When your metabolism takes a wrong turn and ends up in a ‘glut’ of trouble, glutaric aciduria type 1 might be at play. Aciduria is when there is the presence of acidic substances in your urine. The presence of acid is usually due to an abnormal metabolism or some sort of metabolic disorder.  

Glutaric acid is an organic compound that is produced naturally within the body as certain amino acids, such as tryptophan and lysine, mainly group 1 amino acids, are metabolised. When there is a deficiency in the mitochondrial enzyme, glutaryl-coenzyme A (CoA) and some of its derivatives, it causes the onset of glutaric aciduria type 1.  

This condition, when detected early, can aid in better outcomes in treatment that result in the afflicted individuals living a long and healthy life with little to no obstruction. When unable to be diagnosed early and a delay in treatment occurs, it can eventually lead to serious illness and damage to the brain. In recent development, prenatal screening has been highly helpful in detecting early cases of GA1. Babies, when born with GA1, have problems with breaking down amino acids and thereby leads to harmful substances building up in the blood and urine. 

When you eat, your body tends to digest food by breaking down the protein found in it, and the enzymes involved in this process, such as GCDH, then break down the proteins into amino acids for the body to be able to utilise them in daily functioning.  

Where does glutaric aciduria type 1 occur?  

Being of an autosomal recessive nature, it occurs when both parents possess a copy of the gene that is then passed down to their offspring. There have been over 200 variants associated with GA1.³

Although classified as one of the ‘rare’ metabolic disorders, with an incidence of about 1 in 110,000.⁴

There seems to be a skew in this number within members of certain groups, like the Irish Traveller Community or the Amish Community. Ojii-Cree First Nations People seem to have a higher incidence rate of the condition in comparison to the general population.⁵

With about 1 in 250 – 2000 in the above-mentioned communities. This random increase in incidence rate is usually due to something known as the Founder Effect. The Founder Effect can be described as the genomic variability that tends to take place when a smaller part of the population is taken from its original larger population. This overtime leads to the formation of a subpopulation with newer traits that are different to the older population that they separated from. 

Symptoms of glutaric aciduria type 1

Detectable through prenatal screening, the symptoms are visible in individuals quite early, in infants from around the age of 3. 

Certain signs in babies must be looked out for, such as: 

• Delayed development in achieving typical milestones in the infant, such as walking or crawling
• Dystonia or involuntary muscle spasms and contractions
• Poor weight gain
• Acid Reflux due to inability to eat or poor appetite, refluxes could occur, though they may not always immediately be correlated with GA1
• Stunted growth
• Macrocephaly – abnormally large head
• Low muscle tone
• Lack of insulation causes a feeling of getting cold easily
• Drowsiness
• Sensory issues with difficulty processing stimuli
• Cognitive impairment due to stunted growth in children
• Issues with dental hygiene and maintenance
• Seizures, whilst not always possible, could occur due to dystonia and overall health

Diagnosis of glutaric aciduria type 1

Screening methods 

Through screening of newborns for any sort of metabolic abnormality as a part of the general screening process, one can look for and counter any anomalies that may present early on, most often at a time before physical symptoms even present themselves.  

The test is known as a ‘heel prick test’ that is carried out when the newborn is about 5 days old. A dry blood spot is picked, usually from around the heel, and then screening tests are performed to look for a specific enzyme called acylcarnitine (C5-DC) and its presence in the blood. The higher the levels of acylcarnitine in the blood, the more likely the outcome is positive, and the infant has a higher chance of being afflicted with Glutaric aciduria type 1.⁶

Confirmation tests

• Urinary analysis 

Organic acid testing: Since there is a sparse metabolism when it comes to amino acids, it leads to an increase in the excretion of glutaric acid, giving the condition its name. There is also an increase in the excretion of ethylmalonic acid, 3-hydroxyglutaric acid, etc., via the urine. Testing for these excess excretions in one’s urine can help narrow down the condition.  

•  Blood Tests 

Along with the increase in the quantity of C5-DC, there is also an increase in the quantity of glutarylcarnitine and other related compounds within the blood plasma. An amino acid profile is also performed to reveal any abnormal metabolism levels that are out of the ordinary.  

• Imaging Studies 

Since glutaric aciduria type 1 can lead to muscle dysfunction and neurodegeneration, imaging studies such as magnetic resonance imaging (MRI) are often used to detect issues within the brain; at times, followed by computer tomography (CT) scans.

In the event of there being a developmental delay, a cranial ultrasound is done in order to determine the cause of the suspected complications. Followed by an abdominal ultrasound to look for any changes in the liver that could potentially denote changes in function. 

How to manage glutaric aciduria type 1? 

Since the main issue in patients afflicted with glutaric aciduria type 1 is the lack of amino acid metabolism, the main intervention to manage this is via dietary changes and supplementation, such as: 

Low-protein diets 

Done to reduce the protein, with the intention of reducing the number of amino acids found in urine via the reduction of glutaryl-CoA and its related metabolites. A highly specialised diet is incorporated, with the guidance of a licensed dietician, which involves a drastic reduction of legumes, eggs, meat, dairy products, etc. 

Supplementation 

Supplementing amino acids and carnitine can aid the afflicted patient in maintaining a balanced diet as well as keep the accumulation of toxic metabolites at bay. By taking L-carnitine supplements – which should be taken regularly, even if the baby with GA1 is ill -, one can try to increase the fatty acid metabolism.  

By consulting with a dietician, you can learn how to provide your growing infant with the required amino acids and nutrients without making it detrimental for them or harming their health. Your specialist metabolic dietitian will teach you how to measure and control the amount of protein you give to your baby, including breast milk feeds. 

Baby formula specialised to contain lower amounts of tryptophan and lysine is utilised to keep the infant healthy.  

Medical aid 

Long-term solutions via the utilisation of a multi-disciplinary team through genetic counselling by testing the family genetically, followed by a cascade screening to identify the number of asymptomatic carriers. Since it is more likely to be prevalent in more inbred communities.⁷

Written protocols for treatment must be provided to the local hospitals, medical centres, as well as the parents, containing a comprehensive history of the patient’s condition and management strategies and risks, amongst other factors.  

There should be an adequate supply of specialised dietary supplements and medications at home, or if going on holiday, to ensure no serious failure occurs. All local hospitals must be informed when a child is newly diagnosed. In the case of emergencies, immediate treatment can be initiated under the guidance of the centre. 

Summary 

Glutaric aciduria type 1 is a metabolic disorder that is usually marked by the presence of acid in one’s urine, which is because to some sort of mitochondrial enzyme deficiency of glutaryl-CoA dehydrogenase (GCDH). This occurs because of autosomal recessive inheritance that shows greater incidence rates in certain populations, like as the Irish Traveller communities or the Amish.

This can be attributed to the Founder effect. Using early diagnosis techniques and genetic testing can aid in improving the foetuses' long-term outcomes and in reducing neurological damage over time. Managing this by supplementing carnitine and reducing protein in one's diet may help greatly in this, along with consulting with their healthcare provider to come up with the best treatment plans. Long-term care strategies include genetic counselling and the establishment of treatment protocols for affected families and healthcare providers to ensure immediate intervention during medical emergencies. 

FAQs

What causes glutaric aciduria type 1? 

A mutation caused by the miscoding of the GCDH - Glutaryl-CoA dehydrogenase – gene leads to the occurrence of glutaric aciduria type 1. The GCDH gene is responsible for encoding the enzyme Glutaryl-CoA dehydrogenase, an enzyme extremely crucial for the metabolism of amino acids such as tryptophan, hydroxylysine, and lysine. A deficiency in this leads to the accumulation of glutaric acid and its related metabolites, thereby preventing the normal breakdown of proteins.  

What is glutaric aciduria type 1 in the UK? 

In the UK, glutaric aciduria type 1 is flagged as a metabolic disorder, now incorporated into the newborn screening program. An early diagnosis allows for dietary interventions and management to prevent severe neurological damage in the infant.  

How common is glutaric aciduria type 1?

Although rare, glutaric aciduria type 1 occurs in about 1 in 100,000 – 250,000 births; it can vary based on the region and the population. It is much more prevalent in communities such as the Amish, where about 1 in 300 newborns can be affected. This is due to the Founder Effect.

At what age does glutaric aciduria type 1 occur?  

Due to being detectable through prenatal screenings, signs of glutaric aciduria type 1 are often present from a young age. Most likely during the first few years of the foetus's lifespan, it can also be asymptomatic, where although infants may appear healthy and fit at first, metabolic issues present themselves as either health crises or certain developmental delays during growth.