Arginase deficiency


Arginase deficiency

Description, Causes and Risk Factors:

Arginase deficiency is a rare inherited disorder characterized by complete or partial lack of the enzyme arginase. Arginase is one of six enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of the arginase enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood and arginine (hyperarginemia) in the blood and cerebrospinal fluid. Untreated children may exhibit seizures, spasticity, short stature and intellectual disability. Arginase deficiency is inherited as an autosomal recessive genetic disorder.

Arginase deficiency

Arginase deficiency usually becomes evident by about the age of 3. It most often appears as stiffness, especially in the legs, caused by abnormal tensing of the muscles (spasticity). Other symptoms may include slower than normal growth, developmental delay and eventual loss of developmental milestones, intellectual disability, seizures, tremor, and difficulty with balance and coordination (ataxia). Occasionally, high protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting.

In some affected individuals, signs and symptoms of arginase deficiency may be less severe, and may not appear until later in life.

Mutations in the ARG1 gene cause arginase deficiency. Arginase deficiency belongs to a class of genetic diseases called urea cycle disorders (UCD). The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys.

The ARG1 gene provides instructions for making an enzyme called arginase. This enzyme controls the final step of the urea cycle, which produces urea by removing nitrogen from arginine. In people with arginase deficiency, arginase is damaged or missing, and arginine is not broken down properly. As a result, urea cannot be produced normally, and excess nitrogen accumulates in the blood in the form of ammonia. The accumulation of ammonia and arginine are believed to cause the neurological problems and other signs and symptoms of arginase deficiency.

Arginase deficiency is a very rare disorder; it has been estimated to occur once in every 300,000 to 1,000,000 individuals.

Symptoms:

Symptoms associated with arginase deficiency differ from those associated with other disorders of the urea cycle. In most cases, infants with arginase deficiency do not exhibit any symptoms during the first few months to a year of life. Infants with arginase deficiency rarely experience severe hyperammonemia or hyperammonemic coma, which are characteristic of the other urea cycle disorders.

Affected children experience a lag in growth between one and three years and may walk on their toes and develop progressive stiffness and lack of control of voluntary movements of the legs (spastic diplegia). Cognitive development slows or stops and if untreated, children develop severe spasticity, an inability to walk, loss of bowel and bladder control and severe intellectual disability.

All affected children have growth deficiency and many also experience seizures.

Diagnosis:

Beyond the inherent problems in diagnosis of any urea cycle disorder, arginase deficiency is somewhat difficult to diagnose.

The typical crisis associated with hyperammonemia is rare, and random measurement of blood ammonia levels during periods of clinical stability is not helpful.

Arginine excretion in urine is not usually massively increased because of isozyme induction; however, a urinary amino acid excretion pattern can be observed. The excretion pattern is similar to that found in cystinuria, with increased arginine, ornithine, lysine, and, possibly, cystine. It can be observed because of competitive inhibition of dibasic amino acid reabsorption by elevated arginine in the renal proximal tubule.

Plasma arginine levels may not be greatly increased in cases of self-restriction of protein intake; therefore, even experienced clinicians may fail to diagnose the disease. Urine orotic acid is usually mildly increased.Plasma ammonia levels may be mildly increased or normal.

When mild-to-moderate elevated plasma arginine levels are observed in association with developmental delay and spasticity, a red cell arginase assay is indicated for definitive biochemical diagnosis.

Carrier testing may be available. Your metabolic doctor or genetic counselor can answer your questions about carrier testing.

Treatment:

Your baby's primary doctor will work with a metabolic doctor and a dietician to care for your child. Prompt treatment is needed to prevent the build up of arginine and ammonia. You should start treatment as soon as you know your child has the condition.

The following are treatments often recommended for babies and children with arginase deficiency.

Most children need to eat a diet made up of very low protein foods and special medical foods. Your dietician will create a food plan that contains the right amount of protein, nutrients and energy to keep your child healthy. The food plan should be continued throughout your child's life.

One of the main treatments is a low-protein diet. Foods to avoid or strictly limit include:

    Milk, cheese and other dairy products.

  • Meat and poultry.

  • Fish.

  • Eggs.

  • Dried beans and legumes.

  • Nuts and peanut butter.

Eating foods high in protein can cause ammonia and arginine to build up, resulting in the symptoms described above. Many vegetables and fruits have only small amounts of protein and can be eaten in carefully measured amounts.

Do not remove all protein from the diet. Your child still needs a certain amount of protein for normal growth and development. Any changes in the diet should be made under the guidance of a dietician.

There are medical foods such as special low-protein flours, pastas and rice that are made especially for people with amino acid disorders.

Your child may be given a special formula that contains the correct amount of amino acids and nutrients. Your metabolic doctor and dietician will decide whether your child should use this formula and how much to use.

Your child's exact food plan will depend on many things, such as his or her age, weight and general health. Your dietician will fine-tune your child's diet over time.

Other medications can help the body get rid of excess arginine and ammonia. Your metabolic doctor will decide which medications your child should take.

Your child will need to have regular blood tests to measure ammonia and amino acid levels. Your child's diet and medication may need to be adjusted based on blood test results.

NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

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