What Is Glutaric Aciduria Type 2?

Introduction

Aciduria describes a condition where there is excess acid in the urine, often caused by the presence of organic or amino acids in the urine.  Glutaric aciduria type 2 (GA-2) belongs to a group of disorders known as “rare metabolic disorders”.³ As the name suggests, these disorders are characterized by a disruption in the metabolic pathways of an individual.³ Such disorders cause problems with the body’s metabolism. The incidence of GA - 2 is about 1 in 250,000 births.⁵ The disease is autosomal recessive, so it is only inherited if both parents are affected, and even then only 50% of the time.

GA-2 is caused by genetic mutations in one or more of three genes, called ETFDH, ETFA or ETFB. ^{3 These} genes are responsible for the functioning of two mitochondrial enzymes called electron transfer flavoprotein (ETF) and electron transfer flavoprotein dehydrogenase (ETFDH).³ These enzymes help the body break down amino acids and fatty acids from our food to produce energy.³ Hence, the disruption of these enzymes causes problems with our body’s ability to break down certain fats and proteins from the food that is consumed and leads to metabolic crises in patients. 

This disorder can occur in three different ways.⁴ 

1. In newborns that are born with birth defects⁴ 
2. In newborns born without birth defects but that show symptoms within 4 weeks of birth.⁴ 
3. A milder form of the disease that can present later in childhood or adulthood.⁴ The severity of the disease decreases with the age at onset.⁴

Symptoms 

The symptoms of GA-2 depend on the age of the onset of the disease.

In newborns that are born with anomalies, these anomalies can present as:

• Macrocephaly (abnormally large head)
• Abnormal growth and development of kidneys
• Accumulation of fat in the liver and heart
• Underdeveloped lungs
• Small folds in the brain’s surface
• Anomalies in male genitalia
• Reduction in size of the thymus 
• Distinctive facial features.²

Newborns with the neonatal form of this disease, where the above congenital abnormalities are absent, can show a range of symptoms within the first 4 weeks of their life.² Symptoms include:

• Critically low blood sugar levels
• Breathing difficulties
• Inability to effectively move and control their muscles
• Potential abnormalities in the heart, liver and kidneys² 

A distinctive feature of this disease is the presence of an odour that can be described to resemble the smell of sweaty feet.²

In cases where the symptoms show later in childhood or adulthood, these symptoms are less severe and show a  greater diversity. Such patients can exhibit:

• Muscle weakness
• Episodes of vomiting
• Fever
• Lethargy
• Low blood sugar levels.²

Diagnosis

Since the symptoms of this disease are highly variable, diagnosing GA-2 involves a combination of clinical evaluation and biochemical and genetic testing. An experienced clinician will review the clinical and parental history of the patient. Then, they may proceed with urine and/or blood tests to determine the presence of certain metabolites. Common tests used by clinicians are:

1. Urine organic acid analysis – this test assesses the levels of organic acid present in a person’s urine. In GA -2, organic acids like glutaric and lactic acids are elevated and hence can act as a strong indicator of the disease.²
2. Acylcarnitine profile blood test – this is a test to measure the level of acylcarnitines in a person’s blood. Acylcarnitines are molecules that are involved in the breakdown of fatty acids. Hence, the profile of these molecules can help to indicate the presence of a metabolic disorder like GA - 2.²
3. Genetic testing: In cases where urine and blood tests indicate a GA -2 diagnosis, genetic testing is usually carried out to confirm this.² Tests are run to detect the presence of variants (mutations) in the ETFA, ETFB and ETFDH genes that are implicated in GA -2 (see above).²

Treatment 

There are no curative treatments for this disease. ⁴ The treatment plan depends on the severity of symptoms. In cases where infants are born with abnormalities, the prognosis is poor, and often, the infants are only able to survive a few weeks or months after birth. The prognosis is poor for infants born without the defects as well, with only a few with milder symptoms being able to survive months after birth. In these infants that survive and other cases with a late onset milder form of the disease, a few management options exist. There is no definitive treatment, and the goal with these patients is to manage the condition through diet and lifestyle and to avoid episodes of metabolic crisis. The recommended approach includes:

1. Avoid fasting by having more frequent meals.⁴ A large break between meals can lead to problems with energy breakdown as the body’s ability to break down food is impaired
2. Following a low-fat and low-protein diet, the body cannot effectively break down fats and proteins.⁴ 
3. Carnitine supplementation: A deficiency of carnitine, a substance involved in the production of energy from food, is noted in GA - 2. Hence, its supplementation is recommended.⁴ 
4. Riboflavin (vitamin B2) supplementation.⁴ This is often considered one of the most important supplements for GA - 2. As many as 98% of those with the late-onset form of the disease are responsive to this treatment. Riboflavin acts as a helper for enzymes involved in fats' breakdown. Hence, its supplementation helps these enzymes to facilitate better metabolism⁴
5. Coenzyme Q10 (CoQ10)  supplementation: This enzyme helps the mitochondria to function, helping the production of energy.⁴
6. Emergency treatment plan: Affected patients and their families should be in contact with their doctors to look out for acute symptoms of metabolic crises.⁴ Such symptoms, like vomiting and lethargy, can occur if the patient is suffering from another illness. In these cases, the doctor can give glucose, carnitine or fluids intravenously.⁴

Summary

Glutaric aciduria type 2 is a rare metabolic disorder that can affect the body’s metabolism. Although it is very rare, the prognosis is poor for infants. In adults, the disease can be managed through lifestyle and dietary supplementation. Early detection can help the patients and their families manage the disease effectively. It is important to seek out help from your healthcare provider if you feel like you may be experiencing any symptoms.