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Approach to Inborn Approach to Inborn Errors of Metabolism Errors of Metabolism Andrew M. Ellefson MD Andrew M. Ellefson MD Cpt, USA, MC Cpt, USA, MC Pgy-2 NCC Pediatrics Pgy-2 NCC Pediatrics
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Page 1: Inborn Errors of Metabolism

Approach to Inborn Errors Approach to Inborn Errors of Metabolismof Metabolism

Andrew M. Ellefson MDAndrew M. Ellefson MD

Cpt, USA, MCCpt, USA, MC

Pgy-2 NCC PediatricsPgy-2 NCC Pediatrics

Page 2: Inborn Errors of Metabolism

Goals for this lecture:Goals for this lecture:

Discuss acute/emergency management of IEMs.Discuss acute/emergency management of IEMs. Review broad categories of IEMs.Review broad categories of IEMs. Focus on Board favorite zebras.Focus on Board favorite zebras. Complete the Board prep. Objectives in most Complete the Board prep. Objectives in most

recent 2006 edition. recent 2006 edition. Integrate the “Laughing your way through Boards” Integrate the “Laughing your way through Boards”

tips. tips. Have fun with this usually stressful topic. Have fun with this usually stressful topic.

Page 3: Inborn Errors of Metabolism

What we WON’T DO:What we WON’T DO:

Memorize metabolic pathways.Memorize metabolic pathways. Mention, think of, or utter the enzyme Mention, think of, or utter the enzyme αα--

ketoglutarate dehydrogenaseketoglutarate dehydrogenasecomplex.complex.

Laugh at, throw bagels or coffee at, or Laugh at, throw bagels or coffee at, or otherwise mock Drew.otherwise mock Drew.

Discuss the adverse sequelae of the Discuss the adverse sequelae of the Eagle’s Eagle’s previous decision to recruit T.O.previous decision to recruit T.O.

Page 4: Inborn Errors of Metabolism

IEM Board/Prep Goals:IEM Board/Prep Goals: Inheritance patternsInheritance patterns Indication for geneticsIndication for genetics Eval of hypoglycemiaEval of hypoglycemia Eval of acidosisEval of acidosis Vitamin Rx for enzyme Vitamin Rx for enzyme

disordersdisorders Treat HypoglycemiaTreat Hypoglycemia Natural Hx of PKUNatural Hx of PKU Plan/diet for PKUPlan/diet for PKU Manage Glycogen storage Manage Glycogen storage

diseases- Type 1diseases- Type 1

RecognizeRecognize– Urea Cycle defectsUrea Cycle defects– Organic acidemiasOrganic acidemias– S+S of CHO disordersS+S of CHO disorders– S+S of GalactosemiaS+S of Galactosemia– S+S of hyperinsulinismS+S of hyperinsulinism– Glycogen Storage DzGlycogen Storage Dz– Lipoprotein DisordersLipoprotein Disorders– Gaucher + Lipid Storage DzGaucher + Lipid Storage Dz– S+S of Tay-SachsS+S of Tay-Sachs– S+S of Fatty Acid and S+S of Fatty Acid and

Carnitine metabolism Carnitine metabolism

Page 5: Inborn Errors of Metabolism

IEM- Index of Suspicion:IEM- Index of Suspicion:

Rapid deterioration in an otherwise well infant.Rapid deterioration in an otherwise well infant. Septic appearing infant or abnl sepsis such as Septic appearing infant or abnl sepsis such as

E.coli. E.coli. Failure to thrive. Failure to thrive. Regression in milestones. Regression in milestones. Recurrent emesis or feeding difficulty, alterations Recurrent emesis or feeding difficulty, alterations

in respirations, abnl urine/body smell, changing in respirations, abnl urine/body smell, changing MS/lethargy, jaundice, sz, intractable hiccups. MS/lethargy, jaundice, sz, intractable hiccups.

Can masquerade like pyloric stenosis.Can masquerade like pyloric stenosis. Dietary aversion- proteins, carbs. Dietary aversion- proteins, carbs.

Page 6: Inborn Errors of Metabolism

Basic Principles:Basic Principles:

Although individually rare, altogether they Although individually rare, altogether they are 1:800-5000 incidence.are 1:800-5000 incidence.

Broadly Defined: An inherent deficiency in a Broadly Defined: An inherent deficiency in a key metabolic pathway resulting inkey metabolic pathway resulting in– Cellular IntoxicationCellular Intoxication– Energy deprivationEnergy deprivation– Mixture of the twoMixture of the two

Page 7: Inborn Errors of Metabolism

History and Antecedent Events:History and Antecedent Events:

Catabolic state induction Catabolic state induction (sepsis,fasting,dehydration)(sepsis,fasting,dehydration)

Protein intakeProtein intake Change or addition of PO proteins, carbs, Change or addition of PO proteins, carbs,

etc… in formulaetc… in formula **Gotta ask- Consanguinity**Gotta ask- Consanguinity FHx of SIDSFHx of SIDS

Page 8: Inborn Errors of Metabolism

AssessmentAssessment::

Detailed H+PDetailed H+P– Describe szDescribe sz– FeversFevers

-Milestones-Milestones

-FHx-FHx

-Mom’s GsPs-Mom’s GsPs

-NAT questions-NAT questions

**Dysmorphology does not **Dysmorphology does not r/o IEMs** r/o IEMs**

Physical Exam:Physical Exam:– VitalsVitals– Level of alertnessLevel of alertness– Abnl activity/mvmtsAbnl activity/mvmts– CV- perfusionCV- perfusion– Dysmorphology, hair, Dysmorphology, hair,

smell, eyes-corneasmell, eyes-cornea– Abdo- HS megalyAbdo- HS megaly– Neuro- DTRs, tone, etcNeuro- DTRs, tone, etc– Skin- bruise, pigment, Skin- bruise, pigment,

colorcolor

Page 9: Inborn Errors of Metabolism

Emergency Management:Emergency Management:

Can be life threatening Can be life threatening event requiring rapid event requiring rapid assessment and assessment and management.management.

ABC’sABC’s

ABG-acidosisABG-acidosis BMP, Ca and LFTsBMP, Ca and LFTs NH4NH4 Lactate, PyruvateLactate, Pyruvate CBC, Blood Cx if uncertainCBC, Blood Cx if uncertain Coags- PT/PTTCoags- PT/PTT UA-ketones, urine reducing UA-ketones, urine reducing

substances, hold for OA/AAssubstances, hold for OA/AAs Newborn scrn resultsNewborn scrn results LP- r/o Meningitis, but send lactate LP- r/o Meningitis, but send lactate

STAT, AAs, hold tubes for futureSTAT, AAs, hold tubes for future Drug tox screen if indicated.Drug tox screen if indicated. **Hold spun blood or urine sample **Hold spun blood or urine sample

in fridge for later if possbile.in fridge for later if possbile.– **ABG, Lactate are iced STAT **ABG, Lactate are iced STAT

samplessamples– ** NH4 should be free flowing, ** NH4 should be free flowing,

arterial samplearterial sample

Page 10: Inborn Errors of Metabolism

Emergency Management:Emergency Management:

Correct hypotension.Correct hypotension. NPO, reverse NPO, reverse

catabolism with D5-catabolism with D5-D10 1-1.5 x maint.D10 1-1.5 x maint.

Correct hypoglycemia.Correct hypoglycemia. Correct metabolic Correct metabolic

acidosis.acidosis. Dialysis, lactulose if Dialysis, lactulose if

High/toxic NH4 High/toxic NH4 – (nl is <35(nl is <35µmol/L)µmol/L)

Search for and treat Search for and treat precipitants; ie: precipitants; ie: Infection, dehydration. Infection, dehydration.

Low threshold for Low threshold for Sepsis w/u + ABx if Sepsis w/u + ABx if uncertain. uncertain.

Pyridoxine for neonatal Pyridoxine for neonatal sz. if AED no-responsesz. if AED no-response

Ativan, Versed, AEDs Ativan, Versed, AEDs for status epilepticus.for status epilepticus.

Page 11: Inborn Errors of Metabolism

Some quick supplements:Some quick supplements:

CarnitineCarnitine for elimination of for elimination of Organic Acid Organic Acid through creation of carnitine esters.through creation of carnitine esters.

Sodium BenzoateSodium Benzoate, , PhenylacetatePhenylacetate for for Hyperammonemia Hyperammonemia elimination. elimination.

Page 12: Inborn Errors of Metabolism

Stable Patient, Now what?Stable Patient, Now what?

Page 13: Inborn Errors of Metabolism

You could memorize some of You could memorize some of these:these:

Page 14: Inborn Errors of Metabolism

The Daunting Differential List:The Daunting Differential List: Transient Transient

Hyperammonemia of Hyperammonemia of NewbornNewborn

Inborn Errors of Metab:Inborn Errors of Metab:– Organic Acidemias Organic Acidemias – Fatty Acid Oxidation defFatty Acid Oxidation def– Urea Cycle DefectsUrea Cycle Defects– Amino AciduriasAmino Acidurias– Non-ketotic HyperglycinemiaNon-ketotic Hyperglycinemia

Molybdenum Cofactor Molybdenum Cofactor Deficiency Deficiency – Sulfite Oxidase DeficiencySulfite Oxidase Deficiency

Metal Storage Disorders:Metal Storage Disorders: Cholesterol Disorders:Cholesterol Disorders: Leukodystrophies, other…Leukodystrophies, other…

– Krabbe diseaseKrabbe disease

Mitochondrial DisordersMitochondrial Disorders Glycogen Storage Glycogen Storage

DisordersDisorders HyperinsulinismHyperinsulinism Carbohydrate DisordersCarbohydrate Disorders Lysosomal DisordersLysosomal Disorders

– Mucopolysaccharidoses (X-Mucopolysaccharidoses (X-linked Hunter’s, Hurler’s)linked Hunter’s, Hurler’s)

– Gaucher diseaseGaucher disease– Tay-Sachs DiseaseTay-Sachs Disease

Peroxisomal DisordersPeroxisomal Disorders– Zellwegger’s (Cerebro-Zellwegger’s (Cerebro-

Hepato-renal)Hepato-renal)– X-linked X-linked

AdrenoleukodystrophyAdrenoleukodystrophy

Page 15: Inborn Errors of Metabolism

Patient is stabilized. Now what:Patient is stabilized. Now what:

Broad DDx for IEMs scares people.Broad DDx for IEMs scares people. You can group into KEY features. You can group into KEY features. Can focus on initial labs = Can focus on initial labs = Hyperammonia,Hyperammonia,

hypoglycemia,hypoglycemia, metabolic acidosismetabolic acidosis. . Can focus on Prominent neurologic features. Can focus on Prominent neurologic features. Can focus on Dysmorphic features. Can focus on Dysmorphic features. If these don’t exactly fit, resort back to categories If these don’t exactly fit, resort back to categories

of IEMs and Neurodegenerative Disorders. of IEMs and Neurodegenerative Disorders.

Page 16: Inborn Errors of Metabolism

Quick References:Quick References:

MA:MA:*metabolic *metabolic acidosisacidosis

NH4:NH4:

Glu:Glu:

Dz:Dz: *Non-ketotic *Non-ketotic HyperglycineHyperglycine

*Urea Cycle *Urea Cycle defectsdefects

*Fatty Acid *Fatty Acid OxsOxs

*OAemia*OAemia

*OAemia*OAemia *OAemia*OAemia *OAemia*OAemia *Glycogen Strg *Glycogen Strg dfcdfc

*Amino Aciduris*Amino Aciduris

*Carb *Carb Metabolism dfcMetabolism dfc

Page 17: Inborn Errors of Metabolism

Transient Hyperammonemia of Transient Hyperammonemia of Newborn:Newborn:

Markedly Markedly high NH4high NH4 in an infant in an infant less than 24 less than 24 HOL, or first 1-2 DOL before protein intake HOL, or first 1-2 DOL before protein intake occurs.occurs.

Often in context of Often in context of large, premature infantlarge, premature infant with with symptomatic pulmonary disease.symptomatic pulmonary disease.

Very Very sicksick infant. infant. Unknown precipitant, unknown etiology (possible Unknown precipitant, unknown etiology (possible

slow delayed urea cycle initiation), with potential slow delayed urea cycle initiation), with potential for severe sequelae (20-30% death, 30-40% abnl for severe sequelae (20-30% death, 30-40% abnl devo) if not treated. devo) if not treated.

Does not recur after being treated. Does not recur after being treated.

Page 18: Inborn Errors of Metabolism

Organic Acidemias:Organic Acidemias:

*Acidotic*Acidotic with high Gapwith high Gap **Urine KetonesUrine Ketones highhigh *High to nl Ammonia*High to nl Ammonia Often present Often present first 2-7 daysfirst 2-7 days of life after dietary of life after dietary

protein introduced.protein introduced. Drunk appearance in infant. Drunk appearance in infant. *May have low WBC and Plts. *May have low WBC and Plts. Check serum AAs/OAs, Urine AAs/OAs, CSF Check serum AAs/OAs, Urine AAs/OAs, CSF

OAs/AAs. OAs/AAs.

Page 19: Inborn Errors of Metabolism

Organic Acidemias cont:Organic Acidemias cont:

**Multiple Carboxylase Deficiency** **Multiple Carboxylase Deficiency** oror Defect in Biotin UtilizationDefect in Biotin Utilization Biotin is vital cofactor in many pathways, defect results in:Biotin is vital cofactor in many pathways, defect results in: Severe deterioration, dermatitis, alopecia, immune Severe deterioration, dermatitis, alopecia, immune

deficiency- candidal skin infections. deficiency- candidal skin infections. High NH4, acidemic, ketotic like the others. High NH4, acidemic, ketotic like the others. Dx by enzyme assay. Dx by enzyme assay. Rx with Biotin 10mg/kg/d PORx with Biotin 10mg/kg/d PO**Rocky will get this if he consumes too much **Rocky will get this if he consumes too much AvidinAvidin, aka, , aka,

raw eggs. raw eggs.

Page 20: Inborn Errors of Metabolism

Amino Acidurias:Amino Acidurias:

Maple Syrup Urine DiseaseMaple Syrup Urine Disease– Sweet smell of body fluid esp Urine.Sweet smell of body fluid esp Urine.– Classically develops in Classically develops in 11stst week of Life week of Life..– Poor feeding, emesis, lethargy and coma.Poor feeding, emesis, lethargy and coma.– Periods of Periods of HypertonicityHypertonicity..– Secondary Hypoglycemia.Secondary Hypoglycemia.– Possible Metabolic Acidosis, hyperammonemiaPossible Metabolic Acidosis, hyperammonemia– **Obtain serum/urine AAs/OAs****Obtain serum/urine AAs/OAs**– Treatment requires rapid removal of Branched chain Treatment requires rapid removal of Branched chain

AAs, often through dialysis. AAs, often through dialysis.

Page 21: Inborn Errors of Metabolism

Amino Acidurias:Amino Acidurias:

Fresh Urine Fresh Urine Uric acidUric acid and and Sulfite Dipstick Sulfite Dipstick if if neurologic abnormalities are present, low neurologic abnormalities are present, low uric acid is suggestive for uric acid is suggestive for molybdenum molybdenum cofactor deficiency and Sulfite Oxidase cofactor deficiency and Sulfite Oxidase DeficiencyDeficiency. .

Don’t forget Don’t forget PKUPKU. Basic on newborn scrn, . Basic on newborn scrn, but only does good if results followed up. but only does good if results followed up.

Page 22: Inborn Errors of Metabolism

For the Boards:For the Boards:

*Sweaty feet smell**Sweaty feet smell* – Isovaleric AcidemiaIsovaleric Acidemia, think , think ISOTONERISOTONER shoes smell shoes smell

What defect may present with Pulmonary What defect may present with Pulmonary Embolus?Embolus?

Homocystinuria-Homocystinuria- and thereafter may ask which and thereafter may ask which supplement to initiate?supplement to initiate?

PyridoxinePyridoxine- due to residual enzyme activity.- due to residual enzyme activity. Other names to know:Other names to know:

– Methylmalonic Acidemia-Methylmalonic Acidemia- Rx with large dose Rx with large dose vitamin vitamin B12B12

– Propionic Acidemia-Propionic Acidemia- RX with RX with Biotin.Biotin.

Page 23: Inborn Errors of Metabolism

Urea Cycle Defects:Urea Cycle Defects:

All but one of the disorders is autosomal recessive. All but one of the disorders is autosomal recessive. Symptom free period and then emesis->lethargy-->>COMASymptom free period and then emesis->lethargy-->>COMA Key features:Key features:

– High Ammonia, low BUNHigh Ammonia, low BUN– Possible Lactic acidosisPossible Lactic acidosis– *Absence of ketonuria**Absence of ketonuria*– Nl to mild low GlucoseNl to mild low Glucose

**Treat high ammonia, infuse glucose, send plasma **Treat high ammonia, infuse glucose, send plasma AAs/OAs, urine orotic acid, and plasma citrulline.AAs/OAs, urine orotic acid, and plasma citrulline.

Infusion of 6ml/kg 10% Arginine HCl over 90 min may help. Infusion of 6ml/kg 10% Arginine HCl over 90 min may help. Milder forms may show episodic emesis, confusion, ataxia, Milder forms may show episodic emesis, confusion, ataxia,

and combativeness after and combativeness after high protein mealshigh protein meals. .

Page 24: Inborn Errors of Metabolism

For the Boards:For the Boards:

Most common Urea cycle defect and also Most common Urea cycle defect and also only X-linked:only X-linked:

Ornithine Transcarbamylase DeficiencyOrnithine Transcarbamylase Deficiency

Page 25: Inborn Errors of Metabolism

Fatty Acid Oxidation Defects:Fatty Acid Oxidation Defects:

**Autosomal recessive inheritance****Autosomal recessive inheritance** Examples are MCAD, LCAD, VLCADExamples are MCAD, LCAD, VLCAD Defect in Defect in acyl-CoA Dehydrogenaseacyl-CoA Dehydrogenase, , aa mitochondrial duty, mitochondrial duty,

and important in fasting state. and important in fasting state. KEY features:KEY features: Acute attack of life-threatening coma with Acute attack of life-threatening coma with HypoglycemiaHypoglycemia Absence ofAbsence of urine ketones, and reducing substances,urine ketones, and reducing substances, nl nl

serum AAs. serum AAs. +/- mild acidosis, or hyperammonemia, elevated LFTs, abnl +/- mild acidosis, or hyperammonemia, elevated LFTs, abnl

coags. coags. +/-Hepatomegaly-/++/-Hepatomegaly-/+ Dx with serum Dx with serum Acylcarnitine Profile Acylcarnitine Profile oror fibroblast enzyme fibroblast enzyme

assayassay

Page 26: Inborn Errors of Metabolism

For the Boards:For the Boards:

Fetal Defect in LCHAD may result in Fetal Defect in LCHAD may result in Prenatal course complicated by :Prenatal course complicated by :

Maternal HELLP syndromeMaternal HELLP syndrome

Page 27: Inborn Errors of Metabolism

Non-ketotic Hyperglycinemia:Non-ketotic Hyperglycinemia:

Unique entity in that Glucose, NH4, pH are all Unique entity in that Glucose, NH4, pH are all normal. normal.

4 types with varying ages of onset, however, 4 types with varying ages of onset, however, classic form is classic form is NeonatalNeonatal with onset in with onset in 11stst week of week of lifelife. .

Will present just like the other devastating IEMs. Will present just like the other devastating IEMs. Lethargy, emesis, hypotonia, seizures, etc…Lethargy, emesis, hypotonia, seizures, etc…

Uncontrolled hiccups.Uncontrolled hiccups. Dx with Dx with no urine ketones, no urine ketones, and and Elevated Glycine. Elevated Glycine. No effective Rx. Will require diet restriction. No effective Rx. Will require diet restriction. Long term is a devastating disease.Long term is a devastating disease.

Page 28: Inborn Errors of Metabolism

Carbohydrate related Disorders:Carbohydrate related Disorders:

Page 29: Inborn Errors of Metabolism

Galactosemia:Galactosemia:

First 1-2 wks of Life: Presents with First 1-2 wks of Life: Presents with hypoglycemiahypoglycemia, , jaundicejaundice, , emesis. emesis.

Secondary to intolerance of Galactose. Secondary to intolerance of Galactose. Will be in baby’s first Will be in baby’s first

meals of breast milk or lactose containing formulas. meals of breast milk or lactose containing formulas. Also index of suspicion for Also index of suspicion for GramNegGramNeg or or E.coliE.coli sepsis. sepsis. Dx assisted by Dx assisted by Non-glucoseNon-glucose reducingreducing substancessubstances in in urineurine. . Confirmation by Confirmation by Galactose-1-PO uridyl transferase Galactose-1-PO uridyl transferase activity in activity in RBCs. RBCs. Adverse sequelae include Cataracts, MR, persistent liver Adverse sequelae include Cataracts, MR, persistent liver

disease.disease.

Page 30: Inborn Errors of Metabolism

For the Boards:For the Boards:

Which is worse?Which is worse?– Essential FructosuriaEssential Fructosuria– Inherited Fructose IntoleranceInherited Fructose Intolerance

Inherited Fructose IntoleranceInherited Fructose Intolerance– Occurs after ingestion of Fructose (sucrose= glucose + Occurs after ingestion of Fructose (sucrose= glucose +

fructose)fructose)– Severe and life threatening intoxication of F-1-PO4.Severe and life threatening intoxication of F-1-PO4.– Presents with emesis, seizures and profound illness Presents with emesis, seizures and profound illness

after ingestion of fructose. after ingestion of fructose. – May also present similar to Galactosemia.May also present similar to Galactosemia.– Life long avoidance of fructose. Life long avoidance of fructose.

Page 31: Inborn Errors of Metabolism

Glycogen Storage Disorders:Glycogen Storage Disorders:

Type 1= Von Gierke’s:Type 1= Von Gierke’s:– Shortly after birth: Severe lifethreatening Shortly after birth: Severe lifethreatening HypoglycemiaHypoglycemia– Lactic acidosisLactic acidosis –due to isolated glycolysis of G6Po –due to isolated glycolysis of G6Po– Hyper-uricemia, hyper lipidemiaHyper-uricemia, hyper lipidemia– Increased association with epistaxis Increased association with epistaxis – *Hepatomegaly*Hepatomegaly– **Adverse response to Glucagon with worsening Lactic acidosis**Adverse response to Glucagon with worsening Lactic acidosis

Management requires IV glucose, and then as outpt, close Management requires IV glucose, and then as outpt, close NG corn-starch or glucose solution administration to NG corn-starch or glucose solution administration to achieve close to nl glucose homeostasis. achieve close to nl glucose homeostasis.

Frequent snacks and meals. Continuous nighttime glucose Frequent snacks and meals. Continuous nighttime glucose infusions up to the age of 2. infusions up to the age of 2.

Page 32: Inborn Errors of Metabolism

Glycogen Storage Disorders:Glycogen Storage Disorders:

Type 2- Pompe’s disease:Type 2- Pompe’s disease: Normal GlucoseNormal Glucose Do to an accumulation of glycogen in lysosomes. Do to an accumulation of glycogen in lysosomes. **Ancient city of Pompeii was destroyed by Mt. Vesuvius- 79 AD****Ancient city of Pompeii was destroyed by Mt. Vesuvius- 79 AD**

Manifested by massive Manifested by massive CardiomegalyCardiomegaly, , HepatomegalyHepatomegaly, , MacroglossiaMacroglossia. .

Fatal If results in CHF. Fatal If results in CHF. Limited therapies in Neonatal Variant.Limited therapies in Neonatal Variant.

– Attempts at enzyme replacement ongoing.Attempts at enzyme replacement ongoing.

Page 33: Inborn Errors of Metabolism

Mitochondrial Disorders:Mitochondrial Disorders:

Emerging spectrum of diseases with life-time Emerging spectrum of diseases with life-time variation of presentation. variation of presentation.

Infantile/Neonatal: may present with Infantile/Neonatal: may present with encephalopathic picture, regressed milestones, encephalopathic picture, regressed milestones, cerebral cortical atrophy. cerebral cortical atrophy.

Generally lab findings of:Generally lab findings of:– Lactic AcidosisLactic Acidosis– Nl to low serum pyruvate, incomparison to LactateNl to low serum pyruvate, incomparison to Lactate– Nl organic acids.Nl organic acids.– *** Important to check CSF values of the above****** Important to check CSF values of the above***

Page 34: Inborn Errors of Metabolism

Leigh’s DiseaseLeigh’s Disease

AKA- AKA- Subacute necrosing encephalopathySubacute necrosing encephalopathy Due to defects in the mitochondrial electron Due to defects in the mitochondrial electron

transport chain.transport chain. May have devastating presentation with significant May have devastating presentation with significant

developmental regression.developmental regression. Unfavorable natural history.Unfavorable natural history. May respond to host of supplements.May respond to host of supplements. **Other Mitochondrial disorders for completion **Other Mitochondrial disorders for completion

sake**sake**– MELAS, MERRF, Leber’s HONMELAS, MERRF, Leber’s HON

Page 35: Inborn Errors of Metabolism

Leukodystrophies:Leukodystrophies: Krabbe disease:Krabbe disease:

– Type 1- Type 1- “Infantile”= irritability, hypertonia, “Infantile”= irritability, hypertonia, hyperesthesia, and psychomotor arrest, followed by hyperesthesia, and psychomotor arrest, followed by rapid deterioration, optic atrophy, and early death rapid deterioration, optic atrophy, and early death

– Type 2- Type 2- Late infantileLate infantile– Type 3- Type 3- JuvenileJuvenile– Type 4- Type 4- AdultAdult

A demyelination disorder due to CNS A demyelination disorder due to CNS accumulation of galactosylceramide. accumulation of galactosylceramide.

Diagnosis: supported by cortical atrophy on Diagnosis: supported by cortical atrophy on CT/MRI, CT/MRI, High CSF proteinHigh CSF protein and definite evidence of and definite evidence of deficientdeficient GALC assay GALC assay in WBCs or skin fibroblasts.in WBCs or skin fibroblasts.

Page 36: Inborn Errors of Metabolism

Lysosomal DisordersLysosomal DisordersFocus on key differences:Focus on key differences:

Gaucher Disease:Gaucher Disease:– Infantile vs chronic Infantile vs chronic

juvenilejuvenile– OrganomegalyOrganomegaly– Bone painBone pain– Easy bruisabilityEasy bruisability– **low Plts, **low Plts,

osteosclerosis, and lytic osteosclerosis, and lytic bone lesionsbone lesions

– MNEUNOMIC= MNEUNOMIC= “Clumsy Gaucho “Clumsy Gaucho cowboy”cowboy”

Tay-Sachs Disease:Tay-Sachs Disease:– Progressive neurologic Progressive neurologic

degeneration in first degeneration in first YOL and death by age YOL and death by age 4-5 yo4-5 yo

– AR inheritance with AR inheritance with classic Jewish classic Jewish Ashkenazi relationship.Ashkenazi relationship.

– Increased startle reflexIncreased startle reflex– Cherry red maculaCherry red macula– MacrocephalyMacrocephaly

Page 37: Inborn Errors of Metabolism

Peroxisomal DisordersPeroxisomal Disorders

Zellweger SyndromeZellweger Syndrome aka: aka: Cerebro-hepato-renal Cerebro-hepato-renal

syndromesyndrome Typical and easily Typical and easily

recognized dysmorphic recognized dysmorphic facies. facies.

Progressive degeneration Progressive degeneration of Brain/Liver/Kidney, with of Brain/Liver/Kidney, with death ~6 mo after onset.death ~6 mo after onset.

When screening for PDs. When screening for PDs. obtain obtain serum Very Long serum Very Long Chain Fatty Acids-Chain Fatty Acids- VLCFAsVLCFAs

Page 38: Inborn Errors of Metabolism

Further Evaluation in IEMs:Further Evaluation in IEMs:

** Head CT, MRI, Ophtho, Audio, EKG, ** Head CT, MRI, Ophtho, Audio, EKG, EEG** EEG**

Genetics consultation. Genetics consultation. Peds Neuro consultation.Peds Neuro consultation.

Page 39: Inborn Errors of Metabolism

Random Questions for the Boards:Random Questions for the Boards:

Amino Acids responsible for MSUD?Amino Acids responsible for MSUD? Valine, Leucine, IsoleucineValine, Leucine, Isoleucine Name 1 of the 3 classic Name 1 of the 3 classic Metal Storage disorders?Metal Storage disorders? Menke’s Kinky Hair Syndrome (X-link recessive)Menke’s Kinky Hair Syndrome (X-link recessive) Wilson’s DiseaseWilson’s Disease Neonatal HemachromatosisNeonatal Hemachromatosis Lysosomal storage disease associated with Adrenal Gland Lysosomal storage disease associated with Adrenal Gland

calcifications?calcifications? Wolman DiseaseWolman Disease

– Fatty acid deposits, nl lipid panelFatty acid deposits, nl lipid panel– **Mneumo= **Mneumo= Wool Man Disease Wool Man Disease white wool deposits. white wool deposits.

Page 40: Inborn Errors of Metabolism

Recognize that Smell:Recognize that Smell: Musty or Mousy:Musty or Mousy: PKUPKU Boiled CabbageBoiled Cabbage Tyrosinemia or Tyrosinemia or

hypermethioninemiahypermethioninemia Maple SyrupMaple Syrup maple syrup urine diseasemaple syrup urine disease Sweaty feet:Sweaty feet: isovaleric acidemia or glutaric isovaleric acidemia or glutaric

acidemia type II acidemia type II Cat urineCat urine multiple carboxylase multiple carboxylase

deficiencies (Biotin deficiency)deficiencies (Biotin deficiency)

Page 41: Inborn Errors of Metabolism

Follow up Questions ?Follow up Questions ?

Name some classic Mucopolysaccharidosis?Name some classic Mucopolysaccharidosis? Hunter’s (X-linked, no corneal clouding)Hunter’s (X-linked, no corneal clouding) Hurler’s (presence of Corneal clouding)Hurler’s (presence of Corneal clouding) Morquio Syndrome (nl IQ, short, cloudy cornea) Morquio Syndrome (nl IQ, short, cloudy cornea) *tattoo on F*tattoo on FII

-How are mucopolysaccharidoses Diagnosed? -How are mucopolysaccharidoses Diagnosed? Urine MPSs, definite with Skin Fibroblast BxUrine MPSs, definite with Skin Fibroblast Bx How to treat How to treat NeonatalNeonatal HyperinsulinismHyperinsulinism?? Diazoxide- Diazoxide- inhibits pancreatic B-cell insulin secretion. inhibits pancreatic B-cell insulin secretion. Child Dx with PKU, now diet restricted, but with progressive Child Dx with PKU, now diet restricted, but with progressive

neuro deterioration. What else might be deficient?neuro deterioration. What else might be deficient? Tetrahydrobiopterin (BH4)Tetrahydrobiopterin (BH4)

Page 42: Inborn Errors of Metabolism

Finally and to wet your appetite for Finally and to wet your appetite for Sat:Sat:

Name this syndrome and the associated metabolic Name this syndrome and the associated metabolic defect. defect.

Smith-Lemli-Opitz Syndrome:Smith-Lemli-Opitz Syndrome: due to defect in due to defect in cholesterol synthesischolesterol synthesis..

Page 43: Inborn Errors of Metabolism

For Reference:For Reference:

AAP Guidelines to IEMs.AAP Guidelines to IEMs. DOI: 10.1542/peds.102.6.e69 Pediatrics

1998;102;69- Barbara K. Burton

Page 44: Inborn Errors of Metabolism

Quick Algorithms:Quick Algorithms: