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:

o Adrenoleukodystrophy.o Agammaglobulinemia.o Fabry’s disease.o Granulomatous disease.o Hunter’s Syndrome.o Lesch – Nyhan Syndrome.o Menke’s Syndrome.

A few inherited as autosomal dominant trait including:porphyria, hyperlipedemia, hereditary angioedema.

defective enzyme

Substrate(increased)

Product(decreased)

action

Metabolites(increased)

Co-factor A Co-factor B

otherenzymes Metabolites

(decreased)

EFFECT ON OTHER METABOLIC ACTIVITYe.g., activation, inhibition, competition

Theoretical consequences of an enzyme deficiency.

Categories of IEM

Disorders of:

•Amino acids

•Carbohydrates

•Fatty acids

•Lysosomal and peroxisomal function

•Mitochondria

•Organic acids

PROTEIN GLYCOGEN FAT

AMINO ACIDSFRUCTOSE

GALACTOSE

FREE FATTY ACIDS

AMMONIA

UREA

UREA CYCLE

ORGANIC ACIDSGLUCOSE

PYRUVATE

ACETYL CoA

KREBS CYCLE

NADH

KETONES

ATP

LACTATE

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 disstressHypotoniaPoor sucking reflexVomittingDiarrheaDehydratationLethargySeizures

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 OdorGlutaric 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 after normal protein intake, is referred to as classical PKU

• Milder defects associated with levels between 600-1200 are termed hyperphenylalaninemia (HPA).

• Disorders of BH4 metabolism called malignant PKU or malignant HPA.

Clinical PresentationNewborn;

•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 >1200M Classical

PKU– 600-1200 M Hyperphenylalaninemia– <600; >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 dysmorphismMicrocephalyMental retardationDevelopmental delayCongenital 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 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

1. The Glycogen Storage Disorders

2. Disorders of Galactose Metabolism

3. Disorders of the Pentose Phosphate Pathway

4. Disorders of Fructose Metabolism

5. 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:

1.The Liver Glycogenoses

2.The Muscle Glycogenoses

3.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 -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 Glycogen phosphorylase Liver Hers' disease

GSD Type VII Phosphofructokinase Muscle, erythrocytes

Tarui's disease