INBORN ERROR OF METABOLISM

Migmar Tsamchoe

An inherited enzyme deficiency leading to the disruption of normal bodily metabolism

Accumulation of a toxic substrate (compound acted upon by an enzyme in a chemical reaction)

Impaired formation of a product normally produced by the deficient enzyme

Inborn Errors of Metabolism

IEM as a group are not rare: occur 1 in 5000 births collectively

Often treatable if diagnosed Most difficult task for clinician is to know

when to consider IEM and which tests to order for evaluation

Inborn Errors of Metabolism

Every child with unexplained . . . ◦ Neurological deterioration◦ Metabolic acidosis◦ Hypoglycemia◦ Inappropriate ketosis◦ Hypotonia◦ Cardiomyopathy◦ Hepatocellular dysfunction◦ Failure to thrive

. . . should be suspected of having a metabolic disorder

Garrod’s hypothesis

A B C product

deficiency substrate excess D toxic

metabolite

What is a metabolic disease?

Disorders of: Amino acids Carbohydrates Fatty acid Lysosomal and peroxisomal function Mitochondrial Organic acids

Categories of IEM

Phenylketonuria is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional. This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine. When PAH activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which can be detected in the urine.

Phenylketonuria  (PKU)

PHENYLALANINE HYDROXYLASEPHENYLALANINE

Dietry sources, particularly plant proteins

BODY PROTEINS

BREAKDOWN

(b)

(a)

The normal metabolism of phenylalanine (pathways a and b)

TYROSINE

HYDROXYPHENYLACETIC ACID

PHENYLACETIC ACID*

(c)

(c)

The abnormal metabolism in phenylketonuric subjects (pathway c)

PHENYLALANINE*

Dietry sources, particularly plant proteins

BODY PROTEINS

(b)

(a)

PHENYLALANINE HYDROXYLASE

How do people get PKU?

Babies born with PKU usually have no symptoms at first.

But if the disease is left untreated, babies experience severe brain damage.

This damage can cause epilepsy, behavioral problems, and stunt the growth of the baby.

Other symptoms include eczema (skin rash), a musty body odor (from too much phenylalanine), a small head (microcephaly), and fair skin (because phenylalanine is necessary for skin pigmentation).

SYMPTOMS

SYMPTOMS

PREGNANCY (PKU) It is recommended that women with PKU

who are of child bearing age, closely adhere to the low-phenylalanine levels before conception and throughout pregnancy. The risk of miscarriage, mental retardation, microcephaly, and congenital heart disease in the child is high if the mother’s blood phenylalanine is poorly controlled.

Because PKU must be treated early, babies are routinely tested for the disease. A small blood sample is taken from the baby's heel or arm and checked in a laboratory for high levels of phenylalanine.

How do doctors diagnose PKU?

People who have PKU must eat a very low-protein diet, because nearly all proteins contain phenylalanine. Infants are given a special formula without phenylalanine.

Older children and adults have to avoid protein-rich foods such as meat, eggs, cheese, and nuts. They must also avoid artificial sweeteners with aspertame, which contains phenylalanine.

How is PKU treated?

Galactosemia is a rare disorder that affects the body's ability to break down a food sugar called galactose (found in milk and other dairy products).

The body breaks down lactose into galactose and glucose and uses these sugars for energy. Most people with galactosemia are missing an enzyme (called GALT) that helps further break down galactose. Defects in galactose metabolism cause toxic chemicals to build up in cells of the body.

Autosomal recessive mode of inheritance.

What is Galactosemia?

Metabolism of lactose

Signs and SymptomsEarly symptoms may include: Jaundice(yellowing) of the skin and whites

of the eyesVomitingPoor weight gainLow blood sugar Feeding difficulties IrritabilityLethargyConvulsions

How do people get galactosemia?

Defects in galactose metabolism can cause several severe symptoms, including kidney failure, an enlarged liver, cataracts (clouding of the eye lens), poor growth, and intellectual disability.

What are the symptoms of galactosemia?

Using a tiny blood sample taken from the baby's heel, the test checks for low levels of the GALT enzyme. This allows for prompt treatment, which can substantially prevent the serious symptoms of this disorder.

For those families with a history of the disorder, a doctor can determine during a woman's pregnancy whether her baby has galactosemia (1) by taking a sample of fluid from around the fetus (amniocentesis), or (2) by taking a sample of fetal cells from the placenta (chorionic villus sampling or CVS).

How do doctors diagnose galactosemia?

Galactosemia occurs in about 1 in 50,000 births, mainly Caucasians.

Facts

This is a pedigree showing the transmission of galactosemia.

• The only way to treat galactosemia is through dietary restrictions.

• People with the disorder must stay away from foods and drinks containing galactose, including milk, cheese, and legumes(dried beans).

• Any other foods that contain milk or milk products. • They must follow this diet for their entire lives. • Galactosemia is treated with a modified diet. • This diet is called the galactose restricted diet. • It can help prevent severe damage from occurring

to the brain, eyes, liver, and kidneys.

How is galactosemia treated?