Metabolic Disorders

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Questions Received:

  1. Is there something you can do to help lower high ammonia levels faster?

  2. What are metabolic disorders?

  3. Can a metabolic disorder cause a child to have a seizure?

  4. Are there medicines against hyperammonaemia? What are the symptoms of carbamyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency, argininaemia, argininosuccinic aciduria, n-acetyl-glutamate synthetase deficiency, and citrullinaemia?

Responses:

Is there something you can do to help lower high ammonia levels faster?

3rd April 1999

Several factors can lead to increased ammonia levels in the body. These range from relatively normal situations such as intense physical activity to pathological situations such as liver dysfunction. The action required to lower the ammonia levels in each case will be different, so it will be helpful to us if you could specify the problem more fully. In the meantime, here are a few observations that may be of interest.

Ammonia production increases during intense physical exercise (Guezennec et al, 1998) and organs such as the liver and brain are involved in its breakdown. Even the ingestion of a high-protein diet can lead to increased ammonia production (Wagenmakers 1998), so diet has a link with ammonia production.

People with liver dysfunction can experience raised levels of ammonia because the liver is unable to remove ammonia produced by metabolic processes. Interestingly, the micro-organism Helicobacter pylori can exacerbate this problem for people with liver disease. Helicobacter pylori lives in the digestive tract and is one of the main causes of ulceration. Eradication of the organism by treatment with antibacterial or antibiotic drugs is effective in reducing ammonia levels in people with liver dysfunction (Miyaji et al, 1997; Zullo et al, 1998).

Children who have inborn errors involving the urea cycle, and thus high levels of ammonia in the blood, have been treated effectively by liver transplantation (Whitington et al, 1998), and life-threatening levels of ammonia in the blood have been treated by haemodialysis, although not without complications (Vats et al, 1998).

References

What are metabolic disorders?

23rd June 1999

Metabolism is the label given to all the chemical changes that go on inside living systems. Metabolic processes have to be continuously regulated and balanced to maintain homeostasis within the body. If there is a breakdown in normal regulation then metabolic disorders occur.

Many bodily processes are integrated and controlled by the nervous and endocrine systems. These two systems are closely interdependent, and there is a significant interaction between the hypothalamus (part of the nervous system) and the pituitary gland (part of the endocrine system) to keep these two systems in harmony. The endocrine system helps to maintain and regulate many processes within the body, for example: growth and development, reproduction, ionic homeostasis (sodium, potassium, calcium, water, and acid-base balance), responses to stress and injury, and energy metabolism. Therefore, an imbalance in hormone levels or changes in the sensitivity of cells to hormones can seriously affect one or several of these important processes:

If there is a reduced output of one or several pituitary hormones as a result of destruction of pituitary cells, then the consequences can include diminished growth, failure of sexual maturation, disturbances of the menstrual cycle, or diabetes insipidus. On the other hand, if there is a higher than normal output as a result of increased numbers of pituitary cells or overactivity, the consequences can include excessive growth.

Over-secretion of thyroid hormone (hyperthyroidism) produces fatigue, tremor, sweating, weight loss, palpitations, mental agitation, and eye problems. Conversely, under-secretion (hypothyroidism) produces fatigue, hoarseness, decreased sweating, facial puffiness, slow movements, slowing of intellectual activity, and diminished growth in children. Enlargement of thyroid gland (goitre) as a result of iodine deficiency may be associated with hypothyroidism.

Diabetes mellitus may result from the secretion of too little insulin by the islets (type 1 insulin-dependent diabetes), or from insensitivity of body cells to insulin (type 2 non-insulin- dependent diabetes). In both types of diabetes blood glucose levels rise, but cells are unable to absorb the glucose they need. Glucose is excreted in increased quantities of urine, and there is utilisation of fat reserves as an alternative energy source, producing wasting and giving the patient's breath a ‘pear-drop' smell - coma may result. The complications of diabetes include vascular disease, hypertension, coronary or cerebral artery thrombosis, and peripheral ischaemia.

If the adrenal cortex secretes excessive levels of glucocorticoids; the consequences include reduced protein synthesis, thinning of skin and blood vessel walls, and weakening of muscles and bones (Cushing’s syndrome). When there is hyposecretion resulting in reduced levels of glucocorticoids, mineralocorticoids, and androgens; the results are muscle weakness, reduced blood sugar, nausea, loss of appetite, weight loss, and increased pigmentation (Addison’s disease).

Calcium metabolism is regulated by parathyroid hormone, calcitonin, and vitamin D. If there is oversecretion of parathyroid hormone increased bone resorption occurs, and there are widespread changes in other systems. If there are diminished levels of parathyroid hormone secretion, the consequences include tetany, seizures, and mental disturbances.

Can a metabolic disorder cause a child to have a seizure?

23rd June 1999

Yes - neurons are extremely sensitive to changes in the internal environment and changes outside the normal homeostatic range in a metabolism-related parameter might trigger a seizure. (A seizure is a transient change in brain activity associated with the disordered generation of nerve impulses in sets of neurons, particularly in the cortex of the brain.) So for example, a drop in blood calcium levels - perhaps as a result of diminished secretion of parathyroid hormone - can trigger a seizure.

Are there medicines against hyperammonaemia? What are the symptoms of carbamyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency, argininaemia, argininosuccinic aciduria, n-acetyl-glutamate synthetase deficiency, and citrullinaemia?

4th November 1999

Hyperammonaemia is treated by either decreasing ammonia production in the gastrointestinal tract or by increasing ammonia removal from the blood by the liver and skeletal muscle. The metabolic imbalance can be made worse by the presence of co-existing catabolic states such as infections, since these result in an increased breakdown of proteins in the body and hence increased production of ammonia. Peritoneal dialysis and haemodialysis have been used with some success in the treatment of hyperammonaemia (Gortner et al, 1989; Falk et al, 1994). Early therapy with intravenous sodium benzoate and sodium phenylacetate can slow the rate of ammonia accumulation in the blood (Tuchman et al, 1992; Lo et al, 1993). The essential amino acids arginine, citrulline, and carnitine are also useful adjuncts in the treatment of urea cycle disorders (Brusilow, 1984; Hochreutener et al, 1989). Liver transplantation is another option (Todo et al, 1992). New therapeutic approaches are aimed at correcting the neurotransmitter and cerebral energy deficits resulting from hyperammonaemia (Butterworth, 1998).

Urea Cycle< Urea Cycle

Detoxification through the urea cycle is the means by which mammalian organisms dispose of their excess ammonia. In children with inborn errors of metabolism, toxic metabolites accumulate and may lead to acute metabolic crises and long-term neurological dysfunction or death. It is important to reach a diagnosis quickly since the condition of affected children, particularly neonates, will deteriorate over a period of hours. Hyperammonaemia affects neurotransmission and produces changes in mood and personality, eventually precipitating ataxia, convulsions and coma (Butterworth, 1998).

 

 

 

 

 

 

In the second part of your question you ask about the symptoms of specific disorders of the urea cycle. Since these generally result in hyperammonaemia, The main symptoms will be the same as those outlined above. However, the following specific observations may be of some help.

Carbamyl phosphate synthetase catalyses the synthesis of carbamyl-phosphate from ammonia and bicarbonate, the first step in ureagenesis. Deficiency of this enzyme, the consequence of an autosomal recessive condition, may produce tachycardia, apathy, irritability, and metabolic alkalosis followed by coma and fits due to raised ammonia levels (Hochreutener et al, 1989). Unusually, a severe stroke was seen as the main presenting sign in an 18-month-old girl with this deficiency (Sperl et al, 1997).

In argininosuccinic aciduria, hyperammonaemia occurs with the associated symptoms (Zieve, 1986).

Argininaemia is a rare autosomal recessive disorder caused by deficiency in the liver enzyme L-arginine urea-hydrolase (arginase). It is manifested as a neurological disturbance and mental retardation (Todoroki et al, 1998). Plasma arginine and ammonia levels become raised, and there is progressive spastic diplegia (Prasad et al, 1997).

The initial symptoms of ornithine carbamoyl transferase deficiency depend on the age of onset (Bachmann, 1992). Del Valle et al (1982) described an affected male newborn whose main symptoms were tremors, continuous crying, rejection of food, respiratory problems, hypotonia and tonic-clonic convulsions. The baby deteriorated rapidly and died 62 hours after birth. Ornithine transcarbamylase deficiency shows X-linked inheritance with partial dominant expression in carrier females (Vella et al, 1997). Mitochondrial abnormalities are commonly seen in liver cells of patients with ornithine transcarbamylase deficiency, although not in a case described by Capistrano-Estrada et al (1994).

Citrullinaemia is an autosomal recessive disease caused by a deficiency of arginosuccinic acid synthetase and results in hyperammonaemic coma and poor intellectual function. Liver transplantation is an early therapeutic option (Fletcher et al, 1999). Mitochondrial abnormalities are also seen in citrullinaemia and may be related to the accumulation of citrulline (Zamora et al, 1997). Gene therapy offers the possibility of a long-term cure for citrullinaemia (Patejunas et al, 1998).

N-acetyl-glutamate synthetase is a mitochondrial matrix enzyme which catalyzes the synthesis of N-acetyl glutamate, an activator of the urea cycle enzyme carbamylphosphate synthetase I (Vockley, et al, 1992). Cases are rare, and generally present with uncontrollable neonatal hyperammonemia leading to death. There has however been a report of relatively benign cases (Pandya et al, 1991). Within the uea cycle, N-acetyl glutamate is the most important cofactor for optimal enzyme activity in liver cells (Zimmermann et al, 1985). The disorder can be cautiously treated with N-carbamylglutamate (Plecko, Erwa, and Wermuth, 1998).

References

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