2‐Ketoglutarate dehydrogenase deficiency, a rare cause of primary hyperlactataemia: Report of a new case

Abstract

Two new familial cases of 2-ketoglutarate dehydrogenase (2-KGD) deficiency are reported: a girl who died at 10 years and a boy, still alive at 4 years, born to consanguineous parents. The cases developed progressively severe encephalopathy with axial hypotonia, psychotic behaviour, pyramidal symptoms and failure to thrive. Both children exhibited permanent lactic acidosis with acute episodes during emotional stress and various infections, associated with elevated lactate/pyruvate (L/P) ratio and slightly decreased ketone body ratio in plasma. In fibroblasts, the L/P ratio was greatly increased in the boy. No respiratory chain complex deficiency could be demonstrated in cultured fibroblasts or in mitochondria isolated from a muscle biopsy performed on the boy. In muscle isolated mitochondria, a progressive decrease of the rate of glutamate oxidation was observed after ADP addition; the rate of 2-ketoglutarate oxidation was low in the absence of ADP and did not increase after ADP addition. 2-KGD deficiency was demonstrated in fibroblasts from both children and in the boy's muscle and myoblasts. The 2-KGD complex is composed of three separate enzymes: E1, E2 and E3. We could demonstrate in our patient that the E1 and E3 subunits were normal, suggesting that the E2 component could be responsible for the defect.

Dual Mode Action of Mangiferin in Mouse Liver under High Fat Diet

“…Deficiency in Dhtkd1 causes DOOR syndrome [32]. Impairment of Ogdh resulted from mutation causes neurological symptoms and early death in humans [33], [34] [61], [62]. Animals with null mutants of the OgdhC are non-viable [29], [35], [36].…”

Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation

“…In one case, a child died at 5 mo of age from a severe deterioration of neuromuscular, cardiac, and hepatic symptoms after an intermittent infection. Patients with an inherited deficiency of the ␣-KGDH present a progressive, severe encephalopathy with axial hypotonia, psychotic behavior, and pyramidal symptoms (25). Children exhibit permanent lactic acidosis, with acute episodes during emotional stress, and various infections associated with elevated lactate/pyruvate ratio and slightly decreased ketone body ratio in the plasma.…”

Abnormal Substrate Levels That Depend upon Mitochondrial Function in Cerebrospinal Fluid from Alzheimer Patients

“…Lactate is a glycolysis cytosolic end product and is removed by mitochondrial metabolism; therefore, lactate accumulation may be the result of increased glycolysis, cellular respiration failure, or both, and elevation of the lactate to pyruvate ratio may be observed in case of mitochondrial metabolic failure [20]. Reduced PDHC or KGDHC activity may also induce increased lactate formation [21].…”