INBORN INBORN ERRORS OF ERRORS OF

METABOLISMMETABOLISMDr. SAYAN MISRADr. SAYAN MISRA

33rdrd YEAR PGT, MASTERS IN EMERGENCY MEDICINE YEAR PGT, MASTERS IN EMERGENCY MEDICINEGEORGE WASHINGTON UNIVERSITY (USA)GEORGE WASHINGTON UNIVERSITY (USA)

PEERLESS HOSPITAL AND B.K.ROY RESEARCH CENTER PEERLESS HOSPITAL AND B.K.ROY RESEARCH CENTER KOLKATAKOLKATA

Inborn Errors of Metabolism

• Inherited metabolic disorders caused by a defect in the enzymes or their co-factors that metabolize protein, carbohydrate, or fat.

• Generally refer to gene mutations or gene deletions that alter metabolism in the body.

• Incidence of Inborn errors of metabolism (IEMs) individually occur 1 in 1,400 to 1 in 2,00,000 live births.

• Often treatable if diagnosed. Presentation is usually in the neonatal period or infancy but can occur at any time, even in adulthood.

• Difficult task for clinician is to know when to consider IEM and which tests to order for evaluation.

Pathophysiology• Single gene defects result in abnormal metabolism of proteins,

carbohydrates, fats, or complex molecules.

• Due to a defect in an enzyme or transport protein block in a metabolic pathway, effects are due to toxic

accumulations of substrates before the block.

Disorders that result in toxic accumulation

• Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects)

• Disorders of carbohydrate intolerance

• Lysosomal storage disorders

Disorders of energy production, utilization• Fatty acid oxidation defects

• Disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis)

• Mitochondrial disorders

• Peroxisomal disorders

Epidemiology• Incidence ranging from 1 in 1400 to 1 in 200,000 live

births.

• Sex : The male-to-female ratio is 1:1 for autosomal dominant and autosomal recessive transmission. It is also 1:1 for X-linked dominant if transmission is from mother to child.

• Age : varies… onset and severity may be exacerbated by environmental factors such as diet and intercurrent illness.

Ages at which….• Disorders of protein or carbohydrate intolerance,

disorders of energy production during neonatal period or early infancy and tend to be unrelenting and rapidly progressive.

• Fatty acid oxidation defects, glycogen storage, and lysosomal storage disorders tend to present in infancy or childhood.

• Disorders manifested by subtle neurologic or psychiatric features often go undiagnosed until adulthood.

Clinical Presentation: History

The patient’s history may include the following:

• Symptoms that range from abrupt in onset and episodic to chronic and progressive• Poor feeding, vomiting, failure to thrive, lethargy• Developmental delay, sometimes with loss of milestones• Onset of symptoms with change in diet• Decompensation out of proportion to what would be expected from intercurrent

infection• Similar findings of unexplained neonatal or sudden infant deaths in siblings or

maternal male relatives (A negative family history does not rule out IEM.)• Possible parental consanguinity (increases the likelihood of autosomal recessive

IEM)

Neonates....• Consider IEM in any critically ill neonate.

• Most important clue is a history of deterioration, often life-threatening, after an initial period of apparent good health ranging from hours to weeks, usually following an uncomplicated pregnancy and delivery in a term infant.

• In term infants without risk for sepsis who develop the symptoms of sepsis, metabolic disease may be nearly as common as sepsis.

• Diarrhea may accompany carbohydrate metabolism disorders or mitochondrial disease.

• Parents may report an abnormal body or urinary odor, although this is more commonly noted by clinicians.

• Abnormal odor is typical of isovaleric acidemia, glutaric acidemia, and maple syrup urine disease, which, as the name suggests, is accompanied by a characteristic sweet smell of the urine.

Physical Examination The physical examination begins with attention to the

vital signs :-• Tachycardia is often present during acute metabolic crisis.• Hypothermia may accompany many metabolic diseases,

particularly the urea cycle defects and organic acidemias.• Tachypnea without increased work of breathing may be

noted in patients with metabolic acidosis and may result in a respiratory alkalosis.

• Glycogen storage disease, liposomal storage disease, and mucopolysaccharidoses, may manifest with hepatosplenomegaly, growth retardation, poor muscle tone, developmental delay later in childhood.

Physical Examination• Some metabolic disorders have ocular findings, including

cataracts (e.g., galactosemia) or dislocated lenses (e.g., homocystinuria).

• The GU examination is important when adrenal insufficiency is a consideration, because females with one specific defect may show signs of Virilization [A condition that causes a female to develop male-pattern hair growth and other masculine trait.] eg Congenital Adrenal Hyperplasia (Adrenal Insufficiency).

Differentials• Multiple Sclerosis• Pediatrics, Apnea• Pediatrics, Bacteremia and

Sepsis• Pediatrics, Child Abuse• Pediatrics, Crying Child• Pediatrics, Gastroenteritis• Pediatrics, Hypoglycemia• Personality Disorders• Pediatrics,Reye Syndrome

• Pediatrics, Meningitis and Encephalitis

• Pediatrics, Pyloric Stenosis• Pediatrics, Respiratory

Distress Syndrome• Pediatrics, Sudden Infant

Death Syndrome• Pediatrics, Urinary Tract

Infections and Pyelonephritis

Approach

Laboratory Evaluation

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.

• D10 and normal saline should be used as bolus fluid.

• Consider antibiotics in any child who may be in sepsis.

• Apnea, hypoventilation, and hypoxia are treated with positive pressure ventilation or endotracheal intubation and administration of oxygen. Take care when paralyzing the infant in metabolic crisis, because metabolic acidosis can be worsened by respiratory acidosis if insufficient ventilation is provided.

• Avoid hypotonic fluid load due to the risk of cerebral edema, particularly if hyperammonemia is present.

• Discontinue intake of offending agents; provide adequate glucose to prevent catabolism.NPO (especially no protein, galactose, or fructose)

• Dextrose for hypoglycemia, 0.25-1 g/kg (maximum 25 g), D10 neonates, D10 or D25 beyond neonatal period maintain serum glucose level at 120–170 mg/dL.

• Restore circulation with crystalloid boluses, typically 10 to 20 mL/kg in the neonate and 20 mL/kg in the infant, with frequent reassessment and further fluid administration as clinically indicated.

• Even a patient who is not in shock may benefit from a bolus of normal saline (NS) followed by double the usual level of maintenance fluids with dextrose, because aggressive hydration promotes urine output with increased clearing of toxic metabolites.

• Correct metabolic acidosis (pH < 7.0) slowly, cautiously: Sodium bicarbonate: 0.25-0.5 mEq/kg/h (up to 1-2 mEq/kg/h) IV; if intractable acidosis, consider hemodialysis.

Eliminate toxic metabolites

• Hyperammonemia therapy . If Ammonia level <500micromole/L associated with encephalopathy (due to urea cycle defect), administer sodium phenylacetate and sodium benzoate 250 milligrams/kg in D10 is administered through a central venous line or intraosseus line over 90 minutes followed by 250 milligrams/kg/d as a continuous infusion.

• Arginine, 210 milligrams/kg IV/IO in D10 over 90 minutes followed by 210 milligrams/kg/d continuous infusion, should also be provided.

• Early aggressive treatment may eliminate the need for hemodialysis for excessive ammonia removal . Hyperammonia (Ammonia level > 600 Micromole/L) needs dialysis.

• Additional therapy may include empiric Carnitine 400 milligrams IV/IO, which combines with organic acids to form acylcarnitines that are readily excreted from urine.

Other Therapies

Complications• Sepsis: During metabolic crisis the accumulation of various

organic acids can suppress granulopoietic stem cells and thereby cause bone marrow suppression of all cell lines.

• This leads to an immunocompromised state with an increased incidence of sepsis in these patients due to unusual organisms. The incidence is 15% to 30% per 100 episodes

• Therefore it is essential to rule out sepsis in all patients with metabolic crisis.

• Chronic anemia and thrombocytopenia may accompany a number of inborn errors of metabolism and may be exaggerated during metabolic crisis.

• Give empiric broad-spectrum antibiotics such as ceftazidime, 50 milligrams/kg IV.

• Cerebral Edema: Hyperammonemia is a specific risk factor for cerebral edema.

• Cerebral edema is a clinical diagnosis and should be suspected when laboratory parameters improve but altered mental status continues.

• Treatment for cerebral edema is mannitol (0.5 gram/kg IV/IO) and avoidance of hypo-/hyperventilation. Do not give steroids, because steroids exacerbate hyperammonemia.

Disposition and Follow-Up

• All patients in metabolic crisis should be admitted to the hospital or transferred to a tertiary care children's hospital where metabolic specialists are available to help with definitive diagnosis and dietary management.

• Patients with severe metabolic abnormalities requiring hemodialysis require intensive care.

Congenital Adrenal Hyperplasia (Adrenal

Insufficiency)• Depending on the specific enzyme deficiency, cortisol deficiency may be accompanied by mineralocorticoid deficiency leading to hypoaldosteronism with resultant salt wasting

• Because the hypothalamic-pituitary axis is suppressed by cortisol, the deficiency caused by CAH results in increased secretion of adrenocorticotropic hormone (ACTH) without feedback suppression.

• Uninhibited excess ACTH stimulates the adrenal gland, which leads to hypertrophy.

• Elevated ACTH levels can also cause hyperpigmentation of the skin, which is best observed on the labial or scrotal folds and the nipples

• Steroid hormone precursors upstream of the enzyme defect build up and are shunted into alternate pathways.

• Deficiencies in 21-hydroxylase lead to the accumulation of precursors that are metabolized to androgens. This, in turn, causes virilization of affected females, which manifests as clitoromegaly.

• Affected males may go undetected at birth because their genitalia appear normal.

Clinical Features• History: Salt-wasting variants of CAH typically manifest as acute

crisis in the second week of life.

• Symptoms are vague and include lethargy, irritability, poor feeding, vomiting, and poor weight gain.

• Infants may present with significant dehydration or even shock.

• differential diagnosis of adrenal salt-wasting crisis includes sepsis, congenital heart disease, and other inborn errors of metabolism.

Emergency Care• Record vital signs and weight, ABCDs, and assess hydration

and mental status.

• A complete head-to-toe examination.

• Carefully examine the genitalia: females may have fusion of the labia and an enlarged clitoris. Males may have normal genitalia or a small phallus or hypospadias.

• Note any hyperpigmentation, especially in the scrotal or labial folds and around the nipples.

Laboratory Evaluation• Bedside glucose level and serum electrolyte levels.• Hypoglycemia is rare, poor feeding and vomiting may cause

secondary hypoglycemia requiring urgent treatment.• The classic electrolyte abnormality in salt-wasting CAH is

hyponatremia and hyperkalemia.• Serum potassium level may be elevated to between 6 and 12

mEq/L, although changes in cardiac function and ECG are unusual.

• Metabolic acidosis typically accompanies the classic electrolyte abnormalities as a result of aldosterone deficiency and dehydration.

• Definitive diagnosis depends on analysis of blood hormone levels.

• Because the presentation of adrenal salt-wasting crisis is nonspecific, consider alternative diagnoses such as sepsis.

• Although infants with CAH generally tolerate hyperkalemia well, obtain a 12-lead ECG, because hyperkalemic changes may alter emergent therapy and disposition.

Treatment• Circulatory collapse from cortisol deficiency and

dehydration is common, and IV or IO access should be established rapidly.

• Administer IV fluids in the form of 10 to 20 mL/kg NS. Fluid loss in CAH is isotonic, and fluid replacement should be with NS. Treat hypoglycemia with 5 mL/kg D10.

• Initiate steroid hormone replacement urgently: give hydrocortisone, 25 milligrams IV/IO to neonates, 50 milligrams to toddlers and school-aged children, and 100 milligrams to adolescents.

• Although mineralocorticoid deficiency in CAH is primarily treated by sodium repletion with NS, there is some mineralocorticoid effect at these doses of hydrocortisone.

• If hyperkalemia results in ECG changes or arrhythmia, treat with IV calcium gluconate (10%), 100 milligrams/kg (1 mL/kg) and sodium bicarbonate 1 mEq/kg.

• Do not give insulin and glucose for hyperkalemia in infants, because this may result in profound hypoglycemia. The administration of NS and hydrocortisone is usually sufficient to lower serum potassium levels in the absence of cardiac manifestations.