Urea Cycle Disorders
Definition (Vademecum Metabolicum 2004; Pediatr Rev 2009;30:e22)
• Inherited enzyme and transport protein def w/ ↓ removal of excess NH3 from protein metabolism; 6 disorders known
Incidence
• Most common inborn errors of metabolism; 1:8,000
• Usually presents after newborn period, at all ages
Presentation
• Neonates → lethargy, poor feeding, emesis, tachypnea, seizures, encephalopathy
• Infants/children → FTT, feeding problems, vomiting, neuro sx, lethargy, ataxia, szrs
• Teens/adults: Chronic neuro or psych sx, behav probs, lethargy, psychosis
• Of note, arginase deficiency w/o hyperammonemia, p/w progressive neuro deterioration
Diagnosis
• Check NH3, Dx based on abn plasma & urine amino acid levels, routine labs often nml
Ornithine Transcarbamylase Deficiency (OTC)
• Most common; 1:14,000; X-linked, many w/ residual enzyme activity; ↑ orotic acid level
• Can present between 1 mo of age to childhood with significant illness; inc urine orotic acid
Treatment
• Acute therapy → see the previous discussion
• Long-term management: Metabolic team to assess diet, low-protein diets, good fluid intake, vaccinations, and treating infections early
Aminoacidopathies
Definition (Vademecum Metabolicum 2004:57; Pediatr Rev 2009;30:e22)
• Def of enzymes for AA metab → toxic substances accumulate in brain, liver, and kidneys
• If known disorder of AA metabolism and ill → call metabolic team; often p/w acidosis
• Labs as above and emergency Rx glucose as above, stop protein intake, keep Na >140 to prevent cerebral edema, Abx, detox prn w/ diuresis or HD, Vits and carnitine depending on dz
Tyrosinemia (Am J Med Genet C Semin Med Genet 2006;142C:121;
Vademecum Metabolicum 2004:72)
• Accumulation of tyrosine in fluids and tissue
• Type I is the most severe → liver failure, neurologic crises, rickets, hepatocarcinoma
• 1:100,000 newborns; deficiency of fumarylacetoacetate hydrolase (FAH)
• Untreated → death before 2 yo
• Type II: Deficiency of tyrosine aminotransferase (TAT)
• Presents with hyperkeratotic plaques on the hands and soles of the feet and photophobia secondary to tyrosine crystals within the cornea
• Type III: Extremely rare 2/2 deficiency of 4-hydroxyphenylpyruvate dioxygenase
• Treatment → urgent therapy with nitisinone (blocks accumulation of toxic metabolites)
• Long term → phenylalanine and tyrosine restricted diets
Maple syrup urine disease (Pediatrics 2006;118:e934; Vademecum
Metabolicum 2004:70)
• Deficiency in activity of branched-chain α-oxoacid dehydrogenase complex →
accumulation of leucine, isoleucine, and valine
• AR with 1:185,000. More common in the Mennonite population
• Best outcomes when treated within first 2 wk of life
• Encephalopathy at 4–7 d w/ lethargy, feeding probs, somnolence, cerebral edema, coma
• Urine w/ maple syrup/burnt sugar smell. If breast fed, see in 2nd wk (↓ protein intake)
• Intermittent dz may go undx’d until 5 mo–2 yr of age → dx’d during a mild illness
• Intermediate dz → progressive neurologic probs w/ MR & dx’d btw 5 mo & 7 yr
• Dx → ↑ valine, leucine (plasma > 4 mg/dL) and isoleucine in plasma. Urine w/ branched-chain oxo-/hydroxyacids
• Rx → glucose and insulin infusion, avoid deficiency of isoleucine and valine
• Long term → follow these AAs in the plasma and adjust diet
• Must have low level of these AAs for growth and development
• Trial of thiamine supplementation 50–300 mg/d × 3 wk is recommended
Organic Acidurias
Definition (Pediatrics 1998;102:e69; Vademecum Metabolicum 2004:65)
• D/o of intermediary metabolism w/ accumulation of acids in urine
• Presents with systemic illness ± cerebral abnormalities
• Neonatal → metabolic encephalopathy, lethargy, feeding problems, truncal hypotonia, limb hypertonia, myoclonic jerks, cerebral edema, coma, multiorgan failure
• Chronic intermittent → present up to adulthood, recurring ketoacidotic coma, lethargy, focal neurologic signs
• Chronic progressive form → FTT, chronic vomiting, anorexia, osteoporosis, hypotonia, psychomotor retardation, recurrent infections
Presentation
• Ketosis/ketoacidosis, ↑ lactate, ↑ NH3, hypo- or hyperglycemia, neutropenia, thrombocytopenia, pancytopenia, hypocalcemia
Diagnosis
• Abnormal organic acids in the urine
Treatment
• As above with glucose, eliminate protein, supplement with carnitine
• Propionic OA →↓ isoleucine, valine, methionine, threonine in diet. Give L-carnitine 50– 100 mg/kg/d
• Methylmalonic OA → as for propionic + vitamin B12
• Isovaleric OA → L-carnitine 50–100 mg/kg/d ± L-glycine 150–250 mg/kg/d. Low leucine diet, low protein
Fatty Acid Oxidation Defects
Definition (Pediatrics 2006;118:E934; Pediatr Rev 2009;30:e22)
• Unable to use stored fat during fasting
• P/w hypoketotic hypoglycemia & metabolic acidosis, ↑ transaminases & hyperammonemia ± hepatomegaly
Medium-chain Acyl-CoA Dehydrogenase Deficiency (MCAD)
Definition (Pediatrics 2006;118:E934)
• Most common d/o of fatty acid oxidation; AR, 1:6,500–46,000
• Defect in mito β-oxidation → affects liver (unable to Δ fats to ketones → hypoglycemia)
Clinical Manifestations
• Vomiting and lethargy after fasting in a 3–15 mo child
• Most diagnosed <4 yo, undiagnosed mortality = 20–25%
• Hypoketotic hypoglycemia provoked by fasting (do not present in nonfasting conditions) → may develop coma (from hypoglycemia + toxicity of fatty acids and metabolites)
• Muscle weakness worsens with increased delay in diagnosis
Diagnosis
• Detected on NBS
• Confirm dx with plasma acylcarnitine analysis and urinary organic acids
• May need skin bx for enzyme eval of fibroblasts to narrow down actual enzymatic defect
Management
• Avoid fasting or decreased dietary fat intake
• Supplement with L-carnitine (especially during illnesses)
• Treat aggressively even during mild illnesses with IV glucose and carnitine