Why is NH3 poisonous for our body

Urea cycle defects: when ammonia poisons the body

Little Veronika M. never whines at the supermarket checkout. And her parents would be happy sometimes if she begged for a big burger or the latest candy bar. But Veronika is almost always "fat". The 6-year-old girl suffers from the OTC defect, the most common form of urea cycle defects.

Genetically determined metabolic disorder

The OTC defect (ornithine transcarbamylase deficiency) is by no means a widespread disease. The urea cycle defects belong to the "orphan" diseases: diseases that occur extremely rarely, so that these "orphans of medicine" are not taken care of by a large pharmaceutical company.

The research and marketing of such drugs is uneconomical due to the rarity of the diseases. For example, "only" about 1 in 10,000 children is affected by urea cycle defects. The disease often shows up in the newborn because - like most orphan diseases - it is based on a genetic metabolic disorder. Since the disease occurs so rarely, many medical professionals are not even aware of it. It can happen that doctors - in practice as well as in clinic - are never confronted with this condition during their entire professional life.

The long road to diagnosis and therapy

It also took Veronika over 6 months before her serious illness was properly diagnosed and treated. The first symptoms became apparent at 9 months of age. After Veronika no longer breastfed - and was thus fed with a higher protein diet - she repeatedly fell ill with otitis media and other febrile infections. She had severe insomnia and vomited at night. The pediatrician, who was visited several times a week, and the antibiotics administered by him, could not help Veronika. The toddler had to undergo inpatient antibiotic therapy without her health improving.

On St. Nicholas Day 1995, Veronika suffered her first serious metabolic derailment. She was apathetic, even passed out for a short time. The desperate parents were turned away that Wednesday afternoon from two hospitals that do not treat children. No one was able to give the M. family any hints as to whom they could turn to with their seriously ill child.

Ultimately, they drove to a children's clinic, where a simple blood test was used to diagnose an OTC defect and treatment was started. The ammonia content in the blood of little Veronica was then 500 mmol / liter. (In healthy children the value is between 26 and 47 mmol / liter.) A total of 5 days passed from the derailment to the appropriate therapy. In the following year, the little girl's condition was still very unstable, so that even the slightest infection resulted in hospitalization.

A normal child's life?

Family B. does not have everyday life. The Veronika family has to keep her busy every day, motivating her so that she does not withdraw into herself and the illness gains the upper hand. In order to get Veronika to eat and take the numerous medications, incentives must be created constantly. 95% of the time the girl who never feels hungry is fed. In most cases, going without a meal leads to a crisis the very next day.

Medication training plan

In the case of urea cycle defects, in particular, an optimal energy supply must be guaranteed in order to prevent a renewed metabolic derailment. Every weight loss and every infection can result in a life-threatening crisis. This means that the sick child's menu must contain hardly any protein, but a lot of fat, carbohydrates and fluids. For example, Veronika's standard breakfast includes 70 g of cream and 30 to 40 g of maltodextrin with every lunch. So that their daughter does not lose her sense of taste when taking the medication, the parents pack the various medicines in capsules. They have had a machine made for this, with the help of which they can fill a particularly large amount of the substances into the individual capsules. In total, Veronika swallows 44 of the giant capsules throughout the day, sometimes up to 15 at a time. This means that she needs 10 hours a week to take medication alone; and that after her parents have taught her, with a lot of love and patience, how to take medication according to a regular training plan - from the smallest tablet to the extra-large capsule.

The right drug therapy, tailored precisely to the respective severity of the disease - above all with sodium phenylbutyrate (ammonaps) - is vital in the case of urea cycle defects. With this substance, ammonia can be "captured" in a very targeted manner and then excreted with the urine.

Symptoms in the first days of life

Jonas showed the first symptoms of the OTC defect a week after the birth. The boy refused to eat, vomited frequently, was permanently sleepy, and showed unusual moans. Various attempts at therapy failed. It was only after three weeks that the greatly increased ammonia content in Jonas' blood was found in a children's clinic. A metabolism expert from a university clinic gave the treatment strategy over the phone. A taxi picked up the relevant medication from the clinic pharmacy, so that the ammonia level fell to normal in the following days. After two weeks, Jonas was able to leave the hospital.

In order to ensure the high-calorie diet and the intake of medication at home, little Jonas was given a nasogastric tube at the age of 4 months, until at the age of 5 he voluntarily switched to bad-tasting special food and swallowed the numerous, often bitter-tasting medications . In the first five years of his life he still had to be hospitalized about 3 times a year because of severe metabolic disorders. Due to these critical metabolic situations and the associated ammonia poisoning, Jona's development roughly corresponds to that of children three years younger. His fine and gross motor skills as well as the ability to concentrate are impaired, so that the happy boy attends the special school.

Burden for the whole family

Jonas and Veronika are certainly among those children with urea cycle defects who were lucky. But even if Jonas romps outside with his father or Veronika plays with her friends, this cannot hide the enormous stress that the urea cycle defect brings with it for the whole family. Because when Jonas and Veronika are raging, they can never do it unsupervised. After all, fluids and food must be kept ready at all times in order to immediately replace the energy used up while playing. In addition, there is the pressure that parents have to exert on their children again and again so that the little ones consume the right food and medication. Sometimes the only thing that helps is blackmail or the warning of death - an immeasurable burden on the parent-child relationship.

Box text: Therapy is often much too late

Sodium phenylbutyrate is currently the drug of choice for treating urea cycle defects. There is also hope that even more effective treatments in the form of enzyme replacement and gene therapy will become available in the long term.

A definitive healing of the urea cycle defects is at the moment - as with all genetic defects - not yet possible. However, awareness of these rare diseases and the fastest possible diagnosis and therapy can save those affected and their families a lot of suffering.

Box text: Dangerous ammonia poisoning

In the case of urea cycle defects, the protein metabolism is disturbed. The body needs protein in order to gain energy from it or to form other important building blocks. To do this, however, the protein must first be broken down into smaller components with the help of enzymes. This creates ammonia. However, ammonia is poisonous, so it has to be processed quickly. Ammonia detoxification takes place in the liver. There the ammonia is converted into odorless urea and excreted through the kidneys. The detoxification of the ammonia takes place in several steps in a kind of roundabout - hence the name "urea cycle". These breakdown processes are regulated by enzymes. If there is a disorder of the urea cycle, one of the enzymes is missing or it is not working properly. The detoxification of the ammonia in the liver does not take place at all or not completely. This leads to an inundation of tissues and blood from the toxic ammonia.

Box text: Multiple symptoms

The symptoms can appear in very different and varied forms. Some typical signs of urea cycle defects are:

  • Drinking weakness (in infants)
  • Moaning (in infants)
  • repeated vomiting
  • Periods of lack of attention
  • Impaired consciousness
  • unsafe movements (ataxia)
  • Developmental disorders
  • apathy
  • lethargy
  • central nervous symptoms up to coma
  • Cerebral hemorrhage
  • Liver and kidney failure.

If a urea cycle defect is suspected, drug treatment must be started immediately before diagnosis. Time is the most important factor in avoiding brain damage. The patient's condition often deteriorates at a rapid pace, so that by the time the diagnosis is made, they are already in a coma.

Box text: Exemplary newborn screening in Bavaria

Often the urea cycle defect is not diagnosed until after the death of an infant. Urea cycle defects often become noticeable on the second day of the newborn's life. If the diagnosis and treatment are not started immediately, the child will die. Even a simple blood test after the birth enables the correct diagnosis and therapy. Bavaria is a role model here, as it is the only federal state that has introduced nationwide screening for newborns.