NORD gratefully acknowledges Logan Flaherty and Alex Tan, NORD editorial interns from the University of Notre Dame, and Päivi Vieira, MD, PhD, Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Finland, for assistance in the preparation of this report.
PEPCK deficiency is an extremely rare disorder characterized by episodes of low blood sugar (hypoglycemia). It is a disorder of carbohydrate metabolism caused by a deficiency in the enzyme called phosphoenolpyruvate carboxykinase or PEPCK. This enzyme normally converts proteins and fats to glucose during times of fasting, in a process called gluconeogenesis. The glucose is used as a source of energy by the body. PEPCK deficiency is inherited in an autosomal recessive pattern.
The treatment for this disorder is avoidance of fasting and consumption of extra carbohydrates during exercise, illness or other periods when the body needs additional sources of energy.
There are two forms of PEPCK deficiency: PEPCK1 deficiency (cytosolic) and PEPCK2 deficiency (mitochondrial).Both forms represent an inherited deficiency of the PEPCK enzymes. These enzymes are part of a process of converting proteins and fat to glucose (gluconeogenesis) that occurs primarily in the liver. This process is activated when dietary intake of glucose is insufficient, such as fasting or when extra energy is needed, such as during periods of intense exercise. Glucose is essential as the body’s source of energy, and for the functioning of many organs and systems in the body, especially the brain.
The main symptom of this disorder is an abnormally low blood sugar level (hypoglycemia) during times of insufficient glucose intake. Hypoglycemia can present with drowsiness, confusion or loss of consciousness. Severe cases may exhibit loss of muscle tone (hypotonia); abnormal enlargement of the liver (hepatomegaly) inability to gain appropriate weight and grow normally (failure to thrive), small head size and developmental delay. Poor appetite, vomiting, seizures and coma may also occur. If hypoglycemia is not treated, the disease can progress to multiorgan system damage or acute liver failure. Sometimes the presence of excess acid in the circulating blood (lactic acidemia) is noticed.
At birth, babies with PEPCK deficiency may present with hypoglycemia, and may have an enlarged liver, and apneas. Many babies do not show any symptoms, however. Typically, PEPCK deficiency presents in early childhood with symptoms noted during infections or after vigorous exercise, especially after a period of overnight fasting, when gluconeogenesis would normally be activated. These individuals tend to present with fasting hypoglycemia (low blood sugar) and may show shakiness, irritability or even lethargy. Liver impairment may occur and results in abnormal liver enzyme levels found in the blood. Abnormal amounts of other metabolites in the blood or urine can give a diagnostic clue (glutamine, or fumarate and other metabolites of tricarboxylic acid cycle). The symptoms of PEPCK deficiency vary among patients, and not all will exhibit every symptom. Many children develop normally despite episodes of hypoglycemia. The course of this disorder can be very rapid, however, if hypoglycemia is not treated.
Changes (mutations) in the PCK1 gene cause the cytosolic (soluble) form of PEPCK deficiency (PEPCK1) and mutations in the PCK2 gene cause the mitochondrial form of PEPCK deficiency (PEPCK2). Mutations in these genes result in a reduced amount or absence of the PEPCK enzyme. Researchers believe that the severity of disease is based upon the amount of residual enzyme activity that remains.
PEPCK deficiencies, in both forms, are very rare disorders that are inherited in an autosomal recessive pattern, where two copies of the abnormal gene must be present in order for the disease to develop.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
PEPCK deficiency is extremely rare. Prior to 2007, only 10 cases were reported in the medical literature. Since then, there have been at least 6 new cases reported for a total of 16 cases of PEPCK deficiency. Males and females are equally affected..
Diagnosis of PEPCK deficiency may be made shortly after birth based upon the results of the following:
1. Clinical presentation of symptoms
2. Laboratory testing including blood and urine analysis.
3. Molecular genetic testing to confirm mutations of the PCK1 or PCK2 genes
4. Biochemical analysis of fibroblast cells (skin biopsy)
Laboratory testing may include a blood test to identify low blood sugar levels (hypoglycemia) and urinalysis can detect the presence of TCA (tricarboxylic acid cycle) metabolites excreted in urine, especially fumarate. The dysfunctional PEPCK enzyme disrupts the metabolic route leading to gluconeogenesis and causes a buildup of these intermediates that are then excreted in urine.
The mainstay of treatment for PEPCK deficiency is avoidance of fasting. Individuals with this disorder may consume extra carbohydrate such as cornstarch to lower the occurrence of symptoms. This is especially important in the evenings before an overnight fast.
Individuals may be prescribed glucose polymers (high carbohydrate oral replacement) during rigorous exercise, illness, or other times of fasting. Glucose-containing solutions may also be administered intravenously during times of fasting or illness. Regular contact with a dietician is recommended. The dietician can provide the patient with instructions for a so called sick-day regimen, which tells you how much extra carbohydrate is needed during times of illness.
Genetic counseling is recommended for patients and their families. Other treatments of PEPCK deficiency are based upon symptoms presented.
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