MNGIE: TYMP gene, thymidine phosphorylase deficiency and care in the UK

MNGIE is a rare mitochondrial condition. The NHS Rare Mitochondrial Disorders Service explains that it is due not to a defect in mitochondrial DNA itself but to a defect in an enzyme called thymidine phosphorylase. This distinguishes it from conditions such as MERRF or MELAS, which are caused by changes in mitochondrial DNA and inherited through the mother.

The European Medicines Agency summary of an orphan designation describes the sequence of events. Without enough thymidine phosphorylase, the compound thymidine cannot be broken down and builds up in cells, where it damages mitochondrial DNA. The disruption of mitochondrial DNA leads to the symptoms, although the exact way in which this happens is not known.

The name describes the main features: mitochondrial, neuro (nerves), gastrointestinal (gut) and encephalomyopathy (disease of the brain and muscle).

A UK research summary published by the Health Research Authority names the TYMP gene as the gene that codes for thymidine phosphorylase. The summary explains that the enzyme is responsible for breaking down thymidine and deoxyuridine and that, when it is missing, these accumulate and damage mitochondrial DNA.

The NHS service says the pattern of inheritance is autosomal recessive. Both parents carry one faulty copy and usually have no symptoms. In each pregnancy of two carriers there is a 25 per cent chance that the child inherits two changed copies and has the condition, a 50 per cent chance of being a carrier like the parents, and a 25 per cent chance of inheriting two normal copies.

Because inheritance is autosomal recessive, brothers and sisters of an affected person have a chance of being affected or being carriers, and genetic counselling is offered to families so that they can understand their own risks and options.

The NHS service says MNGIE presents predominantly either with disturbances of bowel function or with weakness that is largely due to damaged nerve supply. It can be quite variable in severity, with some people developing severe disease early in life and others developing symptoms much later. The disturbance of bowel function can be severe, as can the muscle weakness, and these are usually the main symptomatic issues.

The European regulator's summary lists the digestive problems as nausea, abdominal pain, diarrhoea and weight loss, and the nervous system effects as weakness, numbness and tingling. It says symptoms can appear at any time from birth but usually start during the second decade of life, and worsen with time.

The NHS service adds that approximately 10 per cent of people may develop cognitive problems. The research summary notes that the condition leads to nutritional failure and muscular disability. The service notes more generally that mitochondrial conditions often mimic other conditions, which can delay diagnosis.

According to the NHS service, the diagnosis of MNGIE is made by measuring thymidine levels in the blood and urine. This is often then confirmed by direct measurement of the enzyme thymidine phosphorylase and by genetic confirmation of the changes in the gene.

The wider diagnostic approach for mitochondrial disease, as set out by the service, includes blood and urine tests, lumbar puncture in children, muscle biopsy and brain imaging with MRI. It stresses that mitochondrial conditions mimic other diseases, which can lead to delay, and that identifying the genetic cause can be like searching for a needle in a haystack.

Diagnosis is therefore usually made or confirmed in a specialist centre. The NHS Highly Specialised Service for Rare Mitochondrial Disorders has centres in London, Newcastle and Oxford.

The NHS service says that at present the condition remains very difficult to treat, but that discussion with specialists in mitochondrial disease is important so that treatment can be considered at an early stage. It adds that research is continuing and that people with the condition may be asked to take part in clinical trials if they feel this would be helpful.

The European regulator notes that at the time of its designation no satisfactory methods had been authorised in the EU for treatment, and that patients were given treatments to help with their symptoms. The Health Research Authority record describes a UK multi-centre, open-label study led from St George's University of London of erythrocyte-encapsulated thymidine phosphorylase, in which the missing enzyme is put inside the person's own red blood cells and given back by infusion. The record states there are no specific treatments for MNGIE whose effectiveness has been evidenced in clinical studies.

Because the study was approved in 2019 and the record is a research summary, it should not be read as an approved treatment. Anyone interested in trials should discuss the current position with their specialist team.

The NHS service's general advice for people with mitochondrial disease applies. It recommends avoiding fasting and dehydration during minor illnesses, taking part in activity at a comfortable level, telling the anaesthetist about the diagnosis before any operation, and checking medicines against the published list of drugs to be used with caution in primary mitochondrial disease.

The service says general anaesthesia carries no specific risk, but the anaesthetist needs to know about the diagnosis because some patients need extra assessment of breathing, swallowing or heart function, and the specialist should be told as early as possible before a planned operation.

Benefits, employment rights and education support are also covered on the service's general advice pages, and a GP or specialist can help with applications.