Arginase deficiency

Other Names:ARG1 deficiency; Hyperargininemia; Argininemia

Arginase deficiency is an inherited metabolic disease in which the body is unable to process arginine (a building block of protien ).It belongs to a group of disorders known as urea cycle disorders.

These occur when the body's process for removing ammonia is disrupted, which can cause ammonia levels in the blood to rise (hyperammonemia)

In most cases, symptoms appear between the ages of one and three years.

Symptoms

Symptoms may include feeding problems, vomiting, poor growth,seizures , and stiff muscles with increased reflexes (spasticity). People with arginase deficiency may also have devlopmental delays , loss of developmental milestones, and intellectual disability . Signs and symptoms may include:

• Poor growth (present in all the people who have arginase deficiency)
• Stiff muscles and increased reflexes
• Loss of previously acquired developmental milestones
• Small head size (microcephaly)
• Problems with balance and coordination

Occasionally, people with arginase deficiency have episodes of severe buildup of ammonia in the blood (hyperammonemia). Although rare, these episodes are more likely to occur following a high-protein meal or during periods of stress caused by illness or fasting. Hyperammonemia can cause irritability, lethargy, refusal to eat, breathing difficulty, movement disorders, vomiting and, in severe cases, coma. If arginase deficiency is undiagnosed or if the person with the disorder is unable to follow the strict low-protein diet, severe intellectual disability and muscle stiffness may develop, as well as loss of the ability to walk and loss of bladder and bowel control

Genetics

Arginase deficiency is caused by mutations in the ''ARG1'' gene and is inherited in an autosomal recessive manner This means that to be affected, a person must have a disease-causing mutations in both copies of the gene  associated with arginase deficiency. The parents of a person with arginase deficiency usually each carry one mutated copy of the gene and are referred to as carriers . Carriers typically do not show signs or symptoms of the metabolic disorder . When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the genetic disorder, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the genetic disorder AND not be a carrier.

Argininemia has an autosomal recessive pattern of inheritance.

Cause

Arginase deficiency is caused by mutations  in the ''ARG1'' , which provides instructions for making an enzyme called arginase. This enzyme plays a key role in the urea cycle, a sequence of reactions that process the excess nitrogen released when the body uses protein . Arginase controls the final step of the urea cycle, which removes nitrogen from arginine and makes a compound called urea. Urea is released by the kidneys in urine. Mutations in ARG1 cause absent or reduced levels of functional arginase. As a result, arginine is not broken down properly, urea cannot be produced, and excess nitrogen builds up in the blood as ammonia. Increased levels of ammonia and arginine are thought to cause the many signs and symptoms associated with arginase deficiency.

Diagnosis

A diagnosis of arginase deficiency is often suspected based on the person's signs and symptoms. Special blood tests to measure levels of arginine and ammonia may then be ordered. A diagnosis of arginase deficiency is confirmed when genetic testing identifies a disease-causing mutation in each copy of the ARG1gene  or a blood test demonstrates reduced arginase enzyme activity in the red blood cells .

Treatment

The main goals in the treatment of arginase deficiency are to lower arginine levels and to prevent buildup of ammonia in the blood (hyperammonemia).They may need frequent blood tests to check arginine levels.

Because arginine is a building block of protein , people with arginase deficiency must follow a diet that is very low in protein. It is often recommended they eat the minimal amount of protein needed to maintain good health, which varies based on many factors including age and weight. They are often advised to drink special formulas and/or buy medical foods in which the protein levels are tailored to fit their needs. People with arginase deficiency may also need to take certain medications (called nitrogen-scavenging drugs) to reduce their levels of arginine. If people with arginase deficiency have episodes of hyperammonemia, they may be given intravenous (IV) fluids. During an episode of severe hyperammonemia, people with arginase deficiency are generally treated in the hospital. They may require dialysis , nitrogen-scavenging medications, intravenous (IV) fluids, or other treatments. These treatments are given to quickly reduce blood ammonia levels and prevent brain damage.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition Glycerol phenylbutyrate (Brand name: Ravicti)

RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements).

NIH genetic and rare disease info

• NIH info on Arginase deficiency

Arginase deficiency is a rare disease.