Dr. Samah Kotb Nasr EldeenLecturer 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 deficitsAtaxiaDysmetriaDiminished bone densityPremature ovarian failureCataract

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 5mM or more.

6. Lactic acidosis

2. The 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.