GA TIPO 2

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La Aciduria Glutárica tipo 2 (GA2)

People with GA-2 have defective genes responsible for the transfer of electrons from the respiratory chain of the mitochondria (organelle of the cell that produces energy for your activity).

People with GA-2 have defective genes responsible for the transfer of electrons from the respiratory chain of the mitochondria (organelle of the cell that produces energy for your activity).

The Argininosuccinic Acidemia type 2 (GTA 2) is a rare genetic disorder that affects the metabolism of fatty acids and certain amino acids, causing a toxic buildup of organic acids in the body. This disease belongs to the Congenital Errors of the Metabolism and is also classified as a aciduria or organic aciduria dicarboxílica multiple .

The AGT-2 are caused by mutations in the genes encoding the flavoprotein electron transfer (ETF) or ETF-ubiquinone oxidoreductase (ETF-QO) , two enzymes critical for cellular energy metabolism. The deficiency in these enzymes alter the process of oxidation of fatty acids and amino acids, disrupting the production of energy and generating an accumulation of toxic substances, such as long-chain fatty acids and dicarboxylic acids in the blood and tissues.

People with GA-2 have defective genes responsible for the transfer of electrons from the respiratory chain of the mitochondria (organelle of the cell that produces energy for your activity).

Results from the deficiency or mutations in any of the three genes, ETFA , ETFB and ETFDH:

  • The genes for the subunits alpha (ETFA: 15q23-q25) of the flavoprotein electron transfer ETF.
  • The genes for the subunits beta (ETFB: 19q13.3-q13.4) of the flavoprotein electron transfer ETF.
  • The flavoprotein dehydrogenase electronic transfer - ubiquinone oxidoreductase (ETFDH-QO: 4q32-q35).

People with mutations that result in a complete loss of any one of the enzymes, are likely to experience more severe symptoms.

Mutations that allow the enzyme to retain activity may result in milder forms of the disorder.

GA 2 causes of the enzymes needed to not function properly or does not occur at all. The function of these enzymes are normally active in the mitochondria (the centers of cells producing energy) is to help generate energy for the body, using the decomposition of fats and proteins from the food we eat and the stored in the body.

These nutrients are only partially degraded, accumulate in the cells and damage them, causing the signs and symptoms of glutaric acidemia type II.

When you lack one of the enzymes, the body cannot break down protein and fat for energy, and must rely on glucose. In the body there is a limited amount of glucose, and when it has timed out (we don't eat for a period of time, we forget a meal or sleep), the body is using fat and proteins. Due to this failure, it does not achieve successfully, and leads to the accumulation of acid glutárico and other harmful substances in the blood. Also causes a low level of sugar in the blood, called hypoglycemia.

Typical illnesses of childhood can cause a formation of acid glutárico in the body, because the body needs more energy and break down its fat and protein to get it.

Defects in the pathway of the mitochondrial complex ETF/ETF-QO that transfers electrons from the first stage of the betaoxidación to the electron transport system, block the beta-oxidation of fatty acids, oxidation of branched-chain amino acids and Glutaril-CoA in the metabolic pathway of lysine, tryptophan and hidrolisina.

The deficiency of acilcoenzima A dehydrogenase multiple sensitive to riboflavin is characterized, among other features, by a decrease in the ability of beta-oxidation of fatty acids. 3 protein uncoupling in muscle (UCP3; 602044 ) positively regulates in conditions that increase the levels of free fatty acid circulating and / or decrease the betaoxidación of fatty acids. All parameters were restored to control values after treatment with riboflavin. is due to the accumulation of fatty acids in muscle / acylCoA.

MADD due to mutations in ETFDH may result in myopathy, isolated with secondary deficiency of coenzyme Q10

Glutaric acidemia type II is a very rare disorder; its precise incidence is unknown. It has been reported in several different ethnic groups. The prevalence at birth is estimated to be 1/200.000, but there are large variations between countries and ethnic groups.

There is a protocol of treatment for the neonatal forms of serious, but early diagnosis and the rapid introduction of a dietary treatment (restriction of proteins and fat), riboflavin (vitamin B2) and coenzyme Q10 you can improve the prognosis, especially in the forms late and miopáticas.

The clinical picture of GA II according to the genetic defect is indistinguishable; as each defect can lead to mild or severe.

According to the clinical features are divided into:

  • Neonatal onset: usually very serious, are characterized by hypoglycemia is not ketotic serious (the descent of the glucose in the blood without ketone bodies), acidosis metabolic involvement multisystem and excretion of large amounts of metabolites derivatives of fatty acids and amino acids.
    • TYPE I: with congenital anomalies (such as the dysmorphia facial, indicating that the effect is already prenatal).
    • TYPE II: without congenital anomalies.
  • Late-onset type III. The symptoms and the age of presentation are highly variable (juvenile, adult) and is characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress and by a metabolic decompensation.
  • Myopathic Type , of late presentation sometimes in adulthood, which causes muscle pain, weakness, exercise intolerance, and myopathy (muscle injury) by deposit of lipids. It is often intermittent and is only evident in periods of disease or catabolic stress.

It is important to note that it has been shown that treatment with riboflavin improves symptoms and metabolic profiles in many patients, particularly those with type III, the late onset and milder form.

The symptoms of GA-2 may be very different from person to person. May appear in the period of the newborn or late in childhood, youth and adulthood.

Some babies have their first symptoms shortly after birth.

  • Rapid breathing
  • Hypotonia
  • Metabolic crisis
  • Smell feet "sweaty"
  • Heart problems, and liver problems.
  • Congenital malformations
  • Comma

If the symptoms occur late, can start at any time from early childhood to adulthood.

  • Intermittent States (cyclic vomiting)
  • Nausea
  • Vomiting
  • Muscle weakness, hypotonia
  • Periods of hypoglycemia (weak, shaky or dizzy with cold, clammy skin)
  • Metabolic crisis

Hypoglycemia and metabolic crisis may occur:

  • After exercise
  • After intake of high amount of protein
  • A lot of time in fasting
  • During illness or infection
  • Deficit carnitine
  • Involuntary movements

Some people with GA-2 never have any symptoms, and only affected after they are diagnosed with a brother or sister.

A small number of newborns with the neonatal type have shown positive effects to the treatment.

In the late onset type with prompt treatment and care, children and adults with GA-2 generally live healthy lives with a normal growth and development.

The goal of treatment is to prevent long-term problems. However, children who have metabolic crisis metabolic may develop learning problems for life.

The treatment is usually needed during the entire life, it is usually individualized, adapted to the characteristics and needs of each child.

  1. Avoid going too long without eating: they need to eat frequently to prevent hypoglycemia or a metabolic crisis. Your doctor will tell you how often you need to feed your child. It is important that infants be fed during the night. It is possible that you need to wake them up to eat if they do not wake up alone. Metabolic specialists will provide you with a protocol of appropriate nourishment for the baby. Your doctor will also explain the "emergency regimen" during illness or other occasions that your child does not eat.

Your metabolic expert should continue advising you on the frequency with which your child should eat as it grows.

  1. Diet
    Usually a low fat diet is recommended , low in protein and high in carbohydrates that give the body the sugar to get the energy they need (bread, cereal, pasta, fruit, vegetables). You should not remove all the fat and protein of the diet, as is needed for the growth and development. But as we've said before, the treatment, including diet, should be adapted to the individual characteristics.

The specialists will create a diet that meets the needs of your child.

3 - Riboflavin: it is associated with clinical improvement. This is a type of B vitamin (vitamin B2). It helps to convert carbohydrates, proteins and fats into energy for the body.

4 - Carnitine-helps the body to generate energy from fat in the food and fat stored in the body. It also helps to rid cells of waste harmful produced during the decomposition of fat. Supplements of carnitine can be used as a treatment for some metabolic disorders.

  1. Call your doctor at the beginning of any disease.
  • Poor appetite
  • Low energy or extreme drowsiness
  • Vomiting
  • Diarrhea
  • Infection
  • Fever

During an illness or infection, children with GA-2 have a much higher chance of developing hypoglycemia or a crisis metabolic. Need to drink liquids and eat carbohydrates extra when they are sick, even if they are not hungry, or they may have a crisis metabolic.

Children who are sick often don't want to eat. If they can't eat, or if they show signs of hypoglycaemia or a crisis metabolic, they may need to be treated in the hospital. Ask your doctor about the metabolic whether you should carry a special letter to travel with medical instructions for the care of your child.

The treatment of the more severe phenotypes consists in the restriction of fats and proteins and the adoption of a diet rich in carbohydrates. It is essential to strictly avoid fasting and other types of attacks precipitant. You must have regimes of urgency to any decompensation, metabolic.

It is also observed a positive effect of supplementation with Coenzyme Q10.  

For cases of moderately severe has used 3-hydroxybutyrate with success, but further studies will be necessary in this regard.

Do not use any supplement without consulting your specialist.

Can cause crisis metabolic. Some of the first symptoms of a crisis metabolic are:

  • Extreme drowsiness
  • Behavior changes
  • Irritable mood
  • Muscle weakness
  • Poor appetite

Other symptoms are followed:

  • Fever
  • Nausea
  • Diarrhea
  • Vomiting
  • Hypoglycemia
  • Increased levels of acidic substances in the blood, called metabolic acidosis

If this is not a crisis metabolic, a child with a GA-2 can develop:

GA2 may cause crisis metabolic.

Some of the first symptoms of a crisis metabolic are:

  • Extreme drowsiness
  • Behavior changes
  • Irritable mood
  • Muscle weakness
  • Poor appetite
  • Fever
  • Nausea
  • Diarrhea
  • Vomiting
  • Hypoglycemia
  • Increased levels of acidic substances in the blood, called metabolic acidosis

If this is not a crisis metabolic, a child with a GA-2 can develop:

PRE-SYMPTOMATIC DIAGNOSIS: The newborn screening or testing of the heel for help at the start of adequate treatment, which prevents many of the irregularities and its potential sequelae. It is available in several european countries, but still there is not enough experience in spite of this, due to the low number of cases.The study of the mutations in the genes coding for the α and β subunits of the gene ETFA/ETFB and ETF-QO confirms the diagnosis.The GA-2 can be confirmed by tests carried out on samples of blood, urine, or skin.– In the blood is observed an increase of acylcarnitines of C4-C18, can present a severe decrease of carnitine.– Usually the analysis of organic acids in urine reveals increments of combinations of dicarboxylic acids, acid glutárico, acid etilmalónico, 2-hidroxiglutarato and glycine.– The flow-oxidative fatty acids in fibroblasts (puncture of the skin) and the analysis of acylcarnitine in fibroblasts after incubation with palmitic acid tend to be anomalous.DIAGNOSIS of SYMPTOMATIC: it is performed on the basis of clinical presentation: the concentration of glucose in the blood is low, with absence of ketone bodies, lactic acidosis and a deficiency of carnitine, increase in times of liver enzymes and creatin kinase. In the late is observed in the decompensation metabolic.

PRENATAL DIAGNOSIS: it Is possible to make a prenatal diagnosis when we have identified two pathogenic mutations in the family.

DIFFERENTIAL DIAGNOSIS:

  • Polycystic kidney disease, autosomal recessive
  • Carnitine deficiency palmitoíl-transferase II
  • Syndrome of Zellweger
  • Alterations in the biosynthesis of sterols

GENETIC counseling: Is inherited as a autosomal recessive, and there is the possibility of genetic counselling.

If you have found both genetic changes in your child, you may perform DNA testing during future pregnancies. The sample needed for this test is obtained by chorionic villus sampling or amniocentesis .

If the DNA tests are not useful, they may perform a test of enzymes in the cells of the fetus. The sample needed for this test is obtained by amniocentesis.

Parents can choose to be tested during pregnancy or wait until the birth to the baby to be examined. A specialist in genetics can explain your options and to answer questions about prenatal testing or the testing of your baby after birth.

GA-2 is inherited in an autosomal recessive.

We all have a pair of genes that produce the enzyme ETF and another pair that produces the enzyme ETF: QO.

In children with GA-2, the gene pair for one of these enzymes is not working properly. These children inherit one non-working gene for the condition from each parent.

A person must inherit two copies mutated in the same gene (one copy of the mutation from each parent) to develop the disease. If a person inherits a mutated copy of a gene and one normal, in most cases it will be a healthy person, carrier, because, the normal copy is going to compensate for the mutated. Be a person, a carrier means that you do not have the disease, but that has a mutated copy of the gene of the pair of genes.

Parents of children with GA-2 usually do not have the disorder; but each parent has a single gene is not functional for GA-2, are carriers . Carriers do not have a deficiency of GA-2 because the other gene of this pair is working correctly.

If both parents are carriers of the same mutation of the gene, it can pass on the mutated gene or the normal to their offspring, and this is going to happen at random. If both parents are carriers of the same mutation of the gene can pass on the mutated gene or the normal to their children and this is going to happen at random.

Each one of the children of parents are carriers of the same mutation gene have a 25% chance (1 of 4 possibilities) of inheriting the mutation from both parents and developing the disease. This also means that there is a 75% chance (3 out of 4 possibilities) that the child is not affected by the disease. This probability remains the same in every pregnancy and in children or girls.

  • In addition, there is a 25% chance (2 out of 4 possibilities) that the child will inherit one copy of the mutated gene from one of their parents, so they will be healthy but the bearer such as their parents.
  • Finally, there is a 25% chance (1 of 4 possibilities) that the child inherits both copies of the normal gene. In this case the child will not be suffering the disease, or be a carrier.
  • These possible outcomes happen at random. The probability remains the same in every pregnancy and between boys and girls.

The brothers and sisters of a baby with a GA-2 have the potential to be carriers or have the disease, even if they have not shown symptoms. It is important to detect because early treatment can prevent serious health problems.

 Treatment standard MAD

LINK: https://www.familiasga.com/wp-content/uploads/2018/10/TRATAMIENTO-ESTANDAR-MAD.pdf

Treatment of decompensation MAD

LINK:

https://www.familiasga.com/wp-content/uploads/2018/10/TRATAMIENTO-EN-DESCOMPENSACI%C3%93N-MAD.pdf

Protocol GA2 2008 BIMDG

LINK:

https://www.familiasga.com/wp-content/uploads/2018/11/PROTOCOLO-GA2-2008-BIMDG.pdf

El protocolo de emergencia es el componente mas importante en la estrategia de tratamiento. Pregúntele al medico especialista si su hijo debe llevar consigo unas recomendaciones medicas sobre su tratamiento .
No use ningún medicamento sin antes consultar con su medico especialista en metabolismo.

Más Información

El tratamiento de emergencia es el componente más importante de la estrategia de tratamiento. Dado que la lesión estriatal aguda ocurre o insidiosamente hasta los 6 años de edad, las recomendaciones de tratamientos para el mantenimiento y el tratamiento de emergencia son estrictas para los pacientes mayores de 6 años de edad. 

Pregúntele al médico especialista si su hijo debe llevar consigo unas recomendaciones médicas sobre su tratamiento.

No use ningún medicamento sin antes consultar con su médico especialista en metabolismo. 

All help is Welcome

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