MANAGEMENT OF INBORN ERRORS OF METABOLISM
Dr. Siddharth Ramji *
Professor and Head of Neonatology, Maulana Azad Medical College, New Delhi Email: sumisid@vsnl.com *
When an

inborn error of metabolism

, such as an organic academia or urea cycle defect, is suspected in a critically ill infant, immediate treatment should be initiated, even if a definitive diagnosis may not yet be established. Within 48 to 72 hours, the results of amino acid and organic acid analysis should be available, allowing

diagnostic confirmation

in most cases. Appropriate and aggressive treatment before the confirmation of a diagnosis may be life-saving and may avert or reduce the neurologic sequelae of some of these disorders. The immediate treatment of infants with disorders in this group has two primary goals. The first is the removal of accumulating metabolites such as organic acid intermediates or ammonia and second is prevention of catabolism.

The

immediate treatment of infants

with disorders in this group has two primary goals. The first is the removal of accumulating metabolites such as organic acid intermediates or ammonia and second is prevention of catabolism.

Emergency Department Care:



Initial ED treatment does not require knowledge of the specific metabolic disease or even disease category. In any critically ill child, airway, breathing, and circulation must be established first. Consider antibiotics in any child who may be septic. Initial treatment of IEMs is aimed at correcting metabolic abnormalities. Even the apparently stable patient with mild symptoms may deteriorate rapidly with progression to death within hours. With appropriate therapy, patients may completely recover without sequelae. Start empirical treatment for a potential IEM as soon as the diagnosis is considered.

Initial ED treatment does not require knowledge of the specific metabolic disease or even disease category.

Eliminate potentially harmful protein or sugars. All oral intake should be stopped.
  • Treat hypoglycemia and prevent catabolism.
  • Correct hypoglycemia, if present, by IV dextrose bolus, 25%, 0.25-0.5 g/kg/dose (1-2 mL/kg); not to exceed 25 g/dose, and followed by continuous IV administration of dextrose.
  • For all patients in whom an IEM cannot be ruled out, give dextrose 10-15% IV at a rate high enough to prevent catabolism (8-10 mg/kg/min).
  • Dextrose will improve most conditions.
  • Add insulin, 0.2-0.3 IU/kg, as needed to maintain normoglycemia.
  • Add electrolytes at maintenance concentrations with appropriate adjustments to correct electrolyte disturbances if present. A standard intravenous order that is applicable to most metabolic disorders and clinical conditions is 10% dextrose in 0.2 normal saline to run at 1.5 times maintenance. If the patient is clearly dehydrated or in hypovolemic shock, a normal saline bolus can be run concurrently through a "Y" connector or a second line. Do not stop the dextrose infusion to give a normal saline bolus. Another option is to give 10 cc/kg of D 5 NS over 30 to 60 minutes. In critical patients, simultaneous insulin and dextrose drips may be beneficial in terminating catabolism rapidly and reversing metabolic acidosis and hyperammonemia. Clinical experience suggests starting at 0.05 units/kg/h of insulin and 10 mg/kg/min of glucose, and titrate both upwards, frequently obtaining rapid blood glucose measurements, until the patient is on 0.1 to 0.2 units/kg/h of insulin, and above 8 to 12 mg/kg/min of glucose. In the converse of the logic employed in the treatment of diabetic ketoacidosis, in critical metabolic decompensation the glucose infusion is titrated to maintain the desired insulin dosage. The goal is to achieve a serum glucose between 120 to 170 mg/dL. If protein-containing feedings have been not tolerated or withheld for greater than about 48 to 72 hours, essential amino acid deficiency can result in a catabolic state regardless of the dextrose infusion, yet will respond to about 0.5 to 0.7 g/kg/d of amino acids delivered in hyperalimentation.
  • Treat acute acidosis and electrolyte abnormalities. The pH and dose at which bicarbonate should be administered are controversial; pH <7.0-7.2, dose 0.35-0.5 mEq/kg/h up to 1-2 mEq/kg/h. When patients are symptomatic or severely hypokalemic, potassium acetate is a useful replacement fluid (1 mEq/kg/h). Rapid correction or overcorrection may have paradoxical effects on the CNS. For intractable acidosis, consider hemodialysis. The acid-base status should be monitored frequently, with therapy adjusted accordingly.

Definitive treatment of IEM requires removal of abnormal metabolites by restricting intake of the offending substrate, by promoting renal excretion of toxic metabolites, in severe cases, by dialysis (preferably hemodialysis). Dialysis should be considered for severely acidotic neonates with organic acidemias, regardless of whether hyperammonemia is present.

Dialysis should be considered for severely acidotic neonates with organic acidemias, regardless of whether hyperammonemia is present.
  • Significant hyperammonemia is life threatening and must be treated immediately upon diagnosis.
  • To reduce ammonia, sodium phenylacetate and sodium benzoate are given.
  • Arginine is an essential amino acid in patients with some urea cycle defects.
  • For ammonia greater than 500-600 mcg/dL, hemodialysis should be initiated. In infants who are comatose or ventilator-dependent, or who exhibit evidence of cerebral edema, dialysis should be instituted immediately without waiting to determine whether there is a response to dietary manipulation, medication, or other less aggressive therapy. Maximal supportive care should be provided simultaneously. In patients suspected of having a urea cycle defect because of significant hyperammonemia without acidosis, an infusion of 6 mL/kg of 10% arginine HCL (0.6 g/kg) can be given intravenously over 90 minutes. In patients with citrullinemia and argininosuccinic aciduria, this often results in a precipitous drop in the plasma ammonia level. An intravenous arginine preparation is available commercially.
  • Two to 3 days of therapy is usually necessary. The goal of HD is to achieve a plasma ammonia concentration of <200 mmol/L, irrespective of the duration of HD. Plasma ammonia concentrations should be measured every hour during the acute HD treatment, and the HD treatment ends on reaching of a level <200 mmol/L. Similarly, the duration of continuous renal replacement therapy is determined by the maintenance of the plasma ammonia concentration <200 mmol/L.
  • L-carnitine may be administered empirically in life-threatening situations associated with primary metabolic acidosis or hyperammonemia.
  • Administration of carnitine to patients with fatty acid oxidation defects is controversial.
  • Pyridoxine should be given to neonates with seizures unresponsive to conventional anticonvulsants.
  • Mega-vitamin therapy: If an organic academia is suspected, vitamin B12 (1 mg) should be given intramuscularly in case the patient turns out to have a B12 responsive form of methylmalonic academia. Biotin (10 mg) should be given orally or by nasogastric tube, because some patients with multiple carboxylase deficiency are biotin-responsive. Many enzymes require co-enzymes derived from vitamins for enzyme activity, and disorders are well recognized in which pharmacological doses of precursor vitamins will increase the enzyme activity. For this reason, it is a common practice to give large doses of many vitamins or co-factor precursors. Administration of vitamin B 12 and biotin is probably justified because vitamin-responsive methylmalonic acidemia and holocarboxylase synthetase can present in the newborn period. The justification for many other vitamins is doubtful, particularly since vitamin responsive forms of inborn errors tend to be milder than other forms and, therefore, seldom present in the neonatal period. Table 1 depicts the drugs commonly prescribed in treatment metabolic disorders.
  • After removing toxic metabolites, the second major goal of therapy in infants with inborn errors of metabolism should be prevent catabolism. Intravenous glucose should be administrated liberally to provide as many calories as possible. Intravenous lipids can be given to infants with urea cycle defects and other disorders in which dietary fat plays no role. Protein should not be withheld indefinitely. If clinical improvement is observed and a final diagnosis has not been established, some amino acid intake should be provided after a maximum of 2 to 3 days of complete protein restriction. Essential amino acids or total protein can be provided orally or intravenously at an initial dose of 0.5 g protein/kg/24 hours. This should be increased incrementally to 1.0 g/kg/24 hours and held at that level until the diagnostic evaluation is complete and plans can be made for definitive long-term therapy. Therapy should be planned in conjunction with a geneticist or specialist in metabolic disease. Until then, supplemental calories and nutrients can be provided orally using protein-free diet powder (product 80056, Mead Johnson, Evansville , IN or Prophree, Rose Laboratories, Columbus , OH ). Once a definitive diagnosis is established, commercial products formulated for individual diseases can be instituted.

Table 1. Treatments commonly employed in neonates with Metabolic disorders

Condition

Medication

Route

Dose

Caution

Most conditions
L-carnitine

IV/PO

100 mg/kg/d
 
Hyperammonemia
Sodium benzoate/sodium phenylacetate/sodium phenylbutyrate

IV

IV: 0.25 g/kg bolus over 24 h, then infusion of 0.25 g/kg over 24 h
Hypernatremia, hypokalemia, acidosis, transient hyperammonemia, confusion, cerebral edema, hypotension
Citrullinemia, Argininosuccinate lyase deficiency
L-arginine

IV

<0.2-0.6 g/kg bolus then infusion of 0.25 g/kg over 24 h
Acidosis, extravasation, can be harmful in some urea cycle disorders
Biotinidase deficiency, multiple carboxylase deficiency
Biotin

PO

10 g/d
 


Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001;138:S309; Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 2001;138:S4655.

Treatment of a baby with a known Metabolic disorder


For several disorders, special synthetic formulas are used to restrict the precursors of the defective enzyme to the minimal intake needed to promote normal growth. The resultant diets are highly unpalatable, and noncompliance by ingesting either too little or too much can result in metabolic decompensation and substantial morbidity. In particular, children with inborn errors of metabolism are highly dependent on maintaining their caloric intake, and any intercurrent illness that causes the refusal or the inability to eat can precipitate a crisis. During viral illnesses, patients are commonly instructed to take a sick-day regimen of protein free juices at home for 24 to 48 hours and to monitor their mental status and urinary ketones by dipsticks. Altered mental status, vomiting, or other feeding intolerance, or "large" ketones (80 or greater) are indications for evaluation by a physician. If the child presents to the Emergency unit, several hours of 1.5 times maintenance with 10% dextrose in 0.2 normal saline may avert the crisis and return the patient's anion gap and urine ketones to normal; hyperammonemia corrects slowly over multiple hours. Antiemetics, especially phenothiazines, which may alter mental status should be used with caution, but the administration of ondansetron may allow a patient to tolerate oral intake. However, if the patient has acute neurologic signs or laboratory abnormalities that persist or worsen, or the child remains unable to take the appropriate formula, he/she will require hospitalization. Patients with methylmalonic academia, propionic academia, glycogen storage disease type 1b, and certain mitochondrial disorders require a complete blood count and differential, as they are prone to neutropenia or thrombocytopenia during periods of acute illness. Certain medications, such as valproic acid, haloperidol, or steroids can precipitate hyperammonemia in some children with metabolic disorders and should be used with caution. Table 2 depicts the step wise management of a child with suspected metabolic disorder.

During viral illnesses, patients are commonly instructed to take a sick-day regimen of protein free juices at home for 24 to 48 hours and to monitor their mental status and urinary ketones by dipsticks.

Table 2. Management of a suspected Metabolic disorder
Stop any "toxic" nutrient
e.g., protein, galactose
Give high-energy intake
usually glucose, orally or intravenously
Neonatal intensive care
correct tissue perfusion, dehydration, acidosis, hypothermia, anemia, etc.
Treat hyperammonemia
sodium benzoate, sodium phenylbutyrate, arginine
Dialysis
haemofiltration/haemodialysis or peritoneal (bicarbonate based)
Insulin
to control hyperglycemia and reduce catabolism
Vitamins e.g., biotin, hydroxocobalamin or pyridoxine
Specific therapy
e.g., carnitine, glycine for isovaleric acidemia


Early Onset seizures


There is increasing evidence that the outlook is improved if early-onset fits can be controlled quickly. Investigations should include plasma and CSF amino acids, plasma very-long-chain fatty acids, plasma urate, blood and CSF lactate, and urine sulphite. The genetic basic has recently been identified for pyridoxine dependency, the commonest cause of vitamin-responsive seizures. All patients should have a trial of pyridoxine (100 mg), which can be given intravenously or enterally, preferably with EEG monitoring. Full resuscitation facilities must be available as patients may collapse after the first dose. If there is no response, pyridoxal phosphate (30 mg/kg) should be given enterally followed, if necessary, by folinic acid (3 mg/kg).

Breast Feeding in Inborn metabolic disorders


Breast feeding has many proven benefits for infants with IEM's except for Galactosemia and long chain fatty acid deficiency. The advantages are:
  • Breast milk is a complex fluid low in protein (table 1), contains long chain fatty acids
  • Has many non-nutritional bioactive compounds
  • Lowers gut propionate; among its other uses

Demand breast feeding for PKU dates back to 1981; when babies were given phenylalanine free formula before feeding, reducing the stimulation but still being breast fed on demand. The children were monitored with phenylalanine levels. Breast feeding commenced within 5 days with a mean of 14 days. The basic methods of feeding babies with protein or aminoacid IEM's are a) give expressed breast milk mixed with other modular mixtures b) breast feeding on demand preceded by protein free formulas. These are particularly true for MSUD, PKU, HCU and Tyrosinemia Types 1 & 2. Protein requirements change with severity of disease and growth rate. In addition strict adherence to frequent short periods of protein free adherence during periods of acute decompensation has an impact on growth rate and intercurrent protein requirements. Human milk being a low protein formula is best for the management and its protein values are depicted in Table 3.

Table 3. Protein content of human milk at different Gestational ages
Gestational age > Protein (gm/100ml) Dewey et al (1984), Lonnerdal et al (1987), Nommsen et al (1991)
46 days 1.26 ± 0.27  

 

1.24 ± 0.2213
720 1.61 ± 0.10
3 Months 1.21 ± 0.15
6 Months 1.14 ± 0.15
9 Months 1.16 ± 0.18
12 Months 1.24 ± 0.15


Special Diets


A sufficient variety of semi synthetic dietary products is now available to permit control of amino acid imbalance in several inborn errors of metabolism. However, they must be used carefully, and their effects monitored closely. Continuing development of products for this type of special diet-to provide a wider variety-is necessary. In India , as they have to be imported.

Stem Cell Transplantation


Haematopoietic stem cell transplantation is an accepted curative therapy for many cancers and inherited non-malignant diseases, including bone marrow failure syndromes, haemoglobinopathies, and inborn errors of metabolism. Umbilical cord blood (UCB) has been successfully used as an alternative stem cell source. It has the advantage of tolerance for a degree of human leukocyte antigen (HLA) incompatibility not possible with adult bone marrow, resulting in greater likelihood of finding an appropriate match. UCB is also stored fully tested and cryopreserved, leading to rapid availability.

Recommended Reading
  1. The Metabolic and Molecular Basis of Inherited Disease. CR Scriver, AL Beaudet, WS Sly, D Calle, eds. 7 th end (1995) McGraw Hill , New York .
  2. Clinical Biochemistry and The Sick Child. BE Clayton, JM. Round. 2 nd edn (1994), Blackwell Scientific Publications, Oxford .
  3. A Clinical Guide to Inherited Metabolic Diseases, JTR Clarke 1996 Cambridge University Press, Cambridge .
  4. Burton BK. Inborn errors of metabolism in infancy : a guide to diagnosis. Pediatrics 1998;102:6.
  5. Neurology of Hereditary Metabolic Diseases of Children; Gilles Lyon; Raymond D Adams Edwin H Kolodny. McGraw-Hill; 2 nd edn.



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