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GLUTARIC ACIDEMIA TYPE 1

Glutaric acidemia type I is one type of organic acid disorder. Glutaric aciduria type 1 (GA1) is a rare but serious inherited condition. It means the body can’t process certain amino acids ("building blocks" of protein), causing a harmful build-up of substances in the blood and urine. Normally, our bodies break down protein foods like meat and fish into amino acids. Any amino acids that aren't needed are usually broken down and removed from the body. Babies with GA1 are unable to break down the amino acids lysine, hydroxylysine and tryptophan. Normally, these amino acids are broken down into a substance called glutaric acid, which is then converted into energy. Babies with GA1 don’t have the enzyme that breaks down glutaric acid, leading to a harmfully high level of this and other substances in the body. This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In order for the body to use protein from the food we eat, it is broken down into smaller parts called amino acids. Special enzymes then make changes to the amino acids so the body can use them.

CAUSES

The genetic cause (mutation) of GA1 is passed on by the parents, who usually don’t have any symptoms of the condition.The way this mutation is passed on is known as autosomal recessive inheritance. This means a baby needs to receive two copies of the mutated gene to develop the condition – one from their mother and one from their father. If the baby only receives one mutated gene, they’ll just be a carrier of GA1. If you’re a carrier of the affected gene and you have a baby with a partner who’s also a carrier, your baby has: a 25% chance of developing the condition a 50% chance of being a carrier of GA1 a 25% chance of receiving a pair of normal genes Although it’s not possible to prevent GA1, it’s important to let your midwife and doctor know if you have a family history of the condition. Any further children you have can be tested for the condition as soon as possible and given appropriate treatment. You may also wish to consider genetic counselling for support, information and advice about genetic conditions.

Genetics of glutaric aciduria type 1

Mutations in the GCDH gene cause glutaric aciduria, type 1. Mutations in this gene reduce or eliminate the activity of glutaryl-CoA dehydrogenase. This enzyme is necessary in breaking down glutaryl-CoA, which is produced during the metabolism of the amino acids lysine, tryptophan, and hydroxylysine. This causes the accumulation of glutaric acid in the blood and results in the symptoms of this condition. This accumulation is especially damaging to the basal ganglia, which causes the movement symptoms seen in this condition.

CLINICAL SYMPTOMS

Generally begin between two months and four years of age, though some infants may be born with macrocephaly. Isolated macrocephaly can be a benign familial trait.
Glutaric aciduria, type 1 causes periods of metabolic crisis.
Early symptoms of a crisis include feeding difficulties, irritability, vomiting, lethargy, and hypertonia.
If untreated, symptoms include muscle spasms, spasticity, metabolic acidosis, dystonia, seizures, subdural hematomas, coma, and death.
Metabolic crises can be triggered by illness/infection, fever, or fasting. Crises are less common as the child ages.
Even without a metabolic crisis, symptoms may include: failure to thrive, hepatomegaly, hypotonia, progressive spasticity, dystonia, fevers, developmental delay, learning delays or intellectual disabilities, and speech problems.

CLINICAL MANIFESTATIONS

The clinical manifestations of GA-1 can vary considerably even between siblings, suggesting an important environmental component. Most patients have macrocephaly at birth or develop it shortly thereafter. Most of these patients have no clinical symptoms beyond a large head. One of our patients had a sudden post-natal increase in head circumference that prompted diagnosis at 11 months of age. Brain imaging performed shortly after birth usually shows the appearance of fronto-parietal brain atrophy with widening of the Sylvian fissures and sometimes arachnoid cysts. This reflects abnormal brain growth during intrauterine life and is therefore hypoplasia rather than atrophy. The reduced amount of brain tissue within an enlarged head has been called micrencephalic macrocephaly . Veins can stretch in the enlarged collection of CSF and are subject to rupture with acute subdural hemorrhages, sometimes following minor head trauma. In some cases, these are accompanied to retinal hemorrhages, raising suspicion of child abuse .

Acute neurological deterioration happens most frequently between 6 and 18 months of age. This can occur acutely usually triggered by a febrile illness with some degree of dehydration or more insidiously, without a well defined triggering event. Following 1-3 days of fever and usually vomiting, children become acutely hypotonic, lose head control, and can have abnormal movements similar to seizures (although, in children identified at our center, electroencephalograms failed to detect seizure activity). Hypotonia then slowly (weeks) improves and is first alternated then substituted by rigidity and dystonia. Patients may have tongue thrusting with decreased coordination of swallowing, impairing their ability to eat. Some children have partial reversal of these symptoms and become able to eat by mouth adequately. Patients not regaining sufficient swallow coordination require placement of a nasogastric tube first and then a permanent gastrotomy tube/button for feeding with a simultaneous Nissen fonduplication if there are concerns for aspiration. Patients remain severely disabled and will not able to walk. Several patients survive to adult life remaining wheel-chair bound and requiring constant assistance. These patients seem to have relatively normal cognition, respond to commands, but have trouble talking or performing tasks because of poor muscle coordination and severe spasticity.

Laboratory abnormalities commonly detected at time of acute attacks include hypoglycemia, ketonuria, and metabolic acidosis with mild to moderate decrease of bicarbonate levels. Some patients have chronically reduced bicarbonate levels while perfectly compensated. Plasma free carnitine levels are usually mildly to severely reduced at time of presentation.

Acute decompensation has not been reported in patients past five years of age. Many of these children have brain atrophy by MRI and in some cases abnormal myelination, but function very well. Patients escaping acute childhood striatal necrosis do generally well, although recently a 19-year-old female was identified with leukoencephalopathy after presenting with recurrent headaches and oculomotor symptoms . In this patient, the intensity and severity of headaches improved after diagnosis and initiation of carnitine supplements .[2]

TREAMMENT

Our baby’s primary doctor will work with a metabolic doctor and a dietician to care for your child.

Prompt treatment is needed to prevent episodes of metabolic crisis. You need to start treatment as soon as you know your child has GA-1. Certain treatments may be advised for some children but not others. Treatment is usually needed throughout life.

The following are treatments often recommended for babies and children with GA-1:

1. Medication

Riboflavin is a vitamin that helps the body process protein. It may also help lessen the amount of glutaric acid made by the body. Your doctor may recommend that your child take riboflavin supplements by mouth. Some children may be helped by L-carnitine. This is a safe and natural substance that helps body cells make energy. It also helps the body get rid of harmful wastes. Your doctor will decide whether or not your child needs L-carnitine supplements. Unless you are advised otherwise, use only L-carnitine prescribed by your doctor.

Do not use any medication without checking with your metabolic doctor.Children with symptoms of a metabolic crisis need medical treatment right away. They often need to be treated in the hospital. During a metabolic crisis, children may be given fluids, glucose, insulin, carnitine and other medications by IV to help get rid of harmful substances in the blood. Ask your metabolic doctor if you should carry a special travel letter with medical instructions for your child’s care.

2. Avoid going a long time without food

Infants and young children with GA-1 need to eat frequently to prevent a metabolic crisis. Your metabolic doctor will tell you how often your child needs to be fed. In general, it is often suggested that infants be fed every four to six hours. Some babies need to eat even more frequently than this. It is important that infants be fed during the night. They may need to be woken up to eat if they do not wake up on their own. Your metabolic doctor and dietician will give you an appropriate feeding plan for your infant. Your doctor will also give you a ‘sick day’ plan, tailored to your child’s needs, for you to follow during illnesses or other times when your child will not eat.

Your metabolic doctor will continue to advise you on how often your child should eat as he or she gets older. When they are well, many older children and adults with GA-1 can go without food for up to 12 hours without problems. They may need to continue the other treatments throughout life.

3. Food plan, including medical foods and formula

Most children need to eat a diet made up of foods low in lysine and tryptophan. Special medical foods and a special formula are usually part of the diet. Your dietician will create a food plan that has the right amount of protein, nutrients, and energy for your child.

Low-protein (lysine and tryptophan) diet

Foods that will need to be avoided or strictly limited include:

milk, cheese, and other dairy products
meat and poultry
fish
eggs
dried beans and legumes
nuts and peanut butter

Many vegetables and fruits have only small amounts of lysine and tryptophan and can be eaten in carefully measured amounts.

Do not remove all protein from the diet. Your child still needs a certain amount of protein for normal growth and development. Any changes in the diet should be made under the guidance of a dietician familiar with GA-1.

Medical foods and formula

There are medical foods such as special low-protein flours, pastas, and rice that are made especially for people with organic acid disorders.

A special medical formula that contains the right level of amino acids and nutrients for your child may be recommended. Your metabolic doctor and dietician will tell you whether your child should be on this formula and how much to use. Some states offer help with payment, or require private insurance to pay for the formula and other special medical foods.

Your child’s exact food plan will depend on many things such as his or her age, weight, general health, and blood test results. Your dietician will fine-tune your child’s diet over time.

The long-term benefits of the special diet and medical foods are not yet known. However, it is important to follow the food plan as long as your doctor advises.

4. Regular blood tests

Your child will have regular blood tests to measure his or her amino acid levels. Urine tests may also be done. Your child’s diet and medication may need to be adjusted based on blood and urine test results.

5. Call your doctor at the start of any illness

For some babies and children, even minor illness can lead to a metabolic crisis. In order to prevent problems, call your doctor right away when your child has any of the following:

loss of appetite
low energy or extreme sleepiness
vomiting
fever
infection or illness
behavior or personality changes Children with GA-1 need to eat more carbohydrates and drink more fluids when they are ill – even if they’re not hungry – or they could have a metabolic crisis.

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

7. Screening Methodology

Primary newborn screening for glutaric aciduria, type 1 utilizes tandem mass spectrometry. Elevated C5- DC (glutaryl carnitine) indicates the possibility of glutaric aciduria, type 1. False positive and false negative results are possible with this screen.

What to do After Receiving Presumptive Positive GA-1 Screening Results

The clinician should immediately check on the clinical status of the baby.
Consultation with a metabolic specialist is essential.
The specialist may request urine organic acid analysis and other labs on the baby.
Call the KS Newborn Screening Program at 785-291-3363 with questions about results.
Report clinical findings to the Newborn Screening Program at 785-291-3363.
Same birth siblings (twins, triplets) of infants diagnosed with glutaric aciduria, type 1 should be re-screened; additional testing of these siblings also may be indicated.
Consider testing older siblings. Some individuals may show no symptoms and will go undiagnosed.

8.Pharmacotherapy

Carnitine supplementation Secondary carnitine depletion in plasma is common in untreated patients, whereas the concomitant intracellular carnitine concentrations are unknown. Conjugation of glutaryl-CoA to form non-toxic C5DC is considered a physiological detoxification, and proposed to replenish the intracellular CoA pool . L-Carnitine supplementation alone or in combination with a low lysine diet is thought to contribute to improved outcome in patients identified during the newborn period . However, no randomized controlled studies are available . To prevent or reverse secondary carnitine depletion, an initial oral dosage of 100 mg L-carnitine/kg per day is commonly used . The dosage is then adjusted to maintain the plasma free L-carnitine concentration in the normal range. Usually, oral L-carnitine supplementation can be reduced to 50 mg/kg per day in children at age 6 years, and further reduced in adolescents and adults. A reduction of L-carnitine can be considered if side effects, such as diarrhoea and fish odor, occur.

Riboflavin Although an improvement of biochemical parameters has been suggested in single patients, there is no firm evidence that riboflavin improves the neurological outcome of this disease . Riboflavin responsiveness in GA-I appears to be exceedingly rare .There is no standardized protocol of how to assess riboflavin sensitivity, or means to predict it based on GCDH gene mutation analysis.

Neuroprotective agents There is no firm evidence that administration of other drugs, such as phenobarbitone, N-acetylcysteine, creatine monohydrate, topiramate, glutamate receptor antagonists and antioxidants are beneficial , though theoretically they may appear to be of value.[3]

DIAGNOSING GA1

At around five days old, babies are now offered newborn blood spot screening to check if they have GA1. This involves pricking your baby’s heel to collect drops of blood to test.

If GA1 is diagnosed, treatment can be given straight away to reduce the risk of serious complications.

With early diagnosis and the correct treatment, the majority of children with GA1 are able to live normal, healthy lives. However, treatment for GA1 must be continued for life.

Without treatment, severe and life-threatening symptoms can develop, including seizures (fits) or falling into a coma. Some children with untreated GA1 are also at risk of brain damage, which can affect muscle movement. This may lead to problems with walking, talking and swallowing.

Confirmation of Diagnosis

The diagnosis of glutaric aciduria, type 1 is confirmed through urine organic acid analysis revealing elevated glutaric acid and 3-hydroxyglutaric acid. If this is not confirmatory, 3-hydroxyglutaric acid in blood and CSF, urine glutarylcarnitine, enzyme analysis using fibroblasts, or molecular analysis can diagnose this condition.

Around 1 in 100,000 children worldwide are thought to be affected by GA1.

Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I

. Metabolic dysfunction associated with glutaric acid production and accumulation results in mitochondrial energy failure with secondary failure of Na/K ATPases and edema initially of neurons and neuronal projections .
Neuronal expansion impinges on capillary blood vessels leading to ischemia, which compounds and expands regions of neuronal swelling. Compression of capillaries leads to shunting of blood to non-exchange vessels with early filling and dilation of the deep venous system .
Lack of valves in cerebral veins allows for symmetric decreased flow from striatum and thalamus. Chronic metabolic dysfunction depletes α KG levels leading to lack of HIF1a degradation and up regulation of VEGF leading to vessel expansion and weakness including mobilization of tight-junction proteins away from blood–brain barrier .
The combination of vessel impingement, shunting and weakened blood–brain barrier likely results in hemorrhages.

CLINICAL FEATURES

Goodman et al. (1974) described glutaric aciduria and acidemia in a brother and sister with a neurodegenerative disorder beginning at about 6 months of age and characterized by opisthotonos, dystonia, and athetoid posturing. The glutaric aciduria was increased by oral administration of L-lysine, which is metabolized through glutaryl-CoA, and was decreased by reduced protein intake. Metabolism of radioactive glutaryl-CoA was deficient in white cells, a result compatible with inherited deficiency of glutaryl-CoA dehydrogenase (Goodman et al., 1975). Brandt et al. (1978)described a 10-year-old girl with progressive dystonic cerebral palsy. The urine contained large amounts of glutaric acid. From a review of this and 4 cases reported earlier, the authors concluded that disorders in the metabolism of organic acids should be sought in patients with progressive dystonic palsy. Lysed leukocytes from their patient showed severe impairment in the ability to metabolize glutaryl-CoA.[4]

REFERENCE

1.http://www.kdheks.gov/newborn_screening/download/ACT/GA1_Info_for_Health_Professionals.pdf

2.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556991/

3.http://www.newbornscreening.info/Parents/organicaciddisorders/GA1.html

4. http://www.omim.org/entry/231670