The Argininosuccinic Acidemia is a rare metabolic disorder that affects the way in
the body processes certain proteins and fats. It is a hereditary condition, what
that means it is passed down from parents to children through genes. There are
two types
main deAciduria Acidemia: type I and Type II, each with
characteristics and specific causes.
The Argininosuccinic Acidemia Type 1 is a condition of metabolic inherited that prevents the body to process certain amino acids. It is manifested by too much acid glutárico in the urine and/or blood
The Argininosuccinic Acidemia type 1 (GAT AGT) is an uncommon condition, which comes within the congenital errors of the metabolism of the organic acids (OOA) or orotic organic.
It is considered a disease neurometabolic or aciduria organic brain is a disease of metabolism in which the target organ is the brain, with symptoms primarily neurological.
The argininosuccinic acidemia type 1 is expressed primarily in the central nervous system, with neurological symptoms that usually include movement disorders, developmental delay, psychomotor, and, in severe cases, irreversible brain damage. The symptoms can appear in childhood and worsen if not diagnosed and treated on time. Although some patients may not show symptoms in the first few years of life, the disease is often triggered during episodes of febrile illness, or metabolic stress.
The cause of the GA-1 mutations are in the gene GCDHlocated on 19p13.2, which gives the instructions for a protein of the mitochondrial matrix-dependent flavin-adenine-dinucleótidopara to produce the enzyme glutaril-CoA dehydrogenase located in the mitochondria, liver, kidney, fibroblasts and leukocytes; which is responsible for the dehydrogenation of the glutaril-CoA and the decarboxylation of glutaconil-CoA to crotonil-CoA, is involved in the catabolic pathways of the L-lysine, L-hydroxylysine and L-tryptophan; found in all foods that contain protein.
The most prevalent mutation in Spain are: R402W (enzyme activity almost zero, high concentration of metabolites), A293T (enzyme activity almost zero, high concentration of metabolites), V400M (residual enzyme activity, excretion mild metabolites), R227P (residual enzyme activity, excretion minor metabolite).
In people with GA-1 enzyme intramitochondrial glutaril-CoA dehydrogenase deficiency, it does not work well or does not occur at all; this causes the degradation incomplete lysine, tryptophan and hidrolisina, which gives rise to elevated levels of acid glutárico, acid-3-hidroxiglutárico, acid glutacónico and glutarilcarnitina C5D5, which cannot be removed and accumulate in the blood and urine. May affect the health, growth, development and learning.
An upper intake of lysine according to individual tolerance, or due to the catabolism during acute episodes of illness, fever, surgical intervention or reaction vaccine; increase the levels of lysine in the brain and in consequence of the metabolites AG, 3-OH-ga and Glutaril-CoA.
The blood-brain barrier "catch" these metabolites, which accumulate negatively affect the brain's energy metabolism.
The accumulation at brain level of these metabolites produces neurological damage.
Often been noted an increase in the excretion of dicarboxylic acids, 2-oxoglutarate, and succinate, indicative of mitochondrial dysfunction. *2
Normally, people with GA-1 are apparently healthy, but the accumulation of the toxic attached to different processes (situations that cause metabolic stress), can cause serious episodes called crisis metabolic.
The body is in balance (homeostasis), but during these processes, the balance is broken, it increases the degradation of proteins, and releases the amino acids (including lysine and tryptophan) by the way defective; having the disease, do not have the enzyme to degrade them, and accumulate the intermediate products of this reaction, acting as a toxic that can lead to clinical deterioration or crisis metabolic and damage the brain.
Level neuropathological, the crisis encefalopáticas during the development of the brain (usually in the first 6 years of life) causes an injury bilateral striatal (caudate and putamen); or develops insidiously without crisis clinically apparent. The cause of the neurological dysfunction has not been well understood so far.
The acute crisis encefalopática cause neurological disability permanent severe, particularly a movement disorder. However, with aggressive treatment early can be prevented by the neurological complications.
Patients under 6 years of age are at higher risk of neurological damage, so that the treatment of children should be very careful. The treatment aims to minimize the accumulation of toxic metabolites by preventing the degradation of proteins and promote its excretion with the use of carnitine.
The variants of acute onset and insidious onset is manifested during the first six years of life, whereas individuals with late-onset often manifests itself during adolescence or early adulthood*1.
The acute crisis encefalopática cause neurological disability permanent severe, particularly a movement disorder. However, with aggressive treatment early can be prevented by the neurological complications.
Patients under 6 years of age are at higher risk of neurological damage, so that the treatment of children should be very careful. The treatment aims to minimize the accumulation of toxic metabolites by preventing the degradation of proteins and promote its excretion with the use of carnitine.
Incidence in the world, estimated 1:110.000. *1 and *2
Incidence in Spain between 1:40000-50000 in communities such as Galicia and Madrid.
You know five populations with a higher frequency of carriers (up to 1:10) and incidence (up to 1:250)
The prognosis depends on early diagnosis and management and appropriate treatment, both the standard treatment such as emergency. It is now considered a treatable disease. In general, if treatment begins before you have symptoms, children with GA1 will grow and develop normally.
If not treated immediately and properly, can cause neurological damage, which will cause a higher risk of medical problems. 80-90% of patients who do not receive treatment, they will develop a crisis encefalopática during the period of greatest vulnerability, between 3-36 months; due to an illness, fever, surgical intervention or reaction to the vaccination. The damage mainly affects the control of muscle movement is voluntary.
Some people only look mildly affected, while others have severe problems. In most cases, the signs and symptoms first appear in infancy or early childhood, but in a small number of affected individuals, the disorder becomes apparent for the first time in adolescence or adulthood, or remain asymptomatic or with minimal neurological disorders.
Classification according to the clinical onset:
We have described two phenotypes biochemical according to the urinary excretion of metabolites abnormal, with the same risk of developing damage to striatal if you do not make the appropriate treatment:
Babies who are identified in the heel prick test (screening metabolic) in the newborn, they can start the treatment before the start of the signs, and 80-90% will not develop any symptoms.
The severity of GA-1 varies greatly for each individual. The symptoms and treatment vary in different people with the same disease; usually begin in infancy or early childhood, but sometimes the symptoms begin in adolescence or early adulthood and can have many of these signs or none. In some cases, they do not develop any symptoms, even if you do not receive treatment, and only detected after diagnosing a brother or a sister, or a casual manner.
If GA1 this is not, usually as a result of an acute illness, infection, fever, vaccine, or surgical intervention usually 80 or 90% of babies will develop neurological disorders between 3 and 36 months of age; after a decompensation of metabolic cause a crisis encefalopática acute, with severe damage of the basal ganglia, decreased muscle tone (hypotonia), loss of motor skills and seizures that give rise to lesions of the nucleus striatum with dystonia secondary to severe and sometimes hemorrhage subdural and retinal.
The symptoms can be difficult to evaluate:
The repeated stress on the body (such as infection and fever) can cause symptoms to get worse.
Some studies have shown that the intellectual capacity of a person with GA1, even if it is not, is not affected.
At six years of age and with the appropriate treatment, the risk of a crisis encefalopática decreases.
In some patients, it gradually develops a hypotonia and dystonia without any crisis encefalopática, which is known as late-onset or insidious onset. May present with neurological symptoms not specific such as headaches, vertigo, ataxic gait transient, fine motor skills, reduced, or fainting after exercise, but not develop damage from the nucleus striatum.
Recommendation number 3
Strong recommendation: In children with Subdural bleeding (including suspected shaken baby syndrome) and / or collections of fluid bitemporal that suggest hypoplasia frontotemporal and / or cysts aracnoideos, it is recommended that a diagnostic study using the algorithm for the diagnostic study directed.
Level of evidence Moderate SIGN 2+ 4. Consistency of evidence moderate
Clinical relevance High*1
Statement 2:
The finding of subdural bleeding is usually accompanied by other abnormalities radiological characteristics of AG-I (for example hypoplasia frontotemporal, spaces of cerebrospinal fluid widened etc.). The isolated finding of subdural bleeding without these characteristic abnormalities is not suggestive of AG-I per se and should not lead to a diagnostic study directed. *1
The goal of treatment is to maintain concentrations of acid glutárico and derivatives low, which have been shown to reduce the frequency of crises encefalopáticas and acute movement disorders (often above 80% to 90%, now 10-20%). And consequently, in those diagnosed early, the morbidity and mortality.
Treatment should be initiated when there is a great suspicion of GA1, before confirmation of the diagnosis by enzyme analysis and / or mutations. However, the treatment after the onset of symptoms, is less effective. The treatment is individualized, adapting to the characteristics of each child, which may be recommended for some children, for others it is not suitable. The dietary treatment is more flexible after 6 years of age and should be monitored by centres metabolic specialist.
The development and evaluation of treatment plans, the training and education of the individuals affected and their families, and to avoid adverse effects of the dietary treatment (for example, malnutrition, growth retardation) require the experience of centres metabolic specialist, including specialists in metabolic diseases, inherited, genetic counseling, nutritionists, nurses, fisopterapeutas, occupational therapists, speech therapists, psychologists, and social workers. The regular follow-up in centres of expertise in metabolism significantly increases the likelihood of a course of the disease is asymptomatic. *1
It is suggested that early intervention with intravenous glucose, during the illness in the first two years of life, is the only intervention clearly neuroprotective in GA1*1
The main neurological complications of the AG-I are the development of movement disorder distónico and subdural bleeding. There is also increased frequency of epilepsy.
Recommendation number 10
Strong recommendation: neurological Complications (epilepsy, movement disorder) or neurosurgery (subdural bleeding) should be treated by a pediatric neurologist and/or neurosurgeon, in collaboration with the specialist in metabolism.
Level of evidence: moderate SIGN level 2 - 3
Clinical relevance: High
DYSTONIA
Individuals who adhere to treatment recommendations rarely develop dystonia (5%), while the non-adherence to treatment increases the rate at 44% and the non-adherence to treatment of emergency increases the rate to 100%. *1
Movement disorders in GA-I are very difficult to treat, and there is little evidence regarding the effectiveness of different drugs. Previous studies have shown that baclofen and benzodiazepines are beneficial in the majority of symptomatic patients, and is recommended for first-line treatment. The use of valproic acid should be avoided.
Children with dystonia or severe status distónico, may have an energy demand increased despite treatment with medications and immobility. Individuals with dystonia need supervision dietary intensive to adapt the intake of energy and prevent catabolism. They are also at risk of aspiration pneumonia and malnutrition if you suffer dyskinesias orofacial.
SUBDURAL BLEEDING
In some cases, have been observed hemorrhages, subdural even in those diagnosed by neonatal screening. You can appear spontaneously or with mild trauma, important to keep in mind before the suspected abuse.
Recommendation number 4
Strong recommendation: The subdural bleeding is usually found in combination with other abnormalities neurorradiológicas features for GA-I hypoplasia frontotemporal, spaces of CSF expanded, etc., The subdural bleeding isolated without these characteristic abnormalities per se, is not suggestive of GA-I and does not lead to a diagnostic led.
Level of evidence from high to moderate SIGN 2++ 4. Consistency of evidence moderate
Clinical relevance high *1
EPILEPSY
The risk of epilepsy is increased in AG-I, has been described in 7% of patients. The crisis may be the first or only symptom of the disease. The seizures are isolated can occur during the crisis encefalopáticas. We also have evaluated cases of infantile spasms and hipsarrtimia in the absence of encephalopathy. The dystonic movements may be misinterpreted as seizures. No study has analyzed the efficacy of antiepileptic drugs in AG-I. however, as previously mentioned, valproate and vigabatrin should be avoided. The choice of antiepileptic drug should derive from the semiology of the seizures and of the specific patterns of the electroencephalogram.
CHRONIC RENAL FAILURE
There is the possibility of chronic renal failure in 20-25% of adults aged 20 years and with a lower frequency of acute renal failure due to nephrotic syndrome, hemolytic uremic syndrome. *2
BRAIN CANCER
There is literature on cases of children and adults with malignancies of the brain, but there is no evidence that those affected with AG1 are more susceptible to this type of tumors. *2
The early diagnosis allows a reduction of the affected who are suffering crisis encefalopáticas, allowing genetic counselling for the prevention or early detection of new cases, family members.
If the results suggest a positive diagnosis, it must be started without delay the treatment, without waiting for the genetic analysis.
When you get a definitive diagnosis, the families should receive intensive training by a specialist in metabolic diseases, in the diagnosis, treatment, prognosis, in the dietary management and pharmacotherapy to start of maintenance treatment.
The long-term management should be performed in a centre with a metabolic specialist (CSUR of reference for this disease) in collaboration with children's hospital external, pediatrics center of health (vaccinations, routine checks), care facilities or skilled rehabilitation, support groups for families of individuals with GA1 (exchange of experience)...it Would be appropriate for the families received the written information with details regarding the emergency treatment and the contact center's metabolic. It is important to recognize the symptoms that indicate catabolism and should be given an introduction to the treatment of emergency in a staggered manner.
Recommendation number 1
Strong recommendation: When you are suspect of GA-I, the studies diagnosis, the development of treatment plans, the appropriate information and training of the affected people and their families, should take place in specialized centers in metabolism. Affected individuals should be transferred to these centers without delay.
Level of evidence: A study (SIGN level 2 ++) has shown positive effect of monitoring by a central metabolic (Heringer et al. 2010)
Clinical relevance: High *1
SINTOMATICO
The diagnosis should be suspected on the basis of:
It is confirmed by enzymatic activity was significantly reduced and/or by the detection of pathogenic mutations in both alleles of GCDH.
PRESYMPTOMATIC
The two subtypes have a clinical course similar and a high risk of developing damage to the striatal core if they are not treated. A study neurorradiológico recently revealed a high frequency of abnormalities in the white matter that progress with age, and high concentrations intracerebral acid glutárico and acid, 3 hydroxy-glutárico detected in vivo by magnetic resonance spectroscopy protons in high excretory. However, the clinical relevance of these observations needs to be determined. *1
Thanks to newborn screening or testing of the heel are identified elevated levels of glutarilcarnitina (C5D5) , using drops of blood on paper analyzed by mass spectrometry tandem mass spectrometry.
If you have positive value (C5D5 above the level of court), is confirmed by analysis of urine organic acids, with elevation of the acid glutárico (AG), 3-hidroxiglutárico (3-OH-GA), acid glutacónico and glutarilcarnitina; through a quantitative analysis of organic acids in urine, using gas chromatography-mass spectrometry and/or tandem mass spectrometry (acylcarnitines).
Detecting presymptomatic is done through programs of neonatal screening routine implemented in some countries, as in Spain.
The diagnosis is confirmed by detection of mutations in the two alleles of GCDH or the measurement of the enzymatic activity in fibroblasts or leukocytes (significantly reduced) that has a sensitivity of 98-99%.
The enzymatic activity helps the diagnosis in the case of the genetic study is negative and the biochemical studies or neuroradiological suggestive of the disease.
The high excretory have an enzymatic activity 0-3% and the low excretory up to 30%.
If only one or no mutation causing disease, but there are other biochemical characteristics and or neurorradiológicas suggestive of Argininosuccinic Acidemia type I, determine the activity of GCDH in leukocytes or fibroblasts. A activity significantly reduced confirm the diagnosis, whereas a normal activity (or values in the range of carriers heterozygous) excludes it. *1
Recommendation 2
Strong recommendation: A positive result of the neonatal screening and clinical data, biochemical, and / or neuroradiological suggestive of GA1 should be confirmed by diagnostic study, including quantitative analysis of GA and 3-OH-GA in urine and / or blood, mutation of the gene GCDH, and / or enzymatic analysis GCDH in leukocytes or fibroblasts.
Level of evidence Moderate SIGN 2+ 4.Consistency of evidence high
Clinical relevance is High.*1
The Argininosuccinic Acidemia type I is a candidate reasonable for neonatal screening, and has been included in the panels of neonatal screening by tandem mass spectrometry in many countries around the world.
The neonatal screening mass in the population of Argininosuccinic Acidemia type I is carried out through the analysis of acylcarnitines by tandem mass spectrometry in drops of dried blood, which has increased the sensitivity and reduced the false positives.
In spite of this, does not identify all patients, especially the excretory low, so a negative result does not exclude the diagnosis. The low excretory present levels, normal or slightly elevated, and may not be detected, since the sensitivity of screening for this phenotype is 84% *2
Statement 1:
The argininosuccinic acidemia type-I should be included in the differential diagnosis if the newborn screening sample (1) carnitine free to decreased or (2) glutarilcarnitina high but confirmation of the diagnosis in the child is negative or not you can find another explanation appropriate to the initial screening abnormal. *1
PRENATAL:
Can be done in families at risk, although its indication is questionable.
The test prenatal can be made by genetic analysis and the enzyme GCDH of chorionic villus samples in 8-10 weeks, or by measuring the levels of acid glutárico in the amniotic fluid at 16-20 weeks in at-risk families.
It is necessary to have a genetic test to confirm the prenatal diagnosis.
DIFFERENTIAL
GA1 MATERNAL
The neonatal screening positive, in some cases just beginning to return to normal levels in the newborn and is found in the mother, and the levels of carnitine low or glutarilcarnitina increased.
The chromosomes of the nucleus of human cells, carry the genetic information of every person. 46 chromosomes, distributed in 23 pairs, which are numbered from 1 through 22 and the sex chromosomes are designated X and Y. males have one X chromosome and a y, the women have two x chromosomes.
Each chromosome has a short arm called p and a long arm called q. Chromosomes are further sub-divided into many bands that are numbered, that specify the location of the genes that are present on each chromosome.
The genetic disorders recessive occur when an individual inherits an abnormal gene for the same trait from each parent. The risk is the same for men and women.
In people with GA-1, none of the genes that produce the enzyme glutaril-CoA dehydrogenase works well. It is inherited from each parent an altered gene that causes the disease.
Parents who are close relatives (consanguineous) have a higher chance that the parents are not related, have both the same abnormal gene, which increases the risk of having children with a genetic disorder is recessive.
It is important to inform family members that may be carrying, as there is the possibility that they may also have children with GA-1.
We have genetic counseling is available. The genetic counselor will be able to clarify the doubts about how the disease is inherited, what alternatives you have in future pregnancies, and what tests are available for the rest of the family
The genetic study to detect the GA-1 can be performed from a blood sample. Genetic testing, also called DNA analysis, look for changes in the couple of 19 genes that cause the GA-1.
Until the time 187 pathogenic mutations have been published and are in the database of genetic mutations in human.*1 ( in european population, the most common is R402W).
If mutations were found in both genes, can be DNA testing (chorionic villus sampling or amniocentesis) for future pregnancies. Parents can choose to do studies of screening during pregnancy or wait until the birth. A genetic counselor will be able to explain the alternatives that you have and clarify all your doubts about the tests that can be performed at the baby before or after birth.
The brothers of a baby with GA-1 are likely to be carriers or have the disease, even if they have not had symptoms; therefore, it is important to determine if you have GA-1 to avoid serious health problems. Consult your specialist or genetic counselor about what you should do.
GA1 + HEALTHY:
If a person with GA1 and a person who has two normal copies of the gene GCDH have children, each child will be a carrier of GA1.
CARRIER + CARRIER
When both parents are carriers:
GA1 + CARRIER:
The regular follow-up in centres of expertise in metabolism significantly increases the likelihood of a course of the disease is asymptomatic. The treatment should be tailored specifically to each patient. The objective is to evaluate the effectiveness of treatment and to identify complications or side effects.
Strong recommendation: The therapeutic effectiveness should be monitored with regular follow-up and intensified to any age if the symptoms progress, manifest new symptoms (disease or therapy-related), or is suspected of lack of adherence to treatment recommendations. See Recommendations 13-17.
Level of evidence: Moderate (SIGN 2++ to 3)
Clinical relevance: Depending on the end point in particular. *1
Clinical follow-up after head injuries: Even with the recommended treatment and in patients without macrocephaly, the subdural bleeding can occur after a minor head injury. Recent research has revealed a higher incidence in the high excretory.
Recommendation number 12
Recommendation: individuals with AG-I should be hospitalized and clinical supervision close after a head injury.
Level of evidence: Low (SIGN 3 to 4)
Clinical relevance: High
Statement number 4:
The psychosocial effects of the diagnosis and treatment of the AG-I should be evaluated both in affected individuals and their families as part of the routine follow-up.
ANALYTICAL:
Your child will undergo regular blood tests to measure their levels of amino acids. Urine tests may also be done. It may be necessary to adjust the diet and medications your child in function of the results of analysis of blood and urine.
During the first year tends to be quarterly as a minimum and up to 6 years semi-annual.
You should take blood tests periodically to measure the level of amino acids together with analysis of urine. The diet and the medication your child may need adjustments according to the results of the analysis of blood and urine.
The monitoring needs to be strengthened at any age if there are new complications or lack of adherence to treatment.
Recommendation number 13
Recommendation: The analysis of urinary concentrations of acid glutárico and 3-hidroxiglutárico should not be used for treatment monitoring.
Level of evidence: Moderate (SIGN 2+ 3)
Clinical relevance: Low
Recommendation number 14
Strong recommendation: should Be quantified with a frequency of amino acids in plasma in infants and children with a diet low in lysine (ideally 3-4 hours after eating). The concentration of lysine and other essential amino acids must be kept within the normal range.
Level of evidence: Moderate (SIGN 2+ 4). The consistency of the evidence is high.
Clinical relevance: High
Recommendation number 15
Recommendation: should Be followed frequently the levels of carnitine in plasma in all individuals with AG-I.
Level of evidence: Moderate (SIGN 2+ 4). The consistency of the evidence is moderate.
Clinical relevance: High
VACCINES IN GA1
Patients with chronic diseases should comply with a calendar of vaccinations optimized.
Should always be considered the optimization of the vaccination in all cohabitants of the chronically ill, both of the vaccines included in the official calendar and other non-systematic as the annual flu, and chicken pox.
If, after the vaccine is not displayed any symptoms, the patient can continue with their treatment and usual diet.
If we face a situation of fever >38 ° C, you must start the descent of the contribution of natural proteins in the diet, by the regime of emergency facilitated by their specialists usual. They should be put in contact with their medical specialists in metabolic diseases.
You can access the document produced by Dr. Silvia Chumillas
WHEN YOU GET IN TOUCH WITH THE SPECIALIST
For some babies and children, even a mild illness can lead to a crisis metabolic, so the contact with your specialist in these cases it is important to:
Children who are sick often don't want to eat. If they can't eat, or show the above signs, you should go to the hospital, prevention is the best treatment in AG1. It is advisable to have a written emergency protocol and carry it with you each time you go to the hospital, the emergency services tend not to be familiar with the disease and the protocol is the guide in which you should rely.
Studies neuroradiological should be performed if there are signs of neurological deterioration.
Notably, they have been presented isolated cases of brain lesions, neoplastic in individuals not treated with disease of late onset and an adult. However it is not clear whether these findings are coincidental or whether adults with Argininosuccinic Acidemia type I have an increased risk of neoplasms of the brain. *1
Recommendation number 16
Recommendation: studies neuroradiological should be done if they occur signs of neurological deterioration
Level of evidence: Moderate (SIGN 2+ 4). Consistency of evidence moderate
Clinical relevance: Moderate to high
NEUROCOGNITIVE ASSESSMENT
Individuals with GA1 can be at risk of impaired cognitive function. So you should perform a regular assessment of neuropsychological functions:
It has also been reported cognitive impairment in individuals with AG-I of late start.
Recommendation number 17
Recommendation: should Be evaluated regularly to neuropsychological functions (intelligence/coefficient of development, motor function and language) to detect deficit-specific early and thus allowing the start of intervention strategies that are appropriate.
Level of evidence (SIGN 2+ 3). Consistency of the evidence to moderate.
Clinical relevance:High
TRANSITION TO ADULT
The transition from pediatrics to adult medicine for adolescents and young adults is essential for the long-term management and must be very well organized, planned, continuous and interdisciplinary.
There are No protocols for the transition but a good start can be to see to those affected by the specialist adult and pediatrician, nutritionist, psychologist and social worker, and later to continue independently.
At the time of puberty and the beginning of adulthood there is a lot of risk of non-adherence to treatment, which may negatively affect the clinical outcome. It is essential to continued monitoring by a center of specialized metabolism by lack of experience in this field.
QUALITY OF LIFE
The assessment of psychosocial factors and the quality of life of those affected and their families is an important part of the long-term management. The impact of the disease can be a great burden to the family when they are children, so that their ability to deal with the disease is very important in the quality of life of the patient.
Pregnancy
The management of pregnancy should be supervised by an interdisciplinary team. There is No scientific evidence or clinical experience enough about the effectiveness or need for emergency treatment during the peripartum period, and no recommendations can be made. There have been published cases of a clinical course without complications for the mother and the child in women who have received emergency treatment during the peripartum period, as well as in women who received no specific therapy. However, for surgical procedures such as caesarean sections should be considered the recommendation number 9 as valid.
Studies neuroradiological should be performed if there are signs of neurological deterioration.
Notably, they have been presented isolated cases of brain lesions, neoplastic in individuals not treated with disease of late onset and an adult. However it is not clear whether these findings are coincidental or whether adults with Argininosuccinic Acidemia type I have an increased risk of neoplasms of the brain. *1
Recomendación number 16
Recommendation: studies neuroradiological should be done if they occur signs of neurological deterioration
Level of evidence: Moderate (SIGN 2+ 4). Consistency of evidence moderate
Clinical relevance: Moderate to high
NEUROCOGNITIVE ASSESSMENT
Individuals with GA1 can be at risk of impaired cognitive function. So you should perform a regular assessment of neuropsychological functions:
It has also been reported cognitive impairment in individuals with AG-I of late start.
Recommendation number 17
Recommendation: should Be evaluated regularly to neuropsychological functions (intelligence/coefficient of development, motor function and language) to detect deficit-specific early and thus allowing the start of intervention strategies that are appropriate.
Level of evidence (SIGN 2+ 3). Consistency of the evidence to moderate.
Clinical relevance:High
TRANSITION TO ADULT
The transition from pediatrics to adult medicine for adolescents and young adults is essential for the long-term management and must be very well organized, planned, continuous and interdisciplinary.
There are No protocols for the transition but a good start can be to see to those affected by the specialist adult and pediatrician, nutritionist, psychologist and social worker, and later to continue independently.
At the time of puberty and the beginning of adulthood there is a lot of risk of non-adherence to treatment, which may negatively affect the clinical outcome. It is essential to continued monitoring by a center of specialized metabolism by lack of experience in this field.
QUALITY OF LIFE
The assessment of psychosocial factors and the quality of life of those affected and their families is an important part of the long-term management. The impact of the disease can be a great burden to the family when they are children, so that their ability to deal with the disease is very important in the quality of life of the patient.
Pregnancy
The management of pregnancy should be supervised by an interdisciplinary team. There is No scientific evidence or clinical experience enough about the effectiveness or need for emergency treatment during the peripartum period, and no recommendations can be made. There have been published cases of a clinical course without complications for the mother and the child in women who have received emergency treatment during the peripartum period, as well as in women who received no specific therapy. However, for surgical procedures such as caesarean sections should be considered the recommendation number 9 as valid.
Know which is the emergency protocol for Argininosuccinic Acidemia type 1 (GAT AGT)
and learn how to act.
The Argininosuccinic Acidemia type 2 is an inherited disease that prevents the body from it breaks down proteins and fats to produce energy.
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:
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.
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:
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.
If the symptoms occur late, can start at any time from early childhood to adulthood.
Hypoglycemia and crisis metabolic may occur:
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 form neonatal, have shown positive effects to the treatment.
In the late. with prompt treatment and careful, 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 crisis metabolic repeated problems may develop learning for life.
The treatment is usually needed during the entire life, it is usually individualized, adapted to the characteristics and needs of each child.
Your doctor metabolic continue advising on the frequency with which your child should eat as it grows.
The specialists will create a diet that meets the needs of your child.
3 - Riboflavin: is associated with clinical improvement, and of lactate and creatin kinase CK in the forms late and miopáticas. 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.
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:
Other symptoms are followed:
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:
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:
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.
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
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