Dr. Samah Kotb Nasr Eldeen Lecturer of Biochemistry Cellular Biochemistry and Metabolism (CLS 333 ) Inborn Errors of Metabolism (IEM)

Introduction

Comprise a group of disorders in which a single gene defect causes a clinically significant block in a metabolic pathway resulting either in accumulation of substrate behind the block or deficiency of the product. Inborn Errors of Metabolism (IEM)

All IEMs are all genetically transmitted typically in an autosomal recessive or X-linked recessive fashion.

Examples of Inborn errors of metabolism

1. Phenyl ketonuria It is most common hereditary disorder of phenylalanine metabolism and indeed of all amino acids.

It is due to a defect in the formation of phenyl alanine hydroxylase enzyme as a result phenyl alanine is diverted into its minor pathway and large amounts of phenyl pyruvate, phenyl lactate, phenyl acetate, phenyl acetyl glutamine and even phenyl alanine itself are excreted in the urine.

The plasma phenylalanine level is increased and principle clinical symptoms are mental retardation and convulsion.

Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. 2. Maple syrup urine disease

The condition gets its name from the distinctive sweet odor of affected infants' urine and is also characterized by poor feeding, vomiting, lack of energy (lethargy), and developmental delay.

If untreated, maple syrup urine disease can lead to seizures, coma, and death.

Causes the urine and sweat to smell like maple syrup. Plasma and urine levels of all branched chain amino acids and their corresponding α keto acids are increased far above normal.

The biochemical defect is the lack of the α keto acid decarboxylase.

Intermittent branched chain ketonuria is a variant of maple syrup urine disease in which the α keto acids decarboxylase deficiency is much less severe.

3. Galactosemia Is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Galactose

Galactosemia follows an autosomal recessive mode of inheritance that confers a deficiency in an enzyme responsible for adequate galactose degradation.

Diagnosis Infants are routinely screened for galactosemia in the United States, and the diagnosis is made while the person is still an infant. Infants affected by galactosemia typically present with symptoms of lethargy, vomiting, diarrhea and jaundice.

None of these symptoms are specific to galactosemia, often leading to diagnostic delays. Luckily, most infants are diagnosed on newborn screening.

If the family of the baby has a history of galactosemia, doctors can test prior to birth by taking a sample of fluid from around the fetus (amniocentesis) or from the placenta (chorionic villus sampling or CVS).

A galactosemia test is a blood test (from the heel of the infant) or urine test that checks for three enzymes that are needed to change galactose sugar that is found in milk and milk products into glucose, a sugar that your body uses for energy.

A person with galactosemia doesn't have one of these enzymes. This causes high levels of galactose in the blood or urine.

Treatment The only treatment for classic galactosemia is eliminating lactose and galactose from the diet. Even with an early diagnosis and a restricted diet, however, some individuals with galactosemia experience long- term complications such as speech difficulties, learning disabilities, neurological impairment (e.g. tremors, etc.), and ovarian failure in females.

Galactosemia is sometimes confused with lactose intolerance, but galactosemia is a more serious condition. Lactose intolerant individuals have an acquired or inherited shortage of the enzyme lactase, and experience abdominal pains after ingesting dairy products, but no long-term effects. In contrast, a galactosemic individual who consumes galactose can cause permanent damage to their bodies.

Long term complication of galactosemia includes: Speech deficits Ataxia Dysmetria Diminished bone density Premature ovarian failure Cataract

4. Hereditary fructose intolerance Is an inborn error of fructose metabolism caused by a deficiency of the enzyme aldolase. Individuals affected with HFI are asymptomatic until they ingest fructose, sucrose, or sorbitol. If fructose is ingested, the enzymatic block at aldolase causes an accumulation of fructose- 1-phosphate.

This accumulation has downstream effects on gluconeogenesis and regeneration of adenosine triphosphate (ATP).

Symptoms of HFI include vomiting, hypoglycemia, jaundice, hemorrhage, hepatomegaly, hyperuricemia and potentially kidney failure. Symptoms

While HFI is not clinically a devastating condition, there are reported deaths in infants and children as a result of the metabolic consequences of HFI. Death in HFI is always associated with problems in diagnosis.

HFI is typically suspected based on dietary history, especially in infants who become symptomatic after breast feeding. This suspicion is typically confirmed by molecular analysis. Treatment of HFI is based around strict avoidance of fructose in the diet. Older patients with HFI typically self-select a diet low in fructose, even before being diagnosed.

Characteristics The key identifying feature of HFI is the appearance of symptoms with the introduction of fructose to the diet. Affected individuals are asymptomatic and healthy, provided they do not ingest foods containing fructose or any of its common precursors, sucrose and sorbitol. In the past, infants often became symptomatic when they were introduced to formulas that were sweetened with fructose or sucrose.

Symptoms such as vomiting, nausea, restlessness, pallor, sweating, trembling and lethargy can also first present in infants when they are introduced to fruits and vegetables. These can progress to apathy, coma and convulsions if the source is not recognized early.

When patients are diagnosed with HFI, a dietary history will often reveal an aversion to fruit and other foods that contain large amounts of fructose. Most adult patients do not have any dental caries.

Fructose metabolism After ingestion, fructose is converted to fructose-1- phosphate by the liver by fructokinase. Deficiencies of fructokinase cause essential fructosuria, a clinically benign condition characterized by the excretion of unmetabolized fructose in the urine. Fructose-1- phosphate is metabolized by aldolase into dihydroxyacetone phosphate and glyceraldehyde. HFI is caused by a deficiency of aldolase.

A deficiency of aldolase results in an accumulation of fructose-1- phosphate, and trapping of phosphate (fructokinase requires adenosine triphosphate (ATP). The downstream effects of this enzyme block are the inhibition of glucose production and reduced regeneration of ATP.

Diagnosis Because of the ease of therapy (dietary exclusion of fructose), HFI can be effectively managed if properly diagnosed. In HFI, the diagnosis of homozygotes is difficult, requiring a genomic DNA screening with allele specific probes or an enzyme assay from a liver biopsy.

Treatment Treatment of HFI depends on the stage of the disease, and the severity of the symptoms. Stable patients without acute intoxication events are treated by careful dietary planning that avoids fructose and its metabolic precursors. Fructose is replaced in the diet by glucose, maltose or other sugars. Management of patients with HFI often involves dietitians who have a thorough knowledge of what foods are acceptable.

5. Multiple carboxylase deficiency  Multiple carboxylase deficiency is a form of metabolic disorder involving failures of carboxylation enzymes.  The deficiency can be in biotinidase or holocarboxylase synthetase.  These conditions respond to biotin.

Forms include: 1) Holocarboxylase synthetase deficiency - neonatal; 2) Biotinidase deficiency - late onset;

If left untreated, the symptoms can include feeding problems, hypotonia, generalized erythematous rash with skin exfoliation and alopecia, seizure, coma, developmental delay, foul smelling urine, metabolic acidosis, ketosis and hyperammonemia.

1. Blood levels of lactic acid are normally less than 1.2 mM. In lactic acidosis, the values for blood lactate may be 5 mM or more. 6. Lactic acidosis

2. T he high concentration of lactate results in lowered blood PH and bicarbonate levels. 3. High blood lactate levels can result from increased formation or decreased utilization of lactate.

4. Tissue anoxia may occur in shock and other conditions that impair blood flow, in respiratory disorders, and in severe anemia.