Inborn errors of metabolism: diagnosis and treatment

Investigators at UCL have developed new diagnostic tests, new treatments and new methods for monitoring treatment of inborn errors of metabolism. Certain of these tests are now used to screen all newborns in the UK, all infants with liver disease and all infants with drug-resistant epilepsy. This is improving outcome for more than 120 UK children per year. For untreatable disorders, prenatal tests prevent the birth of a second affected child in the family.

Inborn errors of metabolism are genetic disorders where a defective protein disturbs an important metabolic pathway. They are individually rare but collectively common diseases, and can cause a very wide range of symptoms and signs, from liver disease to convulsions to movement disorders to loss of consciousness on fasting.

Researchers at the UCL Institute of Child Health have investigated these conditions in depth over the last 30 years, resulting in new diagnostic tests, new treatments and new methods for monitoring treatment. Highlights of the research in five key disorders are presented below.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare genetic condition in which a person has problems breaking down fatty acids for energy. It affects around 1 in 10,000 babies born in the UK each year, and is life threatening if not discovered early, as a drop in an affected baby's blood sugar levels can result in severe illness or death. In 1998, working with Micromass UK Ltd, researchers developed an automatable method for screening for this disorder. A pilot study was then carried out by the MRC Centre of Epidemiology for Child Health at the UCL Institute of Child Health. This pilot study showed good results, and so MCADD screening was adopted in England in 2009 and Wales in 2012 using these methods. Since screening began, around 60 lives have been saved and around 60 cases of long-term disability prevented.

Fabry disease is a rare lysosomal storage disorder, affecting around 1 in 58,000 individuals. The condition has serious complications including severe neuropathic pain, renal failure, cardiomyopathy and coronary artery disease, and strokes. Patients often die prematurely as a result of these complications. In 2002 researchers developed a new way of monitoring enzyme replacement therapy in the disease. This method is now the gold standard test for the screening and monitoring of enzyme replacement throughout the UK and worldwide. The researchers are commissioned to test urine samples from patients receiving enzyme replacement therapy by one of the companies producing the enzyme (Genzyme). Between 2008 and 2013 they analysed 760 samples per year.

The group's diagnostic tests and new treatments for movement disorders are now in use in clinical practice. It was the first to show, in 1993, that parkinsonism/dystonia in infants can be caused by a disorder affecting the synthesis of dopamine (aromatic amino acid decarboxylase [AADC] deficiency). New treatments have been developed by this group and others which build on this early work, and diagnostic tests are now available. Researchers have also shown that dystonia in older children can be caused by a disorder leading to the build-up of manganese in the brain, and found the gene responsible for the manganese disorder, thereby providing a genetic test. With proper diagnosis available, this disorder can be effectively treated with a manganese chelator and iron supplementation.

Research on epilepsy has resulted in new diagnostic tests and better treatment for infants and children now in use. In 2005 the group identified the genetic defect responsible for a severe form of epilepsy in infancy which it had previously shown could be treated effectively with pyridoxal phosphate (the active form of vitamin B6). In 2006 the group showed that severe seizures in the newborn that respond to treatment with pyridoxine (another form of vitamin B6) could be due to another genetic defect (antiquitin deficiency). It now performs diagnostic tests on over 200 urine samples and around 50 DNA samples per year, sent by paediatricians looking after infants and children with severe epilepsy around the country.

The group has shown that liver disease in infancy and neurological disease in older children and adults can be caused by disorders of bile acid synthesis and that these disorders can respond extremely well to bile acid replacement therapy. Without these treatments children can progress to cirrhosis and liver failure, and may require a liver transplant, or die. Over the last five years, around 24 lives have been saved or transplants avoided.

AADC Deficiency is a complex autosomal recessive brain disease causing severe multiple disabilities. The diagnostic tests established by this work have markedly reduced the delays in achieving a diagnosis for an affected child. This is greatly appreciated by our families, not just in the UK but Worldwide, as an earlier diagnosis can lead to a better clinical outcome. The ongoing research is providing real hope for us with regards to the development of effective treatments for our children. - Lisa Flint, mother of a child with AADC and founder of the AADC Research Trust

Funding from Great Ormond Street Hospital Children's Charity, NIHR (Biomedical Research Centre), Wellcome Trust, Genzyme Corporation, Birth Defects Foundation, Medical Research Council, Children's Liver Disease Foundationand EPSRC/DTI Link.

Related links

• Epilepsy and vitamin B6 treatment at Great Ormond Street Hospital
• AADC Research
• AADC Research video
• Publications documenting discovery of the disease and possible treatment