Glutaric Acidemia, type I (GA-1): Description, Causes and Risk Factors:
In the body, the breakdown of protein produces the amino acids lysine, hydroxylysine, and tryptophan, among others. These are further processed into a substance called glutaric acid. An enzyme called Glutaryl-CoA dehydrogenase (GCDH) is then responsible for breaking down glutaric acid. Glutaric acidemia, type I (GAI) occurs when the glutaryl-CoA dehydrogenase enzyme is not working well or is deficient.
The condition is inherited in an autosomal recessive pattern: mutated copies of the gene GCDH must be provided by both parents to cause glutaric acidemia type 1. The GCDH gene encodes the enzyme glutaryl-CoA dehydrogenase. This enzyme is involved in degrading the amino acids lysine, hydroxylysine and tryptophan. Mutations in the GCDH gene prevent production of the enzyme or result in the production of a defective enzyme with very low residual activity, or an enzyme with relatively high residual activity but still phenotypic consequences. This enzyme deficiency allows glutaric acid, 3-hydroxyglutaric acid and (to a lesser extent) glutaconic acid to build up to abnormal levels, especially at times when the body is under stress. These intermediate breakdown products are particularly prone to affect the basal ganglia, causing many of the signs and symptoms of glutaric acidemia type 1.
Researchers have previously shown that astrocytes are preferential cell targets of GA which likely accumulates in astrocytes through glutamate transporters. Remarkably, cultured astrocytes become severely dysfunctional when exposed to GA, with mitochondrial depolarization and secondary oxidative stress. In addition, GA induces astrocytes to actively proliferate by a mechanism involving activation of MAP kinases and oxidative stress. We have also showed that systemic administration of GA to rat pups also resulted in acute increase in postnatal gliogenesis and increased number of undifferentiated astrocytes expressing S100b. However, it is uncertain whether the appearance of such abnormal astrocytes contributes to the striatal degeneration characteristic of the disease.
The severity of glutaric acidemia type 1 varies widely; some individuals are only mildly affected, while others have severe problems. GA-1 can be defined as two clinical entities: GA-1 before the encephalopathic crisis and GA-1 after the encephalopathic crisis.
Glutaric acidemia type 1 occurs in approximately 1 of every 30,000 to 40,000 births.
Clinically, babies with GA-I can present macrocephaly before the appearance of first symptoms typically denoted by encephalopathic crisis. Then, GA-I may evolve to a complex neurological
syndrome simulating a cerebral palsy with extrapyramidal signs such as progressive dystonia and dyskinesia. Symptoms may have a gradual rate of onset and progression, or occur suddenly after an acute metabolic crisis. Pathologically, the characteristic features of GA-I are a loss of neurons in the caudate and putamen and spongiform lesions in the white matter. Increased extracellular GA acts as a potent neurotoxic metabolite having the potential to induce excitotoxicity, disruption of mitochondrial energy metabolism and oxidative stress. In astrocytes, GA-I interferes with sodium-coupled dicarboxylate transporters, thus disrupting the supply of tricarboxylic acid cycle intermediates necessary for ATP and neurotransmitter synthesis in neurons. In spite of this acute metabolic
effect, there is scarce information about other mechanisms by which GA-I may cause astrocytes to trigger progressive neuronal loss in GA-I.
The diagnosis of GA-1 isconfirmed by measuring urine organic acids. Theglutaric acid levels are elevated and the finding of3-OH-glutaric acid is typical. However, levels mayrise and fall and may not be consistently abnormal.Enzyme testing and/or mutation analysis of theGCDH gene may assist in confirming the diagnosis.Diagnostic testing is arranged by specialists at yourregional treatment centre.
Your baby's primary doctor will work with a metabolic doctor and a dietician to care for your child. Prompt treatment is needed to prevent episodes of metabolic crisis. You need to start treatment as soon as you know your child has GA-1. Certain treatments may be advised for some children but not others. Treatment is usually needed throughout life.
The following are treatments often recommended for babies and children with GA-1:
Medication: Riboflavin is a vitamin that helps the body process protein. It may also help lessen the amount of glutaric acid made by the body. Your doctor may recommend that your child take riboflavin supplements by mouth.
Some children may be helped by L-carnitine. This is a safe and natural substance that helps body cells make energy. It also helps the body get rid of harmful wastes. Your doctor will decide whether or not your child needs L-carnitine supplements. Unless you are advised otherwise, use only L-carnitine prescribed by your doctor. Do not use any medication without checking with your metabolic doctor.
Children with symptoms of a metabolic crisis need medical treatment right away. They often need to be treated in the hospital. During a metabolic crisis, children may be given fluids, glucose, insulin, carnitine and other medications by IV to help get rid of harmful substances in the blood. Ask your metabolic doctor if you should carry a special travel letter with medical instructions for your child's care.
Infants and young children with GA-1 need to eat frequently to prevent a metabolic crisis. Your metabolic doctor will tell you how often your child needs to be fed. In general, it is often suggested that infants be fed every four to six hours. Some babies need to eat even more frequently than this. It is important that infants be fed during the night. They may need to be woken up to eat if they do not wake up on their own. Your metabolic doctor and dietician will give you an appropriate feeding plan for your infant. Your doctor will also give you a `sick day' plan, tailored to your child's needs, for you to follow during illnesses or other times when your child will not eat.
Your metabolic doctor will continue to advise you on how often your child should eat as he or she gets older. When they are well, many older children and adults with GA-1 can go without food for up to 12 hours without problems. They may need to continue the other treatments throughout life.
Food plan, including medical foods and formula: Most children need to eat a diet made up of foods low in lysine and tryptophan. Special medical foods and a special formula are usually part of the diet. Your dietician will create a food plan that has the right amount of protein, nutrients, and energy for your child.
Low-protein (lysine and tryptophan) diet: Foods that will need to be avoided or strictly limited include:
Milk, cheese, and other dairy products.
- Meat and poultry.
- Dried beans and legumes.
- Nuts and peanut butter.
- Many vegetables and fruits have only small amounts of lysine and tryptophan and can be eaten in carefully measured amounts.
Do not remove all protein from the diet. Your child still needs a certain amount of protein for normal growth and development. Any changes in the diet should be made under the guidance of a dietician familiar with GA-1.
There are medical foods such as special low-protein flours, pastas, and rice that are made especially for people with organic acid disorders. A special medical formula that contains the right level of amino acids and nutrients for your child may be recommended. Your metabolic doctor and dietician will tell you whether your child should be on this formula and how much to use. Some states offer help with payment, or require private insurance to pay for the formula and other special medical foods.
Your child's exact food plan will depend on many things such as his or her age, weight, general health, and blood test results. Your dietician will fine-tune your child's diet over time.
The long-term benefits of the special diet and medical foods are not yet known. However, it is important to follow the food plan as long as your doctor advises.
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.