AMY T. WALDMAN
HISTORY OF PRESENT ILLNESS
The patient is an 8-month-old boy who was well until 1 week prior to admission when he was found by his mother having a “seizure.” He had shaking and jerking of all extremities that did not stop when his extremities were held. He did not respond to touch or stimulation. There was no cyanosis. The episode lasted approximately 15 minutes. On arrival of Emergency Medical Services, the patient was alert and feeding from a bottle. He was not taken to the hospital. His last feeding was approximately 3 hours prior to the event. Two days later the patient was evaluated by his primary physician who performed the following laboratory evaluation: Glucose (during feeding), 121 mg/dL; alanine aminotransferase (ALT), 73 U/L; aspartate aminotransferase (AST), 93 U/L; gamma glutamyl transferase (GGT), 28 U/L; and cholesterol, 423 mg/dL. These labs were repeated 2 days later with similar results except that the glucose was 16 mg/dL. Head CT and EEG were normal. He was hospitalized for additional evaluation.
The patient was born at 38 weeks gestation with a birth weight of 3400 g. His delivery was complicated by meconium aspiration. He was treated with supplemental oxygen and empiric antibiotics for 3 days. He also had hypoglycemia requiring intravenous dextrose and bottle feedings every 1.5 hours. This resolved and he was discharged home on the fourth day of life. He received oral antibiotics for otitis media diagnosed at 3 months of life. There is no family history of seizures or mental retardation.
T 36.2°C; RR 20/min; HR 90-110 bpm; BP 120/55 mmHg; SpO2 100% in room air
Height 25th percentile; Weight 10th percentile; Head Circumference 25th percentile
On examination, he was thin but playful. The anterior fontanelle was open and flat. The heart sounds were normal and the lungs were clear to auscultation. His abdomen was slightly protuberant with a liver edge that was firm and palpable 6 cm below the right costal margin. The spleen tip was just palpable below the left costal margin. There was no ascites or palpable abdominal mass. The infant was circumcised and had normal male genitalia. The neurological examination was normal. The child was awake and alert and interactive with the parents and examiner. He made excellent eye contact and babbled during the examination. Pupils were equal, round, and reactive to light. Funduscopic examination was normal. He tracked in all directions without nystagmus. Facial movements were symmetric. The gag reflex was intact. He had antigravity movements and normal axial and appendicular tone with passive range of motion and vertical and horizontal suspension. The infant was able to sit without support. He withdrew to pain in all extremities. Deep tendon reflexes were 2+ throughout and symmetric. The plantar responses were flexor (upgoing Babinski, normal for age). There were no hyper- or hypopigmented skin lesions.
Serum chemistries included sodium, 137 mmol/L; potassium, 5.5 mmol/L; chloride, 100 mmol/L; bicarbonate, 13 mmol/L; calcium, 10.5 mg/dL; phosphorous, 6.5 mg/dL; and serum glucose 20 mg/dL. The cholesterol and triglycerides were 465 mg/dL and 4070 mg/dL, respectively. Hepatic function tests included AST, 125 U/L; ALT, 155 U/L; GGT, 564 U/L; total bilirubin 0.6 mg/dL; and albumin 4.0 g/dL. Serum and urinary ketones were present. White blood cell count, hemoglobin, and platelet count, as well as prothrombin and partial thromboplastin times were normal. Blood, urine, and stool cultures were obtained.
COURSE OF ILLNESS
The patient underwent a fasting study which revealed the diagnosis within approximately 4 hours.
DISCUSSION CASE 19-3
This infant had seizures related to hypoglycemia. Hypoglycemia in an infant, defined as a blood glucose concentration ≤40 mg/dL, warrants immediate treatment followed by appropriate investigation. Many inborn errors of metabolism are responsible for hypoglycemia present in the first year of life, while milder defects of glycogen degradation and gluconeogenesis manifest only in childhood after prolonged periods of fasting. Causes of hypoglycemia in an infant include hyper-insulinism, hormone deficiency, and defects in branched-chain amino acid metabolism, fatty acid oxidation, and hepatic enzymes.
Urinary ketones are absent or low in children with hyperinsulinism and fatty acid oxidation defects who present with hypoglycemia. Hypoglycemia secondary to hyperinsulinism most commonly appears during the first year of life. It is usually associated with islet-cell dysplasia and rarely with islet-cell adenomas. Insulin level are elevated (>5 μU/mL) and injection of glucagon elicits a rapid rise in blood glucose levels. Children with disorders of fatty acid metabolism can present with hypoglycemia and profound disturbance of consciousness that may not improve when the plasma glucose is normalized. In addition to hyperketonemia, they have high plasma free fatty acid concentrations, elevated ALT and AST, rhabdomyolysis, cardiomyopathy, and cerebral edema.
The presence of urinary ketones usually suggests hormone deficiency, glycogen storage disease, or defects in gluconeogenesis. Hypoglycemia is a common presentation for an infant with panhypopituitarism, isolated growth hormone deficiency, and absolute (adrenal hypoplasia, Addison disease, adrenoleukodystrophy) or relative (congenital adrenal hyperplasia) glucocorticoid deficiency. Midline defects such as cleft lip or palate, optic dysplasia, and microphallus suggest anterior pituitary hormone deficiency. Hyperpigmentation associated with Addison disease rarely occurs in young children. Addison disease is occasionally associated with hypoparathyroidism (hypocalcemia). Severely compromised adrenal function, as in congenital adrenal hyperplasia, may lead to serum electrolyte disturbances or ambiguous genitalia.
Children with branched-chain ketonuria (maple syrup urine disease) excrete urinary ketoacids that impart the characteristic odor of maple syrup. Clinically, these infants have frequent hypoglycemic episodes, lethargy, vomiting, and muscular hypertonia. Glycogen storage diseases are inherited autosomal recessive defects characterized by either deficient or abnormally functioning enzymes involved in the formation or degradation of glycogen. Hepatomegaly, growth failure, hyper-lipidemia, and hyperuricemia are common clinical features. Other disorders to consider include galactosemia, especially in children with hepatosplenomegaly, jaundice, and mental retardation, and fructose- 1,6-diphosphatase deficiency, in children with hepatomegaly due to lipid storage but only mildly abnormal liver function studies.
After 4 hours, the glucose was 16 mg/dL; lactate, 32 mg/dL (normal range 5-18 mg/dL); and uric acid 14.2 mg/dL (normal range 2-7 mg/dL). He received intravenous glucagon (30 mcg/kg) after which the blood glucose concentration was 22 mg/dL and the lactate level increased to 44 mg/dL. He then received oral glucose and his blood glucose increased to 65 mg/dL and the lactate decreased to 24 mg/dL. These findings suggested type IA glycogen storage disease (von Gierke disease). Liver biopsy demonstrated increased glycogen content and deficient G6P enzyme activity (2 nmol/min/mg protein; normal range, 20-70 nmol/min/mg protein).
INCIDENCE AND EPIDEMIOLOGY OF GLYCOGEN STORAGE DISEASE
The glycogen storage diseases (GSDs) or glycogenoses comprise several inherited diseases caused by deficiency in one of the enzymes that regulate the synthesis or degradation of glycogen. The end result is abnormal accumulation of glycogen in various tissues. GSD type I has an estimated incidence of 1 in 200 000 births. GSD type IA is due to deficiency of the enzyme glucose-6-phosphatase (G6P), which catalyzes the breakdown of stored glycogen into glucose for use by the body. At least 56 different mutations in the gene for G6P enzyme (chromosome 17q21) have been found in patients with GSD type Ia. GSD types IB and IC are caused by failure of the G6P transporter (type IB) and microsomal phosphate transporter (type IC), which ultimately impair G6P activity. The three types of GSD result in similar clinical and biochemical disturbances. G6P is expressed in the liver, kidneys, and intestines.
CLINICAL PRESENTATION OF GLYCOGEN STORAGE DISEASE
GSD type I is characterized by severe hypoglycemia within 3-4 hours after a meal. Although symptomatic hypoglycemia may appear soon after birth, most patients are asymptomatic as long as they receive frequent feeds that contain sufficient glucose to prevent hypoglycemia. Symptoms of hypoglycemia appear only when the interval between feedings increases, such as when the child begins to sleep through the night or when an intercurrent illness disrupts normal feeding patterns.
Patients may have hyperpnea from lactic acidosis. Untreated patients have poor weight gain and growth retardation. Most patients have a protuberant abdomen and hepatomegaly due to glycogen deposition and fatty infiltration. Social and cognitive development are normal unless the infant suffers neurologic impairment after frequent hypoglycemic seizures. Xanthomas may appear on the extensor surfaces of the extremities and buttocks. Older children develop gout.
Fasting study. In GSD, the liver fails to release sufficient glucose from hepatic stores to meet peripheral tissue demands. The consequence of this “fasting state” is hypoglycemia, which causes lipolysis and protein breakdown. Therefore, in GSD, hypoglycemia is accompanied by elevated lactic acid, uric acid, and metabolic acidosis. Serum insulin level is low but serum and urinary ketones are markedly elevated. Glucagon does not significantly alter glucose level and actually increases lactic acid levels. An oral glucose load increases serum glucose and decreased lactic acid levels. At the time of hypoglycemia, serum should be collected for insulin, C-peptide, growth hormone, beta-hydroxybutyrate, lactate, and free fatty acids. Urine may be analyzed for organic acids, ketones, and reducing substances. This combination of studies allows for the diagnosis of GSD as well as the exclusion of other disorders that present with hypoglycemia.
Liver function tests. Mild elevations of AST and ALT occur.
Lipid profile. Markedly elevated serum triglycerides, free fatty acids, and apolipoprotein C-III. Infants with triglyceride levels greater than 1000 mg/dL are at high risk for developing acute pancreatitis. Despite the hypertriglyceridemia, the risk for cardiovascular disease is not increased.
Complete blood count. Neutropenia develops with GSD type IB but not with type IA.
Bleeding time. Although this test is not routinely performed, most children with GSD type I have impaired platelet function due to systemic metabolic abnormalities. This bleeding tendency, manifested by recurrent epistaxis and prolonged bleeding after surgery, resolves with correction of the metabolic abnormalities.
Urinalysis. Glycosuria and proteinuria indicate proximal renal tubular dysfunction that improves with correction of metabolic abnormalities.
Abdominal ultrasound. Hepatic adenomas occur in the majority of patients by the second decade of life but may be noted before puberty. Women also usually have polycystic ovaries, a finding whose clinical significance remains unclear.
Other studies. Measurement of G6P enzyme activity in a fresh liver biopsy specimen can be used to diagnose GSD IA. Molecular analysis to identify mutations on the G6P gene is a reliable alternative to liver biopsy.
Treatment consists of providing a continuous dietary source of glucose to prevent hypoglycemia. When hypoglycemia is prevented, the biochemical abnormalities and growth improve and liver size decreases. Infants require frequent feeding, approximately 2-3 hours during the day and every 3 hours at night. A variety of methods can be followed to provide a continuous source of glucose at night in older children, including intravenous dextrose infusion, continuous intragastric feeding via a nasogastric or gastrostomy tube, and the use of low glycemic index foods such as cornstarch. Orally administered uncooked cornstarch seems to act as an intestinal reservoir of glucose that is slowly absorbed into circulation. It has been used successfully in infants as young as 8 months of age and may obviate the need for continuous intragastric infusion of formula overnight. It can be mixed with water, formula, or artificially sweetened fluids in 4-6-hour intervals overnight. The optimal schedule requires validation by serial glucose monitoring. Allopurinol and lipid-lowering agents are used for severe uric acid and lipid abnormalities. Hepatocyte infusion and liver transplantation may be curative, but the long-term complications in children with GSD are not yet known.
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