GA TIPO 1

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Glutaric Acidemia type 1 (GAT AGT) is an uncommon condition, which comes within the congenital errors of the metabolism of the organic acids (OOA) . 

It is considered a neurometabolic disease or organic brain aciduria , a metabolic disease whose target organ is the brain, with symptoms primarily neurological. 

Glutaric Acidemia type 1 (GAT AGT) is an uncommon condition, which comes within the congenital errors of the metabolism of the organic acids (OOA) . 

It is considered a neurometabolic disease or organic brain aciduria , a metabolic disease whose target organ is the brain, with symptoms primarily neurological.

The Glutaric 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, does not work well or does not occur at all; this causes the incomplete degradation of lysine, tryptophan and hidrolysine, which gives rise to elevated levels of glutaric acid, acid-3-hidroxiglutárico, acid glutacónico and glutarilcarnitina C5D5, which cannot be removed and accumulate in the blood and urine. These may affect the health, growth, development and learning.

A higher 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 "catches" these metabolites, which accumulate and negatively affect the brain's energy metabolism.

  • Glutaril-CoA inhibits the complex 2-oxoglutarate dehydrogenase
  • AG hinders the transport of dicarboxylic acids between astrocytes and neurons
  • Ga and 3-OH-AG indirectly modulate the neurotransmission of GABA and glutamate, causing an imbalance of neurotransmission.
  • 3-OH-AG induces cellular damage, cytotoxic pathway receptors N-methyl-D-aspartate (NMDA) *2

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

  •  
  • The L-lysine is a necessary element for the construction of all the proteins of the organism it plays an important role in the absorption of calcium; in the construction of muscle proteins; in the recovery of surgical interventions or sports injuries, and in the production of hormones, enzymes and antibodies.
  • The L-tryptophan is necessary for the production of serotonin in the nervous system and its lack can cause neurological deficit. So the diet should be low in tryptophan, do not remove it completely.

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 metabolic crisis

  •  
  • Disease or infection. Vomiting and diarrhea are common and should be monitored closely.
  • Fever
  • Prolonged fasting
  • Vaccine
  • Surgery

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) having the disease patients do not have the enzyme to degrade them, and they accumulate the intermediate products of this reaction, acting as a toxic that can lead to clinical deterioration or metabolic crisis and damage the brain.

At a neuropathological level the encephalopathic crisis during the development of the brain (usually in the first 6 years of life) causes a bilateral striatal injury (caudate and putamen); or develops insidiously without a clinically apparent crisis. The cause of the neurological dysfunction has not been well understood so far.

  • Acute phase: first 24 hours, with cytotoxic edema within the basal ganglia, poor cerebral perfusion, and rapid transit of the blood through the gray matter.
  • Subacute stage: 4 to 5 days after the onset of clinical symptoms, decreased perfusion striatal and the uptake of glucose , and vasogenic edema.
  • Chronic stage: the atrophy of striatal.

The acute encephalopathic crisis causes permanent severe neurological disability, particularly a movement disorder. However, with an early aggressive treatment the neurological complications can be prevented

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 encephalopathic crisis causes permanent severe neurological disability, particularly a movement disorder. However, with an early aggressive treatment the neurological complications can be prevented

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.

There are 5 known populations with a higher frequency of carriers (up to 1:10) and incidence (up to 1:250)

  • The Amish community in Lancaster county, Pennsylvania, united States
  • The First Nations Oji-Cree in Manitoba and western Ontario, Canada
  • Irish nomads in Ireland and the United Kingdom
  • The Lumbee in North Carolina, United States
  • The Xhosa, and other subgroups of the population of South Africa

The prognosis depends on early diagnosis, management and appropriate treatment, both the standard treatment as well as emergency treatment.. 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, it can cause neurological damage, which will cause a higher risk of medical problems. 80-90% of patients who do not receive treatment, will develop an encephalopathic crisis 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 voluntary muscle movement .

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:

  • Acute onset: acute onset, the most frequent; neurological and bilateral striatal injury after encephalopathic crisis with psychomotor regression (regression, loss of developmental milestones acquired) and severe movement disorder. 80-90% of untreated children in the first six years of life.
  • Hypotonia of the neck and trunk
  • Stiffness of limbs
  • Athetosis of the hands and feet (involuntary movements)
  • Loss of skills (sitting, standing, sucking, swallow...)
  • Insidious onset: insidious onset, develop neurological and striatal damage without encephalopathic crisis ,less serious (usually in individuals who do not follow dietary recommendations). Corresponds with the 10-20% of those affected with symptoms. In magnetic resonance imaging patients have less extensive lesions usually in the dorsolateral putamen area, with a lag phase without symptoms after their appearance
  • Late start: late on set, nonspecific mild symptoms after six years, without damage of the nucleus striatum. Recent studies have identified changes in the resonance in the high excretory, possibly related to a higher accumulation in the brain and chronic neurotoxicity. In the magnetic resonance imaging we can observe lesions in the periventricular white matter *1 and *2
  • Headache
  • Ataxia (control poor muscle that causes awkward movements volunteers)
  • Macrocephaly
  • Vertigo
  • Fine motor skills, reduced
  • Fainting after exercise
  • Epilepsy
  • Tremor
  • Peripheral neuropathy
  • Dementia
  • Presenting as Reye's syndrome: with metabolic acidosis, hypoglycemia, liver failure, neurological deterioration and coma. *2

We have described two biochemical phenotypes according to the urinary excretion of abnormal metabolites , with the same risk of developing damage to striatal without the appropriate treatment :

  • Low excretory glutaric acid , in its most carry missense mutations (missense) in at least one allele GDHC, resulting in residual enzyme activity of up to 30%. *1 The determination of 3-O-AG is more specific because some low excretory can have normal levels of glutaric acid in urine; despite this low excretory may have fluctuations of the levels of 3-OH-AG
  • High excretory glutaric acid greater than 100 mmol/mol creatinine.

 

Babies who are identified in the heel prick test (metabolic screening in the newborn) can begin 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; it usually begin s 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 in a casual manner.

If GA1 is not treated ,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; a metabolic decompensation will cause an acute encephalopathic crisis 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 severe secondary dystonia and sometimes subdural and retinal hemorrhage

The symptoms can be difficult to evaluate:

  • About 75% of the newborns with GA1 have a large head circumference (macrocephaly), present at birth or shortly after birth.
  • About 50% will have weak muscle tone (hypotonia).
  • Lack of appetite
  • Feeding problems
  • Drowsiness
  • Fatigue
  • Irritability
  • Vomiting/nausea
  • Fever
  • Growth retardation
  • Delay in the prop head
  • Stiff muscles (spasticity)
  • Developmental delays
  • Delays in walking and other motor skills
  • Learning delays
  • Speech problems
  • Large liver
  • Strange behavior, nervousness
  • Muscle spasms
  • Lack of coordination and balance
  • Involuntary movements of the arms and legs (dystonia): the basal ganglia area of the brain that helps control movement. In some children, the brain damage will occur without fever trigger. Damage to the basal ganglia, especially before 6 years of age, can cause a disruption of the complex motion, similar to cerebral palsy. The control of the movement of hands, arms, feet, legs, head, and neck can be very difficult. The movements can be jerky or stiff.
  • Seizures: the frequency of epilepsy is increased in patients with Glutaric Acidemia type I, and in the crisis it may be the initial presentation symptom.
  • There is a time during childhood there is a higher probability of subdural bleeding, which may be confused with child abuse with injury to the head.

The repeated stress on the body (such as infection and fever) can worsen the symptoms

Some studies have shown that the intellectual capacity of a person with GA1, even if it is not treated , is not affected.

At six years of age and with the appropriate treatment, the risk of a encephalopathic crisis decreases.

In some patients, a hypotonia and dystonia gradually develops a without any encephalopathic crisis , which is known as late-onset or insidious onset. Patients may present non specific neurological symptoms such as headaches, vertigo, ataxic transitory gait ,reduced fine motor skills, 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 bitemporal fluid that suggest frontotemporal hypoplasia and / or aracnoideos cysts , a diagnostic study is recommended 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 radiological abnormalities 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 the treatment is to maintain concentrations of glutaric acid and derivatives low, which has shown to reduce the frequency of encephalopathic crises and acute movement disorders (often above 80% to 90%, now 10-20%). And consequently, in those diagnosed early, the morbidity and mortality.

  • Dietary treatment: diet low in lysine, with the nutrients and enough calories for growth and development
  • Supplements of carnitine
  • Emergency treatment: intensified during the intercurrents diseases (catabolism); it is effective and improves the neurological outcome in those individuals diagnosed early.

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 specialized metabolic centers 

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 metabolic specialized centers ,including specialists in metabolic diseases, inherited, genetic counseling, nutritionists, nurses, physiotherapists, occupational therapists, speech therapists, psychologists, and social workers. The regular follow-up in specialized metabolic centers significantly increases the likelihood that 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 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 dystonic status , may have an increased energy demand despite treatment with medications and immobility. Individuals with dystonia need intensive dietary supervision to adapt the intake of energy and prevent catabolism. They are also at risk of aspiration pneumonia and malnutrition if they suffer orofacial dyskinesis

  • Baclofen: along with benzodiazepines, oral baclofen most commonly used and seemingly effective for the long-term treatment of movement disorders in GA1. The baclofen-run intrathecal has been used with success in individuals with GA1 and severe dystonia . In children with axial hypotonia the use of baclofen may be limited because it worsens the muscle tone. Along with benzodiazepines, oral baclofen (in monotherapy or combination therapy) is the most widely used drug and apparently effective for the long-term treatment of movement disorders in AG-I, and should be used in doses according to the general recommendations. The baclofen-run intrathecal has been used with success in individuals with AG-I and severe dystonia. In younger children, with a prominent axial hypotonia , the use of baclofen may be limited by the deterioration of reduced muscle tone
  • Benzodiazepines: diazepam and clonazepam. In individuals with variable symptoms, the daily dose can be adjusted within a certain range; sometimes treatment may be necessary intermittently. Zopiclone has shown positive effects in some individuals affected by reducing the proportion of movement disorders and the general muscle tone. If the treatment with baclofen or benzodiazepines is not effective, or if adverse effects develop second-line anticholinergic drugs should be considered .Diazepam and clonazepam have shown positive effects in more than 90% of symptomatic individuals. The doses should be administered according to the general recommendations. In individuals with variable symptoms, the daily dose can be adjusted within a certain range. To prevent tachyphylaxis treatment can berequired intermittently .Zopiclone, a cyclopyrrolone used as a hypnotic drug mainly in dystonia non-metabolic, has shown positive effects in some individuals affected by reducing the proportion of movement disorders hyperkinetic and overall muscle tone, due to its qualities, sedative, hypnotic, anxiolytic and muscle relaxant. In contrast with other benzodiazepines, its pharmacodynamic effect is mediated by the receptor for gamma-aminobutyric A (GABA-A subunits BZ1 and BZ2) and the modulation of the chloride channel with a low risk of developing tolerance and addiction. Individuals treated are more relaxed and awake during the day, as they are less affected by movement disorder during the night. It is important to tailor the dose with caution and a step by step reduction , and preferably in the regime of hospitalization. If the treatment with baclofen or benzodiazepines is not effective, or if they occur adverse effects, second-line anticholinergic drugs should be considered
  • Anticholinergic drugs: trihexyphenidyl may be effective in the treatment of dystonia, especially in adolescents and adults, but it can also be effective in children if the dose is increased gradually. However, adverse effects occur frequently (for example transient symptoms such as blurred vision and dry mouth, or persistent symptoms such as memory loss and confusion), and may worsen hyperkinetic dystonia. Adults should have regular follow-up of ocular tonometry.
  • Botulinum toxin: can help to prevent hip dislocation and to reduce the dystonia of the limbs. Some individuals may develop antibodies against the toxin, and may require cessation of treatment. Is usually given once every 3-6 months.
  • Drugs with side effects:none of these drugs should be used for dystonia in GA1.
  • The vigabatrin may cause defects in the peripheral visual field
  • Valproate can affect negatively the proportion of mitochondrial acetyl-CoA/CoA
  • Medications with no effect on dystonia:
  • Carbamazepine
  • L-dopa
  • Amantadine
  • Neurosurgery:
  • Stereotactic surgery (pallidotomy) has been carried out in three individuals with AG-I severely dystonic. In two of them, the clinical outcome was poor, however the third showed improvement in the short-term. There have been No published data on the long-term outcome after pallidotomy.
  • Deep brain stimulation has been carried out with some positive results.

    SUBDURAL BLEEDING 

In some cases, subdural hemorrhages have been observed even in those diagnosed by neonatal screening. They can appear spontaneously or with mild trauma, important to keep in mind before the suspicion of abuse.

Recommendation number 4

             Strong recommendation: The subdural bleeding is usually found in combination with other neuroradiological abnormalities typical of GA-I frontotemporal hypoplasia , expanded spaces of CSF, etc., The subdural bleeding isolated without these characteristic abnormalities per se, is not suggestive of GA-I and does not lead to a diagnostic

         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, and has been described in 7% of patients. The crisis may be the first or only symptom of the disease. The isolated seizures can occur during the encephalopathic crises 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 those affected who are suffering encephalopathic crisis , allowing genetic counselling for the prevention or early detection of new cases, family members.

If the results suggest a positive diagnosis, treatment must be started without delay the , 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 , 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 metabolic center's contact. 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

   SYMPTOMATIC

The diagnosis should be suspected on the basis of:

  • Clinical findings: macrocephaly, encephalopathy, damage to the basal ganglia, alteration of white matter, movement disorders (dystonia, chorea), hemorrhages, subdural and retinal, and high concentrations of acid glutárico, acid-3-hidroxiglutárico and glutarilcarnitina in body fluids.
  • Findings neuroradiological: operculum very open, lesions in the basal ganglia, enlargement of the sylvian fissure, increase in the subarachnoid space in the temporal lobes, alteration of the intensity of the signal in the sequences T2 in basal ganglia and white matter, collections, subdural, enlargement of the cisterns mesencephalic, typical images of frontotemporal atrophy bilateral (“bat wings” in the TAC) and by alterations of the white matter in varying degrees in the magnetic resonance imaging of the brain.
    • Hypoplasia front-opercula-temporary cysts bitemporal, pseudocysts subepepndimarios, subdural collections delay in myelination, signs of leukoencephalopathy and areas of increased signal in the striatum.
    • During the encephalopathic crisis abnormalities appear in the striatum associated with abnormalities of signal in the putamen, caudate, pallidum, and periventricular white matter.

It is confirmed by enzymatic activity significantly reduced and/or by the detection of pathogenic mutations in both alleles of GCDH.

   PRESYMPTOMATIC

The two subtypes have a similar clinical course and a high risk of developing damage to the striatal core if they are not treated. A neuroradiological study recently revealed a high frequency of abnormalities in the white matter that progress with age, and high concentrations of intracerebral glutaric acid and acid 3 hydroxy-glutaric detected in vivo by spectroscopy magnetic resonance of 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 glutarilcarnitine are identified (C5D5) , using drops of blood on paper analyzed by tandem mass spectrometry.

If you have a positive value (C5D5 above the level of court), it is confirmed by analysis in urine of organic acids, with elevation of the glutaric acid (AG), 3-hidroxiglutaric (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).

The presymptomatic detection is done through programs of neonatal routine screening 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 case the genetic study is negative and the biochemistry or neuroradiological studies suggest 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 the disease are found but there are other biochemical characteristics and / or neuroradiological suggestive OF Glutaric Acidemia type I, the activity of GCDH in leukocytes or fibroblasts must be determined . An activity significantly reduced confirms 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 Glutaric Acidemia type I is a reasonable candidate for neonatal screening, and has been included in the panels of neonatal screening by tandem mass spectrometry in many countries around the world.

  • It has led to an improvement in the evolution of the disease, preventing associated disability, preventing nerve damage is irreversible and decreasing mortality.
  • Neonatal diagnosis and onset of treatment increase the likelihood of a course of an asymptomatic disease
  • Provides great information to families thanks to the genetic council

The mass neonatal screening in the population of Glutaric Acidemia type I is carried out through the analysis of acylcarnitine by tandem mass spectrometry in drops of dried blood, which has increased the sensitivity and reduced the false positives.

In spite of this, it does not identify all the patients, especially the low excretory , so a negative result does not exclude the diagnosis. The low excretory present normal levels or slightly elevated, and may not be detected, since the sensitivity of screening for this phenotype is 84% *2

Statement 1:

              The Glutaric acidemia type-I should be included in the differential diagnosis if the newborn screening sample (1) carnitine free decreased or (2) high glutarilcarnitine but confirmation of the diagnosis in the child is negative or you can´t find another appropriate explanation to the abnormal initial screening

       PRENATAL:

Can be done in families at risk, although its indication is questionable.

The prenatal test can be done by genetic analysis and the enzyme GCDH of chorionic villus samples in 8-10 weeks, or by measuring the levels of glutaric acid 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

  • Macrocephaly benign family, communicating hydrocephalus
  • Metabolic disorders associated with macrocephaly (for example, Canavan disease)
  • Transmissible metabolic disorders that affect the basal ganglia (for example Leigh syndrome among mitochondrial diseases)
  • Errors of metabolism that cause stroke as the orotic organic classic, disorders of the urea cycle, and mitochondrial diseases (for example syndrome MELAS – myopathy, encephalopathy, lactic acidosis, and episodes like stroke)
  • Causes metabolic damage of the nucleus striatum ( Mycoplasma pneumoniae infection)
  • Transmissible non-metabolic diseases (encephalitis, meningitis, intoxication)
  • Cerebral palsy child or child abuse*1

      GA1 MATERNAL

The positive neonatal screening , in some cases return to normal levels in the newborn and are 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 p and a long arm called q 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 recessive disorders occur when an individual inherits an abnormal gene for the same trait from each parent. The risk is the same for men and women.

  • The risk for two carrier parents to pass the defective gene and, therefore, have an affected child is 25% with each pregnancy.
  • The risk of having a child who is a carrier like the parents, receives one normal gene and one gene for the disease, is of 50% with each pregnancy.
  • The probability that a child will receive normal genes from both parents and be genetically normal for that particular trait is 25%.

In people with GA-1, none of the genes that produce the enzyme glutaril-CoA dehydrogenase works well. An altered gene that causes the disease is inherited from each parent

Parents who are close relatives (consanguineous) have a higher chance than the parents who are not related, both have the same abnormal gene, which increases the risk of having children with a recessive genetic disorder

It is important to inform family members who may be carriers as there is the possibility that they may also have children with GA-1.

We have genetic counseling 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, looks for changes in the pair of 19 genes that cause the GA-1.

Until now 187 pathogenic mutations have been published and are in the database of genetic mutations in humans.*1 ( in European population, the most common is R402W).

If mutations were found in both genes, DNA testing can be done (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 on 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:

  • There is a 25% chance in each pregnancy that the child will have GA -1.
  • 50% chance that the child will be a carrier, as are their parents.
  • 25% chance that the two genes play properly its function

   GA1 + CARRIER:

  • If a person with GA1 and a carrier of GA1 has children, each child has a:
  • 50% chance of having GA1
  • 50% chance of being a carrier

The regular follow-up in metabolism specialized centers significantly increases the likelihood that the course of the disease will be 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.

  • Ensure the adherence to the treatment recommendations: essential to prevent significant neurological damage
  • Anthropometric parameters,
  • Weight
  • Height
  • Head circumference
  • Developmental milestones.
  • Neurological assessment
  • Psychological Tests specific
  • Parameters diet.
  • Consultations with other specialties
  • Neuropediatras
  • Psychologists
  • Physiotherapists
  • Occupational therapist
  • Social work
  • Nutritionists
  • Dietitians

 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 follow up 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.

  • Organic acids.  
  • Amino acids: help to ensure that you receive a proper diet.
  • The levels of lysine should be maintained within the normal range.
  • If you suspect a deficiency of tryptophan, should be measured using liquid chromatography-high-efficiency liquid chromatography (HPLC) or mass spectrometry in tandem.
  • Carnitine: can be evaluated using liquid chromatography-high-efficiency liquid chromatography (HPLC) or mass spectrometry in tandem, and provides information on treatment adherence, must be at the upper limit of normal.
  • Renal function. A recent study found that some adolescents and adults with AG-I have chronic renal failure. Therefore, you should follow the kidney function in adults with AG-I. In a mouse model of AG-I has been observed tubular dysfunction kidney after a test with high protein.
  • Follow-up biochemical during acute illness: there is a risk of dehydration and electrolyte imbalance during periods of recurrent vomiting, diarrhea, and/or intake reduced nutrients and fluids, increasing the risk of a crisis encefalopática.
  • Gas in blood
  • Electrolytes
  • Creatine kinase
  • Profile of acylcarnitine: it does not provide information relevant to the monitoring of 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: The amount of amino acids should be quantified frequently in plasma on 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: the levels of carnitine in plasma in all individuals with AG-1 should be followed frequently

         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.

The optimization of the vaccination in all cohabitants of the chronically ill, should always be considered, both the vaccines included in the official calendar and other non-systematic as the annual flu, and chicken pox.

 

If, after the vaccine no symptoms are displayed , the patient can continue with their treatment and usual diet.

If we face a situation of fever >38 ° C, you must decrease the consumption of natural proteins in the diet, following the emergency regimen facilitated by the specialists. Stay 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:

  • Loss of appetite
  • Low energy, weakness, or extreme drowsiness.
  • Vomiting
  • Fever
  • Infection or disease
  • Alteration of behavior or personality changes

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.

  • Brain concentrations of acid glutárico (GA) and 3-hydroxy-glutárico can be detected by magnetic resonance spectroscopy, non-invasive in vivo (it is not clear whether this method can be used for long-term monitoring and adjustment of treatment).
  • The magnetic resonance imaging (MRI) has shown a characteristic pattern of alterations of gray and white matter , and vast spaces of cerebrospinal fluid in the GA1 (but are highly variable and dynamic). MRI with diffusion sequences enable the detection of lesions of the nucleus striatum more accurately and earlier than the TAC. The RM series can allow for a greater understanding of the neuropathogenesis observing its evolution over time, however, it is not considered essential for the follow-up.
  • The ultrasound head can detect abnormalities in the structure of the brain (pe last trimester of pregnancy).

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:

  • Intelligence
  • Development learning disability
  • Engine functions
  • Fine motor skills
  • Gross motor skills
  • Language (coefficient of development in young children)

 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.

  • Brain concentrations of acid glutárico (GA) and 3-hydroxy-glutárico can be detected by magnetic resonance spectroscopy, non-invasive in vivo (it is not clear whether this method can be used for long-term monitoring and adjustment of treatment).
  • The magnetic resonance imaging (MRI) has shown a characteristic pattern of alterations of gray and white matter , and vast spaces of cerebrospinal fluid in the GA1 (but are highly variable and dynamic). MRI with diffusion sequences enable the detection of lesions of the nucleus striatum more accurately and earlier than the TAC. The RM series can allow for a greater understanding of the neuropathogenesis observing its evolution over time, however, it is not considered essential for the follow-up.
  • The ultrasound head can detect abnormalities in the structure of the brain (pe last trimester of pregnancy).

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:

  • Intelligence
  • Development learning disability
  • Engine functions
  • Fine motor skills
  • Gross motor skills
  • Language (coefficient of development in young children)

 

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.

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

Consultar Protocolos y guías

El tratamiento de emergencia es el componente más importante de la estrategia de tratamiento. Dado que la lesión estriatal ocurre aguda 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 doctor especialista si su hijo debe llevar consigo unas recomendaciones médicas sobre su tratamiento.

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

All help is Welcome

Tu participación, por pequeña que sea, es muy importante y puede añadir mucho valor para mejorar la vida de los afectados y sus familias

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