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AN APPROACH TO INBORN ERRORS OF METABOLISM

Dr Gurpreet Singh

What is inborn error of metabolism ?


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Metabolism : chemical or physical changes undergone by substances in a biological system. Inborn error : an inherited (i.e. genetic) disorder. Genetic mutations can result in alteration of protein structure or amount of protein synthesized. Functional ability of protein whether enzyme, receptor,vehicle, membrane,structural element is compromised leading to biochemical disorders. These hereditary biochemical disorders are collectively termed inborn error of metabolism.

Inborn Errors of Metabolism


An inherited enzyme deficiency leading to the disruption of normal bodily metabolism Accumulation of a toxic substrate (compound acted upon by an enzyme in a chemical reaction) Impaired formation of a product normally produced by the deficient enzyme

What is a metabolic disease?


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substrate excess

C product deficiency D
toxic metabolite

Level Of Metabolic Error


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Small molecule disease


Carbohydrate Protein Lipid Nucleic Acids

Organelle disease
Lysosomes Mitochondria Peroxisomes Cytoplasm

Inborn Errors of 6 Metabolism


IEM as a group are not rare: occur 1

in 5000 births collectively Often treatable if diagnosed Most difficult task for clinician is to know when to consider IEM and which tests to order for evaluation Dont be fooled--other diagnoses like sepsis, ICH, pulm. hem. may accompany IEM Clues to presence of IEM may often be found in FH

Metabolic Diseases Can Grouped as


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Defects of Carbohydrates-Glycogen storage disease(GSD),

Galactosemia, Fructose intolerance, pyruvate dehydrogenase deficiency.


Defects of amino acids-Phenylketonuria(PKU), Alkaptonuria,Urea

cycle defects(UCDs).
Organic acidemias-isovaleric acidemia, propoinic acidemia(PPA),

methylmalonic acidemia(MMA), maple syrup urine disease(MSUD).


Defects of lipids-Mitochondrial fatty acid oxidation defects,

peroxisomal disorders ,lysosomal disorders ,mucopolysaccharidoses. Defects of purines and pyrimidines-Lesh-nyhan syndrome,AMPdeaminase deficiency,orotic aciduria. Miscellaneous wilson disease,alpha-1-anti trypsin deficiency.

Every child with unexplained . . .

Neurological deterioration Metabolic acidosis Hypoglycemia Inappropriate ketosis Hypotonia Cardiomyopathy Hepatocellular dysfunction Failure to thrive

. . . should be suspected of having a metabolic disorder

Infant Symptoms indicating possibility of an IEM (one or all) Infant becomes acutely ill after period of normal behavior and feeding; this may occur within hours or weeks Neonate or infant with seizures and/or hypotonia, especially if seizures are intractable Neonate or infant with an unusual odor Symptoms indicating strong possibility of an IEM, particularly when coupled with the above symptoms Persistent or recurrent vomiting Failure to thrive (failure to gain weight or weight loss) Apnea or respiratory distress (tachypnea) Jaundice or hepatomegaly Lethargy Coma (particularly intermittent) Unexplained hemorrhage Family history of neonatal deaths, or of similar illness, especially in siblings Parental consanguinity Sepsis (particularly Escherichia coli)

10 Index of suspicion Family History

Most IEMs are recessive - a negative family history

is not reassuring! CONSANGUINITY, ethnicity, inbreeding unexplained neonatal deaths, fetal losses maternal family history

males - X-linked disorders like ornithine transcaarbamylase(OTC),lesch-nyhan syndrome,fabry disease. Mitochondrial disorders as mitochondrial DNA is acquired from mother.

A positive family history may be helpful!

General dysmorphisms (abnormality in shape or

Index of suspicion Physical examination


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size), ODOUR H&N - cataracts, retinitis pigmentosa CNS - tone, seizures, tense fontanelle Resp - Kussmauls, tachypnea CVS - myocardial dysfunction Abdo - HEPATOMEGALY Skin - jaundice

Time and Pattern of Onset


Intoxication phase
Infants is born healthy. Deteriorates after symptom free period. Poor feeding and vomiting followed by neurological symptoms. Lethargy, apnea, seizures and coma Organic acidemias and UCDs

Energy Deficiencies
Most common presentation Overwhelming neurologic illness.

Apnea ,seizures,and coma No symptom free period Miochondrial and Peroxisomal disorders Primary lactic acidosis

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Patterns

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Presentation

Neurological abnormalities
Disorders of acid base status Hypoglycemia Liver dysfunction Dysmorphic features Cardiac diseases Abnormal urine and body odour

Patterns of Neurological Abnormalities in IEMs


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Acute encephalopathy Neonatal or early infancy Gray matter involvement Seizures, hypotonia,apnea Small molecule Intoxication type Associated with vomiting, lethargy, abnormal respiration , coma

Chronic Progressive encephalopathy Late infancy or childhood White matter involvement Spasticity,ataxia,hypereflexia Large molecule Energy deficiency or intoxication type Associated with liver dysfunction , cardiomyopathy, weakness

NEUROLOGICAL ABNORMALITIES 15
Encephalopathy,seizures seen in organic

acidemias,UCDs,MSUD fatty acid oxidation defects


Seizures predominantly present in

pyridoxine dependent seizures, NKH , peroxisomal disorders Few IEM presents with predominant hypotonia such as peroxisomal disorders,respiratory chain disorders.

Disorders of Acid-Base Status 16


Metabolic acidosis with raised anion

gap is an importanat feature of many IEMs. Organic acidemias, FAO defects, and defects of glycogenesis, gluconeogensis, pyruvate metabolism, respiratory chain. Respiratory alkalosis is a/w hyperammonemia.

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Hypoglycemia
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Hypoglycemia if severe and

persistent without any other etiology suspect IEMs. Hypoglycemia a/w metabolic acidosis suggests an organic acidemia ,defects of gluconeogenesis such as glycogen storage disease,fructose1,6-diphosphatase deficiency

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Liver Dysfunction
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Jaundice may be unconjugated (G6PD

Deficiency, Gilbert and Crigler-Najar syndromes) Conjugated(galactosemia, tyrosinemia, fructose intolerance). Hepatomegaly-asymptomatic in GSD, tyrosinemia. Hypoglycemia wih hepatomegaly in galactosemia,GSD. Hepatocellular dysfunction in alpha-1antitrypsin deficiency, GSD IV and III,

CARDIAC DYSFUNCTION
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Associated with mitochondria disorders,FAO

defects,GSDII(Pompe disease). Most IEM presents as cardiomyopathy. Few can present with arrthymias(fabry disease),coronary artery disease(familial hypercholesterolemia)

Dysmorphic Features
Peroxisomal disorders
Zellweger syndrome Pyruvate dehydrogenase deficiency

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Large fontalle,prominent forehead, flat nasal bridge, epicanthal folds,hypoplastic supraorbital ridges
Epicanthal folds, flat nasal bridge,small nose with aneverted flared alae nasi,long philtrum. Inverted nipples,lipodystrophy

Glycosylation disorders

Hair and skin abnormalities


Menkes disease: spares kinky scalp hair

associated with hypotonia, intractable seizure and developmental delay PKU: Fair skin and blonde hair Multiple carboxylase deficiency skin rash and partial alopecia

Eye abnormalities
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Cataract:galactosemia,adrenoleukodystrophymuco

polysacharidosis Lens dislocation: homocystinurea, marfan Blue sclera in osteogenesis imperfecta Cherry red spot in lysosomal disorder such as aysachs disease, sandhoff disease, niemann-pick disease,metachromatic leukodystrophy

25 Abnormal body and urine odors

Odors :-

Glutaric acidemia type 2 sweaty feet Isovaleric acidemia sweaty feet MSUD maple syrup Hypermethioninemia boiled cabbage Multiple carboxylase deficiency tomcat urine PKU mousy or musty Tyrosinemia rancid fishy or cabbage like

Laboratory Assessment of Neonates Suspected of Having an Inborn Error of Metabolism


Routine Studies Blood lactate and pyruvate Complete blood count and differential Plasma ammonia Plasma glucose Plasma electrolytes and blood pH Urine ketones Urine-reducing substances Special Studies

Plasma amino acids Plasma carnitine Urine amino acids Urine organic acids

ANION GAP METABOLIC ACIDOSIS

27 Index of suspicion Laboratory

Normal anion gap metabolic acidosis


Respiratory alkalosis Low BUN relative to creatinine

Hypoglycemia especially with hepatomegaly non-ketotic ketotic

Lab tests results seen with IEM


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CBC-Neutropenia and thrombocytopenia seen in

organic acidemias,GSD type Ib. Electrolytes and ABG-Persistent metabolic acidosis w/o asphyxia,shock,compromised perfusion points towards organic acidemias, congenital lactic acidosis. Respiratory alkalosis alkalosis in non ventilated babies suggests hyperammonemia. Plasma Ammonia-should be done in all sick infants with features of unexplained lethargy and neurological intoxication,raised in UCDs.

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LFTs-abnormal in galactosemias,tyrosinemia,alpha-

1-antitrypsin deficienncy. Urinary ketones , reducing substances, smell.

30 Specialized biochemical testing

Plasma amino acid analysis

Maple syrup urine disease with increase leuocine, valine and isoleuocine Hyperglycinemia: increase glycine Urinary organic acid : in patients of metabolic acidosis, seizures, hyperammonemia, ketonuria and used for diagnosing organic acidemias. Carnitine level-elevation seen in FAO defects, organic acidemias. Increased level of long chain fatty acid with perioxisomal disorder.

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

METABOLIC DISORDER OBTAIN PL. NH3

INFECTION

HIGH OBTAIN BLOOD Ph & CO2

NORMAL OBTAIN BLOOD Ph & CO2

NORMAL
UREA CYCLE DEFECTS

ACIDOSIS
ORGANIC ACIDEMIAS

NORMAL
AMINOACIDOPATHIES GALACTOSEMIA

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Stumbling Blocks in Diagnosing Inborn

Errors of Metabolism
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Signs and symptoms are often nonspecific

Routine childhood illnesses excluded 1st Inborn errors considered only secondarily Unfamiliarity with biochemical interrelationships/ diagnostic tests Inappropriate sample collection Inappropriate sample storage

Galactosemia
Deficiency of galactose-1 phosphate uridyl

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transferase 1/50,000 Start early after feeding Autosomal recessive on chromosome 9p13 with male=female Affect brain, liver, kidney and ovaries

Manifestation
Symptoms begin after lactose feeding or breast

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milk feeding
Lethargy irritability and vomiting Feeding difficulty and poor weight gain Jaundice, hypoglycemia, hepatomegaly

Ascites
Hepatic cirrhosis

Others
Polydipsia, polyurea Rickets Mental retardation Seizure

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Cataract: perinuclear haziness to complete

opacification Fulminant E-coli sepsis

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Investigation
Positive clinitest and negative clinistix Urine galactose by chromatography Direct hyperbilirubinemia

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Blood galactose 1 phosphate uridyl transferase

activity assay (beutler test).


Increase galactose 1phosphate in RBC

Management
Lactose free formula Control seizure Consult ophthalmology Genetic counseling

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PKU

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Autosomal recessive inborn error of metabolism Incidence of 1:10,000 to 1:15,000 Normally: phenylalanine tyrosine by liver

enzyme phenylalanine hydroxylase (PAH)

Two Types
Deficiency of PAH

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PAH Deficient (97% of cases)

Non-PAH Deficient (3% of cases) Defects in tetrahydrobiopterin or other

components in related pathways

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Symptoms
Severe intellectual impairment
Microcephaly Eczema

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Seizures
Hypopigmentation Hyperactivity

Autistic behavior

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Diagnostic Criteria
Normal: 120 360 mol/L

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PAH Deficient: Mild: 600 1200 mol/L Classical: > 1200 mol/L Non-PAH Deficient: < 600 mol/L
Guthrie Bacterial Inhibition Assay

Ferric chloride test on urinary metabolites.

Treatment
Decrease amount of phenylalanine in diet

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Possible supplementation of tyrosine to promote normal

growth and development Food diary Frequent monitoring of phenylalanine levels Once weekly during 1st year Twice monthly from 1 12 years Monthly after 12 years Provide parental and professional support to promote normal growth and development

Tyrosinemia
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Decreased activity of enzyme fumaryl acetoacetate. Tyrosine and methionine levels are high. Presents with hepatosplenomegaly,fanconi like

syndrome,hyperbilirubinemia,growth retardation. Leads to chronic liver disease. Restriction of phenylalanine,tyrosine,methionine.

ALKAPTONURIA
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Deficiency of enzyme homogentistic acidoxidase. Homogenistic acid is excreted in urine . Accumulation in articular tissues leading to

degeneration and osteoarthritis like changes. Pigment stones and nephrosis also seen. Urine shows black reaction with fehlings or benedicts s test.

HOMOCYSTINURIA
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Deficiency of cystathionine synthatase. Elevated levels of homocystine and methionine. Patients presents with subluxation of lens,recurrent

thrombo embolic episodes with marfanoid features. Convulsions and cerebrospinal lesions seen due to thrombo-embolic phenomenon.
Restriction of methionine and pyridoxine

replacement.

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Homocystinuria

Maple Syrup Urine Disease


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Autsomal recessive , deficiency of branched-chain alpha-ketoacid

dehydrogenase. Poor feeding, vomiting during first week. Lethargy, seizures, coma, muscular rigidity with severe opisthotonus, maple syrup odor in body fluids. High plasma and urine levels of leucine, isoleucine, valine and their respective ketoacids. Ketoacids detected in urine by 2,4-DNPH reagent forming yellow precipitate. Quick removal of branched chain amino acids and their metabolities from tissues ,body fluids Special low branched amino acids diet

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Organic Acidemias
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Autosomal reccesive disorders due to deficency of

degradative enzymes involving catabolism of branched amino acids valine,leuine,isoleucine. Most infants presents with severe vomiting, anion gap metabolic acidosis, poor feeding , lethargy, hypotonia, convulsions, coma. Labroratory findings severe ketoacidosis , neutropenia, thrombocytopenias, metabolic acidosis with large anion gap, hypoglycemia, hyperammonemia.

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Most common organic acdemias are isovaleryl

acidemia (IVA), Propionyl acidemia(PPA), Methyl malonic acidemia(MMA). Management includes hydration and infusion of bicarbonate to correct acidosis. 10% glucose solution with electrolytes correction with intravenous lipids . Restriction of protein intake (1-2 g/kg/24hr) alongwith carnitine ( 50-1oo mg/kg/24hr).

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Urea Cycle Defects


Disorders present in infants:

Symptoms:

: Infants presents with poor feeding, vomiting, lethargy, hypotonia, hyperventilation b/w age of 1 to 5 days. Patients may have seizures, apnea, coma, and increased intracranial pressure. High index of suspicion should be kept for neonates thought to septic without microbiological evidence of infection.

Diagnosis: Plasma ammonia in the blood is higher than


300mmol/L(in range of 500-1500mmol/L) elevated circulating glutamine -Other samples include plasma amino acids, urinary amino acids, organic acids, orotic acid determination.
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Most common UCD is Ornithine Transcarbamylase (OTC)

Deficiency with lab. Features of hyperammonemia, without any specific increase in any amino acid and marked increase in urinary orotic acid . Carbamyl phosphate synthatase and Nacetylglutamate(NAG) synthatase deficiencies presents with hyperammonemia with out any specific amino acid elevation. All other UCDs presents with elevation of specific amino acid elevation prior to their enzymatic deficiency.

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Management of hyperammonemia
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Adequate calories, fluid and electrolyes are

provided i.v. with minimal amount of proteins. Priming doses of sodiun benzoate , sodium phenylacetate, arginine is given. Intiate of hemodialysis or peritoneal dialysis.

Alternate Pathways for Removal of Ammonia 64

Sodium benzoate
SODIUM BENZOATE + GLYCINE HIPPURATE

Cleared by the kidney at 5X the GFR Each mole of benzoate removes one mole of ammonia as glycine

Alternate Pathways for Removal of Ammonia


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Sodium phenylacetate
PHENYlACETYL GLUTAMINE

PHENYL- + GLUTAMINE ACETATE

Easily excreted in the urine One mole of phenylacetate removes 2 moles of ammonia as glutamine

Alternate Pathways for Removal of Ammonia


Arginine supplementation provides the urea cycle with

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ornithine and n-acetylglutamate Abbreviated version of the urea cycle continues not recommended for use in arginase deficiency or organic acidemias

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Management of acute 68 metabolic disease


Rule out : Infection, Asphyxia, Intracranial hemorrhage Treatment include : 1) Hydration 2) Correction of biochemical abnormalitiesMetabolic Acidosis Hypoglycemia Hyperammonemia

Contd.
3) Reversal of catabolism/Promotion of anabolism 4)Elimination of toxic metabolite 5)Treatment of precipitating factor 6)Cofactor supplementation
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Monitoring
Mental state changes Overall fluid balance Evidence of bleeding (thrombocytopenia) Evidence of infection (Neutropenia) Biochemical parameters Complete blood count Urine for ketones and specific gravity
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Newborn Screening
PKU - must do on all infants in NICU even if

not advanced to full feeds. GalactosemiaHypothyroidism Sickle cell anemia Biotinidase def, CAH (21-OHase def), MSUD

What to do for the Dying Infant Suspected of Having an IEM


Autopsy--pref. performed within 4 hours of death Tissue and body fluid samples Blood-clotted and heparinized Urine samples CSF (ventricular tap) skin biopsy-for chromosomal and enzyme assay liver biopsy-frozen in liquid nitrogen Photographs and skeletal radiological screening for dysmorphic features

Case 1
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Patrick: 2 yr 4 mo male
Developmental delay Seizures

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Birth History: Full Term, 3,620 gm


Uncomplicated Pregnancy, Labor & Delivery Mother 24 yr old, healthy

No Prenatal exposure to alcohol, drugs, infection,

known teratogens Discharged home on day of life 2

Case 1 (CONTINUED)
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Seizure History
First 11 m Generalized, tonic/clonic Total 4 seizures EEG diffuse slowing, no focal spike/wave MRI decreased grey/white differentiation and cortical atrophy

Developmental Hx Rolled over 3 months Social smile - 4 m


Stand alone 14 m
First word 18 m Phrases not yet Walk alone 2 yr

Case 1 (CONTINUED)
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Seizure History
First 11 m Generalized, tonic/clonic Total 4 seizures EEG diffuse slowing, no focal spike/wave MRI decreased grey/white differentiation and cortical atrophy

Developmental Hx Rolled over 3 months Social smile - 4 m


Stand alone 14 m
First word 18 m Phrases not yet Walk alone 2 yr

Case 1(Cont)
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Physical Exam Growth Blond hair, blue eyes Non-dysmorphic child Neurological exam:
Decreased

tone, brisk reflexes

DIAGNOSIS- ???

78 A week old baby boy Breast milk only Lethargic, recurrent vomiting, dehydrated, and hypotonic RR 40, intercostal recession, and grunting CXR- no abnormalities Metabolic acidosis, ketotic,NH4 50mmol/l, high plasma. Start convulsing Thrombocytopenia, neutropenia with normal LFT

CASE STUDY-2

What is the diagnosis?

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NEONATAL SEPSIS

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Severe
Hurler MPS I H
Severe mental retardation More progressive Severe respiratory disease Obstructive airway disease Death before age 10 years

Spectrum of Disease Intermediate


Hurler-Scheie MPS I H/S
Little or no intellectual defect Respiratory disease Obstructive airway disease Cardiovascular disease Joint stiffness/contractures Skeletal abnormalities Decreased visual acuity Death in teens and 20s

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Mild
Scheie MPS I S

Normal intelligence Less progressive physical problems Corneal clouding Joint stiffness Valvular heart disease Death in later decades

Multi-systemic Involvement
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MPS I leads to disease in multiple tissues/organ systems


-L-iduronidase deficiency

Lysosomal Storage of GAG

Respiratory Connective tissue Cardiovascular Gastrointestinal Ocular Neurologic Skeletal

Argininosuccinic acidemia

Metabolic Diseases of the Urea Cycle


Anginase Deficiency

Type II

Hyperammonemia:
Citrullinuria Type I
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87 Flow Diagram to Evaluate Hyperammonemia

Sig incr
Plasma amino acids citrulline

citrullinemia Nl. Or sl. increased ASA

Nl.

THN

Incr. low urine Orotic acid Low or absent Incr.

ASA

CPS OTC

Treatment of Ammonemia Prior to Further 88 Diagnosis


Prevent further catabolism by providing adequate

calories, fluids and electrolytes Minimize protein intake Provide alternate pathways for ammonia removal May require exchange transfusion, peritoneal dialysis or hemodialysis for ammonia removal

Tay-Sachs

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TSD is a fatal genetic disorder in children that

causes progressive destruction of the central

nervous system

Chromosome and Type of Mutation


Tay Sachs is caused by a mutation in the Hex A gene on

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chromosome 15. Hex A normally codes for the alpha sub unit of the hexosaminidase A protein, which is necessary for breaking down GM2 gangliosides in nerve cells. The accumulation of GM2 is toxic and eventually causes death.

Symptoms and Conditions 92


Symptoms of classical Tay-Sachs disease first appear at

4 to 6 months of age when an apparently healthy baby gradually stops smiling, crawling or turning over, loses its ability to grasp or reach out and, eventually, becomes blind, paralyzed and unaware of its surroundings. Death occurs by age 5. There is also adult Tay-Sachs and the symptoms include muscle weakness, cramps, slurred speech, and behavioral changes.

There is no cure or effective treatment for Tay-

Treatment 93

Sachs disease. However, researchers are pursuing several approaches to finding a cure. Scientists are exploring enzyme replacement therapy to provide the Hex-A that is lacking in babies with Tay-Sachs. Bone marrow transplantation has been attempted also, but to date has not been successful in reversing or slowing damage to the central nervous system in babies with Tay-Sachs. Another avenue of research is gene therapy in which scientists transfer a normal gene into cells to replace an abnormal gene. This approach holds great promise for curing Tay-Sachs.

Gaucher Disease
Lysosomal storage disease (Sphingolipidose) Deficiency of glucocerebrosidase causes buildup of glucocerebroside Gaucher cells, store sphingolipid in spleen, liver, bone marrow, alveolar spaces, brain tissue

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Symptoms
Anemia
Reduced platelet count Bone demineralization

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Jaundice
Hepatosplenomegaly Neurologic effects (ataxia, seizures, )

Diagnosis 96
Three recognized types: Type I (Noncerebral juvenile)
Most

common in Ashkenazi Jew lineage (1:450)

Type II (Infantile cerebral)


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in 100,000 live births Death usually occurs w/in 1 year

Type III (Chronic neuropathic/Norbottnian)


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in 50,000 live births

Treatment 97
Splenectomy (rarely cures) Gene therapy Enzyme replacement

Placental glucorcerebrosidase (Ceredase)

$382,200/year for 70kg patient!

Bone marrow transplantation

Treatment of choice in advanced disease Chemical chaperone treatment Found to aid folding of N370S mutation

IEM Associations
All are AR inherited other than

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Leach Nyhan syndrome XLR. OTC deficiency XLR. Fabrys disease XLR. Hunters syndrome XLR( vs Hurlers syndrome AR)

IEM Associations
Cherry red spot

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Sialidosis Nieman Picks disease

Gauchers disease (flank shaped osteolytic lesions)


GM1 gangliosidosis Tay- Sachs disease ( eastern european Jews)

Sandoffs disease ( pan ethnic)

IEM Associations 100


Wolmans syndrome adrenals enlarged & calcified.

Farbers disease arthropathy , painful joints

.subcutaneous nodules. Metachromatic leukodystrophy ataxia , dementia. Lesch-Nyhans self mutilation , hyperuricemia , hyperuricosuria , gouty arthritis , urate ureterolithiasis)

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Gene Therapy
Gene therapy is an experimental treatment

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that involves introducing genetic material (DNA or RNA) into a persons cells to fight disease. These genes are inserted via viruses or liposomes.

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Gene Therapy
Normal gene inserted into defective cell Compensates for the missing or dysfunctional gene, in somatic cells only Can be inserted into mature cell (ly) Can be inserted into stem cell (bone marrow) Used to treat e.g. ADA deficiency, CF,

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A novel way to treat metabolic disease 106


Gene therapy : The treatment of inherited disease of humans

by administration of genes Etiology of metabolic disease : accumulation of metabolic intermediates or loss of products
Inborn errors of metabolism or function treat by replacing the

gene rather than to replace the defective or missing enzymes Logic : to fix what is broken Lesh-Nyhan syndrome, adenosine deaminase deficiency, sickle cell anemia, thallasemias, hemophilia, Gauchers disease, cystic fibrosis, alpha-1 antitrypsin deficiency, inborn errors of metabolism

Case Description
A female baby was delivered normally after an uncomplicated pregnancy. At the time of the infants second immunization, she became fussy and was seen by a pediatrician, where examination revealed an enlarged liver. The baby was referred to a gastroenterologist and later diagnosed to have Glycogen Storage Disease Type IIIB

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When108 to Suspect Metabolic Diseases?


History of parental consanguinity

Unexplained neonatal deaths


Severe illness in the immediate

family.

How do metabolic diseases present in the 109 neonate ??


The sick newborn infant Cardiomegaly/cardiomyopathy Eye anomalies / Gastrointestinal

abnormalities Hair and skin abnormalities Hematological / Hepatic dysfunction Sepsis Unusual odor

GSDs with predominant liver dysfunction


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TypeI GSD with Features of hepatomegaly,

hypoglycemia, ketosis, acidosis. TypeIII and Type IV

Glycogenolysis

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Type II GSD or pompes disease presents with lysos

osmal storage of glycogen in skeletal muscles,cardiac muscles,CNS. Dilated cardiomyopathy with left axis deviation short PR interval, large QRS complexes.

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