- An insight into the biochemistry of inborn errors of metabolism for a clinical neurologist

Glucose is of essential, fundamental importance for brain metabolism. The major source of glucose to the brain is the blood supply; and, a fall in the blood glucose level may lead to severe encephalopathy. Hypoglycemia (blood glucose, <45 mg/dl; in neonates, <30 mg/dl), is a common nonspecific problem in severely ill neonates and young children irrespective of the illness. In adults, there are varied causes of hypoglycemia but are noted most often in diabetic patients and are usually secondary to changes in medication or overdoses, infection or changes in diet or activity. Other causes include islet cell/extrapancreatic tumors, adrenal insufficiency, hypopituitarism, severe hepatic dysfunction, sepsis or starvation. The most frequent causes of persisting neonatal hypoglycemia are hormonal disturbances, e.g., hyperinsulinism or hypopituitarism, or regulatory disturbances (e.g., ketotic hypoglycemia or glycogen storage disorders). Various etiologies of genetic hypoglycemias are classified according to the time of manifestation [Table 5].[29] The laboratory investigations during symptomatic hypoglycemia should include blood counts, C-reactive protein (CRP), liver function tests, creatine kinase (CK), uric acid, triglycerides, blood gases and electrolytes, lactate, and ammonia, ketones in urine, organic acids (in first urine sample after hypoglycemia), plasma amino acids, carnitine and acylcarnitines, plasma insulin, C-peptide, glucagons, cortisol, IGF-1 and isoelectric focussing for transferrin (if indicated).

[Figure 2] presents an overview of a biochemical approach to the diagnosis of hypoglycemia, which focuses primarily on the disease caused by inherited neurometabolic disorders. The presence of non-glucose-reducing substances in the urine is characteristic of untreated classical galactosemia and hereditary fructose intolerance. This can be determined at the bedside by testing a few drops of urine with Benedict's test and the glucose strip (Uristix). A positive Benedict's test with a negative test with uristix for glucose indicates that the reducing substance is not glucose. Patients with galactosemia show other evidences of hepatocellular dysfunction and hereditary fructose intolerance is associated with marked lactic acidosis.

The normal physiological response to decreased glucose production is increased mitochondrial fatty acid b-oxidation and the production of ketones. Accordingly, increased urinary ketones provide an indirect evidence of whether hypoglycemia is the result of inadequate production or overutilization of glucose. In older infants, children and adults, the absence of ketones in urine is usually a strong indication of increased glucose utilization. Increased glucose utilization (hypoketotic hypoglycemia) occurs as a result of either hyperinsulinism or of primary or secondary defect in fatty acid oxidation. The two situations are distinguishable by measuring plasma free fatty acid levels. One of the physiological effects of insulin is inhibition of hormone-sensitive lipase in adipose tissue. Low free fatty acid levels during hypoglycemia are a strong indication of abnormally elevated insulin levels. The timing of the hypoglycemia and other laboratory findings render differentiation of this condition relatively simple. Hyperinsulinemic hypoglycemia occurs due to insulin hypersecretion by the  Islets of Langerhans More Details. Focal islet cell hyperplasia is associated with mutation of sulfonylurea receptor (SUR1) or inwardly rectifying potassium channel (Kir.2) genes. A few cases of syndromic hyperinsulinemia such as hyperinsulinism associated with Usher syndrome type Ic, congenital disorder of glycosylation (CDG) Ia or Ib, Beckwith Wiedemann's syndrome, Perlman's or Sotos' syndrome have been described. Infants with mutations in glutamate dehydrogenase gene (GLUD I) present with recurrent hypoketotic hypoglycemia, elevated plasma insulin and persistent hyperammonemia.

Most hypoglycemias associated with permanent hepatomegaly occur due to an inherited metabolic disorder.[30] All conditions, acquired or inherited, associated with severe liver failure can result in severe hypoglycemia, which appears after 2-3 h of fasting and manifests with moderate lactic acidosis and no ketosis. When hepatomegaly is the most prominent feature without hepatic insufficiency, deficiencies of glucose-6-phosphatase (GSD I), fructose 1,6-bisphosphastase (FBP), glycogen debrancher (GSD III) or glycogen synthase (GSD 0) should be considered as the most probable diagnosis. In GSD I, laboratory examination typically shows lactic acidosis, hyperuricemia, hypertriglyceridemia and hypophosphatemia. Hypoglycemia is characteristically unresponsive to glucagon administration. A distinguishing feature of this disorder is a significant increase in plasma lactate in response to glucagon. In FBP deficiency, however, the response to glucagon is preserved. An oral glucose test can differentiate GSD I from GSD III. A moderate increase in blood lactate is observed in GSD III, whereas blood lactate drops precipitously in GSD I. The rare glycogen synthase deficiency presents with fasting hypoglycemia, ketosis and postprandial hyperlactacidemia. A definitive diagnosis of these disorders requires measurement of the relevant enzymes. Respiratory chain disorders can present with hepatic failure and hypoglycemia.

Hypoglycemia is a prominent secondary metabolic phenomenon in all mitochondrial fatty acid b-oxidation defects. The diagnosis can be confirmed by demonstrating the presence of high concentration of C6-C10 dicarboxylic acids (adipic, suberic and sebacic acids) and the characteristic acylcarnitines in plasma during acute decompensation. Fasting hypoglycemia and marked hepatomegaly associated with early-onset renal tubular dysfunction characterised by polyuria, hypophosphatemic rickets, hyperchloremic metabolic acidosis, and severe growth retardation is typical of Fanconi-Bickel syndrome. This condition is caused by mutation in GLUT 2 gene coding for the hepatic-type glucose transporter.

Patients with genetic endocrine disorders due to defects such as growth hormone (GH) gene deletion, mutation in GH-releasing hormone (GHRH) receptors, insulin-like growth factor-1 (IGF-1) defects or malformations of the hypothalamic area leading to multiple pituitary hormone deficiencies can present with fasting hypoglycemia. Hypoglycemic responsiveness to glucagon is variable-mild, absent or dramatic-the latter response being similar to that observed in hyperinsulinism. Hypoglycemia associated with isolated adrenocorticotrophic hormone (ACTH) deficiency is rare. Glucagon deficiency can also be associated with hypoglycemia.

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