1 metabolic disorders inborn errors of metabolism dr. abdullah alomair mb chb, mrcp (edin), frcp...

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1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics Consultant Pediatrician Department of Pediatrics PRESIDENT SAUDI PEDIATRIC ASSOCIATION

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Page 1: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

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Metabolic Disorders

Inborn Errors Of Metabolism

DR. ABDULLAH ALOMAIR

MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.)

Associate Professor of PediatricsConsultant PediatricianDepartment of Pediatrics

PRESIDENT SAUDI PEDIATRIC ASSOCIATION

Page 2: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

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Inborn Errors Of Metabolism (IEM) -A large group of hereditary biochemical diseases.-In autosomal dominant disorders, the structural abnormality dominates over the chemical abnormality. -Specific gene mutation cause abnormal or missing proteins that lead to altered function.

Metabolic Disorders Metabolic Disorders

Inborn Errors Of MetabolismInborn Errors Of Metabolism

Page 3: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

SINGLE GENE DEFECTS in synthesis or catabolism of proteins, carbohydrates, or fats.

Defect in an ENZYME or TRANSPORT PROTEIN , which results in a block in a metabolic pathway.

EFFECTS :

- toxic ACCUMULATION of substrates before the block,

- intermediates from ALTERNATIVE pathways

- defects in ENERGY production and utilization caused by a deficiency of products beyond the BLOCK.

Every metabolic disease has several forms that vary in AGE OF ONSET , clinical severity and, often, MODE OF INHERITANCE.

Pathophysiology

Page 4: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics
Page 5: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics
Page 6: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Classification

Transient Hyperammonemia of Newborn

Inborn Errors of Metab:• Organic Acidemias • Fatty Acid Oxidation def• Urea Cycle Defects• Amino Acidurias• Non-ketotic Hyperglycinemia

Molybdenum Cofactor Deficiency

• Sulfite Oxidase Deficiency Metal Storage Disorders: Cholesterol Disorders: Leukodystrophies, other…

• Krabbe disease

Mitochondrial Disorders Glycogen Storage Disorders Hyperinsulinism Carbohydrate Disorders Lysosomal Disorders

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

• Gaucher disease• Tay-Sachs Disease

Peroxisomal Disorders• Zellwegger’s (Cerebro-

Hepato-renal)• X-linked

Adrenoleukodystrophy

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Metabolic Disorders• Due to inherited reduced activities of proteins

involved in the synthesis, breakdown or transport of amino acids, organic acids, fats, carbohydrates and complex macromolecules.

• Most are autosomal recessive due to mutations that result in reduced enzyme activity or reduced amount of enzyme.

• Pathogenesis may include: accumulation of a toxic intermediate, reduced amount of a necessary end product or activation of an alternate pathway.

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Metabolic Disorders

From history:

Parental history :

Consanguineous parents

Previous unexplained neonatal deaths

Particular ethnic group (in certain diseases)

Features suggestive of metabolic disorder :

Page 9: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Features suggestive of metabolic disorder :

Metabolic Disorders Metabolic Disorders

Examination findings:

Organomegaly (e.g. hepatomegaly) in the absence of viral infection.

Cardiac disease

Ocular involvement (e.g. cherry red spot)

Skin manifestations e.g. pigmentations.

Unusual odour. Due to change in the chemicals of the urine.

Non-specific neurological findings. In a non-meningitis child you have to think of metabolic disorders.

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Neonatal and Post Neonatal Presentation

Neonatal presentationNormal-appearing child at birth (some conditions are associated with dysmorphic features)

• poor feeding• lethargy• vomiting• seizures• coma• unusual odour• Hypoglycaemia is very dangerous, acidosis (in some

defects)

Page 11: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Neonatal and Post Neonatal Presentation

Post neonatal presentation

• Encephalopathy without the presence of infection.

• Developmental regression• Reye syndrome ( damage of the brain and

liver eventually leading to encephalopathy).

• Motor deficits• Seizures• Intermittent episodes of vomiting, acidosis,

hypoglycaemia and/or coma triggered by

stress e.g. infections, surgery.

Page 12: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Newborn Screeningthe earlier its detected the fewer the complications

PKU - in NICU even if not advanced to full feeds Galactosemia Hypothyroidism Hemoglobinopathies Biotinidase defic, CAH (21-OH’ase def), Maple syrup urine disease ( MSUD )

- GUTHRIE TEST: it’s a cheap test that requires only one drop of blood to check for multiple metabolic disorders.

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Specific Tests:

• Direct biochemical assays of metabolites or their metabolic by-products, or of an enzyme’s function.

• DNA studies

• Neuro-radiology

PROCEDURES FOR DIAGNOSIC CONFIRMATION

Non – Specific Tests:

• Blood glucose, ammonia, bicarbonate and pH

• Peripheral Blood smear – WBC or bone marrow vacuolization , foam cells or granules.

• C.S.F. glycine , other amino acids , lactate. Amino acids shouldn’t be present in the CSF if its there it indicates a metabolic disorder.

Bone marrow transplantation is a treatment of both inborn errors of metabolism

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Inborn Error of MetabolismInborn Error of Metabolism Urine OdorUrine Odor

Gultaric AcidemiaGultaric Acidemia Sweaty feetSweaty feet

Maple Syrup urine diseaseMaple Syrup urine disease Maple syrupMaple syrup

HypermethioninemiaHypermethioninemia Boiled cabbageBoiled cabbage

PhenylketonuriaPhenylketonuria Mousy or mustyMousy or musty

TrimethylaminuriaTrimethylaminuria Rotten fishRotten fish

INBORN ERRORS OF AMINO ACID METABOLISM ASSOSIATED WITH ABNORMAL ODOR

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Page 16: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

They may come with flattened mid-face, indistinct philtrum, low nasal bridge and single palmar crease.

Small chin is called micrognathia

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Low-set ears: >1/3rd of the ears lower than the line connecting the 2 pupils.Low nasal bridge: common sign, which is also seen in Down.

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Genetic:

Establish diagnosis.

Carrier testing.

Pedigree analysis, risk counseling.

Consideration of Prenatal diagnosis for pregnancies at risk.

MANAGEMENT OF IEMMANAGEMENT OF IEM

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Family counseling and support.

Education to promote increased compliance with special form of therapy such as Protein – restricted diet.

Assessment of community resources and support groups.

PSYCHOSOCIAL , EDUCATIONAL , FAMILIALPSYCHOSOCIAL , EDUCATIONAL , FAMILIAL

MANAGEMENT OF IEMMANAGEMENT OF IEM

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TREATMENT OF GENETIC DISEASES

• Modify environment, e.g., diet, drugs

• Avoid known environmental triggers

• BMT• Surgical, correct or repair defect or organ transplantation

• Modify or replace defective gene product, megadose vitamin therapy or enzyme replacement

• Replace defective gene

• Correct altered DNA in defective gene

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Galactosemia

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: Carbohydrates

GalactosemiaEnzyme deficiency: Galactose-1-phosphate uridyl transferase deficiency.

It is a rare autosomal recessive.

● Follows feeding with lactose containing (breast milk / formula) ● Patient feeds poorly , have vomiting, jaundice, hepatomegaly and

hepatic failure● Chronic liver disease● Cataracts● Developmental delay develop if condition is untreated., if they were

given galactose free diet you will avoid the social and mental damage but they might complain of dyslexia.

Page 24: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

CYSTIC FIBROSIS

Cause : Loss of 3 DNA bases in a gene for the protein that transports Cl ions so salt balance is upset. Causes .a build up of thick mucus in lungs and digestive organs. It is diagnosed by sweat test: measuring the chloride concentration in the sweat

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AMINO ACID DISORDERS

Phenyl Ketonuria (PKU)

Phenylalanine TyrosineHydroxylase

Phenylalanine

Phenyl ethylamine Phenyl pyruvic acid

Phenyl pyruvic acid is what gives the urine its smell because its ketonic and acidic.

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Phenylketonuria PKU

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1. Hyperactivity, athetosis, vomiting.

2. Blond.

3. Seborric dermatitis or eczema skin.

4. Hypertonia.

5. Seizures.

6. Severe mental retardation.

7. Unpleasant odor of phenyl acetic acid.

PKU PKU

DIAGNOSISDIAGNOSIS

• Screening : Guthrie Test.

• High Phenylalanine > 20 mg/dl.

• High Phenyl pyruvic acid.

TREATMENTTREATMENT

• DIET.

• BH4 (Tetrahydrobiopterin).

• L – dopa and 5- hydroxytryptophan.

CLINICAL CLINICAL FEATURES FEATURES

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PKU

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Albinism

Page 30: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Iris had fibrous tissue, and it’s colourless and is red due to vessels.

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Homocystinuria

Elevated homocystine levels affect collagen , result in a Marfanoid habitus, ectopia lentis but lens dislocation in homocystinemia is downward unlike in marfan its upward, mental retardation and strokes, its harmful to the bones and body. Araachnodyctly.

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METHIONINE CYSTATHIONINE

Homocystinuria

Cysathionine

Synthatase

DIAGNOSIS:

High methionine and homocystine.

TREATMENT:

•High dose of B6 and Folic Acid.•Low methionine and high cystine diet,•Betain (trimethylglycine)

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Homocystinuria

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Amino acid disorders :Urea cycle defects and hyperammonemia

All present with lethargy, seizures, ketoacidosis, neutropenia, and

hyperammonemia

Ornithine carbamyl transferase (OTC) deficiency

Carbamyl phosphate synthetase deficiency

Citrullinemia

Arginosuccinic Aciduria

Argininemia

Transient tyrosinemia of prematurity

Page 35: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

First Steps in Metabolic Therapy for IEM

• Reduce precursor substrate load

• Provide caloric support

• Provide fluid support

• Remove metabolites via dialysis

• Divert metabolites

• Supplement with cofactor(s)

Page 36: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Therapeutic Measures for IEM

• D/C oral intake temporarily• Usually IVF’s with glucose to give 12-15

mg/kg/min glu and at least 60 kcal/kg to prevent catabolism (may worsen pyruvate dehydrogenase deficiency)

• Bicarb/citrate Carnitine/glycine• Na Benzoate/arginine/citrulline• Dialysis--not exchange transfusion• Vitamins--often given in cocktails after labs

drawn before dx is known• Biotin, B6, B12, riboflavin, thiamine, folate

Page 37: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Important IEM Treatment supplements:

• Carnitine for elimination of Organic Acid through creation of carnitine esters.

• Sodium Benzoate, phenylacetate and phenylbutyrate for Hyperammonemia elimination.

Page 38: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

CARNITINE METABOLISMCARNITINE METABOLISM

• An essential nutrient found in highest concentration in red meat.

• Primary function : Transport long-chain fatty acids into mitochondria for oxidation.

• Carnitine supplementation in fatty acid oxidation disorders and organic acidosis may augment excretion of accumulated metabolites , but may not prevent metabolic crises in such patients .

• Carnitine is an endogenous metabolite but can be given as supplementations.

Page 39: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

CARNITINE METABOLISM

• Primary defects of carnitine transport manifest as Reye syndrome , cardiomyopathy or skeletal myopathy with hypotonia

• Secondary carnitine deficiency is due to diet ( esp. I.V alimentation or ketogenic diet ) , renal losses , drug therapy ( esp. valproic acid) and other metabolic disorders ( esp. disorders of fatty acid oxidation and organic acidemias )

• Prognosis depends on the cause of the carnitine abnormality.• Free and esterified carnitine can be measured in blood.• Oral or I.V. L-carnitine is used in carnitine deficiency or lnsufficiency in

doses of 25-100mg/kgm/day or higher.

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Page 40: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

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ORGANIC ACIDEMIA

Disorder

• Methyl malonic Acidemia.

• Propionic Acidemia.

• Multiple carboxylase deficiency.

• Ketothiolase deficiency .

Enzyme

• Methyl malonyl COA mutase.

• Propionyl COA Carboxylase.

• Malfunction of all carboxylase.

• 2 methylacetyl COA thiolase def.

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ORGANIC ACIDEMIA

Clinical Features

Vomiting, ketosis.

Thrombocytopenia , neutropenia.

Osteoporosis.

Mental retardation.

Treatment

Hydration / alkali.

Calories to catabolic state.

Exchange transfusion.

Low protein diet.

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ORGANIC ACIDEMIA

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LYSOSOMAL STORAGE DISORDERS

• Glycogen Storage Diseases

• Sphingolipidoses common in eastern jews

(Lipidoses And Mucolipidoses)

• Mucopolysaccharidoses

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Lysosomal Storage DiseaseLysosomal Storage DiseaseDiseaseDisease Enzyme Defiency Enzyme Defiency Major Accumulating Major Accumulating

MetaboliteMetabolite

GlycogenosisGlycogenosis

Type II (Pompe disease)Type II (Pompe disease) GlucosidaseGlucosidase GlycogenGlycogen

SphingolipidosesSphingolipidoses

GGM1M1 gangliosidoses gangliosidoses

GGM2 M2 gangliosidosesgangliosidoses

Tay-Sachs diseaseTay-Sachs disease Gaucher diseaseGaucher disease Niemann-Pick diseaseNiemann-Pick disease

ββ-galactosidase-galactosidase

Hexosaminidase AHexosaminidase AGlucocerebrosidasGlucocerebrosidaseeSphingomyelinaseSphingomyelinase

GGM1M1 gangliosides, gangliosides, galactose-containing galactose-containing oligosaccharidesoligosaccharides

GGM2 M2 gangliosideganglioside

GlucocerebrosideGlucocerebrosideSphingomyelinSphingomyelin

MucopolysaccharidosMucopolysaccharidoseses

MPS I H (Hurler)MPS I H (Hurler)

MPS II (Hunter)MPS II (Hunter)(X-linked recessive)(X-linked recessive)

αα--L-IduronidaseL-Iduronidase

L-Iduronosulfate L-Iduronosulfate sulfatasesulfatase

Heparan sulfateHeparan sulfateDermatan sulfateDermatan sulfate

Heparan sulfateHeparan sulfateDermatan sulfateDermatan sulfate

Page 45: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Glycogen Storage Diseases

Page 46: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Name Enzyme Symptoms Type O Glycogen synthetase Enlarged, fatty liver; hypoglycemia when fasting

von Gierke (Type IA)

Glucose-6-phosphatase Hepatomegaly; slowed growth; hypoglycema; hyperlipidemia

Type IB G-6-P translocase Same as in von Gierke's disease but may be less severe; neutropenia Pompe

(Type II) Acid maltase Enlarged liver and heart, muscle weakness

Forbe (Cori) (Type III)

Glycogen debrancher Enlarged liver or cirrhosis; low blood sugar levels; muscle damage and heart damage in some people

Andersen (Type IV)

Glycogen branching enzyme Cirrhosis in juvenile type; muscle damage and CHF

McArdle's (Type V)

Muscle glycogen phosphorylase

Muscle cramps or weakness during physical activity

Her (Type VI)

Liver glycogen phosphorlyase Enlarged liver; often no symptoms

Tarui (Type VII)

Muscle phosphofructokinase Muscle cramps during physical activity; hemolysis

Type VIII Unknown Hepatomegaly; ataxia, nystagmus Type IX Liver phosphorylase kinase Hepatomegaly; Often no symptoms Type X Cyclic 3-5 dependent kinase Hepatomegaly, muscle pain (1 patient) Type XI Unknown Hepatomegaly. Stunted growth, acidosis, Rickets

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Principle Groups of Glycogen Storage Diseases

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Von Gierke Disease

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LYSOSOMAL STORAGE DISORDERS

Lipidoses And Mucolipidoses

Page 50: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

50Gauch. cell

In gaucher liver is enlarged but the rest of the body is very thin

Page 51: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

In gaucher you see the cherry red spot appearance in the macula

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52Sandhoff - Dense thalam

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Cerebral palsy --- scissoring of the legs

Lipid-retina

Lipid accumalation around the retinal arteries and veins

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LYSOSOMAL STORAGE DISORDERS

Mucopolysaccharidoses

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Clinical And Pathological Ultra structure Of Mucopolysaccharidoses

DiseaseDisease Clinical ManifestationClinical Manifestation Ultrastructure of Stored Ultrastructure of Stored MaterialMaterial

MPS type IMPS type I

HurlerHurler

Earliest, most severe Earliest, most severe developmental regressiondevelopmental regression

coarse facial featurescoarse facial features

HepatosplenomegalyHepatosplenomegaly

dystosis of bonedystosis of bone

cardiac involvementcardiac involvement

corneal clouding present in hurler corneal clouding present in hurler but absent in hunterbut absent in hunter

Fibrillogranular Fibrillogranular mucopolysaccharides in cells of mucopolysaccharides in cells of viscera and brainviscera and brain

MPS type IIMPS type II

HunterHunterX-linkedX-linked

Later developmental regressionLater developmental regression

coarse facial featurescoarse facial features

hepatosplenomegaly hepatosplenomegaly

dystosis of bone dystosis of bone

cardiac involvementcardiac involvement

minimal corneal cloudingminimal corneal clouding

Fibrillogranular Fibrillogranular mucopolysaccharides in cells of mucopolysaccharides in cells of viscera and brainviscera and brain

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56Hurler’s

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57Hurler’s

In hurler :Nasal bridge is depressed , increase distance of philthrum , epicanthal folds, bossing of the head , thick eyebrows , upturn nostrils

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59 Mcopolysacch. Morquio

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Peroxisomes = Subcellular organelles involved in various essential anabolic or catabolic processes, biosynthesis of Plasmalogens and bile acids.

Due to dysfunction of a single or multiple peroxisomal enzymes, or to failure to form or maintain a normal number of functional peroxisomes.

PEROXISOMAL DISORDERSPEROXISOMAL DISORDERS

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Hypotonia.

Dysmorphia.

Psychomotor delay and seizures.

Hepatomegaly.

Abnormal eye findings such as retinitis pigmentosa or cataract.

Hearing impairment.

PEROXISOMAL DISORDERSPEROXISOMAL DISORDERS Clinical Manifestations:

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Peroxisomal Disorders

• Zellweger Syndrome is autosomal recessive disorder.

(Cerebro-hepato-renal syndrome)

• Typical and easily recognized dysmorphic facies.

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

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

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63Zellweger

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Diagnosis:

Immunochemical studies for Peroxisomes.

V. Long Chain FA ( VLCFA ) level.

Chor. Vill. Samp. or/ amniocytes culture Plasmalogens

synthesis.

PEROXISOMAL DISORDERSPEROXISOMAL DISORDERS

Treatment:

Supportive, multidisciplinary interventions.

Diet: VLCFA, phytanic acid.

Organ transplantation.

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Peroxisomal Disorders

GROUP II : PERSOXISOMAL

ENZYME DEFECTS

GROUP I : GROUP I : BIOGENSISBIOGENSIS OF PEROXISOME OF PEROXISOME

GROUP III GROUP III :: POSITIVE PEROXISOMES BUT POSITIVE PEROXISOMES BUT MULTIPLEMULTIPLE DEFECTIVE DEFECTIVE ENZYME ENZYMEZellweger syndrome

(cerebrohepatorenal syndrome).

Neonatal adrenoleukodystrophy.

Infantile Refsum disease.

Hyperpipecolic acidemia.

Refsum disease.

X - linked Adreno-Leuko-Dystrophy.

Pseudo – Zellweger syndrome.

Hyperoxaluria….etc.

Zellweger – Like.

Pseudo – infantile Refsum disease.

Rhizomelic chondro-dysplasia

punctata

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Mitochondrial Disorders

Classically involve mutations in mitochondrial DNA

Follow a maternal pattern of inheritance

Highly variable with regard to penetrance and expressivity based on the variability in tissue distribution of abnormal mitochondria

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Mitochondrial Syndromes Presenting in Childhood to Adult

SyndromeSyndrome Most Common Most Common Clinical Clinical PresentationPresentation

Other Clinical Other Clinical FeaturesFeatures

Mt DNA Mt DNA DefectDefect

MELAS: myopathy, MELAS: myopathy, encephalopathy, encephalopathy, lactic acidosis and lactic acidosis and stroke-like episodesstroke-like episodes

Stroke-like episodes Stroke-like episodes in the first and in the first and second decade of second decade of life often associated life often associated with migraine with migraine headache, blood headache, blood lactate lactate

Deafness, Deafness, myopathy, diabetes myopathy, diabetes mellitusmellitus

mtDNA mutations at mtDNA mutations at 3243, 3271 3243, 3271 tRNA mutationstRNA mutations

MERRF: Myoclonic MERRF: Myoclonic epilepsy with ragged epilepsy with ragged red fibersred fibers

Progressive Progressive myoclonic epilepsymyoclonic epilepsy

Ataxia, myopathy Ataxia, myopathy deafness, short deafness, short staturestature

MtDNA A8344G MtDNA A8344G tRNA mutationtRNA mutation

NARP: Neurogenic NARP: Neurogenic weakness, ataxia weakness, ataxia and retinitis and retinitis pigmentosapigmentosa

Peripheral Peripheral neuropathy, neuropathy, myopathy, seizuresmyopathy, seizures

Leigh syndromeLeigh syndrome MtDNA 8993 MtDNA 8993 Complex V Complex V deficiencydeficiency

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Page 69: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Transient Hyperammonemia of Newborn:

Markedly high NH4 in an infant less than 24 HOL (hours of life), or first 1-2 DOL (day of life) before protein intake occurs.

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

Very sick infant.

Unknown precipitant, unknown etiology (possible slow delayed urea cycle initiation), with potential for severe sequelae (20-30% death, 30-40% abnl dev.) if not treated.

Does not recur after being treated.

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Clinical AbnormalityClinical Abnormality Abnormal Amino AcidAbnormal Amino Acid Presumptive DiagnosisPresumptive Diagnosis

Acute neonatal Acute neonatal presentation with presentation with ketoacidosisketoacidosis

Leucine, isoleucine, Leucine, isoleucine, valinevaline

Organic Acid DisordersOrganic Acid Disorders

Maple syrup urine disease Maple syrup urine disease Methylmalonic acidemia Methylmalonic acidemia

Propionic acidemiaPropionic acidemia

Isovaleric acidemiaIsovaleric acidemia

Acute neonatal Acute neonatal presentation with presentation with hyperammonemiahyperammonemia

Arginine, CitrullineArginine, Citrulline Urea cycle disordersUrea cycle disorders

Ornithine transcarbamylase Ornithine transcarbamylase deficiency Argininosuccinate deficiency Argininosuccinate synthase deficiency synthase deficiency Argininosuccinate lyase Argininosuccinate lyase deficiencydeficiency

Marfanoid, Marfanoid, strokes, ectopia strokes, ectopia lentis, lentis, mental mental retardationretardation

Homocystine & Homocystine & methioninemethionine

HomocystinuriaHomocystinuria

Severe Severe developmental developmental delaydelay

PhenylalaninePhenylalanine PhenylketonuriaPhenylketonuria

Clinical Presentation of Amino Acid Disorders

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Predominanat Predominanat Biochemical Biochemical Clinical FindingsClinical Findings

OtherOther Most Common DiagnosisMost Common Diagnosis

KetoAcidosisKetoAcidosis

LethargyLethargy

OdorOdor

Ammonia: Normal or slightly Ammonia: Normal or slightly elevated Ketones: Elevated elevated Ketones: Elevated Glucose: Normal Glucose: Normal

Maple syrup urine diseaseMaple syrup urine disease

AcidosisAcidosis

LethargyLethargy

OdorOdor

Ammonia: Elevated Ammonia: Elevated Glucose: Normal or Glucose: Normal or decreased Ketones: decreased Ketones: May be elevated May be elevated Lactate: Slightly elevatedLactate: Slightly elevated

Methylmalonic acidemia Methylmalonic acidemia Propionic acidemia Propionic acidemia Isolvaleric Isolvaleric acidemiaacidemia

Lactic AcidosisLactic Acidosis

LethargyLethargy

Acidosis: Usually present Acidosis: Usually present Ammonia: Normal or slightly Ammonia: Normal or slightly elevated elevated Ketones: May be elevated Ketones: May be elevated

Pyruvate dehydrogenase Pyruvate dehydrogenase Pyruvate carboxylase Pyruvate carboxylase deficiency Respiratory chain deficiency Respiratory chain disorderdisorder

HypoglycemiaHypoglycemia

LethargyLethargy

Ammonia: Lactate Acidosis Ammonia: Lactate Acidosis Ketones: Absent or Ketones: Absent or inappropriately lowinappropriately low

Fatty acid oxidation defectsFatty acid oxidation defects

HyperammonemHyperammonemiaia

LethargyLethargy

Acidosis: Absent Acidosis: Absent Respiratory Alkalosis Respiratory Alkalosis

Urea cycle disordersUrea cycle disorders

Metabolic Profiles Organic and Amino Acid Disorders Metabolic Profiles Organic and Amino Acid Disorders

Newborn screening is available dependent on population frequency for some

Expanded newborn screening for fatty acid defects recently offered

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CHILDREN AFTER THE NEONATAL PERIOD Clinical Manifestation

Mental retardation, Macro/Microcephaly.

Coarse facial features/dysmorphia.

Developmental regression.

Convulsion.

Myopathy / cardiomyopathy.

Recurrent emesis with coma and hepatic dysfunction.

Hypertonia / hypotonia.

Failure to thrive.

Ophthalmic – related problems : e.g. cataract, corneal

cloudiness, cherry red spot, optic atrophy.

Renal failure or renal tubular acidosis.

Page 73: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics
Page 74: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics
Page 75: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics
Page 76: 1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics

Management of IEM - NICU

• Stop nutrient triggering disorder e.g. protein, galactose

• Give high-energy intake

• NICU care to correct tissue perfusion, dehydration, acidosis

• Hyperammonemia Rx with Na benzoate, Na phenylbutyrate, arginine

• Dialysis

• Insulin to control hyperglycemia and reduce catabolism

• Vitamins e.g Biotin, B6, B12

• Specific therapy e.g. carnitine, glycine

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Dependent on diagnosis and severity:Dietary or vitamin therapy

Drug therapy

BMT

Avoid known environmental triggers

Surgery

MEDICALMEDICAL