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At a glance

Characterized by hypotonia and metabolic acidosis and hyperlactatemia immediately after birth. The life expectancy is limited to about 30 months. Death is caused by neurologic deterioration. Other clinical features include axial hypotonia with no head control until later in childhood. Metabolic acidosis with acute episodes of acidotic decompensation and sometimes hypoglycemia may occur during emotional or physical stress and infections.

Synonyms

Alpha-KGD Deficiency; 2-Alpha-Ketoglutarate Dehydrogenase Deficiency; Oxoglutaric Aciduria; Oxoglutarate Dehydrogenase Deficiency.

Incidence

Has not been established, but a total of nine patients with isolated Alpha-Ketoglutarate Dehydrogenase Deficiency have been reported to date.

Genetic inheritance

All reported cases are from Northern Africa, mostly Algeria and Tunisia. It is believed that this medical condition that has been mapped to chromosome 7p13 and is inherited as an autosomal recessive trait with consanguinity being a significant risk factor.

Pathophysiology

Alpha-Ketoglutarate Dehydrogenase is an enzyme of the Krebs cycle that catalyzes the oxidation of alpha-ketoglutarate to succinyl-CoA. It is one of three alpha-ketoacid dehydrogenase enzymes beside pyruvate dehydrogenase and branched-chain ketoacid dehydrogenase. Each of these enzymes is a complex of multiple units and each unit has three distinct subunits: The E1 (alpha-ketoacid decarboxylase) and E2 (dihydrolipoyl transacetylase), which are unique to each enzyme, whereas the E3 (dihydrolipoyl dehydrogenase or lipoamide dehydrogenase) subunit is common to all three alpha-ketoacid dehydrogenases.

Clinical aspects

At birth, most of these infants appear normal, but will develop muscular hypotonia with mild motor delay already in the first year of life. The clinical presentation includes severe hypotonia, metabolic acidosis, persistent, congenital lactic acidosis, and death in early childhood. Dysmorphic craniofacial features such as dolichocephaly with prominent forehead, delayed closure of the anterior fontanelle, bilateral epicanthus, dysmorphic and low-set ears, short nose with broad, depressed nasal bridge, short columella, and long philtrum have been described. Hypertrophic cardiomyopathy was described in one boy who suddenly died at 32 months of age. Laboratory investigations reveal hyperlactatemia, alpha-ketoglutarate dehydrogenase deficiency, elevated glutamate levels (a precursor of alpha-ketoglutarate), and glutaric aciduria of variable amount. Muscle biopsy shows atrophy of Type II fibers, multiple sudanophilic lipid droplets in Type I fibers, and numerous peripheral, subsarcolemmal mitochondrial aggregates.

Precautions before anesthesia

There is no literature available on the anesthetic implications of this syndrome. From the description of the craniofacial dysmorphic signs, airway management is not expected to be difficult. Preoperative laboratory testing should include an arterial blood gas analysis, serum electrolytes, transaminases, creatine kinase, creatinine and a complete blood cell count with differential. An echocardiogram should be obtained if cardiomyopathy is suspected or cannot be excluded clinically. It appears to be beneficial if these patients are started on an intravenous, electrolyte-balanced fluid solution beginning with the preoperative fasting period and obvious electrolyte and acid-base anomalies being ...

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