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

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

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

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

Liver dysfxn + mental status changes

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.

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

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

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

Consult metabolic specialist

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

2nd goal: Prevent catabolism

If unclear diagnosis: Continue glucose drip, review history

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

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

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

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

Labs as above, Rx according to primary diagnosis

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

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

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

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

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

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

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

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

Acylcarnitine in dried blood spots

Must contact metabolic team immediately

NH₃ >500 → central line, art line, HD

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

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

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

Lactose is broken down into glucose and galactose for absorption

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

“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

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-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)

Persistent liver disease, cataracts, mental retardation

Many die of E. coli sepsis

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

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

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

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