Glutaric Aciduria

What is glutaric aciduria?

Glutaric aciduria means ‘glutaric acid in the urine’. This inherited metabolic condition is also known as glutaric acidaemia – or ‘glutaric acid in the blood’. It normally manifests in infancy and early childhood. There are two distinct forms.

In type I glutaric aciduria, abnormal processing or ‘metabolism’ of lysine, hydroxylysine and tryptophan generates toxic by-products that cause severe brain damage. Lysine, hydroxylysine and tryptophan are amino acids – the building blocks of proteins. After eating proteins, the body breaks them down into amino acids. Animal proteins include dairy products, meat, eggs and fish. Proteins are also found in plants including soy, legumes, grains and nuts. The body uses the amino acids to make its own proteins essential for life – for example enzymes; structural proteins in muscles, hair, skin, cells and cartilage; proteins that generate movement in muscles; or those involved in cell functioning or immune responses. In periods of starvation, amino acids can be redirected to generate energy for the body. When lysine, hydroxylysine and tryptophan are not metabolised properly, intermediate breakdown products (glutaric acid, glutaryl-CoA, 3-hydroxyglutaric acid and glutaconic acid) accumulate in body fluids and brain tissue. The build-up of metabolites is especially pronounced when the body is under stress. Characteristically, between the ages of 6 and 18 months the child experiences a metabolic ‘crisis’. This sudden episode occurs during periods of illness or fever or after immunisation, lack of food or minor head injury. The crisis seems to be a turning point in the condition and triggers significant brain damage. The basal ganglia of the brain, which helps control movement, is most affected. In addition, the metabolites cause damage to other organs, although to a lesser extent. It is not known how glutaric acid and the other metabolites exert their destruction. The risk of crises diminishes as the child gets older.

Type II glutaric aciduria is linked to a deficiency in enzymes involved in processing fats and proteins. Partly metabolised fats and proteins accumulate in the body and cause the blood and tissues to become dangerously acidic. Like type I, metabolic crises triggered by common childhood illnesses or stress worsen the condition. In this scenario they trigger the body to break down its own stores of protein and fats thus generating the toxic by-products that cause the body harm. Liver and brain damage are characteristic.

The biochemical alterations in both types of glutaric aciduria can hamper the production of carnitine, a product of lysine metabolism important for generating energy from dietary fats.

How common is glutaric aciduria?

Type I glutaric aciduria is rare. Prevalence studies are limited but suggest that the disease occurs in 1 in 40,000 Caucasian births, although a study in Sweden estimated an incidence of 1 in 30,000 births in its population. It is more common in genetically close communities such as the Ojibway Indian population in Canada or the Amish in the USA where the incidence may reach as many as 1 in 300 newborns. However, a tendency for misdiagnosis may mean that these figures underestimate the true frequency.

Type II glutaric aciduria is thought to be even more rare than its counterpart, although the precise incidence is not known.

What causes glutaric aciduria?

Glutaric aciduria is a genetic disorder in which mutations in certain genes cause a deficiency or reduce the efficiency of certain enzymes. The enzymes are normally active in the mitochondria, which represent the energy-producing hub of cells.

In type I glutaric aciduria, the error occurs in the gene coding for the enzyme glutaryl-coenzyme A dehydrogenase (GCDH), which would normally metabolise lysine, hydroxylysine and tryptophan.

In type II disease, a deficiency is seen in either of two enzymes – enzyme electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH). Mutations in any of three genes can result in the deficiency, since the ETF enzyme has two sections each created by a separate gene. People with residual enzyme activity show milder symptoms, while severe disease develops in those in whom the enzyme is missing completely.

The conditions are recessive in nature, meaning that a child would only have the condition if both parents ‘carry’ the genetic mutation. Genes are arranged in structures called chromosomes that contain two strings or ‘alleles’. Offspring inherit one allele from their father and one from their mother. Carrying one copy of the mutated gene does not affect health, but when two mutated copies come together, the linked enzyme is deficient either in quantity or effect and the disease is expressed. For each and every pregnancy, there is a 1 in 4 chance of two carriers of the glutaric aciduria mutation having a child with the disease.

What are the symptoms and signs of glutaric aciduria?

From birth, babies with type I glutaric aciduria have unusually large heads, due to abnormalities in brain development. Sufferers may be asymptomatic before a crisis, particularly if they eat a low-protein diet and have few illnesses. Or they may show only general symptoms such as irritability, abnormal muscle tone or feeding difficulties. In some, abnormal bleeding occurs in the brain or eyes. However, after a crisis has triggered brain damage, the child will show difficulty moving, spasms, jerking, rigidity or decreased muscle tone, weakness and a tendency for seizures. Head and body control may diminish and the suck and swallow reflexes may be lost. Prolonged muscle contractions make the arms and legs stiff, with twisting of the hands and feet. The symptoms, which vary in severity and worsen over time, show similarities to those of cerebral palsy. Intellectual function may be affected.

In type II disorder, metabolic crises cause weakness, poor feeding, reduced activity, nausea and vomiting. Blood sugar levels can drop dramatically after exercise causing severe weakness, shakiness, dizziness and difficulties breathing. The events triggered by a crisis can be life threatening. Again, the condition ranges in severity. In mild cases, children may be affected only during times of metabolic stress. Indeed, muscle weakness in adulthood may be the first sign. Those with more severe disease are born with brain malformations, an enlarged liver and heart, fluid-filled cysts in the kidneys, abnormalities in the kidneys and external genitals in males and unusual facial features. There is also a characteristic smell on the breath that resembles sweaty feet.

How is glutaric aciduria diagnosed?

Diagnosis of this rare condition can be difficult. The disease is relatively silent and therefore not suspected unless a metabolic crisis occurs. The large head size in type I disease may be detected during routine infant screening and triggers further investigation. In some, abnormalities in biochemicals may be detected as part of routine neonatal screening. Post-crisis symptoms in type I are often mistaken for cerebral palsy. Unfortunately, abnormal bleeding is often misdiagnosed as the result of abuse in these children.

A blood or urine test for glutaric acid is a key diagnostic feature of glutaric aciduria. Furthermore, low levels of carnitine in the blood are characteristic and measuring the activity of the specific enzymes can support the diagnosis. Cranial ultrasound, magnetic resonance imaging (MRI) and computed tomography (CT) may be used to assess the presence and extent of neurological damage in type I glutaric aciduria. In type II disease, liver biopsies are useful to identify abnormal fat accumulations.

Screening siblings of children affected by glutamic aciduria facilitates early identification and intervention.

How is glutaric aciduria treated?

The mainstay of treatment for type I glutaric aciduria is dietary manipulation aimed at reducing the production of glutaric acid and other intermediate metabolites. The diet involves restricting the intake of natural protein and of lysine specifically. Tryptophan is reduced but not eliminated as this amino acid is important for producing serotonin – a chemical messenger in the brain. Lysine-rich foods include fish, meat and meat products, cow’s milk and dairy products, eggs, potatoes, soy, nuts, lentils and spinach. Tryptophan-rich foods include chocolate, oats, dairy products, bananas, mangoes, fish, meat and meat products. Such a diet must be managed carefully to avoid malnutrition in certain amino acids. It should strike a balance between the need for protein for growth versus its restriction for avoidance of adverse effects. This complex task should be undertaken only with the advice of a dietician. A generally low-protein diet is advised, alongside supplementation with lysine-free, low-tryptophan amino acid mixtures to ensure supply of the other amino acids essential for optimal health. The diet should include a high carbohydrate and fat content to provide sufficient calories. Adequate fluid levels should be maintained and vitamin and mineral intake optimised. The ability to process protein improves with age and the diet should be reviewed regularly to adapt to the changing nutritional needs of the children. A range of lysine-free and low-tryptophan formulas is available, designed specifically to meet the nutritional needs of children at different ages.

Since illness worsens the condition, therapy is intensified during these periods to prevent brain damage. This involves increasing carbohydrate and fat intake, temporarily ceasing all protein intake, increasing carnitine supplementation and monitoring the child closely.

After the crisis, the permanent brain injury becomes the focus of treatment, with intervention designed to reduce the frequency of seizures and prevent further deterioration. The anti-spasticity drug baclofen can reduce abnormal muscle tone and improve motor function to some degree. Benzodiazepines, which slow the central nervous system, are useful for treating seizures.

It is possible that use of special constraint seating can limit abnormal movements in type I glutaric aciduria. However, such occupational therapy may worsen the increased body tone and spasms. Aids that provide support in the upright position without constraint (such as baby bouncers that hang from door frames) may be more suitable and can reduce body rigidity in infants.

In type II glutaric aciduria, a low-protein and low-fat diet is advised. A small quantity of protein and fat are needed, but carbohydrates should deliver the majority of calories for energy and growth. Again, a dietician should be consulted. The child should drink additional fluids during periods of illness to combat the rising levels of glutamic acid. Also, protein should be excluded and energy-rich food such as sugar-based snacks should be eaten to prevent the body needing to use its own stores of protein.

In both types, carnitine depletion is treated with oral carnitine supplements, although these may not raise carnitine levels in muscle. Regular intravenous carnitine replacement could be more effective. The vitamin riboflavin may be given to increase carnitine levels and promote improved growth and greater muscle strength. Multivitamin and mineral supplements are also advised. In type II disease, choline supplements are useful to increase exercise capacity and tone in the trunk and improve general well-being.

Treatment, particularly diet modification, is effective in both types of glutaric aciduria. Hence, early diagnosis of this rare metabolic disease is essential. This is most acute in type I disease where early intervention can reverse many of the pre-crisis symptoms and may provide some protection against brain damage in the event of a crisis.