Inborn Errors of MetabolismInborn Errors of MetabolismNamrata Singh M.DNamrata 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.

Intro. Contd…

• In some instances the substrate is diffusible & affects distant organs & in some there is just a local effect ( lysosomal storage disease ).

Intro. Contd…

• 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:-

– 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

IEM~~ General approach

• Some clues to look for :-– *Symptoms accompany changes in diet.– *Developmental regression. – *History of food preferences or aversions.– *History of consanguinity in parents.– *Family history of MR , unexplained deaths in

cousins or siblings etc.

IEM ~~ General approach

• Physical exam:- common findings—– Alopecia or abnormal hair– Retinal cherry red spot– Cataracts or corneal opacities– Hepatosplenomegaly– Coarse features– Skeletal changes ( gibbus)– Ataxia– FTT– Micro or macrocephaly– Rash / jaundice /hypo or hypertonia

IEM ~~ General approach

• Lab tests:- almost always needed—– Serum electrolytes– Ph ( anion gap & acidosis )– Se lactate– Se pyruvate– Ammonia

IEM ~~ General approach

• Labs:- more specific labs—– Serum & urine amino acids– Urine organic acids– DNA probes– Glycine in CSF (glycine encephalopathy)– Urine ketones

• If + in neonates IEM

• If – in older child IEM ( defect in f.a. oxidation )

IEM – Clinical situations

• MR or dev delay – Can occur alone.– Seen in urea cycle ,a.a disorders.– Also in organic acidemias ,peroxisomal &

lysosomal storage disorders.– Serum & urine a.a .– Urine for mucopolysacchiduria.

IEM – Clinical situations

• Ill neonate :-– Clinically indistinguishable from sepsis.

– Usually disorders of protein & CHO metabolism.

– Acidosis or altered mental status out of proportion to systemic symptoms.

– 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 :-– Same studies !!

IEM – Clinical situations

• Hypoglycemia :-– Seen in fatty acid oxid defects ,glycogen

storage diseases ,hereditary fructose intolerance & organic acidemias.

– Other labs:- Urine ketones ~(+) in GSD & organic acidemias.

~(-) in HFI & f.a. oxidation disorders

IEM Clinical situations

• Hypoglycemia contd…– Other labs:-

• NH3 elevated in organic acidemias & fatty acid oxidation defects.

• Urine reducing subst.– (+) in galactosemia ,HFI.

• Urine organic acids

IEM Clinical situations

• Hyperammonemia :-– initially – poor appetite , irritability . Then , vomiting ,

lethargy , seizures & coma.

– Tachypnea – direct effect on resp. drive.

– Seen in (1)- urea cycle disorders (2)- organic acidemias (3)- transient hyperammonemia of the newborn.

– Resp alkalosis : urea cycle disorders & transient hyperammonemia of newborn.

– Acidosis : organic acidemias

HYPERAMMONEMIA

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

IEM Contd…

– Early urea cycle defects :• OTC Defect

– incr. Urine orotic acid levels

– Fam hx of male newborn deaths

– X- linked trait

IEM Contd…

• Acidosis :-– With recurrent vomiting.

– With elevated NH3.

– Out of proportion to clinical picture.

– Difficult to correct.

– Seen in organic acidemias , MSUD ,GSD , disorders of gluconeogenesis.

– Increased anion gap (ketoacids ,lactic acid , methylmalonic acid.)

IEM Contd…

• Acidosis :- additional tests—– Se glucose– NH3– Urine pH– Ketones– Amino & organic acids– Blood lactate & pyruvate

IEM Contd…

• Lactate & pyruvate—– Measure in arterial blood.– Normal Ratio is 10:1 to 20:1.– High ratio

• Mitochondrial disorders.• Pyruvate carboxylase deficiency.

– Normal or low ratio• Glycogen storage disease.• Pyruvate dehydrogenase deficiency

IEM~~ Management

• Broad management :-– Problems severe acidosis , hypoglycemia ,

hyperammonemia . Can lead to coma & death!

– Stop all oral intake.

– Give I/V glucose to stop catabolism.( most respond favorably to glucose – some do not eg. Primary lactic acidosis in pyruvate dehydrogenase deficiency .)

– Bicarb.

– Hyperammonemia – may need dialysis .

IEM ~~ Management

• Specific interventions :-– Urea cycle disorders-

• * preventing protein catabolism ( high calorie diet , arginine supplementation )

• * decreasing NH3 load (protein restriction )

• * utilizing NH3 scavengers ( benzoate ,phenylbutyrate)

IEM~~ Management

– PKU-• *Avoid enzyme substrate in diet.

• *Diet low in phenylalanine ( Lofenelac , Phenylfree, Analog XP , Maxamaid XP )

• *Protein restriction.

– Galactosemia-• *galactose free diet ( soy formulas contain sucrose

rather than lactose )

IEM~~Management

– Isovaleric acidemia-• Pharmacotherapy to remove accumulated substrate

–( glycine treatment).

– Methylmalonic acidemia-• Provide co-enzyme ( vit B12)

– Gauchers disease-• Provide normal enzyme (enzyme infusions)

IEM~~Management

– Wilsons disease-• Liver transplantation.

– HFI-• Restriction of fruits & fruit juices .

IEM Some associations

• Sweaty feet odor only 2 disorders !!– Isovaleric acidemia– Glutaric acidemia type 2

• Glutaric acidemia type 1– Extra pyramidal movement disorders– Retinal hemorrhages /IC bleeding (like shaken baby

syndrome)

IEM Associations

• Fatty acid oxidation defects –– LC Acyl CoA dehydrogenase deficiency

cardiomyopathy!!

– MC Acyl CoA dehydrogenase deficiency no cardiomyopathy!!

– Both have hypoketotic hypoglycemia.

• Carnitine deficiency cardiomyopathy ( carnitine is essential for transportation of LCFA into mitochondria for metabolism )

IEM Associations

• All are AR inherited other than– Lesch Nyhan syndrome – XLR.– OTC deficiency – XLR.– Fabry’s disease – XLR.– Hunter’s syndrome – XLR ( vs Hurler’s

syndrome – AR)

IEM Associations• Odors :-

– Glutaric acidemia type 2– sweaty feet– Isovaleric acidemia – sweaty feet– Hawkinsuria – swimming pool– MSUD – maple syrup– Methionine malabsorption – cabbage– Multiple carboxylase deficiency – tomcat urine– Oasthouse urine disease– hops like– PKU – mousy or musty– Trimethlyaminuria – rotting fish– Tyrosinemia – rancid fishy or cabbage like

IEM Associations

• Cherry red spot – Sialidosis– Nieman –Pick’s disease– Gaucher’s disease (flank shaped osteolytic

lesions)– GM1 gangliosidosis– Tay- Sach’s disease ( eastern european Jews)– Sandoff’s disease ( pan ethnic)

IEM Associations

• Wolman’s syndrome adrenals enlarged & calcified.

• Farber’s disease arthropathy , painful joints .subcutaneous nodules.

• Metachromatic leukodystrophy ataxia , dementia.

• Lesch-Nyhan’s self mutilation , hyperuricemia , hyperuricosuria , gouty arthritis , urate ureterolithiasis)

IEMAssociations

• Corneal clouding– Seen in mucopolysaccharidosis.– Seen in Hurler’s, Scheie’s & Morquio’s.– Hurler’s – AR, HSM, umbilical hernia , coarse

facies , corneal clouding , gibbus , heart disease).

– Hunter’s – X –linked ( all the above but no corneal clouding & no gibbus.)

INITIAL FINDINGS ( POOR FEEDING , VOMITING , LETHARGY, CONVULSIONS ,COMA )

METABOLIC DISORDER INFECTION

OBTAIN PL. NH3

HIGH NORMAL

OBTAIN BLOOD Ph & CO2 OBTAIN BLOOD Ph & CO2

NORMALACIDOSIS

NORMAL

UREA CYCLE DEFECTS ORGANIC ACIDEMIAS AMINOACIDOPATHIES

GALACTOSEMIA