ASL Deficiency: An introduction

ASL Deficiency, or Argininosuccinic acid lyase deficiency, is a rare condition* which is the result of the deficiency of an enzyme called Argininosuccininate lyase.

(protein pathway with and without presence of ASL)

Argininosuccinate lyase is one of several enzymes found in the urea cycle, a series of chemical reactions that occur in the bodies of organisms which work to remove ammonia. The deficiency in Argininosuccinate lyase means that the body either does not produce Argininosuccinate lyase or produces a damaged enzyme and is thus incapable of removing ammonia effectively, if at all. This will eventually result in a build-up of ammonia which is highly toxic to the body and can have some dire results on the body which will be elaborated on in later posts.

This condition is known by several different names:

•      Argininosuccinate lyase deficiency
•      Argininosuccinic acidemia
•      Argininosuccinicaciduria
•      Argininosuccinyl-CoA lyase deficiency
•      Arginosuccinase deficiency
•      ASA
•      ASAuria
•      ASL deficiency

*1 in 70, 000 are born with this condition

http://www.newbornscreening.info/Parents/aminoaciddisorders/ASAL.html#6

http://en.wikipedia.org/wiki/Argininosuccinic_aciduria

http://ghr.nlm.nih.gov/condition/argininosuccinic-aciduria

Symptoms of ASL Deficiency

When there is the presence of ammonia inside our body, ammonia would be converted into a substance called 'urea'. Urea is removed via urinating. Ammonia is very harmful to our body. It would build up in our blood if it is not changed to urea. With high levels of ammonia, serious brain damage can happen.

Different people develop symptoms and different stages. There are 2 main forms of Argininosuccinate Lysase deficiency. The most common form happens shortly after birth. The milder form happens late in infancy or early childhood.

ASAL deficiency in newborns
Infants might be healthy at birth but within a few days of life, symptoms can be developed quickly. Some of the first symptoms of high blood ammonia are:

• poor appetite
• excess sleepiness or lack of energy
• irritability
• vomiting

If not treated, high ammonia levels can cause:

• muscle weakness
• decreased or increased muscle tone
• breathing problems
• problems staying warm
• seizures
• swelling of the brain
• coma, and sometimes death

Other effects of ASAL deficiency can include:

• poor growth
• enlarged liver
• delays in learning or intellectual disability

Without treatment, many babies die within the first few weeks of life.

ASAL deficiency in childhood
In this milder form, symptoms start later in infancy or childhood. Some common symptoms in children who are not treated are:

• poor growth
• dry, brittle hair
• hyperactivity
• behavior problems
• learning disabilities or intellectual disability
• avoidance of meat and other high protein foods
• enlarged liver
• small head size
• episodes of excess ammonia in the blood

Episodes of high blood ammonia often happen:

• after long periods of going without food
• during illness or infection
• after high-protein meals

In children, some of the first symptoms of high blood ammonia are:

• poor appetite
• intense headache
• vomiting
• extreme sleepiness or lack of energy
• slurred speech
• poor coordination and balance problems

If not treated, children with high blood ammonia levels can develop:

• breathing problems
• swelling of the brain
• seizures
• coma, sometimes leading to death

Some people have very mild symptoms and are only found to be affected after a brother or sister is diagnosed. 

Treatment of ASAL

You should consult 

• Medical geneticist
• Metabolic disease specialist
• Pediatric critical care specialist
• Dietitian

*When your/a child has symptoms of ASAL Deficiency, it is advised to seek immediate treatment so as to prevent build-up of ammonia.*

Henceforth are treatment methods often recommended for children/babies diagnosed:

1.  Low-protein diet and/or special medical foods and formula

The diet that ASAL deficient children need to eat consists of very low-protein foods, special medical foods and possibly a special formula. The dietician will come up with a meal plan that contains sufficient quantity of protein, nutrients and energy (calorie). This meal plan should be continued throughout the child’s life.

A low-protein diet is the most effective treatment. Foods that need to be avoided or strictly limited include:

• milk, cheese and other dairy products

• meat and poultry, eggs, fish

• dried beans and legumes

• nuts and peanut butter

Consuming high-protein foods will cause accumulation of ammonia in the blood, harmful to the body. It is necessary to still consume protein. Examples such as vegetables and fruits can be eaten, in measured amounts.

Medical foods and formula

There are special foods that cater to people with amino acid disorders. Examples are special low-protein flours, pastas and rice. Special formula that contains the right amount of nutrients may be given as well. The above mentioned meal plan will always be adjusted under the guidance of a dietician, with the growth of a child.

2.  Medication
Most ASAL deficient children are given oral arginine supplements. Arginine helps the body to remove ammonia from the blood. There are also other medications for prevention of high ammonia levels. In the event of high blood ammonia, children should be taken to the hospital. More often, IV is one way medication is introduced into the body. Sometimes dialysis is needed to remove ammonia from the blood.

3.  Blood tests  
Regular blood tests is needed to measure amino acid and ammonia levels of the child. The child's diet and medication may need to be adjusted based on blood test results.

4.  Call the doctor at the start of any illness:
For some babies and children, even minor illness can lead to build up of ammonia. In order to prevent problems, call a doctor right away when your child has any of the following:

• loss of appetite
• low energy or extreme sleepiness
• vomiting
• fever
• infection or illness
• behavior or personality changes
• difficulty walking or balance problems

5. Liver transplantation
Liver transplant surgery has been tried in some children with ASAL who do not respond to dietary treatment. Liver transplant in children with ASAL deficiency does not cure the underlying disease and is only done when necessary.

This major surgical procedure is associated with risks, and individuals who have had a liver transplant must take medication for the rest of their lives to prevent their body from rejecting the donor liver. Many factors must be considered before surgery and this option should be discussed thoroughly with your child’s doctors.

Getting ASL Deficiency

ASLD is a genetic condition, and as such, is not contagious, and cannot be passed from person to person, unless it is inherited.

ASLD is an autosomal recessive condition. Autosomal means that the genes that code for the condition are found in non-sex-linked chromosomes**. Recessive means that two copies of the mutated gene must be present in the person’s genome in order for him to be affected. If not, the person just ends up a carrier.

Carriers are people who have only one copy of the gene and are thus unaffected, but perfectly capable of passing on the condition. Two carriers are required in order to produce an affected offspring. However, the chances of that happening are still 1 in 4, showing why ASLD is such a rare condition.

**Sex linked chromosomes refer to the X and Y chromosomes

http://bionews-tx.com/wp-content/uploads/2013/10/Autosomal-recessive-diseases.png

The Biochemistry of Argininosuccinate Lyase Deficiency Part I: The Urea Cycle

The Urea cycle, as mentioned before, is a series of chemical reactions which aid in the removal of ammonia from the body. In the process, it produces two amino acid called arginine and ornithine. Both are important to the body in their own ways, and patients of ASLD have to find alternate ways to introduce these into their systems.

Besides producing amino acids, the urea cycle serves to remove nitrogenous metabolic wastes from the body mainly in the form of ammonia mostly by converting it to urea which can then be excreted. As can be seen from the diagram above, reaction 4 involves argininosuccinate being converted to Fumarate and L-Arginine. The enzyme which catalyses this reaction is argininosuccinate lyase. Without this enzyme, the metabolic products from previous reactions build up. Imagine a traffic jam, where argininosuccinate lyase has gotten into an accident, blocking up the road. Eventually, all the preceding products will build up to dangerous levels, ending finally in hyperammonmemia

In a nutshell, the Urea Cycle is a series of processes which convert nitrogenous metabolic wastes, mostly in the form of ammonia, into Urea for removal from the body system, while synthesizing necessary amino acids such as Arginine and Ornithine needed for different processes in the body.

http://medicine.academic.ru/pictures/medicine/398.jpg
http://www.pearsonhighered.com/mathews/ch20/c20uc.htm

The Biochemistry of Argininosuccinate Lyase Deficiency Part II: More about Arginine

In the previous post, we talked about how Argininosuccinate Lyase is an enzyme in the urea cycle that catalyzes the reversible argininosuccinate, producing amino acid arginine and dicarboxylic acid fumarate.

So what exactly is Arginine?

(structure of L-Arginine)

Arginine in its 'L' form is a semi-essential α-amino acid. Because L-arginine is involved in many metabolic processes, it is significant for the execution of many physiological processes. These processes include hormone secretion, an increase in growth hormone output, the removal of toxic waste products from the body, and immune system defenses.

In the body, the amino acid arginine is a precursor of nitric oxide (NO). Nitric oxide is a powerful neurotransmitter that helps blood vessels relax and also improves circulation. it is often used for treating conditions such as chest cramping [angina], high blood pressure, heart disease, and sexual dysfunction. Arginine is also used in the treatment of male and female infertility.

There are also other functions of Arginine such as:

• Helping to reduce insulin resistance and increase glucose tolerance and insulin sensitivity in type 2 diabetes mellitus
• Amino acids supplement, such as Arginine is able to detoxify high level of ammonia as part of the urea cycle
• Arginine supports the production of collagen and is therefore an important contributor to bone growth

Even though the body normally makes enough of it, supplementation is sometimes needed. As our body is not able to produce sufficient amount of Arginine, it is important to consume food high in Arginine. 

Here are some examples of food that are high in Arginine:

1. Nut
2. Spinach and Lentils
3. Whole Grains
4. Red Meat
5. Seafood
6. Soy
7. Eggs

The Biochemistry of Argininosuccinate Lyase Deficiency Part III: The Dangers of Ammonia

Argininosuccinate lyase deficiency is a deficiency of the urea cycle. A result of this metabolic disorder is hyperammonemia, or elevated ammonia levels.

Ammonia is a highly toxic biochemical by-product which is the result of the metabolism of certain amino acids. In a person with ASL Deficiency, the body is incapable of completing the process of converting ammonia into urea, a less toxic form which can be easily removed from the body primarily through urine.

Ammonia is harmful enough when it is encountered in the environment, capable of causing burns on exposed surfaces. On the inside of the body, it is capable of causing even more problems. Elevated ammonia levels in the blood acts as a toxin and may affect the brain, resulting in a number of symptoms, some of which include confusion, lethargy, and change in mood, personality and behaviour among others, all of which are symptoms of Argininosuccinate Lyase Deficiency.

http://www.healthgrades.com/conditions/elevated-blood-ammonia-level--symptoms

Curing ASLD

As of right now, there still aren’t any viable cures for ASL deficiency; only treatment, to improve the quality of life of a patient. The treatment is fairly simple, consisting mostly of watching protein intake, and taking certain supplements to manage the block in the urea cycle and on the rare occasion of a metabolic emergency, haemodialysis. (more information can be found in previous posts) While these are effective, the only way to “be rid” of this condition, seeing as it is genetic, is a liver transplant.

Such treatment is life-long, and the slightest mistake could end in disaster, ranging from neurological damage, to death. As such, researchers continue to search for cures to ASLD. Some researchers have been looking into gene therapy as a possible solution, and even now, continue to study the genetics behind this condition.

http://medical-dictionary.thefreedictionary.com/Krebs-Henseleit+cycle

https://public.health.oregon.gov/LaboratoryServices/NewbornScreening/Documents/arginino.pdf