inborn errors of click on the following: metabolism...

Inborn Errors of Metabolism

(IEM)

Investigations

↑ NH4+

Metabolic Acidosis

No Acidosis

No ↑NH4+

Hypoglycemia

Blood Work Urine

Clinical Presentation

General Treatment

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copyright UBC peds iTeam 2012

Inborn Errors of Metabolism

• Individually rare, collectively common – ~1 : 800-1500

• Inherent deficiency in a key metabolic pathway: – Carbohydrate vs. Fat vs. Protein

• Pathophysiology : – Build up of toxic products cellular intoxication

– Cellular energy deprivation

– Combination of the above


Clinical Presentation

Infant

• Looks like sepsis! – Lethargy

– Hypotonia

– Decreased level of consciousness (LOC)

– Seizures

– Poor feeding

– Vomiting

– Sudden deterioration

Children • Mental retardation • Regression • Failure to thrive • Coarse facial features • Skeletal abnormalities • Hernias • Dietary aversion

(protein/carbs) • Deterioration after:

– New foods introduced – Fasting


Blood Work Blood Work Rationale/Predicted Result

CBC+ Diff Blood Culture

-Rule out sepsis -Pancytopenia (finding in some types of IEM)

Blood gas -Metabolic Acidosis -Alkalosis (seen initially in urea cycle defects from high NH4

+ )

Electrolytes + Ca/Mg/Phos

-Signs of dehydration -Electrolyte derangements can have similar presentation

Blood glucose -Hypoglycemia

Serum ketones -Hydroxybutyrate: should be present if patient hypoglycemic

NH4+ (ammonia) -↑↑*** NO tourniquet , send on ice and process immediately

Lactate *** NO tourniquet , send on ice and process immediately

AST, ALT, AlkPhos, GGT, bili, albumin, coags

-Elevated liver enzymes

Acyl-carnitine profile, (Pyruvate)

*** NO tourniquet , send on ice and process immediately -Pyruvate: only done if lactate high (only needed for pyruvate/ lactate ratio), need Biochemical/genetics lab approval + need special collection tubes.

Plasma amino acids

Newborn screen Must call to unlock the results


Newborn Screen (BC)

• 22 disorders tested in British Columbia

• Other provinces test for a spectrum

• Pertinent to IEM: Amino acid disorders PKU

MSUD Citrullinemia Agininosuccinic Aciduria Homocystinuria **Tyrosinemia Type 1 - (not yet included but possibly added soon!)

Fatty acid oxidation defects

VLCAD LCHAD (Not LCAD- Long-chain 3-hydroxyacyl-CoA dehydrogenase) ****TFP (trifunctional protein deficiency) – severe form of LCHAD MCAD

Organic Acid Defects PROP (Propionic acidemia) MUT (Methylmalonic Acidemia) Cobalamin Disorders Glutaric Aciduria, Type I Isovaleric Acidemia

Galactosemia Galactosemia copyright UBC peds iTeam 2012

http://raredisorders.ca/documents/CanadaNBSstatusupdatedApril182012_000.pdf

http://www.bcwomens.ca/NR/rdonlyres/CD0E67F3-9D7F-48F1-BC4F-9124E748D227/48239/NewbornDisordersScreened.pdf

PKU

- Cause: phenylalanine hydroxylase enzyme deficiency

- Ddx: rare forms of BH4 Cofactor deficiency

- mousy odour

- Light complexion

- Eczema

- Mental retardation and hyperactivity


MSUD

- 1st week of life

- Smells sweet

- Periods of hypertonicity

- Secondary hypoglycemia

- Ketosis


Tyrosinemia Type 1

- Smells of boiled cabbage


MCAD

- Encephalopathy

- Hypoglycemia


Isovaleric Acidemia

- Smells like sweaty feet


Glutaric Aciduria, Type 1

• Subdural bleeds

• Needs to be included in the non-accidental injury work up


Galactosemia • Mechanism:

– Deficiency of galactose-1-phosphate uridyl transferase – Leads to ↑galactose-1-phosphate

• Clinical presentation: – Presents @ ~end of 1st, start of 2nd week of life – Recurrent Escherichia coli sepsis – Galactose-1-phosphate is toxic to the liver:

• **Jaundice • Vomiting • Diarrhea • Poor weight gain • Cataracts

• Investigations: – Urine for reducing substances: looking for non-glucose reducing

substances

• Treatment: – Stop galactose containing feeds – Only time an infant needs SOY formula

• Only ISOMIL will work!


Homocystinuria

• ***Increased risk of stroke

• Clinical Presentation:

– Marfanoid appearance

• Dislocated lens etc.

– Mental retardation

• Treatment:

– pyridoxine


Urine

Urine Tests Rationale/Predicted Result

Urinalysis - Rule out sepsis - Ketones

- In infants, should only be present if hypoglycemic!

Urine Culture - Rule out sepsis

Urine organic acids

Urine reducing substances

-Useful in galactosemia (non-glucose reducing substances), fructose intolerance, tyrosinemia


General Treatment Treatment Rationale

STOP protein intake -Urea cycle defects/organic acid/amino acid defect -Prophree formula (has no protein)

IV glucose (D10@ infusion rate of 8-10 mmol/kg/min)

- Treats hypoglycemia - Provides calories to prevent protein catabolism - May need insulin to control glucose levels **may add IV lipids if no signs of fatty acid oxidation defect

IV arginine (6ml/kg 10% arginine HCl over 90 min)

-Essential amino acid -Helps to excrete the excess nitrogen waste products in Argininosuccinic Aciduria and Citrullinemia

IV sodium benzoate IV phenylacetate

-Increases excretion of ammonia by activating alternate pathways

IV carnitine -Fatty acid oxidation defects: treats possible carnitine deficiency -Organic acidurias: binds toxic organic acids for excretion in urine

Cofactors/vitamin -Organic acidemia: hydroxycobalamin, biotin

Specific treatments -Please see individual disorders for specific treatments

Hemodialysis -Arrange with ICU/Neprhology -Recall reasons for dialysis (AEIOU)

-Acid/Base disorders, Electrolyte disorders (including Ammonia!), Intoxication, Overload, Uremic encephalopathy


↑NH4+

Presentation

<24 hours old

Transient Hyperammonemia

of the Newborn

(Most likely…)

pH N - ↑

(possible 1o respiratory alkalosis)

Normal lactate

↑↑↑NH4+

Urea Cycle Defect

Acidosis

↑ Anion gap

± ↑ Lactate

±Ketosis

± Hypoglycemia

↑↑NH4+

Organic Acidemia

Hypoglycemia

No Ketosis

↑LFTs

↑NH4+

Fatty Acid Oxidation Defect


Transient Hyperammonemia of the Newborn

• Clinical Presentation: – Extremely sick

– Usually large premature neonate (~36wks)

– Symptomatic pulmonary disease (respiratory distress) • Caused by compensatory respiratory alkalosis

• Does not recur!

• Treatment:

– Follow treatment for ↑NH4+


• Ornithine Transcarbamylase Deficiency

– The only X-linked urea cycle defect

– All other urea cycle defects are autosomal recessive


Urea Cycle Defect

Fatty Acid Oxidation Defect • Two mechanisms:

– Impaired capacity to use stored fat as fuel in periods of fasting with depleted glycogen stores

– Defect in carnitine which transports fatty acids during oxidation

• Recall

• Defects lead to a decrease in Acetyl CoA and therefore ketone production • Thus presentation is most often a non ketotic hypoglycemia • Screening:

– Urine Organic Acids – Plasma acyl-carnitine profile

• Examples • Treatment:

– IV glucose – Carnitine supplementation (except in LCHAD where carnitine can lead to

accumulation of toxins that cause severe arrhythmias and cardiomyopathy)


Examples

• VLCAD = Very Long Chain Acyl-CoA Dehydrogenase Deficiency

• LCHAD = Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency

• MCAD = Medium Chain Acyl-CoA Dehydrogenase Deficiency

• Clinical presentation: – Non ketotic hypoglycemia – Reye like reaction – ALTE/Sudden death

• May have family history of SIDS

– Fat accumulation in liver or muscle


Organic Acidemia

• 4 key examples:

Organic Acid Defect Treatment (cofactor/vitamin to ↑ residual enzyme activity)

Methylmalonic Acidemia Hydroxocobalamin(B12)

Proprionic Acidemia PO/NG Biotin

Multiple carboxylase PO/NG Biotin

Glutaric acidemia type 1 Riboflavin


Metabolic

Acidosis

Normal Anion Gap

NOT IEM!!!

(No ketosis, Normal Lactate)

- RTA

- Diarrhea

Increased Anion Gap

(MUDPILES)

Acidosis

↑ Anion gap

± ↑ Lactate

±Ketosis

± Hypoglycemia

↑↑NH4+

Organic Acidemia

↑Lactate

Normal Glucose

Mitochondrial Disorders


Organic Acidemia

• 4 key examples:







(MUDPILES)

• ↑anion gap In IEM, hidden anions are lactate or organic acids

M Methanol

U Uremia

D DKA

P Peraldehyde

I Isoniazid, Iron

L Lactate

E Ethylene Glycol

S Salicylates copyright UBC peds iTeam 2012

No Acidosis

No ↑NH4+

Non Ketotic Hyperglycinemia

Homocystinuria


Non-Ketotic Hyperglycinemia

• Clinical Presentation

– Severe and progressive encephalopathy

– Uncontrolled hiccups and apnea

– Myoclonic seizures

– Hypotonia

• Investigations:

– No urine/serum ketones

– Increased glycine in blood and CSF


Homocystinuria

• ***Increased risk of stroke

• Clinical Presentation:

– Marfanoid appearance

• Dislocated lens etc.

– Mental retardation

• Treatment:

– pyridoxine


Hypoglycemia

Acidosis

↑ Anion gap

± ↑ Lactate

±Ketosis

± Hypoglycemia

↑↑NH4+

Organic Acidemia

± ↑Lactate

Hepatomegaly

Glycogen Storage Disorder (GSD)

**Note: some exceptions!

Liver Failure

Tyrosinemias

GSD IV

Galactosemia

Neimann Pick

(Type C)

Hypoglycemia

±Ketosis

↑LFTs

↑NH4+

Fatty Acid Oxidation Defects

Hyperinsulinemia


Organic Acidemia

• 4 key examples:







Fatty Acid Oxidation Defect • Two mechanisms:

– Impaired capacity to use stored fat as fuel in periods of fasting with depleted glycogen stores

– Defect in carnitine which transports fatty acids during oxidation

• Recall

• Defects lead to a decrease in Acetyl CoA and therefore ketone production • Thus presentation is most often a non ketotic hypoglycemia • Screening:

– Urine Organic Acids – Plasma acyl-carnitine profile

• Examples • Treatment:

– IV glucose – Carnitine supplementation (except in LCHAD where carnitine can lead to

accumulation of toxins that cause severe arrhythmias and cardiomyopathy)


Glycogen Storage Disorder (GSD)

• Mechanism: – Unable to release glucose from glycogen

• Several types assigned #s based on order of discovery – Liver types: Type 0, I, III, VI, IX

• Hypoglycemia is presenting symptom

– Muscle types: Type II (Pompe), V, VII • Presents with rhabdomyolysis and weakness


Galactosemia • Mechanism:

– Deficiency of galactose-1-phosphate uridyl transferase – Leads to ↑galactose-1-phosphate

• Clinical presentation: – Presents @ ~end of 1st, start of 2nd week of life – Recurrent Escherichia coli sepsis – Galactose-1-phosphate is toxic to the liver:

• **Jaundice • Vomiting • Diarrhea • Poor weight gain • Cataracts

• Investigations: – Urine for reducing substances: looking for non-glucose reducing

substances

• Treatment: – Stop galactose containing feeds – Only time an infant needs SOY formula

• Only ISOMIL will work!


inborn errors of click on the following: metabolism...

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