Pyruvate Dehydrogenase Phosphatase Deficiency

A number sign (#) is used with this entry because of evidence that pyruvate dehydrogenase phosphatase deficiency is caused by homozygous mutation in the PDP1 gene (605993) on chromosome 8q22.

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

Clinical Features

Robinson and Sherwood (1975) reported a male infant who presented on the first day of life with lactic acidosis and died at age 6 months. Activity of the pyruvate dehydrogenase complex in tissue homogenates preincubated with ATP was reduced by 60 to 75% in liver of the patient and controls because of the inactivation of the enzyme by pyruvate dehydrogenase kinase (see, e.g., PDK1, 602524). Addition of calcium and magnesium to the inactivated enzyme caused a prompt return of the activity to normal in controls, but not in the patient's cells. Robinson and Sherwood (1975) concluded that the defect in the patient, which was apparent in muscle and liver but not in brain, was caused by a markedly reduced activity of pyruvate dehydrogenase phosphatase (605993).

Robinson (2001) suggested that the patients reported by Sorbi and Blass (1982) and DeVivo et al. (1979) had pyruvate dehydrogenase phosphatase deficiency.

Ito et al. (1992) provided follow-up on 3 patients reported by Naito et al. (1988) with disorders of pyruvate metabolism. Clinical features included mental and developmental retardation beginning in infancy, muscle hypotonia, seizures, and lactic acidosis. Two patients had CT findings consistent with Leigh syndrome (256000).

Maj et al. (2005) reported 2 brothers, born of consanguineous parents, who presented with neonatal hypotonia, elevated lactate, and less than 25% native pyruvate dehydrogenase complex (PDHc) activity in skin fibroblasts compared with controls.

Cameron et al. (2009) reported a female infant, born of consanguineous Pakistani parents, with genetically confirmed pyruvate dehydrogenase phosphatase deficiency. She had mild truncal hypotonia, and brain MRI showed increased T2 signal in the posterior white matter consistent with edema, without diffusion restriction. There was normal myelination, no structural brain lesion, and the brain stem appeared normal. After diagnosis and treatment, she remained clinically stable and showed signs of appropriate developmental progression, including starting to sit, responding to her name, and speaking some words. At 6 months of age, the patient developed acute respiratory distress and died; no autopsy was performed.

Biochemical Features

By developing an assay method to measure pyruvate dehydrogenase phosphatase activity in cultured skin fibroblasts, Ito et al. (1992) found that all 3 patients had a decrease in enzyme activity to 50.7%, 64.6%, and 63.1% of that in controls. Noting that the PDH complex is inactivated by phosphorylation, the authors concluded that a decrease in PDH phosphatase activity increases the proportion of inactive PDH complex, resulting in the clinical phenotype.

Molecular Genetics

In 2 brothers, born of consanguineous parents, with pyruvate dehydrogenase phosphatase deficiency, Maj et al. (2005) identified a 3-bp deletion in the PDP1 gene, resulting in loss of leu213 (605993.0001). The activity of the PDHc could be restored to normal values by preincubation of the cells with dichloroacetate or by treating cell extracts with calcium.

In a female infant with lactic acidosis due to pyruvate dehydrogenase phosphatase deficiency, born of consanguineous Pakistani parents, Cameron et al. (2009) identified homozygosity for a nonsense mutation in the PDP1 gene (605993.0002).