Genetics & Metabolism



Genetics & Metabolism


Alyssa R. Letourneau

Marsha F. Browning

Vivian E. Shih



Inborn Errors of Metabolism


Definition



  • Inherited enzyme mutation alters metabolism → excess or lack of certain metabolites


Incidence



  • 1:1400–200,000 live births; NBS screens for many of the disorders


Neonatal Presentation

(Pediatrics 1998;102:E69; Vademecum Metabolicum 2004:3)



  • 24–72 hr of life


  • Ill infant w/ nonspecific sx’s: Lethargy, diff feeding, vomiting, abn resp, hypotonia and szr’s


  • Abnormal body or urinary odor



    • MSUD: Urine smells of maple syrup or burnt sugar


    • Isovaleric acidemia and glutaric acidemia type II → pungent, unpleasant “sweaty feet” odor


Late Presentation

(Crit Care Clin 2005;21:S9; Vademecum metabolicum 2004:3)



  • >28 d of life; recurrent vomiting, lethargy, or fasting → coma with nonfocal neuro exam


  • Liver dysfxn + mental status changes


Adolescent/Adults Presentation

(J Inherit Metab Dis 2007;30:631)



  • Psychiatric d/o, recurrent rhabdo, myoglobinuria, cardiomyopathy


  • Acute recurring confusion → urea cycle defect, porphyria, homocysteine remethylation defect


  • Chronic psych sx’s → homocystinuria, Wilson dz, adrenoleukodystrophy, some lysosomal d/o


  • Mild mental retardation and personality Δ → homocystinuria, nonketotic hyperglycemia, other.


Specific Triggers of Decompensation

(Vademecum Metabolicum 2004:3)



  • Vomiting, fasting, infection, fever, vaccinations, surgery, accident or injury, changes in diet → protein or carbohydrate metabolism disorders


  • High- protein diet and/or catabolic state → aminoacidopathies, organic acidemia, urea cycle def


  • Fruit, sugar (sucrose), liquid medicines → fructose intolerance


  • Lactose → galactosemia


  • High fat → Fatty acid oxidation disorders


  • Drugs → porphyria, glucose-6-phosphate-dehydrogenase deficiency


  • Extensive exercise → disorders of fatty acid oxidation, glycolysis, respiratory chain


Emergencies


Critical Labs

(Pediatrics 1998;102:E69; Vademecum Metabolicum 2004:4)



  • Stat D-stick, CBC w/diff, chem 7, blood gas, NH3, lactate, plasma and urine amino acids, U/A, urine reducing substances, urine ketones, urine organic acids, ESR


  • CRP, CK, ALT, AST, coagulation studies


  • Store plasma samples for amino acids, acylcarnitine and filter paper (“Guthrie” card)


  • If LP done → freeze CSF for further studies


  • Consider ECG, echo, head imaging


Emergent Treatment

(Pediatrics 1998;102:E69; Vademecum Metabolicum 2004:5)



  • Start Rx before confirmed dx; stop protein, fat, galactose, and fructose intake


  • Consult metabolic specialist


  • 1st goal: Remove metabolites (organic acid intermediates or ammonia)



    • Hyperammonia: Immediate HD for coma, vent dependency, or signs of cerebral edema.


    • Urea cycle defects: 6 cc/kg of 10% arginine HCL IV over 90 min.


    • Organic acidemia: Vit B12 (1 mg) IM for B12-responsive form of methylmalonic acidemia. Biotin (10 mg) PO or NGT for biotin-responsive carboxylase deficiency


    • Acidosis: Give bicarb with frequent ABGs; severely acidotic: HD


  • 2nd goal: Prevent catabolism



    • IV glucose (calories and substitute for nml liver glucose prod) → D10, 150 cc/kg/d w/ lytes


    • Stop protein as above, IV lipids for urea cycle defects



  • If unclear diagnosis: Continue glucose drip, review history



    • Follow lytes, glucose, lactate, ABG, keep Na >135 to avoid cerebral edema


    • Ref: www.childrenshospital.org/newenglandconsortium/NBS/Emergency_Protocols.html


Metabolic Acidosis and Ketosis


Definition

(Pediatrics 1998;102:E69; Vademecum Metabolicum 2004:11)



  • ABG with anion gap ≥16. Decreased pH, HCO3, Paco2 (if resp compensation)


  • Ketosis present as response to fasting, catabolic state, or ketogenic diet


Presentation



  • Acute metab encephalopathy → lethargy, poor feeding, vomiting, coma, szr’s, ↓ tone, resp distress, or apnea


Ddx



  • Renal bicarb loss → renal Fanconi syndrome, RTA, cystinosis, osteopetrosis → tyrosinemia, fructose intolerance, glycogen storage disease type I, mitochondrial diseases, methylmalonic aciduria (chronic renal damage)


  • GI loss of bicarb → diarrhea


  • ↑ organic acids → lactate production or ketosis →infxn, sepsis, ↑ catabolic state, tissue hypoxia, dehydration, intoxication, DKA


Diagnostic Studies and Management



  • Labs as above, Rx according to primary diagnosis


Hypoglycemia


Definition

(Pediatrics 1998;192:E69; Vandemecum Metabolicum 2004:6)



  • Glucose <2.6 mmol/L (45 mg/dL) at all ages


History and Clinical Manifestations

Determine time since last meal, drugs



  • Check hepatomegaly, liver failure signs (palmar erythema, spider angiomata, gynecomastia, jaundice), small genitals, hyperpigmentation, short stature


Ddx



  • Disorders of protein intolerance, carbohydrate metabolism, or fatty acid oxidation


  • Hepatic glycogen storage dz (except Pompe); no glycogenolysis (worse with fasting)


  • In neonate: Need to rule out sepsis, SGA, maternal diabetes; maybe slow adaptation


  • Persistent neonatal hypoglycemia → hyperinsulinemia or hypopituitarism


Labs While Hypoglycemic



  • As above + insulin, cortisol, lactate, free fatty acids, 3-hydroxybutyrate, Ketostix (urine)


  • Acylcarnitine (dried blood spots or plasma); for fatty acid ox disorders + organic acidurias, C-peptide level


  • Spare tube for additional labs


  • Organic acids in the urine




image



Treatment



  • IV glucose at 7–10 mg/kg/min, for calories and to replace normal liver glucose production → D10% glucose, 110–150 cc/kg/d with electrolytes


  • Keep FS >100; If glucose needs >10 mg/kg/min → likely hyperinsulinism


Hyperammonemia


Definition

(Pediatrics 1998;192:E69; Vandemecum Metabolicum 2004:8)



  • Suspect metabolic dz in neonate if NH3 >200 μmol/L; All other ages NH3 >100 μmol/L


Ddx

Always consider medication effect



  • Urea cycle defects (no acidosis) and organic acidemias (+ metabolic acidosis), liver failure


  • Neonates can have transient hyperammonemia of the newborn → sx’s w/in 24 hr of birth; large premature infants with pulm dz. Usually no recurrent hyperammonemia


Labs

Labs as above; must have uncuffed venous or arterial sample, on ice, sent stat



  • AA in plasma and urine, organic acids and orotic acid in urine


  • Acylcarnitine in dried blood spots


Treatment



  • Must contact metabolic team immediately


  • NH3 >500 → central line, art line, HD


  • 1st infusion: 12 cc/kg D10 over 2 hr with lytes



    • Arginine hydrochloride 360 mg/kg


    • Na-benzoate 250 mg/kg (alternate pathway for nitrogen excretion)


    • Carnitine 100 mg/kg


    • Ondansetron 0.15 mg/kg IV bolus in noncomatose (to prevent N/V)


  • Follow glucose, add insulin if needed, check ammonia after 2 hr


  • Ref: Neonate: www.childrenshospital.org/newenglandconsortium/NBS/neonate2.html


  • Infant/child: www.childrenshospital.org/newenglandconsortium/NBS/infant_child.html


Abnormal Newborn Screen


Newborn Screen

(Vademecum Metabolicum 2004:53)

www.childrenshospital.org/newenglandconsortium/NBS/Emergency_Protocols.html



  • Started in the 1960s for PKU → broadened to many disorders w/ regional variations


Galactosemia


Definition

(Pediatrics 1998;102:E69; Pediatrics 2006;118:E934; Vademecum Metabolicum 2004:3)



  • Lactose is broken down into glucose and galactose for absorption


  • AR deficiency in enzymes → accumulation of glactose-1-phosphate and galactitol


Incidence



  • “Classic galactosemia”: Most common with galactose-1-phosphate uridyltransferase (GALT) deficiency → 1:47,000 newborns


  • Galactokinase (GALK) def → 1:1,000,000; Galactose-4′-epimerase (GALE) def → rare


Presentation



  • Progressive jaundice and liver dysfunction


  • First 2 wk of life → V/D, poor weight gain, cataracts, indirect hyperbili from hemolysis


  • Most states screen for it on NBS:



    • Galactose (total) 20–30 mg/dL; No Rx. Outpatient review



      • Repeat screening of dried blood spot, galactose, GALT activity


    • Galactose (total) 30–40 mg/dL; repeat as above



      • Start lactose-free milk, outpt review, follow-up repeat labs


    • Galactose (total) >40 mg/dL; hospitalization, lactose-free diet



      • Check liver and kidney function, coagulation and ultrasound


      • Check galactose, galactose-1-phosphate, GALT activity



Treatment



  • Galactose-free formula


  • If ill: Supportive care, Vit K, FFP, Abx for presumed Gram-negative sepsis and phototherapy for hyperbilirubinemia


  • Usually improve w/ removal of galactose; check all meds after dx (many contain galactose)


Prognosis



  • Persistent liver disease, cataracts, mental retardation


  • Many die of E. coli sepsis


Phenylketonuria/Phenylalaninemia


Definition

(Pediatrics 2006;118:E934; Vademecum Metabolicum 2004:71)



  • Abnormal increase in amino acid phenylalanine in blood


  • Deficiency of liver enzyme phenylalanine hydroxylase → impairs neurotransmitter production


  • If >20 mg/dL with accumulation of phenyl ketones → phenylketonuria (PKU)


  • Can be a benign process


Incidence



  • 1:13,500–19,000 for PKU; non-PKU hyperphenylalaninemia 1:48,000


  • AR w/ >400 mutations; if untreated → severe brain damage, MR, seizures, spasticity


Treatment



  • Early Rx important → admit to the hospital, inverse relationship between time to treatment and IQ


  • Positive NBS → check quantitative level of phenylalanine and tyrosine concentration


  • Provide with medical protein sources low in phenylalanine


  • Follow phenylalanine levels and keep low


Management of Known Inborn Errors of Metabolism


Urea Cycle Disorders


Definition

(Vademecum Metabolicum 2004)



  • Inherited enzyme and transport protein def w/ ↓ removal excess NH3 from protein metabolism


Incidence



  • Most common inborn errors of metabolism; 1:8000


  • Usually presents after newborn period, at all ages


Presentation



  • Neonates → lethargy, poor feeding, hyperventilation, seizures, encephalopathy


  • Infants/children → FTT, feeding problems, vomiting, neuro sx’s, lethargy, ataxia, szr’s


  • Teens/adults: Chronic neuro or psych sx’s, behav probs, disorientation, lethargy, psychosis


Diagnosis



  • Based on abnormal plasma and urine amino acid levels


Ornithine Transcarbamylase Deficiency (OTC)



  • Most common; 1:14,000 incidence; X-linked, many w/ residual enzyme activity


  • Can present between 1 mo of age to childhood with significant illness; inc urine orotic acid


Treatment



  • Acute therapy → see 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)



  • 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


  • 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)

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Jun 19, 2016 | Posted by in PEDIATRICS | Comments Off on Genetics & Metabolism

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