A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene ( PDP1) causing pyruvate dehydrogenase complex deficiency

Jirair K Bedoyan, Leah Hecht, Shulin Zhang, Stacey Tarrant, Ann Bergin, Didem Demirbas, Edward Yang, Ha Kyung Shin, George J Grahame, Suzanne D DeBrosse, Charles L Hoppel, Douglas S Kerr, Gerard T Berry, Jirair K Bedoyan, Leah Hecht, Shulin Zhang, Stacey Tarrant, Ann Bergin, Didem Demirbas, Edward Yang, Ha Kyung Shin, George J Grahame, Suzanne D DeBrosse, Charles L Hoppel, Douglas S Kerr, Gerard T Berry

Abstract

Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fluoride) PDC activities in lymphocytes and fibroblasts, normal activity of other mitochondrial enzymes in fibroblasts, and novel biallelic frameshift mutation in the PDP1 gene, c.575dupT (p.L192FfsX5), with absent PDP1 product in fibroblasts. Unexpectedly, the patient also had low branched-chain 2-ketoacid dehydrogenase (BCKDH) activity in fibroblasts with slight elevation of branched-chain amino acids in plasma and ketoacids in urine but with no pathogenic mutations in the enzymes of BCKDH, which could suggest shared regulatory function of PDC and BCKDH in fibroblasts, potentially in other tissues or cell types as well, but this remains to be determined. The clinical presentation of this patient overlaps that of other patients with primary-specific PDC deficiency, with neonatal/infantile and childhood lactic acidosis, normal lactate to pyruvate ratio, elevated plasma alanine, delayed psychomotor development, epileptic encephalopathy, feeding difficulties, and hypotonia. This patient exhibited marked improvement of overall development following initiation of ketogenic diet at 31 months of age. To the best of our knowledge, this is the fourth case of functional PDC deficiency with a defined mutation in PDP1.

Synopsis: Pyruvate dehydrogenase phosphatase (PDP) regulates pyruvate dehydrogenase complex (PDC) and defective PDP due to PDP1 mutations leads to PDC deficiency and congenital lactic acidosis.

Keywords: PDP1; branched‐chain 2‐ketoacid dehydrogenase; developmental delay; lactic acidosis; pyruvate dehydrogenase complex deficiency; pyruvate dehydrogenase phosphatase deficiency.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Sequence chromatograms for the genomic DNA region of PDP1 flanking the mutation (A) and protein expression in patient fibroblasts (B). A, Red arrow shows the duplicated T at c.575 in proband DNA compared with reference sequence. The c.576 position in parents consists of equal amounts of T and G consistent with a carrier status for each parent. B, Immunoblot analysis using antibodies against PDP1 and GAPDH (loading control). C, Patient fibroblast (P) shows absent PDP1 protein expression vs a control sample

References

    1. Harris RA, Bowker‐Kinley MM, Huang B, Wu P. Regulation of the activity of the pyruvate dehydrogenase complex. Adv Enzyme Regul. 2002;42:249‐259.
    1. Solmonson A, DeBerardinis RJ. Lipoic acid metabolism and mitochondrial redox regulation. J Biol Chem. 2018;293:7522‐7530.
    1. O'Brien M, Chalker J, Slade L, Gardiner D, Mailloux RJ. Protein S‐glutathionylation alters superoxide/hydrogen peroxide emission from pyruvate dehydrogenase complex. Free Radic Biol Med. 2017;106:302‐314.
    1. Mathias RA, Greco TM, Oberstein A, et al. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell. 2014;159:1615‐1625.
    1. Sperl W, Fleuren L, Freisinger P, et al. The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders. J Inherit Metab Dis. 2015;38:391‐403.
    1. Ferriero R, Nusco E, De Cegli R, Carissimo A, Manco G, Brunetti‐Pierri N. Pyruvate dehydrogenase complex and lactate dehydrogenase are targets for therapy of acute liver failure. J Hepatol. 2018;69:325‐335.
    1. Maj MC, Cameron JM, Robinson BH. Pyruvate dehydrogenase phosphatase deficiency: orphan disease or an under‐diagnosed condition? Mol Cell Endocrinol. 2006;249:1‐9.
    1. Huang B, Gudi R, Wu P, Harris RA, Hamilton J, Popov KM. Isoenzymes of pyruvate dehydrogenase phosphatase. DNA‐derived amino acid sequences, expression, and regulation. J Biol Chem. 1998;273:17680‐17688.
    1. Maj MC, MacKay N, Levandovskiy V, et al. Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation. J Clin Endocrinol Metab. 2005;90:4101‐4107.
    1. Huang B, Wu P, Popov KM, Harris RA. Starvation and diabetes reduce the amount of pyruvate dehydrogenase phosphatase in rat heart and kidney. Diabetes. 2003;52:1371‐1376.
    1. Turkan A, Gong X, Peng T, Roche TE. Structural requirements within the lipoyl domain for the Ca2+‐dependent binding and activation of pyruvate dehydrogenase phosphatase isoform 1 or its catalytic subunit. J Biol Chem. 2002;277:14976‐14985.
    1. Larner J, Price JD, Heimark D, et al. Isolation, structure, synthesis, and bioactivity of a novel putative insulin mediator. A galactosamine chiro‐inositol pseudo‐disaccharide Mn2+ chelate with insulin‐like activity. J Med Chem. 2003;46:3283‐3291.
    1. DeVivo DC, Haymond MW, Obert KA, Nelson JS, Pagliara AS. Defective activation of the pyruvate dehydrogenase complex in subacute necrotizing encephalomyelopathy (Leigh disease). Ann Neurol. 1979;6:483‐494.
    1. Ito M, Kobashi H, Naito E, et al. Decrease of pyruvate dehydrogenase phosphatase activity in patients with congenital lactic acidemia. Clin Chim Acta. 1992;209:1‐7.
    1. Koster JF, Slee RG, Fernandes J. Lactic acidosis due to a defect in the pyruvate dehydrogenase complex: a possible brain pyruvate dehydrogenase phosphatase deficiency. Monogr Hum Genet. 1978;9:7‐11.
    1. Naito E, Ito M, Takeda E, Yokota I, Yoshijima S, Kuroda Y. Molecular analysis of abnormal pyruvate dehydrogenase in a patient with thiamine‐responsive congenital lactic acidemia. Pediatr Res. 1994;36:340‐346.
    1. Naito E, Kuroda Y, Takeda E, Yokota I, Kobashi H, Miyao M. Detection of pyruvate metabolism disorders by culture of skin fibroblasts with dichloroacetate. Pediatr Res. 1988;23:561‐564.
    1. Robinson BH, Sherwood WG. Pyruvate dehydrogenase phosphatase deficiency: a cause of congenital chronic lactic acidosis in infancy. Pediatr Res. 1975;9:935‐939.
    1. Sorbi S, Blass JP. Abnormal activation of pyruvate dehydrogenase in Leigh disease fibroblasts. Neurology. 1982;32:555‐558.
    1. Cameron JM, Maj M, Levandovskiy V, et al. Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype. Hum Genet. 2009;125:319‐326.
    1. Christodoulou JNM, Crawford J, Brown RM, et al. Mutations in pyruvate dehydrogenase phosphatase regulatory subunit (PDPR) are a novel cause of fatal neonatal cardioencephalopathy with corneal clouding and lactic acidosis. Baltimore, MD: American Society of Human Genetics; 2015.
    1. Bedoyan JK, Yang SP, Ferdinandusse S, et al. Lethal neonatal case and review of primary short‐chain enoyl‐CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab. 2017;120:342‐349.
    1. Chuang DT, Hu CW, Patel MS. Induction of the branched‐chain 2‐oxo acid dehydrogenase complex in 3T3‐L1 adipocytes during differentiation. Biochem J. 1983;214:177‐181.
    1. Kerr D, Grahame G, Nakouzi G. Assays of pyruvate dehydrogenase complex and pyruvate carboxylase activity. Methods Mol Biol. 2012;837:93‐119.
    1. Ye F, Hoppel CL. Measuring oxidative phosphorylation in human skin fibroblasts. Anal Biochem. 2013;437:52‐58.
    1. Hoppel CL, Kerr DS, Dahms B, Roessmann U. Deficiency of the reduced nicotinamide adenine dinucleotide dehydrogenase component of complex I of mitochondrial electron transport. Fatal infantile lactic acidosis and hypermetabolism with skeletal‐cardiac myopathy and encephalopathy. J Clin Invest. 1987;80:71‐77.
    1. Krahenbuhl S, Chang M, Brass EP, Hoppel CL. Decreased activities of ubiquinol:ferricytochrome c oxidoreductase (complex III) and ferrocytochrome c:oxygen oxidoreductase (complex IV) in liver mitochondria from rats with hydroxycobalamin[c‐lactam]‐induced methylmalonic aciduria. J Biol Chem. 1991;266:20998‐21003.
    1. Krahenbuhl S, Talos C, Wiesmann U, Hoppel CL. Development and evaluation of a spectrophotometric assay for complex III in isolated mitochondria, tissues and fibroblasts from rats and humans. Clin Chim Acta. 1994;230:177‐187.
    1. Shin HK, Grahame G, McCandless SE, Kerr DS, Bedoyan JK. Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab. 2017;122:61‐66.
    1. DeBrosse SD, Okajima K, Zhang S, et al. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. Mol Genet Metab. 2012;107:394‐402.
    1. Imbard A, Boutron A, Vequaud C, et al. Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein. Mol Genet Metab. 2011;104:507‐516.
    1. Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012;106:385‐394.
    1. Quintana E, Gort L, Busquets C, et al. Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency. Clin Genet. 2010;77:474‐482.
    1. Robinson BH, MacMillan H, Petrova‐Benedict R, Sherwood WG. Variable clinical presentation in patients with defective E1 component of pyruvate dehydrogenase complex. J Pediatr. 1987;111:525‐533.
    1. Scholl‐Burgi S, Holler A, Pichler K, Michel M, Haberlandt E, Karall D. Ketogenic diets in patients with inherited metabolic disorders. J Inherit Metab Dis. 2015;38:765‐773.
    1. Sofou K, Dahlin M, Hallbook T, Lindefeldt M, Viggedal G, Darin N. Ketogenic diet in pyruvate dehydrogenase complex deficiency: short‐ and long‐term outcomes. J Inherit Metab Dis. 2017;40:237‐245.
    1. Wexler ID, Hemalatha SG, McConnell J, et al. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology. 1997;49:1655‐1661.
    1. Ferdinandusse S, Friederich MW, Burlina A, et al. Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis. 2015;10:79.
    1. Huang X, Bedoyan JK, Demirbas D, et al. Succinyl‐CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion. Mol Genet Metab. 2017;120:213‐222.
    1. Harris RA, Bowker‐Kinley MM, Wu P, Jeng J, Popov KM. Dihydrolipoamide dehydrogenase‐binding protein of the human pyruvate dehydrogenase complex: DNA‐derived amino acid sequence, expression, and reconstitution of the pyruvate dehydrogenase complex. J Biol Chem. 1997;272:19746‐19751.
    1. Reed LJ, Damuni Z, Merryfield ML. Regulation of mammalian pyruvate and branched‐chain alpha‐keto acid dehydrogenase complexes by phosphorylation—dephosphorylation. Curr Top Cell Regul. 1985;27:41‐49.
    1. Wynn RM, Li J, Brautigam CA, Chuang JL, Chuang DT. Structural and biochemical characterization of human mitochondrial branched‐chain alpha‐ketoacid dehydrogenase phosphatase. J Biol Chem. 2012;287:9178‐9192.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi