Arginase-1 Deficiency

 Arginase-1 Deficiency

Summary

Arginase-1 deficiency is a rare inherited disorder characterized by complete or partial lack of the enzyme arginase in the liver and red blood cells. 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, progressive spasticity, short stature and intellectual disability. Most affected infants can now be identified at birth through newborn screening. Arginase-1 deficiency is inherited as an autosomal recessive genetic disorder.

Introduction

The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood. In arginase-1 deficiency the accumulation of arginine in the body and not excess ammonia is the predominant biochemical and pathological abnormality.

SIGNS & SYMPTOMS

Symptoms associated with arginase-1 deficiency differ from those associated with other disorders of the urea cycle. Most infants with arginase-1 deficiency do not exhibit any symptoms during the first few months to a year of life. Infants with arginase-1 deficiency infrequently experience severe hyperammonemia or hyperammonemic coma, which are characteristic of the other urea cycle disorders.

Affected children may 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.

Almost all affected children have growth deficiency and many also experience seizures.

CAUSES

Arginase-1 deficiency is inherited as an autosomal recessive genetic disorder and is caused by changes (mutations or pathogenic variants) in the ARG1 gene. Mutations in the ARG1 gene result in production of an abnormal arginase enzyme.

Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same altered gene, which increases the risk to have children with a recessive genetic disorder.

DIAGNOSIS

Most affected infants are now identified at birth through newborn screening. Arginase enzyme activity is usually not detectable in red blood cells from affected individuals. Molecular genetic testing is available to confirm the diagnosis. If two pathogenic variants the ARG1 gene are not found, red blood cell enzyme testing is used to confirm the diagnosis

Treatment

Treatment should be coordinated by a metabolic specialist and is based on reducing plasma ammonia and arginine concentration, preventing excess ammonia from being formed, and reducing the amount of nitrogen in the diet.

Reduction of plasma ammonia concentration is accomplished by dialysis and several different methods are available. This should be used only when the high levels are producing severe symptoms.

The nitrogen scavenger drugs sodium phenylacetate and sodium benzoate provide an alternative pathway for removing excess nitrogen. Intravenous and oral forms of these medications are available (Ammonul). Phenylbutyrate (Buphenyl) has a less offensive odor than the other medications but is available as oral therapy only. Ravicti is a form of phenylbutyrate that is less irritating to the gastrointestinal track and easier to take.

Dietary restrictions in individuals with arginase-1 deficiency are aimed at limiting the amount of arginine and protein intake. Children with arginase-1 deficiency are placed on a low-protein, arginine-restricted diet supplemented by essential amino acids.

Seizures are treated with phenobarbital or carbamazepine. Valproic acid should be avoided, as it can increase blood ammonia levels.

Affected individuals should receive periodic blood tests to determine the levels of ammonia and arginine in the blood and to be sure that liver function is not impaired. Excessive levels of ammonia or arginine should be promptly treated.

Genetic counseling is recommended for affected individuals and their families.

TYPE OF DOCTOR AND DEPARTMENT: General Physician SPECIALIST CAN DIAGNOSE THIS DISEASE.