Argininemia

Definition

Definition of Argininemia
Argininemia, also called arginase deficiency, is an autosomal recessive urea cycle disorder where a deficiency of the enzyme arginase causes a build up of arginine and ammonia in the blood.

Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Symptoms

Symptoms of Argininemia
Patients with Argininemia may present from two months to four years of age. Symptoms are progressive spastic paraplegia, failure to thrive, delayed milestones, hyperactivity and irritability, with episodic vomiting, hyperammonemia and seizures. Mental retardation is a result of cerebral atrophy which leads to microcephaly. Hepatomegaly may be present.

Causes

Causes of Argininemia
This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

Diagnosis

Diagnosis of Argininemia
Argininemia 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, mental retardation, 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.

Treatment

Treatment of Argininemia
Argininemia is a rare disorder and few patients have been treated from an early age, prior to onset of disabling symptoms. Dietary restriction of protein is the basic treatment, with supporting therapy to prevent and control the hyperammonemia.

Because the diagnosis and therapy of argininemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

Prognosis

Prognosis of Argininemia

1. Good prognosis if disorder is treated prospectively from birth
2. Progressive neurological manifestations if untreated

Genetics

Genetics of Argininemia
Argininemia belongs to a class of genetic diseases called urea cycle disorders. 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. The accumulation of guanidino metabolites also contribute to the neurotoxicity of the disease.