Pyruvate Carboxylase Deficiency Type C: A Rare Cause of Acute Transient Flaccid Paralysis with Ketoacidosis

Abstract

Pyruvate carboxylase (PC) is a biotin-containing enzyme that is responsible for the adenosine triphosphate-dependent carboxylation of pyruvate to oxaloacetate, a key intermediate in the tricarboxylic acid cycle. PC deficiency (OMIM 266150) is a rare autosomal recessive metabolic disease, causing elevation of pyruvate, lactate, and alanine. Three types of PC deficiency have been described in the literature; A, B, and C. Type A PC deficiency, also called infantile or North American type, is characterized by infantile onset acidosis, failure to thrive, and developmental delay. The second subtype or type B, the neonatal or French form, presents usually in the neonatal period, mostly in the first 72 hours of life with severe lactic acidosis, truncal hypotonia, and seizures. The third type is called type C, is extremely rare with few cases published in the literature. In this case report, we present an 11-month-old girl who presented with acute flaccid paralysis, lethargy, and constipation with elevated ketones and lactate. She was confirmed genetically and biochemically to have PC deficiency type C. The patient's unusual presentation expands the clinical phenotype of this extremely rare disease.

Keywords

pyruvate carboxylase - flaccid paralysis - ketosis - lactic acidosis - hypotonia

Statement of Location

This work was done in BC Children's Hospital, University of British Columbia

• References

• 1 Marin-Valencia I, Roe CR, Pascual JM. Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab 2010; 101 (01) 9-17
• 2 Utter MF, Keech DB. Formation of oxaloacetate from pyruvate and carbon dioxide. J Biol Chem 1960; 235: PC17-PC18
• 3 Robinson BH. Lactic acidemia and mitochondrial disease. Mol Genet Metab 2006; 89 (1-2): 3-13
• 4 Atkin BM, Buist NR, Utter MF, Leiter AB, Banker BQ. Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh's disease. Pediatr Res 1979; 13 (02) 109-116
• 5 Hommes FA, Polman HA, Reerink JD. Leigh's encephalomyelopathy: an inborn error of gluconeogenesis. Arch Dis Child 1968; 43 (230) 423-426
• 6 Yoshida T, Tada K, Konno T, Arakawa T. Hyperalaninemia with pyruvicemia due to pyruvate carboxylase deficiency of the liver. Tohoku J Exp Med 1969; 99 (02) 121-128
• 7 Saudubray JM, Marsac C, Cathelineau CL, Besson Leaud M, Leroux JP. Neonatal congenital lactic acidosis with pyruvate carboxylase deficiency in two siblings. Acta Paediatr Scand 1976; 65 (06) 717-724
• 8 Robinson BH, Oei J, Sherwood WG. , et al. The molecular basis for the two different clinical presentations of classical pyruvate carboxylase deficiency. Am J Hum Genet 1984; 36 (02) 283-294
• 9 Coude FX, Ogier H, Marsac C, Munnich A, Charpentier C, Saudubray JM. Secondary citrullinemia with hyperammonemia in four neonatal cases of pyruvate carboxylase deficiency. Pediatrics 1981; 68 (06) 914
• 10 Van Coster RN, Fernhoff PM, De Vivo DC. Pyruvate carboxylase deficiency: a benign variant with normal development. Pediatr Res 1991; 30 (01) 1-4
• 11 Hamilton J, Rae MD, Logan RW, Robinson PH. A case of benign pyruvate carboxylase deficiency with normal development. J Inherit Metab Dis 1997; 20 (03) 401-403
• 12 Arnold GL, Griebel ML, Porterfield M, Brewster M. Pyruvate carboxylase deficiency. Report of a case and additional evidence for the “mild” phenotype. Clin Pediatr (Phila) 2001; 40 (09) 519-521
• 13 Wang D, Yang H, De Braganca KC. , et al. The molecular basis of pyruvate carboxylase deficiency: mosaicism correlates with prolonged survival. Mol Genet Metab 2008; 95 (1-2): 31-38
• 14 Stern HJ, Nayar R, Depalma L, Rifai N. Prolonged survival in pyruvate carboxylase deficiency: lack of correlation with enzyme activity in cultured fibroblasts. Clin Biochem 1995; 28 (01) 85-89
• 15 Vaquerizo Madrid J, Val Sánchez de León JM, Sánchez Alarcón J, Remón Alvarez-Arenas J. [Congenital oculomotor apraxia and partial deficiency of pyruvate carboxylase] [Article in Spanish]. An Esp Pediatr 1997; 47 (06) 663-664
• 16 Pyal A, Paramasivam A, Meena AK, Bhavana VB, Thangaraj K. MPV17 hepatocerebral mitochondrial DNA depletion syndrome presenting as acute flaccid paralysis - A case report. Mitochondrion 2017; 37: 41-45
• 17 Strassburg HM, Koch J, Mayr J, Sperl W, Boltshauser E. Acute flaccid paralysis as initial symptom in 4 patients with novel E1alpha mutations of the pyruvate dehydrogenase complex. Neuropediatrics 2006; 37 (03) 137-141
• 18 Walker ME, Baker E, Wallace JC, Sutherland GR. Assignment of the human pyruvate carboxylase gene (PC) to 11q13.4 by fluorescence in situ hybridisation. Cytogenet Cell Genet 1995; 69 (3-4): 187-189
• 19 Monnot S, Serre V, Chadefaux-Vekemans B. , et al. Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency. Hum Mutat 2009; 30 (05) 734-740