in early infancy with decreased muscle tone (hypotonia), lethargy, and lactic acidosis.

Lactic acidosis can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. Symptoms typically occur in episodes that may be triggered by illness, injury, or other stresses on the body. Affected infants often do not survive their initial episode or may die within the first few years of life during a recurrent episode.

Children who live beyond the first two to three years often have growth delays and neurological problems such as intellectual disability, spasticity, ataxia, and seizures. However, normal intellect has been reported in a few people with the early-onset form of DLD deficiency.

Isolated liver involvement, which can range from hepatomegaly (enlarged liver) to life-threatening liver failure, can also occur in the newborn period, or as late as the 3rd decade of life. A few people with DLD deficiency have become affected later in childhood with ataxia and dystonia, with normal cognitive development. Rarely, affected people have muscle weakness (particularly during exercise) or a weakened heart muscle (cardiomyopathy).

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Generalized [[hypotonia](Decreased muscle tone)
• Global developmental delay
• Increased serum lactate
• Lactic acidosis(Increased lactate in body)
• Neurodevelopmental delay
• Vomiting(Throwing up)

30%-79% of people have these symptoms

• Elevated hepatic transaminase(High liver enzymes)
• Elevated plasma branched chain amino acids
• Feeding difficulties(Feeding problems)
• Hepatic encephalopathy
• [[Hepatomegaly](Enlarged liver)
• Hypercoagulability
• Hypoglycemia(Low blood sugar)
• Increased urine alpha-ketoglutarate concentration
• Lethargy
• Seizure
• Spasticity(Involuntary muscle stiffness, contraction, or spasm)

5%-29% of people have these symptoms

• Abnormal cardiac ventricular function
• Ataxia
• Behavioral abnormality(Behavioral changes)
• Cardiomyopathy(Disease of the heart muscle)
• Decreased liver function(Liver dysfunction)
• Decreased plasma carnitine
• Failure to thrive(Faltering weight)
• Hepatic failure(Liver failure)
• Hyperammonemia(High blood ammonia levels)
• Hyperisoleucinemia(High blood isoleucine concentration)
• Microcephaly(Abnormally small skull)
• Muscle spasm
• Reduced visual acuity(Decreased clarity of vision)

Diagnosis

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

Supportive laboratory findings

Newborn screening (NBS). Citrulline is elevated on NBS dried blood spot

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)

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.

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).
• Occasionally elevated transaminases, lactate, and other metabolic abnormalities.

When laboratory findings suggest the diagnosis of DLD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Treatment

There are currently no consensus recommendations for the management of dihydrolipoamide dehydrogenase (DLD) deficiency. Management can be hard because various metabolic pathways are affected and 3 enzyme complexes are involved. Deficiencies in enzyme pathways vary depending on the specific mutation(s) each affected person has.

Unfortunately, the treatments that have been attempted in children with the early-onset neurologic form do not appear to significantly alter the course of the disease. Even with treatment, children often do not survive infancy or have varying degrees of chronic neurologic impairment if they survive the initial episode. Depending on individual enzyme complex deficiencies, treatment may involve certain dietary restrictions or certain diets; use of medical foods; and/or supplementation of specific amino acids or other substances.

There is limited data for the chronic management of people with the primarily hepatic (liver-related) form of the disease. Management typically involves supportive therapy during times of acute liver injury or failure, and may include nutritional support; IV glucose for hypoglycemia; correction of metabolic acidosis; correction of coagulopathy; and avoidance of liver-toxic medications.

Prognosis

• The long-term outlook (prognosis) for people with dihydrolipoamide dehydrogenase (DLD) deficiency depends on the specific symptoms and severity in each person. Children diagnosed in the newborn period often do not survive their first episode or die within the first few years of life. However, multiple people have been reported surviving into their second and third decade of life. Those who survive past early childhood often have delayed growth and various neurological problems including intellectual disability, spasticity, ataxia, and seizures.
• Those who become symptomatic after the neonatal period typically have milder signs and symptoms, with a significantly lower mortality rate. However, given the limited amount of information available in the medical literature, the degree of morbidity that surviving people experience is difficult to determine. The frequency of acute episodes reportedly decreases with age in most people with DLD deficiency.

NIH genetic and rare disease info

• NIH info on Dihydrolipoamide dehydrogenase deficiency

Dihydrolipoamide dehydrogenase deficiency is a rare disease.

Dihydrolipoamide dehydrogenase deficiency Resources
Latest articles Most recent articles Ongoing trials	Wikipedia