Pyruvate Dehydrogenase E2 Deficiency

A number sign (#) is used with this entry because of evidence that pyruvate dehydrogenase E2 deficiency is caused by homozygous mutation in the DLAT gene (608770) on chromosome 11q23.

For a general phenotypic description and a discussion of genetic heterogeneity of pyruvate dehydrogenase deficiency, see 312170.

Clinical Features

Robinson et al. (1990) described a black infant who presented at 2 weeks of age with hyperammonemia and profound lactic acidosis. Control of blood lactates was achieved by carbohydrate restriction and bicarbonate supplementation, but at age 3.5 years she had profound psychomotor retardation and was microcephalic. Deficiency in the E2 dihydrolipoyl transacetylase activity of the pyruvate dehydrogenase complex was demonstrated enzymatically, and a very low E2 protein component was found on Western blotting of fibroblast proteins. The inheritance pattern was unclear.

Head et al. (2005) reported 2 unrelated patients with pyruvate dehydrogenase E2 deficiency. Both patients were born of first-cousin parents, indicating autosomal recessive inheritance. The first patient developed nystagmus, jerky head movements, and episodic clenching of his hands at age 5 months. Other features included general hypotonia and delayed psychomotor development. By age 4 years, he had ataxia with gross and fine motor delay, oculomotor apraxia, dystonic movements of the face, hands, and feet, and hyperreflexia. Treatment with lipoic acid, thiamine, and a ketogenic diet resulted in marked clinical improvement. The second patient developed dystonic episodes at age 11 months, consisting of arching of the back with stiffening of the limbs and eye rolling. By age 8 years, he had developmental delay, borderline mental retardation, and generalized dystonia. Biochemical analysis showed reduced activity of the pyruvate dehydrogenase complex in both patients, with an intermediate reduction in the unaffected parents. MRI of both patients showed abnormal signals in the globus pallidus bilaterally, although only the first patient showed increased serum and CSF lactate.

Friedman et al. (2017) reported a patient with pyruvate dehydrogenase E2 deficiency who also had paroxysmal exercise-induced dyskinesia. The patient was born to consanguineous Iraqi parents. He had developmental delay with a cognitive assessment at age 8 years showing an IQ of 44. At age 3, he developed paroxysmal episodes after 5 to 15 minutes of ambulation, characterized by dystonic arm and leg posturing, sometimes with leg shaking and with progressive inability to stand. The episodes would resolve with rest, but would recur multiple times daily with repeated exertion. The patient also had microcephaly, disconjugate gaze with limitation of upward right eye excursion, mildly increased tone, brisk lower extremity reflexes without clonus, and left Babinski sign. EMG showed probable myopathic features. Brain MRI showed abnormal symmetric hypointensity in the bilateral globus pallidus bilaterally. Pyruvate dehydrogenase complex (PDC) enzyme activity in blood lymphocytes was reduced. Treatment with thiamine reversed the patient's deterioration, but not his exercise-induced paroxysmal symptoms. Ketogenic diet was initiated, but was not tolerated.

Molecular Genetics

In 2 unrelated patients with pyruvate dehydrogenase E2 deficiency, Head et al. (2005) identified 2 different homozygous mutations in the DLAT gene (c.361del3, 608770.0001 and F576L, 608770.0002).

In a patient with PDHDD and paroxysmal exercise-induced dyskinesia, who was born to consanguineous Iraqi parents, Friedman et al. (2017) identified a homozygous mutation in the DLAT gene (V157G; 608770.0003).