Phosphoenolpyruvate Carboxykinase Deficiency, Cytosolic

A number sign (#) is used with this entry because of evidence that cytosolic phosphoenolpyruvate carboxykinase deficiency (PCKDC) is caused by homozygous mutation in the PCK1 gene (614168) on chromosome 20q13.

Description

Cytosolic phosphoenolpyruvate carboxykinase deficiency causes a defect in gluconeogenesis that results in a 'biochemical signature' of fasting hypoglycemia with high tricarboxylic acid cycle intermediate excretion, particularly of fumarate. Other biochemical anomalies that may be seen during metabolic crisis include ketonuria, dicarboxylic aciduria, and urea cycle dysfunction (Vieira et al., 2017).

See PCKDM (261650) for a discussion of mitochondrial PCK (PEPCK2; 614095) deficiency.

Clinical Features

Sovik et al. (1975) reported a boy who developed generalized seizures on the second day of life and was found to have severe hypoglycemia. He also had frequent attacks of cyanosis and apnea. At age 8 weeks, he showed general retardation and atrophy of the optic nerve. At age 3.5 months, he underwent subtotal pancreatectomy and treatment with diazoxide to inhibit insulin production. However, poor response of the hypoglycemia to this treatment prompted the authors to consider a defect in gluconeogenesis. By studies on the patient's liver, Vidnes and Sovik (1976, 1976) demonstrated that he had a defect of gluconeogenesis due to deficiency of cytosolic phosphoenolpyruvate carboxykinase (PCK1; 614168). The total activity of the enzyme was normal, but the enzyme showed an abnormal subcellular distribution, with virtually no activity detected in the cytosolic fraction of a liver homogenate. He died at age 2 years, 10 months. Postmortem examination showed severe cerebral atrophy, atrophy of the optic nerve, fatty infiltration of the liver, kidney, and heart, and hyperplasia of the pancreatic islets of Langerhans. The findings suggested that cytosolic PCK initiates gluconeogenesis at birth.

Adams et al. (2014) reported 2 sisters, born of nonconsanguineous parents of Ashkenazi Jewish ancestry, who had cytosolic phosphoenolpyruvate carboxykinase deficiency due to mutation in the PCK1 gene. The older sister first presented at age 20 months with fasting hypoglycemia, which was associated with fever, lethargy, and ketonuria, as well as appropriately elevated growth hormone (GH1; 139250) and cortisol levels, undetectable insulin, and normal C-peptide levels. Over the subsequent 5 years, she had at least 12 similar episodes of illness- or fasting-related hypoglycemia, sometimes associated with significant lactic acidemia. Liver biopsy at age 4 years showed no iron deposits and no abnormal lipid or glycogen, although there was mild to moderate portal inflammation, mild portal fibrosis, and patchy moderate macrovesicular steatosis. The younger sister presented at age 8 months with illness-related lethargy, fasting hypoglycemia, elevated urine lactate, and ketonuria, and like her older sister, had repeated episodes of illness- or fasting-related hypoglycemia, sometimes associated with acidosis. In addition, both sisters exhibited intellectual and motor delays, as well as dysmorphic features in the older sister. In addition to mutation in PCK1, each sister carried a mutation in a different gene known to be associated with a mental retardation phenotype (see MOLECULAR GENETICS).

Santra et al. (2016) described a 4-year-old Pakistani boy, born of third-cousin parents from a multiply consanguineous family, who presented at age 9 months with encephalopathy after 3 days of persistent diarrhea and vomiting. Evaluation revealed mild hyperammonemia and acute liver failure, with massively elevated alanine (GPT; 138200) and aspartate (GOT1; 138180) transaminases, as well as coagulopathy, hypoalbuminemia, mild hypoglycemia, and hyperlactatemia. His level of consciousness rapidly normalized after administration of intravenous dextrose. Quantitative plasma amino acid analysis was suggestive of a proximal urea cycle defect, with a strongly elevated glutamine together with low citrulline and arginine. Analysis of urine organic acids during the presenting illness showed prominent tricarboxylic acid (TCA) cycle metabolites, especially fumarate but including succinate, malate, and alpha-ketoglutarate. Liver biopsy revealed diffuse macrosteatosis without fibrosis or inflammation, and ultrasound showed a normal-sized liver for age, but with hyperechoic parenchyma. Treatment for a proximal urea cycle defect, including dietary protein restriction, was commenced. Repeat organic and amino acid analysis a month after recovery showed no evidence of the previous abnormalities and values remained normal after return to an unrestricted diet. Growth and development were normal at age 4 years.

Tangeraas et al. (2016) provided a brief report of a previously healthy Norwegian girl who presented at age 16 months with severe gastrointestinal hemorrhage following an episode of gastroenteritis, associated with extremely high alanine and aspartate aminotransferases, slightly increased coagulation time, and slightly decreased albumin level. She subsequently experienced 2 episodes of infection-associated ketotic hypoglycemia, metabolic acidosis, and elevated lactate levels. A similar biochemical profile was confirmed during a controlled fasting test, which provoked hypoglycemia after 17 hours. Urine after a 12-hour fast showed increased excretion of 3-hydroxybutarate as well as fumaric and glutaric acids.

Vieira et al. (2017) studied a Finnish sister and brother, born of distantly consanguineous parents, and an unrelated Finnish boy, with unexplained childhood hypoglycemia. The Finnish girl required a glucose infusion during the first 24 hours of life for hypoglycemia noted due to tremor and irritability; she experienced a second episode of hypoglycemia at age 14 months after an overnight fast of about 12 hours. Blood lactate and alanine aminotransferase were slightly elevated, and ammonia was normal. Ultrasound of the liver showed increased size and echogenicity suggestive of diffuse parenchymal damage. Her younger brother had no significant health issues until age 15 months, when he was found to be hypoglycemic after a 13-hour fast, with slightly elevated alanine aminotransferase but normal ammonia. Liver ultrasound 3 months later showed size at the upper limit of normal, with normal echogenicity. The third Finnish patient, an unrelated boy, was well until 4.5 years of age, when he had a seizure in the morning and was found to be hypoglycemic. He had no signs of infection, but had been very active the night before. Lactate, pyruvate, and ammonia were normal, free fatty acids were elevated, and GPT was slightly elevated. In all 3 patients, semiquantitative urine organic acid analysis demonstrated prominent TCA cycle metabolites, particularly fumarate. All were instructed in a low-fat, high-carbohydrate diet with frequent feedings, and all showed normal growth and development, at ages 5 years, 2.5 years, and 6.8 years, respectively. Except for an illness-related episode of low glucose in the girl at age 2.75 years, there were no further episodes of hypoglycemia.

Molecular Genetics

In 2 sisters who experienced multiple episodes of hypoglycemia and lactic acidosis associated with illness or fasting, who were born of nonconsanguineous parents of Ashkenazi Jewish ancestry, Adams et al. (2014) performed whole-exome sequencing and identified homozygosity for a missense mutation in the PCK1 gene (I45T; 614168.0001). Each sister was also heterozygous for a de novo mutation in another gene, RAI1 (607642) and GRIN2B (138252), respectively, each of which was known to be associated with intellectual and developmental delay, causing Smith-Magenis syndrome (SMS; 182290) in the older sister and mental retardation-6 (MRD6; 613970) in the younger sister. Adams et al. (2014) concluded that this family demonstrated that complex medical disorders can represent the cooccurrence of multiple diseases.

In a 4-year-old Pakistani boy, born of third-cousin parents from a multiply consanguineous family, who presented at age 9 months with transient acute liver failure and biochemical patterns suggestive of disturbed urea cycle, Santra et al. (2016) performed whole-exome sequencing and identified homozygosity for a 12-bp deletion in the PCK1 gene (614168.0002) that segregated fully with disease in the family. Analysis of a liver biopsy at age 3 years excluded coexistent glycogen storage disease type IX (see 306000) as a contributory factor to the patient's presentation. The authors suggested that the amino acid profile reminiscent of a proximal urea cycle defect might be due to accumulation of TCA cycle metabolites, triggering increased flux through alternative cataplerotic reactions. They noted that PEPCK deficiency may be an underrecognized but treatable cause of childhood liver failure associated with illnesses causing prolonged starvation.

In 2 Finnish sibs and an unrelated Finnish boy with unexplained childhood hypoglycemia, Vieira et al. (2017) performed whole-exome sequencing and identified homozygosity for a missense mutation in the PCK1 gene (G309R; 614168.0003) that segregated with disease in both families. Vieira et al. (2017) noted that the G309R mutation had been previously reported in a congress abstract (Tangeraas et al., 2016) as having been found in compound heterozygosity in a patient with hypoglycemia, liver dysfunction, and gastrointestinal hemorrhage. The other mutation in the latter patient was a 1-bp deletion, predicted to cause a frameshift and premature termination codon.