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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
Inborn Errors Of Metabolism
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
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.
Transient Hyperammonemia of Newborn Inborn Errors of Metab: • • • • •
Molybdenum Cofactor Deficiency •
Organic Acidemias Fatty Acid Oxidation def Urea Cycle Defects Amino Acidurias Non-ketotic Hyperglycinemia
Sulfite Oxidase Deficiency
Metal Storage Disorders: Cholesterol Disorders: Leukodystrophies, other… •
Mitochondrial Disorders Glycogen Storage Disorders Hyperinsulinism Carbohydrate Disorders Lysosomal Disorders • • •
Mucopolysaccharidoses (Xlinked Hunter’s, Hurler’s) Gaucher disease Tay-Sachs Disease
Peroxisomal Disorders • •
Zellwegger’s (CerebroHepato-renal) X-linked Adrenoleukodystrophy
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.
Metabolic Disorders Features suggestive of metabolic disorder : From history:
Parental history : Consanguineous parents Previous unexplained neonatal deaths Particular ethnic group (in certain diseases)
Metabolic Disorders Features suggestive of metabolic disorder : 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.
Neonatal and Post Neonatal Presentation Neonatal presentation • • • • • • •
Normal-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)
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.
Newborn Screening the 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.
PROCEDURES FOR DIAGNOSIC CONFIRMATION Non – Specific Tests:
Direct biochemical assays of metabolites or their metabolic byproducts, or of an enzyme’s function.
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
INBORN ERRORS OF AMINO ACID METABOLISM ASSOSIATED WITH ABNORMAL ODOR
Inborn Error of Metabolism
Maple Syrup urine disease
Mousy or musty
They may come with flattened mid-face, indistinct philtrum, low nasal bridge and single palmar crease.
Small chin is called micrognathia
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.
MANAGEMENT OF IEM Genetic: Establish diagnosis. Carrier testing. Pedigree analysis, risk counseling. Consideration of Prenatal diagnosis for pregnancies at risk. 19
MANAGEMENT OF IEM PSYCHOSOCIAL , EDUCATIONAL , FAMILIAL
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.
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
Galactosemia Enzyme 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. 23
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
AMINO ACID DISORDERS
Phenyl Ketonuria (PKU) Phenylalanine
Phenyl pyruvic acid
Phenyl pyruvic acid is what gives the urine its smell because its ketonic and acidic.
Screening : Guthrie Test.
High Phenylalanine > 20 mg/dl.
High Phenyl pyruvic acid.
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.
• L – dopa and 5hydroxytryptophan. 27
Iris had fibrous tissue, and it’s colourless and is red due to vessels.
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.
Cysathionine CYSTATHIONINE Synthatase
High methionine and homocystine. TREATMENT:
•High dose of B6 and Folic Acid. •Low methionine and high cystine diet, •Betain (trimethylglycine) 32
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
Transient tyrosinemia of prematurity
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)
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
Important IEM Treatment supplements:
• Carnitine for elimination of Organic Acid through creation of carnitine esters.
• Sodium Benzoate, phenylacetate and phenylbutyrate for Hyperammonemia elimination.
CARNITINE 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.
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.
ORGANIC ACIDEMIA Disorder
Methyl malonic Acidemia.
• Methyl malonyl COA mutase.
• Propionyl COA Carboxylase.
Multiple carboxylase deficiency.
• Malfunction of all carboxylase.
Ketothiolase deficiency .
• 2 methylacetyl COA thiolase def.
ORGANIC ACIDEMIA Clinical Features Treatment Vomiting, ketosis.
Hydration / alkali.
Thrombocytopenia , neutropenia.
Calories to catabolic state.
Exchange transfusion. Low protein diet. 41
LYSOSOMAL STORAGE DISORDERS •
Glycogen Storage Diseases
Sphingolipidoses common in eastern jews (Lipidoses And Mucolipidoses)
Lysosomal Storage Disease Disease
Major Accumulating Metabolite
GM1 gangliosides, galactose-containing oligosaccharides
Hexosaminidase A Glucocerebrosidase Sphingomyelinase
GM2 ganglioside Glucocerebroside Sphingomyelin
MPS I H (Hurler)
Heparan sulfate Dermatan sulfate
MPS II (Hunter) (X-linked recessive)
Heparan sulfate Dermatan sulfate
Glycogenosis Type II (Pompe disease)
Sphingolipidoses GM1 gangliosidoses GM2 gangliosidoses Tay-Sachs disease Gaucher disease Niemann-Pick disease
Glycogen Storage Diseases
Name Type O von Gierke (Type IA) Type IB Pompe (Type II) Forbe (Cori) (Type III) Andersen (Type IV) McArdle's (Type V) Her (Type VI) Tarui (Type VII) Type VIII Type IX Type X Type XI
Enzyme Glycogen synthetase Glucose-6-phosphatase
Symptoms Enlarged, fatty liver; hypoglycemia when fasting Hepatomegaly; slowed growth; hypoglycema; hyperlipidemia
G-6-P translocase Acid maltase
Same as in von Gierke's disease but may be less severe; neutropenia Enlarged liver and heart, muscle weakness
Enlarged liver or cirrhosis; low blood sugar levels; muscle damage and heart damage in some people Cirrhosis in juvenile type; muscle damage and CHF
Glycogen branching enzyme Muscle glycogen phosphorylase Liver glycogen phosphorlyase
Muscle cramps or weakness during physical activity
Muscle cramps during physical activity; hemolysis
Unknown Liver phosphorylase kinase Cyclic 3-5 dependent kinase Unknown
Hepatomegaly; ataxia, nystagmus Hepatomegaly; Often no symptoms Hepatomegaly, muscle pain (1 patient) Hepatomegaly. Stunted growth, acidosis, Rickets
Enlarged liver; often no symptoms
Principle Groups of Glycogen Storage Diseases
Von Gierke Disease
LYSOSOMAL STORAGE DISORDERS
Lipidoses And Mucolipidoses
In gaucher liver is enlarged but the rest of the body is very thin
In gaucher you see the cherry red spot appearance in the macula
Sandhoff - Dense thalam
Cerebral palsy -- scissoring of the legs
Lipid accumalation around the retinal arteries and veins Lipid-retina
LYSOSOMAL STORAGE DISORDERS
Clinical And Pathological Ultra structure Of Mucopolysaccharidoses Disease
Ultrastructure of Stored Material
MPS type I
Earliest, most severe developmental regression coarse facial features Hepatosplenomegaly dystosis of bone cardiac involvement corneal clouding present in hurler but absent in hunter
Fibrillogranular mucopolysaccharides in cells of viscera and brain
MPS type II
Later developmental regression
coarse facial features
Fibrillogranular mucopolysaccharides in cells of viscera and brain
dystosis of bone
hepatosplenomegaly cardiac involvement
minimal corneal clouding
In hurler : Nasal bridge is depressed , increase distance of philthrum , epicanthal folds, bossing of the head , thick eyebrows , upturn nostrils Hurler’s
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 DISORDERS Clinical Manifestations:
Psychomotor delay and seizures.
Abnormal eye findings such as retinitis pigmentosa or cataract.
Hearing impairment. 61
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 AcidsVLCFAs
PEROXISOMAL DISORDERS Diagnosis:
Immunochemical studies for Peroxisomes.
V. Long Chain FA ( VLCFA ) level.
Chor. Vill. Samp. or/ amniocytes culture
Supportive, multidisciplinary interventions.
Diet: VLCFA, phytanic acid.
Organ transplantation. 64
Peroxisomal Disorders GROUP I : BIOGENSIS OF PEROXISOME
Zellweger syndrome (cerebrohepatorenal syndrome). Neonatal adrenoleukodystrophy. Infantile Refsum disease. Hyperpipecolic acidemia. GROUP II : PERSOXISOMAL ENZYME DEFECTS
GROUP III : POSITIVE PEROXISOMES BUT MULTIPLE DEFECTIVE ENZYME
Zellweger – Like. Pseudo – infantile Refsum disease. Rhizomelic chondro-dysplasia punctata
Refsum disease. X - linked Adreno-Leuko-Dystrophy. Pseudo – Zellweger syndrome. Hyperoxaluria….etc. 65
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 66
Mitochondrial Syndromes Presenting in Childhood to Adult
Most Common Clinical Presentation
Other Clinical Features
Mt DNA Defect
MELAS: myopathy, encephalopathy, lactic acidosis and stroke-like episodes
Stroke-like episodes in the first and second decade of life often associated with migraine headache, blood lactate
Deafness, myopathy, diabetes mellitus
mtDNA mutations at 3243, 3271 tRNA mutations
MERRF: Myoclonic epilepsy with ragged red fibers
Progressive myoclonic epilepsy
Ataxia, myopathy deafness, short stature
MtDNA A8344G tRNA mutation
NARP: Neurogenic weakness, ataxia and retinitis pigmentosa
Peripheral neuropathy, myopathy, seizures
MtDNA 8993 Complex V deficiency
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.
Clinical Presentation of Amino Acid Disorders Clinical Abnormality
Abnormal Amino Acid
Acute neonatal presentation with ketoacidosis
Leucine, isoleucine, valine
Organic Acid Disorders Maple syrup urine disease Methylmalonic acidemia Propionic acidemia Isovaleric acidemia
Acute neonatal presentation with hyperammonemia
Marfanoid, strokes, ectopia lentis, mental retardation
Homocystine & methionine
Ornithine transcarbamylase deficiency Argininosuccinate synthase deficiency Argininosuccinate lyase deficiency
Severe Phenylalanine developmental delay 70
Urea cycle disorders
Metabolic Profiles Organic and Amino Acid Disorders Predominanat Biochemical Clinical Findings KetoAcidosis Lethargy Odor Acidosis Lethargy Odor Lactic Acidosis Lethargy Hypoglycemia
Most Common Diagnosis
Ammonia: Normal or slightly elevated Ketones: Elevated Glucose: Normal
Maple syrup urine disease
Ammonia: Elevated Glucose: Normal or decreased Ketones: May be elevated Lactate: Slightly elevated
Methylmalonic acidemia Propionic acidemia Isolvaleric acidemia
Acidosis: Usually present Ammonia: Normal or slightly elevated Ketones: May be elevated
Pyruvate dehydrogenase Pyruvate carboxylase deficiency Respiratory chain disorder
Ammonia: Lactate Acidosis Ketones: Absent or inappropriately low
Fatty acid oxidation defects
Acidosis: Absent Respiratory Alkalosis
Urea cycle disorders
Newborn screening is available dependent on population frequency for some Expanded newborn screening for fatty acid defects recently offered
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. 72
Clinical Symptomatology of Inborn Errors of Metabolism (IEM) in the Neonate or 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 r ecurrent 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 simila r illness, especially in siblings Parental consanguinity Sepsis (particularly Escherichia coli)
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
Plasma amino acids Plasma carnitine Urine amino acids Urine organic acids
Inborn Errors of Metabolism of Acute Onset: Nonacidotic, Nonhyperammonemic Features Neurologic Features Predominant (Seizures, Hypotonia, Optic Abnormality) Glycine encephalopathy (nonketotic hyperglycinemia) Pyridoxine -responsive seizures Sulfite oxidase/santhine oxidase deficiency Peroxisomal disorders (Zellweger syndrome, neonatal adrenoleuko dystrophy, infantile refsum disease)
Jaundice Prominent Galactosemia Hereditary fructose intolerance Menkes kinky hair syndrome a1-antitrypsin deficiency Hypoglycemia (Nonketotic) : Fatty acid oxidation defects (MCAD, LCAD, carnitine palmityl transferase, infantile form) Cardiomegaly Glycogen storage disease (type II phosphorylase kinase b deficiency Fatty acid oxidation def ects (LCAD) Hepatomegaly (Fatty): Fatty acid oxidation defects (MCAD, LCAD) Skeletal Muscle Weakness : Fatty acid oxidation defects (LCAD, SCAD, multiple acyl -CoA dehydrogenase
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
MEDICAL Dependent on diagnosis and severity: Dietary or vitamin therapy Drug therapy BMT Avoid known environmental triggers Surgery