Metabolic cad

In Born Error of Metabolism (IEM)

(congenital metabolic diseases)

A Guide to Diagnosis

However, for me…However, for me…

Copyright Roche Diagnostics GmbH, 1993, used with permission

Objectives

• Understand grand concepts of metabolic diseases and inborn errors of metabolism (IEM) in infants

• Raise clinical suspicion for these diseases

• Form conceptual framework for initial diagnosis and management of IEM in infants

• Individually-very rare, Collectively-very Individually-very rare, Collectively-very commoncommon– Hyperphenylalaninemia 1:10,000– Galactosemia 1:50,000– Homocystinurea 1:200,000– Estimated overall incidence 1:2000

• Many of metabolic diseases are under diagnosed

• More than 500 identified IEM’sMore than 500 identified IEM’s

• Variable presentationsVariable presentations– Mild to severeMild to severe– Subtle to overtSubtle to overt

Common Conception

• Biochemical pathway are impossible to remembe– Pathways are not the important part of the

evaluation– general approach is more important

Continue

• Few metabolic diseases are treatable– Should give more consideration to treatable

conditions– Gene therapy hold a promise

Metabolism is the sum total of all the chemical reactions that occur as part of the continuing process

of breakdown and renewal in the body

A B C

D

Enzyme

Classificasion:• Disorders of carbohydrate metabolism

– E.g., glycogen storage disease

• Disorders of amino acid metabolism – E.g., phenylketonuria ,

maple syrup urine disease, glutaric acidemia type 1

• Disorders of organic acid metabolism (organic acidurias) – E.g., alcaptonuria

Disorders of fatty acid oxidation and mitochondrial metabolism – E.g.,

Medium-chain acyl-coenzyme A dehydrogenase deficiency (often shortened to MCADD.)

• Disorders of porphyrin metabolism – E.g., acute intermittent porphyria

• Disorders of purine or pyrimidine metabolism – E.g., Lesch-Nyhan syndrome

• Disorders of steroid metabolism – E.g., congenital adrenal hyperplasia

• Disorders of mitochondrial function – E.g., Kearns-Sayre syndrome

• Disorders of peroxisomal function – E.g., Zellweger syndrome

• Lysosomal storage disorders – E.g., Gaucher's disease– E.g., Niemann Pick disease

4 Common Presentations4 Common Presentations

• Encephalopathy with metabolic acidosisEncephalopathy with metabolic acidosis

• Encephalopathy without metabolic acidosisEncephalopathy without metabolic acidosis

• Neonatal hepatic syndromeNeonatal hepatic syndrome

• Non-immune fetal hydropsNon-immune fetal hydrops

Triggers1.Ingestion of certain sugars (ie, galactosemia, hereditary fructose

intolerance)

2.Ingestion of protein may trigger urea cycle defects, organic acidemias, amino acid disorders, and hyperinsulinism with hyperammonemia.

3.Ingestion of carbohydrate may trigger pyruvate dehydrogenase deficiency, mitochondrial respiratory chain disorders, or hyperinsulinism..

4. Infection ,fever, fasting, or catabolism may trigger amino acid disorders, organic acidemias, fatty acid oxidation disorders, urea cycle defects, and disorders of gluconeogenesis and glycogenolysis.

5.Anesthesia or surgery may trigger thromboembolic events in homocystinuria

6. drugs may in porphyria and glucose-6-phosphate dehydrogenase deficiency

Suspicion

1.Exaggerated Response to Intercurrent Illness

Children with IEOM which might be well compensated most of the time , often decompensate during intercurrent illness i.e staying sicker longer than siblings with the same illness as infection

2.Poor response to treatment of an illness presumed to be acquired

3.A Condition resembling an infectious disease, but no organism is isolated* Signs of metabolic disease often mimics severe systemic infections* Clues:

Absence of fever ( unreliable sign in newborn )

No focus for infectionFailure to isolate a pathogenic organism

4.A Condition resembling an intoxication, but without a history of ingestion or exposure and with negative drug screen

5.Catastrophic Illness in the newborn

• Normal pregnancy Normal full-term baby Symptom-free period Relentless deterioration with no apparent cause and no response to symptomatic therapy

• Associated abnormal tone, posture or abnormal movements

• Unusual Odor

6.A Positive Family History• Consanguinity

• A sibling with similar illness

• Unexplained death

7.Acute Encephalopathy in an Infant or a Child, especially if Recurrent andParticularly if associated with any combination of:HypoglycemiaMetabolic AcidosisHyperammonemia

8.Developmental Regression

• A widely recognized feature

• Frank regression usually occurs after a period of weeks-years

9.Recurrent Reye Syndrome

VomitingLethargy, stuporHepatomegaly Fatty acid Oxidation defect Hepatic dysfunction ( MCAD )Hypoglycemia

Alright, I suspect it,Alright, I suspect it,now what should we do?now what should we do?

• ABC’s, OABC’s, O22, IV, MONITOR, IV, MONITOR• Brief history and directed physicalBrief history and directed physical• Remember differential of critically ill neonateRemember differential of critically ill neonate• Eliminate intake and production of toxic metaboliteEliminate intake and production of toxic metabolite• Accelerate removal of toxic metaboliteAccelerate removal of toxic metabolite• Cautiously correct acidosisCautiously correct acidosis• Investigate causeInvestigate cause

Common screening tests used in the last sixty years

• Ferric chloride

• Ninhydrin paper chromatography

• Guthrie bacterial inhibition assay

• Quantitative measurement of amino acids in plasma and urine

• Urine organic acid analysis by Gas chromatography-mass spectrometry

• Plasma acylcarnitines analysis by mass spectrometry

• Urine purines and pyrimidines analysis by Gas chromatography-mass spectrometry

Specific diagnostic tests

• Tissue biopsy : liver, muscle, brain, bone marrow• Skin biopsy and fibroblast cultivation for specific

enzyme testing• Specific DNA testing

treatment• Dietary restriction

– E.g., reduction of dietary for phenylketonuria and other amino acid disorders

• Dietary supplementation or replacement – E.g., oral ingestion of cornstarch several times

a day glycogen storage diseases

• Vitamins – E.g., thiamine supplementation benefits several

types of disorders that cause lactic acidosis., , arginine, and arginine, and Nabenzoate/phenacetate/phenylbutyrateNabenzoate/phenacetate/phenylbutyrate

– Consider pyridoxine, biotin, B12, carnitineConsider pyridoxine, biotin, B12, carnitine

• Dialysis

• Enzyme replacement E.g. Acid-alpha glucosidase for Pompe disease

• Gene therapy

• Bone marrow or organ transplantation

• Treatment of symptoms and complications

• Prenatal diagnosis and avoidance of pregnancy or abortion of an affected fetus

The case• A 10month-old male presented with history of

repeated vomiting when he was 5 month old form that time till now several time admitted to hospital he received iv fluid , sent for him inv. during hospitalization became better.for his condition went to Erbil tell the family may need op.

• Prenatal,natal,postnatal• 3 time blood trasfusion• Developmental delay• Immunazation complete • Feeding his.:breast feed,weaning

• Family history:consanguinity +

• He has 2 sibling.

• Treatment On Suspicion

Conclusion

• The key point in diagnosis is to think of the problem

• The initial investigation & management does not require adetailed knowledge of biochemistry

• Appropriated first aid is often life-saving

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References

– 1,^ a b c d e f g h i j k l Applegarth DA, Toone JR, Lowry RB (January 2000). "Incidence of inborn errors of metabolism in British Columbia, 1969-1996". Pediatrics 105 (1): e10. doi:10.1542/peds.105.1.e10 . PMID 10617747. 

– 2^ Charles Scriver, Beaudet, A.L., Valle, D., Sly, W.S., Vogelstein, B., Childs, B., Kinzler, K.W. (accessed 2007). The Online Metabolic and Molecular Bases of Inherited Disease . New York: McGraw-Hill. - Summaries of 255 chapters, full text through many universities. There is also the OMMBID blog.

– 3^ Fernandes, J.; Saudubray, J.M.; van den Berghe, G.; Walter, J.H. (2006). Inborn Metabolic Diseases : Diagnosis and Treatment (4th ed.). Springer. p. 561 p. http://www.springer.com/dal/home/medicine/pediatrics?SGWID=1-10079-22-97001537-0. 

– 4^ Clarke, J.T.R. (2005). A Clinical Guide to Inherited Metabolic Diseases (3rd ed.). Cambridge: Cambridge University Press. p. 358 p. doi:10.2277/0521614996 . ISBN 978-0521614993. http://www.cambridge.org/uk/catalogue/catalogue.asp?isbn=9780521614993 . 

– ^ Blau, N.; Duran, M.; Blaskovics, M.E.; Gibson, K.M. (2002). Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases (2nd ed.). Springer. p. 716 p. ISBN 978-3-540-42542-7. http://www.springer.com/dal/home?SGWID=1-102-22-2083693-0&changeHeader=true.

• 

• Growth failure, failure to thrive, weight loss

• Ambiguous genitalia, delayed puberty, precocious puberty

• Developmental delay, seizures, dementia, encephalopathy, stroke

• Deafness, blindness, pain agnosia

• Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps

• Dental abnormalities• Immunodeficiency, thrombocytopenia,

anemia, enlarged spleen, enlarged lymph nodes

• Many forms of cancer• Recurrent vomiting, diarrhea, abdominal pain• Excessive urination, renal failure, dehydration

, edema• Hypotension, heart failure, enlarged heart,

hypertension, myocardial infarction

• Hepatomegaly, jaundice, liver failure

• Unusual facial features, congenital malformations

• Excessive breathing (hyperventilation), respiratory failure

• Abnormal behavior, depression, psychosis

• Joint pain, muscle weakness, cramps

• Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus

History and PhysicalHistory and Physical• Period of normalcy, rapidity of onset, consanguinity, Period of normalcy, rapidity of onset, consanguinity,

FHx of neonatal death, odd odor to infant, birth hxFHx of neonatal death, odd odor to infant, birth hx• Subtle signs or symptomsSubtle signs or symptoms

– Feeding difficulty, odd cry, vomiting, diarrhea, tachypnea, Feeding difficulty, odd cry, vomiting, diarrhea, tachypnea, dyspnea, hypotonia/hypertonia, tachycardia, mental status dyspnea, hypotonia/hypertonia, tachycardia, mental status changeschanges

• Overt signs or symptomsOvert signs or symptoms– Persistent hypoglycemia, acidosis, dehydration, shock, Persistent hypoglycemia, acidosis, dehydration, shock,

apnea, seizures, abnormal mental status, temperature apnea, seizures, abnormal mental status, temperature instability, arrhythmia, cardiomyopathy, sudden deathinstability, arrhythmia, cardiomyopathy, sudden death

• Dysmorphic features, strange odor, signs of abuse, Dysmorphic features, strange odor, signs of abuse, rashes, jaundice, organomegalyrashes, jaundice, organomegaly

Critical InterventionsCritical Interventions

• Initial laboratory work-upInitial laboratory work-up– CBC, blood cultureCBC, blood culture

– CMP, lactate, pyruvate, CMP, lactate, pyruvate, ammoniaammonia

– ABGABG

– PT/PTTPT/PTT

– UA, urine culture, reducing UA, urine culture, reducing substancessubstances

– CSF studies if stableCSF studies if stable• Routine studies plus Routine studies plus

lactate and amino acidslactate and amino acids

• Secondary labsSecondary labs– Repeat initialRepeat initial

– Carnitine/acylcarnitine Carnitine/acylcarnitine profileprofile

– Serum amino acidsSerum amino acids

– Urine organic acidsUrine organic acids

– Urine amino acidsUrine amino acids

– Urine acylglycinesUrine acylglycines

Critical InterventionsCritical Interventions

• Eliminate toxinEliminate toxin– NPO and eliminate proteinNPO and eliminate protein

– IV glucoseIV glucose• 2-4mL/kg D10W-D25W; may need glucagon2-4mL/kg D10W-D25W; may need glucagon

• 8-10 mg/kg/min D10W; may need higher infusions8-10 mg/kg/min D10W; may need higher infusions

• If acidosis worsens, suspect pyruvate dehydrogenase deficiencyIf acidosis worsens, suspect pyruvate dehydrogenase deficiency

– Consider hemodialysis for hyperammonemia, along with Consider hemodialysis for hyperammonemia, along with arginine, and Na benzoate/phenacetate/phenylbutyratearginine, and Na benzoate/phenacetate/phenylbutyrate

– Consider pyridoxine, biotin, B12, carnitineConsider pyridoxine, biotin, B12, carnitine