Other IEMs

Homocystinuria³

What causes homocystinuria?

Homocystinuria is an inherited disorder, caused by a faulty gene. It is very rare. Around one in 100,000 babies born in Australia and New Zealand has homocystinuria. However, some will not develop any symptoms until adulthood, and some are not able to be diagnosed by newborn screening tests, so this means that only one or two babies a year are diagnosed with homocystinuria.

For a child to inherit homocystinuria, both parents must carry the faulty gene. Boys and girls have an equal chance of inheriting homocystinuria.

People with homocystinuria are born with a deficiency of an enzyme called cystathionine beta-synthase. This is one of the enzymes needed to process an amino acid called methionine, found in foods containing protein.

Because people with homocystinuria can’t process methionine adequately, levels of the amino acid methionine and its product homocystine build up in the blood. High levels of homocystine damage the body. People with homocystinuria still need methionine, but only a small amount.

How homocystinuria is detected?

All babies born in Australia and New Zealand are tested for homocystinuria soon after birth, usually on the second or third day, as part of the newborn screening heel prick test. If the results are high, more tests are done to confirm that the baby has homocystinuria. This newborn screening test for homocystinuria has only recently been introduced in Australia and New Zealand, so children born before screening started will be diagnosed when symptoms suggest to the doctor that the person has the disorder. The newborn screening test is also unlikely to detect babies with the form of homocystinuria which responds to vitamin B6.

Treatment

The treatment of each person with homocystinuria will vary. About half of all people with the disorder respond well to large doses of vitamin BB 6 (pyridoxine), and the biochemical changes in the blood return to normal. Babies, children and adults not responsive to vitamin B6 need another medication (betaine) and a low protein diet. Most will also need treatment with other vitamins known as folic acid and vitamin B12.

Maple Syrup Urine Disease (MSUD)⁴

What causes MSUD?

MSUD is an inherited disorder, caused by a faulty gene. It is very rare. Around one in 150,000 babies born in Australia and New Zealand has MSUD. This means that only one or two babies a year are diagnosed with it.

For a child to inherit MSUD both parents must carry the faulty gene; boys and girls have an equal chance.

People with MSUD are born with a deficiency of an enzyme in the liver and muscles called the branched chain alpha-keto acid dehydrogenase complex. This is needed to process amino acids called leucine, isoleucine and valine, found in foods containing protein.

How MSUD is detected?

All babies born in Australia and New Zealand are tested for MSUD soon after birth, usually on the second or third day, as part of the newborn screening heel prick test. If the results are high, further tests are done to confirm that the baby has MSUD. Sometimes babies with the classical form of MSUD are already unwell by the time the result is available, and this result allows appropriate management to be started quickly.

Treatment

MSUD is treated with a low protein diet and a nutritional supplement, both of which need careful monitoring. Regular blood tests to measure the leucine, isoleucine and valine levels and regular clinic visits are part of the treatment. People with MSUD can’t break down the large amount of leucine, isoleucine and valine in protein foods, so the amount of protein in the diet is restricted. A special formula or supplement replaces some of the protein, minerals and vitamins that would normally be in the diet. The supplement contains all the amino acids except leucine, isoleucine and valine. The amount of protein tolerated and other nutrients will come from food.

Tyrosinaemia Type I & Type II⁶

What causes tyrosinaemia?

Tyrosinaemia is an inherited disorder, caused by a faulty gene. It is very rare. Only one or two babies a year are diagnosed with tyrosinaemia in Australia and New Zealand.

For a child to inherit tyrosinaemia both parents must carry the faulty gene; boys and girls have an equal chance.

People with tyrosinaemia are born with a deficiency of one of the enzymes involved in the breakdown of tyrosine in the body. Tyrosine is an amino acid, found in foods containing protein.

Tyrosinaemia type 1 and tyrosinaemia type 2 are caused by deficiency of different enzymes:

Tyrosinaemia type 1 is caused by deficiency of the enzyme fumarylacetoacetase (sometimes called fumarylacetoacetate hydrolase) and, if untreated, damages the liver and kidneys and brain which can result in liver failure or cancer and death during childhood.

Tyrosinaemia type 2 (sometimes called Richner-Hanhart syndrome) is caused by deficiency of the enzyme tyrosine aminotransferase. If untreated crystals of tyrosine build up in the eyes causing painful inflammation. High tyrosine levels also cause a build up of skin tissue (callouses) on the palms of the hands and soles of the feet. There have also been some reports in the medical literature of slow intellectual development in some children, but this has not been the case in any patients seen in Australia.

How tyrosinaemia is detected?

All babies born in Australia and New Zealand are tested for tyrosinaemia soon after birth, usually on the second or third day, as part of the newborn screening heel prick test. If the results are high, more tests are done to confirm that the baby has tyrosinaemia and which type. Type 2 is easily detected by these tests but at the moment it is not possible to guarantee that all cases of tyrosinaemia type 1 will be detected. Testing for tyrosinaemia has only recently been introduced in Australia and New Zealand, so children born before the start of screening will not have been tested at birth. Diagnosis in other babies, children or adults occurs when symptoms suggest to the doctor that the person has tyrosinaemia. Some newborn babies with severe forms of tyrosinaemia type 1 can become very sick, very quickly. As soon as the diagnosis is made, treatment will be started. The baby will be given a special formula, also called a supplement, to lower the tyrosine to a safe level, and medications if needed.

Treatment

The treatment for Tyrosinaemia Type 1 is treated with a medication called NTBC and a special diet. NTBC blocks an enzyme higher up in the tyrosine breakdown chain than the block in tyrosinaemia type 1. This stops the build up of harmful metabolites that damage the liver, kidneys and brain. NTBC does not lower tyrosine levels so a diet low in tyrosine and phenylalanine is needed to prevent the potential damage caused by high tyrosine levels. NTBC, particularly if started early, greatly reduces the risk of early development of liver cancer – whether it does in the long term is not yet known. It seems to be a safe treatment with side effects not being described at the time of writing. Before the introduction of NTBC a liver transplant was the only effective treatment for tyrosinaemia type 1, as diet alone improved the child’s health but did not prevent the liver cancer.

Tyrosinaemia type 2 can be successfully treated with a diet low in tyrosine and phenylalanine. NTBC is not effective in tyrosinaemia type 2 as the block in type 2 is before NTBC’s point of action.

Urea cycle disorders⁷

Carbamyl phosphate synthetase (CPS) deficiency, N-acetylglutamate synthetase (NAGS) deficiency, Ornithine transcarbamylase (OTC) deficiency, Arginosuccinicaciduria, Arginase deficiency, Arginosuccinic acid synthetase (Citrullinaemia type 1)

What causes a urea cycle disorder?

Urea cycle disorders are inherited disorders, caused by faulty genes. These disorders are very rare. Around one in 50,000 babies born in Australia and New Zealand has a urea cycle disorder.

People with urea cycle disorders are born with a deficiency of one of a group of enzymes in the liver needed to process protein

Three urea cycle disorders may be detected: argininosuccinnate synthase deficiency (citrullinaemia) and argininosuccinnate lyase deficiency (argininosuccinic aciduria) in which blood citrulline levels are high, and some cases of ornithine transcarbamylase (OTC) deficiency, where citrulline levels are very low.

People with urea cycle disorders cannot make urea properly so levels of other nitrogen products, including ammonia, build up in the blood and damage the brain. People with urea cycle disorders still need protein, but in smaller amounts.

How urea cycle disorders are detected?

All babies born in Australia and New Zealand are tested for some of the urea cycle disorders soon after birth. However not all of the urea cycle disorders can be detected in this way. The test is usually done on the second or third day, as part of the newborn screening heel prick test. If the results are abnormal, more tests are done to confirm that the baby has the disorder. Babies with a severe form of a urea cycle disorder are usually already unwell by the time the result is available, and this result allows appropriate management to be started quickly. The newborn screening test for some of the urea cycle disorders has only recently been introduced in Australia and New Zealand so that most children and adults will not have been tested at birth. Some babies and children will be diagnosed because of a family history of the disorder. For many babies, children and adults with urea cycle disorders, diagnosis is made when there are symptoms that suggest to the doctor that the person may have the disorder. This can happen at any age because the effects of these disorders can range from severe to mild. As soon as the diagnosis is suspected, treatment will be started to lower levels of ammonia and other harmful metabolites in the blood.

Treatment for urea cycle disorders

Urea cycle disorders are treated with a low protein diet and medications, which need careful monitoring. Regular blood tests and regular attendance at the Metabolic Clinic are part of the treatment. Some children with severe urea cycle disorders will benefit from a liver transplant. The medications used to treat urea cycle disorders can act by removing nitrogen in other ways. This helps reduce the levels of harmful metabolites such as ammonia. People with urea cycle disorders can’t break down large amounts of protein properly, so the amount of protein in the diet is restricted. A special protein supplement or vitamin and mineral supplements may be necessary to obtain the nutrients needed for a balanced diet.

Organic acidurias⁵

Organic acidaemias Glutaric aciduria type 1, Isovaleric acidaemia, Methylmalonic acidaemia, Propionic acidaemia, Holocarboxylase synthetase deficiency.

What causes an organic acid disorder?

Organic acid disorders are inherited disorders, caused by faulty genes. These disorders are very rare. About one in 50,000 or 60,000 babies born in Australia and New Zealand has one of the organic acid disorders. This means that only five to six babies a year are diagnosed.

For a child to inherit one of these organic acid disorders, both parents must carry the faulty gene; boys and girls have an equal chance.

People with organic acid disorders are born with a deficiency of one of a group of enzymes needed to process protein.

How organic acid disorders are detected?

All babies born in Australia and New Zealand are tested for these organic acid disorders soon after birth, usually on the second or third day, as part of the newborn screening heel prick test. If the results are abnormal, further tests are done to confirm that the baby has the disorder. Sometimes babies with positive results are well, so parents do not suspect there is any problem. Others may be unwell by the time the result is available, and this result allows appropriate management to be started quickly. The newborn screening test may not detect some cases. Testing for these disorders has also only recently been introduced in Australia and New Zealand so that older children and adults will not have been tested at birth. Some babies and children will be diagnosed because of a family history of the disorder. Others will be diagnosed when symptoms suggest to the doctor that the person may have the disorder. This can happen at any age. Those people with severe conditions are more likely to become ill as newborn babies, milder forms of the disorders may not become apparent until later in childhood.

Treatment

Organic acid disorders are treated with a low protein diet and medications, both of which need careful monitoring. Regular blood tests and clinic visits are part of the treatment. Some children with severe forms of MMA or PA will benefit from a liver transplant.