Inborn errors of metabolism

1. INBORN ERRORSINBORN ERRORS
OF METABOLISMOF METABOLISM
Dr. SAYAN MISRADr. SAYAN MISRA
33rdrd
YEAR PGT, MASTERS IN EMERGENCY MEDICINEYEAR PGT, MASTERS IN EMERGENCY MEDICINE
GEORGE WASHINGTON UNIVERSITY (USA)GEORGE WASHINGTON UNIVERSITY (USA)
PEERLESS HOSPITAL AND B.K.ROY RESEARCH CENTERPEERLESS HOSPITAL AND B.K.ROY RESEARCH CENTER
KOLKATAKOLKATA

2. 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.

3. 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.

4. 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

5. 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

6. 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.

7. 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.

8. 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)

9. 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.

10. • 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.

11. 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.

12. 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).

13. 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

14. Approach

15. Laboratory Evaluation

16. 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.

17. • 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.

18. • 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.

19. • 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.

20. 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.

21. • 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.

22. Other Therapies

23. 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.

24. • 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.

25. 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.

26. 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.

27. • 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.

29. 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.

30. 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.

31. 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.

32. • 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.

33. 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.

34. • 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.

35. • 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.