Pyruvate Dehydrogenase Complex Deficiency

Pyruvate Dehydrogenase Complex Deficiency (PDHCD) is a mitochondrial disease that leads to lactic acidosis without hypoglycemia.

Pyruvate Dehydrogenase Deficiency.

The exact incidence is unknown, but several hundred cases have been described.

All the components of the pyruvate dehydrogenase complex are encoded by nuclear genes and are synthesized in the cytoplasm before being transported into the mitochondria. Most of these genes are autosomal, but the E1α subunit gene has been mapped to Xp22.3. Hence, most cases of pyruvate dehydrogenase complex deficiency are X-linked with more severe consequences in males than in heterozygous females; the frequency, however, is the same for both genders.

Pyruvate dehydrogenase (PDH) is an enzyme complex consisting of three catalytic subunits, pyruvate dehydrogenase (E1, a tetramer), dihydrolipoamide acyltransferase (E2, a monomer), and dihydrolipoamide dehydrogenase (E3, a dimer), and two cofactors, thiamine pyrophosphate and lipoic acid. A sixth component, previously named X-protein and recently renamed E3-binding protein (E3-BP), has been found to be mutated in a few patients. The enzyme complex converts pyruvate—after it enters the mitochondria—into acetyl-CoA, one of two essential substrates (oxaloacetate being the other) in the production of citrate. PDHCD therefore leads to a limited production of citrate and because citrate is the first substrate in the tricarboxylic acid (citric acid or Krebs) cycle, the cycle is blocked and other metabolic pathways need to be stimulated to produce acetyl-CoA. Nevertheless, the decreased level of energy substrates (ATP) primarily affects the CNS, because brain acetyl-CoA is synthesized almost exclusively from pyruvate. The most common deficiency involves the E1 subunit, a heterotetramer consisting of two alpha and two beta subunits with the defect located on the alpha subunit (E1alpha), which contains several serine phosphorylation sites and seems to be involved in the regulation of the whole complex. Mutations in E2, E3, and E3-BP are less often the cause for PDHCD. The enzyme defect causes more pyruvate to be metabolized to lactate and leads to lactic acidosis.

The combination of an otherwise unexplained lactic acidosis with early-onset neurological disease and structural brain anomalies should always include PDHCD in the differential diagnosis. In addition to pyruvate carboxylase deficiency, defects in the mitochondrial chain of electron transport or in gluconeogenesis should be considered. However, lactic acidosis in the absence of hypoglycemia does not match with a defect in gluconeogenesis, whereas a defect in the mitochondrial respiratory chain would also affect other organ systems, such as muscle, heart, liver, and kidneys. In contrast to a respiratory chain defect, the blood lactate/pyruvate ratio in PDHCD is normal and both lactate and pyruvate decrease after fasting. Specific enzyme assays are available to measure the total PDH activity, as well as that of the individual components of the enzyme complex. However, measured residual enzyme activity does not always correlate with the clinical picture.

The range of clinical expression is wide and has four different ways of presentation: fatal infantile lactic acidosis, psychomotor retardation, progressive neurological deterioration (Leigh disease), and carbohydrate-sensitive ataxia.

Fatal infantile lactic acidosis: These patients (most often boys) have very low levels of residual enzyme activity (approximately 15% of the norm value) and present in the neonatal period with brain anomalies (agenesis of the corpus callosum, cystic brain lesions) and severe, chronic, lactic acidosis refractory to treatment, most often resulting in death in the first 6 months of life.

Psychomotor retardation: Although these children (more often girls than boys) suffer from mild to moderate lactic acidosis, significant acid-base changes only occur intermittently, usually related by an intercurrent infection, prolonged fasting, or stimulation of gluconeogenesis. Hypotonia, confusion, and coma may occur. The residual activity of PDH is about 28% of the norm. It is not unusual that these patients go undetected until developmental delay has been diagnosed. MRI and/or CT scanning of the head may reveal cortical atrophy, basal ganglia defects, and internal hydrocephalus.

Leigh Disease (Cytochrome Oxydase Deficiency Disease; Progressive Neurological Deterioration): These children develop the typical signs of Leigh disease within the first 5 years of life, which is characterized by developmental delay, seizures, ataxia, episodic weakness, progressive neuropathy, and basal ganglia and brainstem dysfunction (e.g., loss of respiratory control) caused by cystic lesions and necrosis in these areas. The residual activity of PDH is about 22% of the norm.

Carbohydrate-Sensitive Ataxia: These patients are all male, are without significantly elevated lactate serum levels, and suffer from either episodic or chronic ataxia. Ataxia is often carbohydrate-induced and can be controlled by ketogenic diet (i.e., the dietary caloric intake is composed of 65 to 80% from fat, and carbohydrates and proteins are restricted to less than 5% and 15%, respectively). The residual activity of PDH is about 30% of the norm.

About one-third of patients with PDHCD suffer from facial anomalies quite similar to fetal alcohol syndrome (i.e., thin upper lip, long philtrum, microcephaly, broad nasal bridge, anteverted nostrils, frontal bossing, short palpebral fissures, maxillary hypoplasia, cleft lip or palate). Cardiac defects (ventricular septal defect), hydronephrosis, and short neck have been described in a few cases.

Obtain a complete history focused on neurological symptoms, metabolic exacerbations, and their triggers. Ask about the diet and tolerance to fasting. During the fasting period, it is strongly recommended to give to these patients (except the subgroup with carbohydrate-sensitive ataxia) on a dextrose-containing intravenous solution to provide glucose at a rate of 8 to 10 mg/kg/min. Laboratory investigations should include a complete blood count, serum electrolytes, glucose and lactate levels, and a venous or arterial blood gas analysis. Anesthesia-related morbidity and mortality is linked to the preoperative status of the child. Elective procedures should be canceled in the presence of decompensated acid-base status, infections, or fever. These patients may have an abnormal response to both hypoxia and hypercarbia, and may require postoperative mechanical ventilation. Because lactate levels are already elevated in these patients, lactate-containing intravenous solutions must be avoided. Assess the facial dysmorphism for features predictive of difficult airway management. Patients with psychomotor retardation may be better off with sedative or anxiolytic premedication; however, the abnormal respiratory drive requires careful titration and monitoring.

Because the hypothalamus and the brainstem is often involved in the disease process, meticulous care should be devoted to perioperative maintenance of temperature and control of respiration (if the maintenance of spontaneous breathing is an option). Hypocapnia should be avoided because it inhibits pyruvate decarboxylase and further increases lactate levels. Avoid hypothermia, because rewarming hypermetabolism can result in decompensated metabolic acidosis and hypoglycemia. Maintain normal blood glucose levels by providing perioperative dextrose supplements and repeatedly check blood glucose and lactate concentrations. A stress-free anesthesia decreases the metabolic response to surgery, as well as lactate production. Maintain normovolemia and adequate preand afterload to prevent lactic acidosis secondary to inappropriate tissue perfusion. The use of regional anesthesia is recommended when applicable.

The presence of a mitochondrial disease is not considered as a risk factor for malignant hyperthermia.

Leigh Syndrome: Severe, progressive, necrotizing encephalopathy caused by a mitochondrial disorder impeding oxidative phosphorylation.

Pyruvate Carboxylase Deficiency: Mitochondrial disease impairing synthetic pathways and leading to hypoglycemia and severe lactic acidosis.