What Effect of Urea Cycle Abnormality and OTC Deficiency?

What is that?

Urea cycle diseases are diseases characterized by the abnormal accumulation in the body of toxic compounds resulting from the breakdown of proteins . They can appear at any age, mainly through neurological disorders and digestive disorders. Their treatment is mainly based on an extremely strict diet, which must be started as early as possible and continued for life.

Why?

Breaking down the protein we eat releases nitrogen, which circulates in our blood as ammonia, which is then transformed into urea to be eliminated in the urine. The transformation of ammonia into urea takes place in the liver cells via a set of six enzymes which constitute the “urea cycle”. If one of the enzymes is faulty, i.e. absent or functionally ineffective, ammonia accumulates and its concentration increases in the blood. The signs and symptoms of the disease then appear, either suddenly or insidiously.

A deficiency is described for each urea cycle enzyme.

The most common is ornithine carbamyl-transferase (OTC) deficiency.

Urea cycle diseases are genetic diseases . OTC deficiency is linked to the presence of a mutation (abnormality) in a gene located on the X chromosome and is transmitted in an X-linked recessive fashion. Classically, this means that a woman carrying the mutation on one of her two X chromosomes will not be affected by the disease -or in a much more moderate form than a man-, but that she risks transmitting this disease. mutation to:

– half of her sons who will develop the disease,

– half of her daughters who, like her, will remain asymptomatic but may in turn transmit the disease (known as “carriers”).

A man with the disease has no risk of having an affected boy; on the other hand, all his daughters will be drivers.

That said, the reality is more complex in the context of OTC deficiency:

– on the one hand, some boys carrying the mutation may have no

Symptoms well beyond the neonatal period,

– On the other hand, some girls carriers can develop the disease at any age, with extremely variable presentations ranging from simple protein aversion to severe neurological or psychiatric manifestations.

The other diseases of the urea cycle are transmitted according to an autosomal recessive mode: for a child to be affected, he must have received a mutated gene from each of his parents. The child is then homozygous for the gene. His parents who have an altered copy of the gene and a normal copy are heterozygous; they will never develop the disease but may have several sick children (1 in 4 risk with each pregnancy, regardless of the sex of the child).

What symptoms and what consequences ?

In the severe forms, the symptoms appear from the neonatal period, after an interval of a few hours to several days after birth, in a previously normal newborn, born after an unremarkable pregnancy and delivery. The disease is revealed by an acute neurological deterioration inaugurated by disorders of consciousness (lethargy) which can go as far as coma. In the less severe forms, the symptoms appear more gradually, in the first months or years of life and combine:

Digestive disorders : nausea, vomiting, loss of appetite (anorexia), and sometimes growth retardation;

Neurological signs: convulsions (epileptic seizures), ataxia (disorders in the coordination of voluntary movements), hypotonia, psychomotor retardation of extremely variable intensity, specific learning disorders (dyslexia, etc.), executive function disorders; neuropsychiatric symptoms: confusion, attention deficit, behavioural disorders (irritability, agitation, etc.);  An increase in the size of the liver.

In the absence of treatment, the aggravation will continue and can lead to coma and even death. Urea cycle diseases can sometimes reveal themselves even later, in adolescence or even in adulthood, through chronic digestive disorders (nausea, vomiting, etc.), neurological signs (epilepsy, cognitive disorders), or psychiatric symptoms (depression, mood disorders, behavioral disorders), which often progress by attacks . Between bouts, some young people have no signs, while others present with mental retardation or a psychiatric illness. People with a urea cycle disorder sometimes report an intolerance or aversion to protein-rich foods, which leads them to gradually change their eating habits and adopt a vegetarian diet.

With appropriate treatment, most symptoms will regress even if sequelae are possible, particularly on the cognitive level. But symptoms can reappear later on the occasion of decompensation of the disease, which can in particular be triggered by:

Some numbers

Urea cycle diseases are rare diseases; their cumulative frequency is estimated at between 1/25,000 and 1/45,000 births, depending on the region of the world. In more than half of the cases, it is an OTC deficiency.

Treatment

The treatment aims to normalize and then maintain the concentration of ammonia in the blood in the norm and to prevent decompensation, but also to ensure normal height-weight growth and psychomotor development for the child and for the adult, satisfactory nutritional status.

A. Treatment in the emergency phase,

 During diagnosis or on the occasion of decompensation of the disease:

This is a vital emergency: a delay in treatment can either be the cause of serious cerebral sequelae , is fatal. Hospitalization for a few days is often necessary. The treatment is based on:

– strict dietary measures (“emergency diet”) with an increase in lipid and carbohydrate calorie intake and the elimination of all protein intake; in the event of digestive disorders, it is sometimes necessary to feed the child using a tube placed directly in the stomach;

– purifying drugs to limit the accumulation of

– Sometimes the use of other treatment techniques, such as dialysis;

– close clinical and biological monitoring (in particular of the level of ammonia in the blood or ammonia).

Over time, long-term treatment is gradually resumed.

B. Long-term treatment:

This is a lifelong treatment, which combines a strict diet and medication. The diet should be reassessed regularly by a specialist dietitian; monitoring medical consultations and blood tests are necessary at regular intervals.

1- Dietary measures:

The diet aims to drastically limit the intake of animal and vegetable proteins (“low-protein” diet), while covering the needs for vitamins, minerals, trace elements and maintaining sufficient caloric intake. Certain foods are prohibited, generally for life (meat, fish, eggs, bread, certain sweets, etc.) while other foods are authorized in limited quantities and must be weighed (green vegetables, dairy products, starchy foods). Specific substitute foods make it possible to diversify the diet. To avoid deficiencies, amino acid supplementation is sometimes provided in a complementary way.

2- Purifying drugs

Such as sodium benzoate and sodium phenylbutyrate) are administered before each meal. In high-risk circumstances (see above), these measures are reinforced to prevent decompensation: a high-calorie and more strictly low-protein diet is started and the doses of purifying drugs are increased. The child must be carefully monitored at home by the parents.

C. Management of neurological disorders,

 If any: Depending on the nature and intensity of any difficulties, rehabilitation is sometimes necessary: ​​management in psychomotricity or physiotherapy is often started in motor difficulties or fine motor disorders. It can be supplemented by occupational therapy sessions, especially if there are significant praxis disorders. The management of language disorders is essentially based on speech therapy.

Consequences on school life

Due to surveillance consultations, possible rehabilitation sessions, the need to monitor children at home in the event of an infectious episode to prevent decompensation and possible hospitalizations, diseases of the urea cycle are likely to generate a school absenteeism.

To limit the risk of decompensation, it is essential to allow the student to follow his diet without deviation. Writing an Individualised Reception Plan (PAI) is therefore necessary most of the time.

Learning difficulties are inconstant, and of extremely variable intensity from one child to another. Some children can attend regular schooling. For others, support from a school life assistant (AVS), or the adjustment of timetables so that re-education takes place during school time require the development of a Personalized Schooling Project (PPS). It is sometimes necessary to consider a ULIS-type inclusion system, or even a referral to a specialized establishment.

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