Inborn Error of Metabolism

Inborn errors of metabolism (IEM) are individually rare but collectively numerous genetic diseases, in which specific gene mutation cause abnormal or missing proteins that lead to alter function.

Genetic Characteristics of IEM IEM are usually Autosomal recessive. Consanguinity is always relatively common. Some are x-linked recessive condition including: Adrenoleukodystrophy. Agammaglobulinemia. Fabry’s disease. Granulomatous disease. Hunter’s Syndrome. Lesch – Nyhan Syndrome. Menke’s Syndrome. A few inherited as autosomal dominant trait including: porphyria, hyperlipedemia, hereditary angioedema.

Theoretical consequences of an enzyme deficiency. defective enzyme Substrate (increased) Product (decreased) action Co-factor B Co-factor A other enzymes Metabolites (decreased) Metabolites (increased) EFFECT ON OTHER METABOLIC ACTIVITY e.g., activation, inhibition, competition

Categories of IEM Disorders of: Amino acids Carbohydrates Fatty acids Lysosomal and peroxisomal function Mitochondria Organic acids

An integrated view of the metabolic pathways GLYCOGEN FAT PROTEIN FRUCTOSE GALACTOSE AMINO ACIDS GLUCOSE FREE FATTY ACIDS ORGANIC ACIDS AMMONIA PYRUVATE LACTATE ACETYL CoA UREA CYCLE KETONES UREA KREBS CYCLE NADH ATP An integrated view of the metabolic pathways

Pathophysiology Group 1. Disorders which give rise to intoxication Inborn error of intermediary metabolism, that lead to intoxication from the accumulation of toxic compounds proximal to metabolic block. Ex. IE of aminoacid catabolism Organic aicdurias Congenital urea cycle defects Metal intoxication (Wilson D., Menkes D. ) Porphyrias

Pathophysiology Group 2. Disorders involving energy metabolism a) Mitochondrial energy defects; mostly severe and generally untreatable Ex. Congenital lactic acidemias Fatty acid oxidation defects b) Cytoplasmic energy defects; generally less severe and they partly treatable Ex. Disorders of Glycogen metabolism Disorders of Glyconeogenesis

Pathophysiology Group 3. Disorders involving complex molecules Almost none are treatable acutely, but enzyme replacement is now available for several disorders in this group. Ex. Lysosomal storage disorders Peroxisomal disorders

Signs and Symptoms of IEM Early symptoms in the antenatal and neonatal preiod (non-specific) Later-onset acute and recurrent attacks of symptoms such as coma, ataxia, vomiting and acidosis Chronic and progressive generalized symptoms which can be mainly gastrointestinal, muscular or neurological Specific and permanent organ presentations suggestive cardiomyopathy, hepatomegaly, lens dislocation etc.

Acute symptoms in neonatal period and early infancy The neonate has a limited repertoire of responses to severe illness. IEM may present with nonspecific symptoms; Respiratory disstress Hypotonia Poor sucking reflex Vomitting Diarrhea Dehydratation Lethargy Seizures

Later onset acute and recurrent attacks In about 50% of the patients with IE intermediary metabolism disorders onset later. The symptom free period is often longer than one year and may extend into late childhood, adolescence or even adulthood. Each attack can follow a rapid course ending either in spontaneous improvement or unexplained death. Between attacks the patient may appear normal Coma,strokes and attacks of vomiting with lethargy Acute psychiatric symptoms (UCD, congenital hyperammonemia) Dehydratation

Chronic and progressive general symptoms Gastrointestinal symptoms occur in a wide variety of IEM; persistent anorexia, feeding difficulities chronic vomiting, diarrhea Muscle symptoms such as severe hypotonia, muscular weakness Neurological symptoms are very frequent in IEM; progressive psychomotor retardation seizures defects of peripheral and central nervous system psychiatric symptoms

Specific organ symptoms A number of clinical and biological abnormalities can be associated with inherited IEM; Cardiac (cardiomyopathy, cardiac failure, arrythmias) Dermatology (alopecia, hyperkeratosis, xanthoma) Hepatic (jaundice, cirrhosis, liver failure) Ocular (cataracts, corneal opacity) Dysmorphism (coarse face)

Main Metabolic Presentations Metabolic acidosis Ketosis Hyperlactatemia Hyperammonemia Hypoglycemia

Metabolic acidosis Metabolic acidosis is a very common finding in pediatrics. It can be observed in a large variety of acquired conditions, including infections, severe catabolic states, tissue anoxia, severe dehydration, and intoxication, all of which should be ruled out. pH <7.35 Excess H+ HCO3 deficit Calculate anion gap Na – (Cl + HCO3) Normal is 8-16meq/l

Metabolic Acidosis If Chloride is increased- HCO3 wasting GI or renal disorders If Chloride is Normal and Anion gap is > 16--- excess acid production Approach is to give Na HCO3 If unresponsive to HCO3-- IEM

Ketosis Ketonuria should always be considered abnormal in neonates, while it is a physiological result of catabolism in late infancy, childhood and even adolescence. A general rule, hyperketosis at a level that produces metabolic acidosis isn’t physiological.

Hyperlactatemia Lactate and pyruvate are normal metabolites. Their plasma levels reflect the equilibrium between their cytoplasmic production from glycolysis and their mitochondrial consumption by different tissues. The blood levels L/P ratio reflect redox state of the cells.

Hyperammonemia Normal ammonia level- < 50 umol/l > 200 -- IEM If within 24 hours of life; preterm After 24 hours- IEM The differential diagnosis of hyperammonemia is wide. In the neonatal period, the most common DD are organic acidemias (Propionic and methylmalonic).

Hypoglycemia Glucose level helps in the differential diagnosis Approach to hypoglycemia is based on four major clinical criteria; Liver size Characteristic timing of hypoglycemia Association with lactic acidosis Association with hyperketosis or hypoketosis

Approach to the patient with IEM 1. Determine if there is metabolic acidosis 2. Is anion gap >16? 3. Is there hypoglycemia? 4. Is there hyperammonemia? Within 24 hours of life After 24 hours of life

Metabolic acidosis + hyperammonemia Request for specific lab studies Consult metabolic specialist Initial therapy- stabilize patient! Long term treatment- based on specific IEM

Copyright ©1998 American Academy of Pediatrics

Newborn Screening for IEM Basic concept Goal is to detect diagnostic markers of metabolic disease in asymptomatic infants Disease should be frequent enough to have a favorable cost-benefit ratio Should screen for diseases we can do something for, i.e., therapy available Low false positive and false negative rates

Newborn Screening for IEM First applied to the detection of phenylketonuria (PKU) by a bacterial inhibition assay in 1961 by Guthrie.

Newborn Screening In Turkey.. PKU Congenital hypothyroidism

Disorders of Amino Acid Metabolism

IE of Amino Acid Metabolism with Abnormal Urine Odor IEM Urine Odor Glutaric acidemia typeII Sweaty feed Hawkinsuria Swimming pool Isovaleric acidemia Sweaty feed Maple Syrup Urine Disease Maple Syrup Hypermethioninemia Boiled cabbage Multiple carboxylase def. Tomcat urine PKU Mousy Tyrosinemia Boiled cabbage

Phenylketonuria (PKU) Autosomal recessive inherited IEM caused by mutations in the gene of phenylalanine hydroxylase (PAH) enzyme. (500 different mutations) Defects in either phenylalanine hydroxylase PAH or the production of tetra hydrobiopterin (BH4) may result hyperphenilalaninemia. (dihydropterine reductase deficiency)

Phenylketonuria (PKU) Severe PAH deficiency which results in blood phenylalanine greater than 1200 mM after normal protein intake, is referred to as classical PKU Milder defects associated with levels between 600-1200mM are termed hyperphenylalaninemia (HPA). Disorders of BH4 metabolism called malignant PKU or malignant HPA.

Clinical Presentation Newborn; Vomiting Urine odor (mouse) Late childhood Severe mental retardation Reduced hair, skin and iris pigmentation Microcephaly Epilepsy Eczema

Prevalence of PKU varies between different populations: Turkey 1/4200 Finland 1/1.000.000 Consanguineous marriage Compound heterozygosity NEWBORN SCREENING!!!

Diagnosis Newborn Screening : Blood PHE is normal at birth but rises rapidly within the first days of life (after feeding) Positive result requiring further investigation ; Blood PHE levels >1200mM Classical PKU 600-1200 mM Hyperphenylalaninemia <600mM; >5% residual PAH activity Cofactor defects (BH4) Malignant PKU

Treatment The principle of treatment in PKU is to reduce blood PHE concentration sufficiently to prevent the neuropathological effects. DIET BH4 (Tetrahydrobioptein). L – dopa and 5-hydroxytryptophan.

Maternal PKU !!! The offspring born to mothers with PKU are at risk of damage from the teratogenic effects of PHE. High PHE in maternal blood associated with; Facial dysmorphism Microcephaly Mental retardation Developmental delay Congenital heart diseases Girls with PKU = life-long diet

Disorders of Tyrosine Metabolism Five inherited disorders of tyrosine metabolism; 1- Tyrosinemia typeI 2-Tyrosinemia type II 3-Tyrosinemia type III 4- Alkaptonuria 5- Hawkinsuria

Alkaptonuria First disease to be interpreted as an IEM in 1902 by Garrod. Homogentisate dioxygenase deficiency. Darkening of urine when exposed to air !! Clinical symptoms first appear in adulthood. Symptoms relate joint and connective tissue, aortic or mitral valve calcifications and urolithiasis.

Disorders of Methionine Metabolism Homosistinemia type I Cystathione b-synthase deficiency leads to tissue accumulation of methionine, homocysteine. Homosistinemia type II Homosistinemia type III Sistationemia

Branched-Chain Organic Acidemias / Acidurias Result from an abnormality of specific enzymes involving the catabolisms of branched-chain amino acids (BCAA) Maple Syrup Urine Disease (MSUD) Isovaleric Aciduria (IVA) Propionic Aciduria (PA) Methylmalonic Aciduria (MMA)

Disorders of the Urea Cycle Enzymes Six inherited disorders of the Urea Cycle are well described; Carbamoyl phosphate synthetase deficiency Ornitine transcarbamoylase deficiency Argininosuccinate synthetase deficiency Argininosuccinate lyase deficiency Arginase deficiency N-acetylglutamate synthetase deficiency All these defects are characterized by hyperamonaemia

Disorders of Carbohydrate Metabolism

The Glycogen Storage Disorders Disorders of Galactose Metabolism Disorders of the Pentose Phosphate Pathway Disorders of Fructose Metabolism Disorders of Glucose Transport

Glycogen Storage Disorders The glycogen storage diseases (GSD) are caused by defects of glycogen degradation, glycolysis and paradoxically glycogen synthesis. Glycogen is found in most tissues, but is especially abundant in liver and muscle. Despite some overlap the GSDs can divided in 3 main groups: The Liver Glycogenoses The Muscle Glycogenoses The Generalized Glycogenoses and Related Disorders

Deficient Enzyme Main Tissue Common Name GSD Type I glucose-6-phosphatase Liver, kidney Von-Gierke's disease GSD Type II Lysosomal a-glucosidase General (lysosomes) Pompe disease GSD Type III Debranching enzyme Liver, muscle Cori's disease GSD Type IV Branching enzyme Liver Andersen disease GSD Type V Glycogen phosphorylase Muscle McArdle disease GSD Type VI Hers' disease GSD Type VII Phosphofructokinase Muscle, erythrocytes Tarui's disease