Inborn Errors of Metabolism
By:Namrata Singh M.D
Introduction to IEM
* Usually a single gene defect that causes a block in metabolic pathways.
* Problems are because of accumulation of enzyme substrate behind the metabolic block or deficiency of the reaction product.
* In some instances the substrate is diffusible & affects distant organs & in some there is just a local effect ( lysosomal storage disease ).
* Clinical presentation is varied mild to severe forms ( mutations even in the same gene may be different in different people ).
* Can present at any time.
* Can affect any organ system.
IEM General approach
* DIAGNOSIS : Some clinical presentations:-
o Consider in DDx . when dealing with :-
+ Critically ill infant
+ Seizures
+ Encephalopathy (Reyes like syndrome )
+ Liver disease
+ MR or developmental delay or regression
+ Recurrent vomiting
+ Unusual odor
+ Unexplained acidosis
+ Hyperammonemia
+ hypoglycemia
* Some clues to look for :-
o *Symptoms accompany changes in diet.
o *Developmental regression.
o *History of food preferences or aversions.
o *History of consanguinity in parents.
o *Family history of MR , unexplained deaths in cousins or siblings etc.
* Physical exam:- common findings—
o Alopecia or abnormal hair
o Retinal cherry red spot
o Cataracts or corneal opacities
o Hepatosplenomegaly
o Coarse features
o Skeletal changes ( gibbus)
o Ataxia
o FTT
o Micro or macrocephaly
o Rash / jaundice /hypo or hypertonia
* Lab tests:- almost always needed—
o Serum electrolytes
o Ph ( anion gap & acidosis )
o Se lactate
o Se pyruvate
o Ammonia
o Serum & urine amino acids
o Urine organic acids
o DNA probes
o Glycine in CSF (glycine encephalopathy)
o Urine ketones
+ If + in neonates IEM
+ If – in older child IEM ( defect in f.a. oxidation )
IEM – Clinical situations
* MR or dev delay
o Can occur alone.
o Seen in urea cycle ,a.a disorders.
o Also in organic acidemias ,peroxisomal & lysosomal storage disorders.
o Serum & urine a.a .
o Urine for mucopolysacchiduria.
* Ill neonate :-
o Clinically indistinguishable from sepsis.
o Usually disorders of protein & CHO metabolism.
o Acidosis or altered mental status out of proportion to systemic symptoms.
o Labs:
+ Lytes , NH3, gluc , ketones , urine ph ,glycine in CSF.
+ Se & urine for a.a & o.a (* before oral intake is stopped or pt is transfused)
IEM – Clinical situations
* Vomiting & encephalopathy :-
* Hypoglycemia :-
o Seen in fatty acid oxid defects ,glycogen storage diseases ,hereditary fructose intolerance & organic acidemias.
o Other labs:-
Urine ketones ~(+) in GSD & organic acidemias. ~(-) in HFI & f.a. oxidation disorders
o Other labs:-
+ NH3 elevated in organic acidemias & fatty acid oxidation defects.
+ Urine reducing subst.– (+) in galactosemia ,HFI.
+ Urine organic acids
* Hyperammonemia :-
o initially – poor appetite , irritability . Then , vomiting , lethargy , seizures & coma.
o Tachypnea – direct effect on resp. drive.
o Seen in (1)- urea cycle disorders (2)- organic acidemias (3)- transient hyperammonemia of the newborn.
o Resp alkalosis : urea cycle disorders & transient hyperammonemia of newborn.
o Acidosis : organic acidemias
RESP ALKALOSIS
ACIDOSIS
UREA CYCLE DEFECTS
TRANSIENT HYPERAMMONEMIA OF NEWBORN
ORGANIC ACIDEMIAS
SE CITRULLINE—LOW– EARLY UREA CYCLE DEFECT
SLIGHTLY ELEV– TRANSIENT HYPERAMMONEMIA OF NB
MARKEDLY ELEV– CITRULLINEMIA & ARGINOSUCCINIC ACIDEMIA
* Acidosis :-
o With recurrent vomiting.
o With elevated NH3.
o Out of proportion to clinical picture.
o Difficult to correct.
o Seen in organic acidemias , MSUD ,GSD , disorders of gluconeogenesis.
o Increased anion gap (ketoacids ,lactic acid , methylmalonic acid.)
* Acidosis :- additional tests—
o Se glucose
o NH3
o Urine pH
o Ketones
o Amino & organic acids
o Blood lactate & pyruvate
* Lactate & pyruvate—
o Measure in arterial blood.
o Normal Ratio is 10:1 to 20:1.
o High ratio
+ Mitochondrial disorders.
+ Pyruvate carboxylase deficiency.
o Normal or low ratio
+ Glycogen storage disease.
+ Pyruvate dehydrogenase deficiency
* Broad management :-
o Problems severe acidosis , hypoglycemia , hyperammonemia . Can lead to coma & death!
o Stop all oral intake.
o Give I/V glucose to stop catabolism.( most respond favorably to glucose – some do not eg. Primary lactic acidosis in pyruvate dehydrogenase deficiency .)
o Bicarb.
o Hyperammonemia – may need dialysis .
* Specific interventions :-
o Urea cycle disorders-
+ * preventing protein catabolism ( high calorie diet , arginine supplementation )
+ * decreasing NH3 load (protein restriction )
+ * utilizing NH3 scavengers ( benzoate ,phenylbutyrate)
o PKU-
+ *Avoid enzyme substrate in diet.
+ *Diet low in phenylalanine ( Lofenelac , Phenylfree, Analog XP , Maxamaid XP )
+ *Protein restriction.
o Galactosemia-
+ *galactose free diet ( soy formulas contain sucrose rather than lactose )
o Isovaleric acidemia-
+ Pharmacotherapy to remove accumulated substrate –( glycine treatment).
o Methylmalonic acidemia-
+ Provide co-enzyme ( vit B12)
o Gauchers disease-
+ Provide normal enzyme (enzyme infusions)
IEM Some associations
INITIAL FINDINGS ( POOR FEEDING , VOMITING , LETHARGY, CONVULSIONS ,COMA )
METABOLIC DISORDER
INFECTION
OBTAIN PL. NH3
HIGH NORMAL
OBTAIN BLOOD Ph & CO2
ACIDOSIS
NORMAL
UREA CYCLE DEFECTS
ORGANIC ACIDEMIAS
AMINOACIDOPATHIES
GALACTOSEMIA
Inborn Errors of Metabolism.ppt
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