Argininosuccinic aciduria

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Argininosuccinic aciduria is an inherited disorder that causes ammonia to accumulate in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Argininosuccinic aciduria usually becomes evident in the first few days of life. An infant with argininosuccinic aciduria may be lacking in energy (lethargic) or unwilling to eat, and have a poorly controlled breathing rate or body temperature. Some babies with this disorder experience seizures or unusual body movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delay and intellectual disability. Progressive liver damage, high blood pressure (hypertension), skin lesions, and brittle hair may also be seen.

Occasionally, individuals may inherit a mild form of the disorder. These individuals can have an accumulation of ammonia in the bloodstream only during periods of illness or other stress, or mild intellectual disability or learning disabilities with no evidence of elevated ammonia levels.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the ASL gene cause argininosuccinic aciduria. This condition belongs to a class of genetic diseases called urea cycle disorders because they are caused by problems with a process in the body called the urea cycle. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle breaks down excess nitrogen, which is made when protein is used by the body, to make a compound called urea. Urea is removed from the body in urine. Breaking down excess nitrogen and excreting it as urea prevents it from accumulating in the body as ammonia.

The ASL gene provides instructions for making an enzyme called argininosuccinate lyase, which is needed for the fourth step of the urea cycle. The specific role of the argininosuccinate lyase enzyme is to start the reaction in which the amino acid arginine, a building block of proteins, is produced from argininosuccinate, the molecule that carries the waste nitrogen collected earlier in the urea cycle. The arginine is later broken down into urea, which is excreted, and ornithine, which restarts the urea cycle.

In people with argininosuccinic aciduria, argininosuccinate lyase is dysfunctional or missing. As a result, the urea cycle cannot proceed normally, arginine is not produced, and nitrogen is not broken down efficiently. The excess nitrogen accumulates in the blood in the form of ammonia. This buildup of ammonia damages the brain and other tissues and causes neurological problems and other signs and symptoms of argininosuccinic aciduria. It is unclear how a lack of arginine contributes to the features of this condition.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Argininosuccinic aciduria occurs in approximately 1 in 70,000 to 218,000 newborns. Most cases of this condition are detected shortly after birth by newborn screening.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Aminoaciduria · Very frequent (99-80%)

An increased concentration of an amino acid in the urine.

Hyperammonemia · Very frequent (99-80%)

An increased concentration of ammonia in the blood.

Hyperglutaminemia · Very frequent (99-80%)

The concentration of glutamine in the blood circulation is above the upper limit of normal.

Hypoargininemia · Very frequent (99-80%)

The concentration of arginine in the blood circulation is below the lower limit of normal.

Argininosuccinic aciduria · Frequent (79-30%)

Increased amount of argininosuccinate in the urine.

Ataxia · Frequent (79-30%)

Ataxia refers to impaired coordination of voluntary muscle movement. Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).

Drowsiness · Frequent (79-30%)

Abnormal feeling of sleepiness or difficulty staying awake.

EEG abnormality · Frequent (79-30%)

Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.

Other findings in the same source

From: Orphanet

Additional reported features include Elevated circulating hepatic transaminase concentration (Frequent (79-30%)); Elevated plasma citrulline (Frequent (79-30%)); Hepatomegaly (Frequent (79-30%)); Hypertension (Frequent (79-30%)); Increased circulating argininosuccinic acid (Frequent (79-30%)); Intellectual disability (Frequent (79-30%)); Lethargy (Frequent (79-30%)); Monilethrix (Frequent (79-30%)); Neurodevelopmental delay (Frequent (79-30%)); Respiratory alkalosis (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Argininosuccinic aciduria is Metabolic Medicine, with a metabolic specialist / clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with metabolic specialist / clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Is a biochemical or molecular result needed to clarify the diagnosis?
• Does this condition require an individual plan for illness or reduced food intake?
• Should nutrition advice come from a specialist metabolic dietitian?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Argininosuccinic aciduria. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.