Metabolic Disorders
Inborn Errors of Metabolism
Shari Simone
Background
Genetic metabolic disorders, also known as inborn errors of metabolism (IEM), are individually rare, but collectively numerous and occur in 1 of 1,500 children.
Most metabolic disorders are inherited as autosomal recessive traits.
Definition
Genetic metabolic disorders are a group of disorders that result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, or fats.
Most disorders result from the absence or abnormality of an enzyme or its cofactor essential for normal function of specific metabolic pathways.
The disrupted metabolic pathway has various consequences, including a deficiency of a particular end product or excessive, toxic accumulation of a substrate.
General Classification
Disorders of protein metabolism.
Amino acid disorders (e.g., phenylketonuria or PKU).
Organic acid disorders (e.g., propionic acidemia).
Urea cycle disorders (e.g., ornithine transcarbamylase (OTC) deficiency).
Disorders of glucose metabolism.
Glycogen storage disease (GSD) (e.g., Pompe disease).
Other carbohydrate disorders (e.g., galactosemia).
Disorders of fat metabolism.
Fatty acid oxidation disorders (e.g., medium-chain acyl-CoA dehydrogenase (MCAD) deficiency).
Disorders of organelles.
Mitochondrial disorders (e.g., Leigh syndrome).
Lysosomal storage disorders (e.g., mucopolysaccharidosis such as Hurler syndrome, sphingolipidoses such as Tay-Sachs disease).
Peroxisomal disorders (e.g., Zellweger syndrome).
Other disorders: purine and pyrimidine disorders, porphyrias, metal disorders (e.g., Wilson disease).
These disorders are extremely rare and only Wilson disease will be discussed.
Pathophysiology
In normal circumstances, the dietary intake of glucose and tissue glycogen stores is sufficient for adenosine triphosphate (ATP) production (Figure 9.1).
If the supply of glucose cannot be maintained, the body changes to a catabolic state and fat and protein are mobilized to supply substrates to make ATP.
Protein metabolism (Figure 9.2).
Protein is made up of amino acids, composed of an amino and an organic acid group.
The amino group is metabolized in the form of ammonia, which is degraded in the urea cycle and forms blood urea nitrogen (BUN).
Organic acids are metabolized into intermediates of energy pathways (e.g., pyruvate, acetyl CoA, and ketones) and are converted to ATP through a cascade of reactions when they enter the Krebs cycle.
Amino acid metabolism also involves conversion of some amino acids to other amino acids.
Failure of, or deficiencies in, any of these pathways can lead to toxic accumulation of proteins or by-products of protein metabolism.
Carbohydrate metabolism.
Glucose is generated by mobilization of glycogen tissue stores or dietary intake of carbohydrates, and through the
process of glycolysis, it is converted to pyruvate and acetyl CoA and then enters the Krebs cycle.
FIGURE 9.1 • Production of ATP under Normal Condition.
FIGURE 9.2 • Protein Metabolism.
In the Krebs cycle, acetyl CoA is converted to nicotinamide adenine dinucleotide (NADH).
NADH is then carried through a cascade of reactions within the mitochondria, known as oxidative phosphorylation, in which the chemical energy locked within NADH is transferred to ATP.
Fat metabolism (Figure 9.3).
Triglycerides are hydrolyzed and broken down into fatty acids and glycerol.
Through the process of β-oxidation, 2-carbon units (acetyl CoA) are removed from the fatty acid molecule and enter the Krebs cycle to produce ATP.
During fat breakdown, the massive flux of acetyl CoA results in formation of ketone bodies and produces ketosis.
Carnitine is a cofactor and helps transport fatty acids into the mitochondria.
Metal metabolism.
A small amount of copper is needed for the body to function properly.
Excess copper is toxic.
Normally, excess copper is metabolized through the liver and excreted in the bile.
In Wilson disease, copper is not excreted in the bile, and builds up in the liver, releasing copper into the bloodstream.
Results in damage to brain, kidneys, and eyes.
General findings of IEM (Table 9.1).
Disorders often mimic other diseases or infections.
Most common presentations are feeding intolerance, history of vomiting, and altered mental status.
General urine odors associated with IEM: see Table 9.2.
Characteristic urine odors are associated with some amino acid and organic acid disorders.
General diagnostic evaluation for acute presentation of IEM.
Blood and urine laboratory screening tests should be obtained upon suspicion of a metabolic disorder (Table 9.3).
Consider head CT or MRI if neurologic symptoms.
FIGURE 9.3 • Fat Metabolism.
TABLE 9.1 General Acute vs. Chronic Findings of IEM
Acute Findings
Chronic Findings
Seizures/lethargy/coma
Hypotonia
Poor feeding/vomiting
Failure to thrive
Hypoglycemia
Recurrent unexplained illnesses
Signs of sepsis
Developmental delay/loss of milestones
Hyperammonemia
Cardiomegaly
Ketosis
Macro/Microcephaly
Metabolic/Lactic acidosis
Eye/Hair/Skin abnormalities
Abnormal urine odor
“Coarse” appearance
TABLE 9.2 Urine Odors Associated with IEM
Disorder
Urine Odor
Maple syrup urine disease
Maple syrup
Phenylketonuria
Musty
Isovaleric/Glutaric acidemia
Sweaty feet
Tyrosinemia
Boiled cabbage
Trimethylaminuria
Fishy
TABLE 9.3 Blood and Urine Laboratory Screening Tests for IEM
First Set of Screening Laboratory: Blood Tests
First Set of Screening Laboratory: Urine Tests
Complete blood count (CBC)
Urinalysis
Blood gas (evaluate pH)
Urine pH
Serum glucose (evaluate for hypoglycemia)
Urine color and specific gravity
Serum electrolyte panel (evaluate anion gap)
Odor
Liver function tests Ammonia (evaluate for hyperammonemia)
Urine ketones (evaluate for inappropriateness for state of nutrition)
If abnormality of any of the above tests raises suspicion for IEM, then obtain:
Blood Tests
Urine Tests
Plasma amino acids
Urine amino acids
Acylcarnitine profile
Urine organic acids
Lactate
Urine-reducing substances
Check newborn screen; however, normal results do not exclude IEM.
General management principles for acute presentation of IEM.
Maintain a high index of suspicion.
Suspect diagnosis based on history, physical examination, and diagnostic studies, especially if no improvement seen with standard therapy (e.g., continued metabolic acidosis despite fluid resuscitation).
Early genetic consultation as treatment is disease-specific.
NPO to stop intake of suspected toxic substrate (e.g., protein, galactose).
Stop catabolism by providing high energy with glucose infusion of D10 plus electrolytes at 1.5 times maintenance.
If hyperammonemia is present, correct to a goal of <100 mmol/L.
Reduce ammonia serum level by discontinuing protein intake.
Consider intravenous arginine or sodium benzoate.
Hemodialysis indicated for severe hyperammonemia and encephalopathy or if refractory to pharmacologic treatment.
Correct acidosis and dehydration.
Treat the “trigger” (e.g., infection).
Treat complications (e.g., increased intracranial pressure).
Initiate any specific therapies guided by genetics consult (e.g., carnitine, biotin).
Specific Metabolic Disorders
Disorders of Protein Metabolism
Amino acid disorders.
Pathophysiology.
A defect in the metabolic pathways of amino acids resulting in abnormal accumulation of amino acids in the plasma.
Examples: PKU, nonketotic hyperglycinemia.
Clinical presentation.
Often presents in newborns who may initially be well and then become acutely symptomatic.
May experience metabolic decompensation with poor feeding and lethargy after a period of protein feeding.
Symptoms in newborn range from none to metabolic acidosis, hyperammonemia, hypoglycemia, ketosis, and liver dysfunction.
May progress to encephalopathy, coma, or death if not recognized.
Diagnostic evaluation.
Quantitative plasma amino acids and qualitative urine organic acids.
Specific enzyme analysis.
Management.
Complete protein restriction initially, then change to amino acid-restricted diet (i.e., phenylalanine-restricted diet) when specific amino acid disorder identified.
Infants and children should be monitored regularly during the developmental period.
Strict dietary therapy is recommended to be continued for life for some disorders (i.e., maple syrup urine disease).
Urea cycle disorders.
Pathophysiology.
Deficiency of an enzyme or cofactor that transforms nitrogen to urea for excretion and results in the accumulation of ammonia and other precursor metabolites.
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