Alternative titles; symbols
SNOMEDCT: 1003847003; ORPHA: 765, 79246; DO: 3649;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q22.1 | Pyruvate dehydrogenase phosphatase deficiency | 608782 | Autosomal recessive | 3 | PDP1 | 605993 |
A number sign (#) is used with this entry because of evidence that pyruvate dehydrogenase phosphatase deficiency (PDHPD) is caused by homozygous mutation in the PDP1 gene (605993) on chromosome 8q22.
Pyruvate dehydrogenase phosphatase deficiency (PDHPD) is an autosomal recessive disorder of pyruvate metabolism characterized by neonatal/infantile and childhood lactic acidosis, normal lactate to pyruvate ratio, elevated plasma alanine, delayed psychomotor development, epileptic encephalopathy, and hypotonia (summary by Bedoyan et al., 2019).
For a general phenotypic description and a discussion of genetic heterogeneity of pyruvate dehydrogenase (PDH) deficiency, see 312170.
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 brainstem 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.
Bedoyan et al. (2019) reported a 7-year-old Hispanic boy who was hypotonic at birth. He had failure to thrive, gross motor delays, and limited physical endurance. At age 8 months, he developed seizures, which were controlled with medication. A brain MRI at age 15 months showed abnormal signal in the front subcortical white matter. At age 25 months, he was found to have lactic acidosis, and urine organic acid analysis revealed large amounts of 2-keto-isocaproic and 2-keto-isovaleric acids. At age 28 months, a repeat brain MRI showed abnormal T2 hyperintensity and diffusion restriction in the globus pallidus, signal abnormalities in the medial caudate heads and posterior left putamen, and patchy T2 hyperintensity in the left parietal deep white matter. He was started on a ketogenic diet and had improved physical endurance. Due to oral feeding difficulties, he received a gastrostomy tube. With continued ketogenic diet treatment, his growth and development significantly improved. He spoke fluent Spanish and English and attended class for children with special needs.
The transmission pattern of PDHPD in the family reported by Cameron et al. (2009) was consistent with autosomal recessive inheritance.
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.
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).
In a 7-year-old boy with PDHPD, Bedoyan et al. (2019) identified homozygosity for a 1-bp duplication in the PDP1 gene (605993.0002). Both activated and inactivated pyruvate dehydrogenase complex activities were low in patient fibroblasts and lymphocytes, whereas dihydrolipoamide (E3) activity was normal. Branched-chain 2-ketoacid dehydrogenase (BCKDH) activity was also reduced in patient fibroblasts, leading Bedoyan et al. (2019) to hypothesize that there may be a shared regulatory function for PDP1 in PDHC and BCKDH.
Bedoyan, J. K., Hecht, L., Zhang, S., Tarrant, S., Bergin, A., Demirbas, D., Yang, E., Shin, H. K., Grahame, G. J., DeBrosse, S. D., Hoppel, C. L., Kerr, D. S., Berry, G. T. A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency. JIMD Rep. 48: 26-35, 2019. [PubMed: 31392110] [Full Text: https://doi.org/10.1002/jmd2.12054]
Cameron, J. M., Maj, M., Levandovskiy, V., Barnett, C. P., Blaser, S., MacKay, N., Raiman, J., Feigenbaum, A., Schulze, A., Robinson, B. H. Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype. Hum. Genet. 125: 319-326, 2009. [PubMed: 19184109] [Full Text: https://doi.org/10.1007/s00439-009-0629-6]
DeVivo, D. C., Haymond, M. W., Obert, K. A., Nelson, J. S., Pagliara, A. S. Defective activation of the pyruvate dehydrogenase complex in subacute necrotizing encephalomyelopathy (Leigh disease). Ann. Neurol. 6: 483-494, 1979. [PubMed: 119480] [Full Text: https://doi.org/10.1002/ana.410060605]
Ito, M., Kobashi, H., Naito, E., Saijo, T., Takeda, E., Huq, A. H. M., Kuroda, Y. Decrease of pyruvate dehydrogenase phosphatase activity in patients with congenital lactic acidemia. Clin. Chim. Acta 209: 1-7, 1992. [PubMed: 1327585] [Full Text: https://doi.org/10.1016/0009-8981(92)90327-m]
Maj, M. C., MacKay, N., Levandovskiy, V., Addis, J., Baumgartner, E. R., Baumgartner, M. R., Robinson, B. H., Cameron, J. M. Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation. J. Clin. Endocr. Metab. 90: 4101-4107, 2005. [PubMed: 15855260] [Full Text: https://doi.org/10.1210/jc.2005-0123]
Naito, E., Kuroda, Y., Takeda, E., Yokota, I., Kobashi, H., Miyao, M. Detection of pyruvate metabolism disorders by culture of skin fibroblasts with dichloroacetate. Pediat. Res. 23: 561-564, 1988. [PubMed: 2839811] [Full Text: https://doi.org/10.1203/00006450-198806000-00005]
Robinson, B. H., Sherwood, W. G. Pyruvate dehydrogenase phosphatase deficiency: a cause of congenital chronic lactic acidosis in infancy. Pediat. Res. 9: 935-939, 1975. [PubMed: 172850] [Full Text: https://doi.org/10.1203/00006450-197512000-00015]
Robinson, B. H. Lactic acidemia: disorders of pyruvate carboxylase and pyruvate dehydrogenase.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill (pub.) 2001. P. 2284.
Sorbi, S., Blass, J. P. Abnormal activation of pyruvate dehydrogenase in Leigh disease fibroblasts. Neurology 32: 555-558, 1982. [PubMed: 7200213] [Full Text: https://doi.org/10.1212/wnl.32.5.555]