Published: 18 Jun 2025

ICD9: 270.7      ICD10: E72.3      ICD11: 5C50.4

Glutaric acidemia and glutaric aciduria (GA) are terms that are often used interchangeably, but they refer to a group of inherited metabolic disorders in which the body is unable to properly process certain amino acids, particularly lysine, hydroxylysine, and tryptophan.
This leads to a buildup of harmful substances, especially glutaric acid, in the body. There are two main types:

Glutaric Acidemia Type 1 (GA-1) or Glutaric Aciduria Type 1 (GA1)

This is the more common and well-studied type. It's caused by a deficiency in the enzyme glutaryl-CoA dehydrogenase (GCDH). GCDH is crucial for breaking down lysine, hydroxylysine, and tryptophan. When it's not working correctly, these amino acids are converted into toxic byproducts, including glutaric acid, 3-hydroxyglutaric acid, and glutaconic acid. These substances accumulate in the blood, brain, and other tissues, causing damage.
Symptoms: GA1 can have variable presentation. Some individuals never experience symptoms (asymptomatic excretors). Others may develop symptoms in infancy or early childhood, often triggered by illness or stress (metabolic crisis). Symptoms can include:
Encephalopathic crises: sudden onset of neurological symptoms such as seizures, loss of motor skills, muscle rigidity, and coma
Macrocephaly: abnormally large head size
Dystonia: involuntary muscle contractions and movements
Hypotonia: reduced muscle tone, especially in infancy
Developmental delay or regression
Feeding difficulties
Vomiting
Lethargy
Diagnosis: Newborn screening programs in many countries test for GA1 by measuring levels of certain acylcarnitines in blood samples. Further testing, such as urine organic acid analysis, plasma amino acid analysis, and GCDH enzyme activity in fibroblasts, can confirm the diagnosis. Genetic testing for mutations in the *GCDH* gene is also available.
Treatment: Treatment for GA1 focuses on reducing the production of toxic metabolites and preventing metabolic crises. This includes:
Dietary management: A low-lysine diet, often supplemented with carnitine.
Emergency protocols: During illness, special emergency protocols are followed to increase caloric intake and prevent catabolism (the breakdown of muscle tissue).
Carnitine supplementation: Carnitine helps to remove excess organic acids from the body.
Riboflavin supplementation: Some individuals with GA1 respond to riboflavin (vitamin B2) supplementation, which may improve GCDH enzyme activity.
Early intervention: Physical therapy, occupational therapy, and speech therapy can help manage motor impairments and developmental delays.

Glutaric Acidemia Type 2 (GA-2) or Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)

GA2 is a different disorder caused by a deficiency in the electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) enzyme system. This system is involved in the breakdown of many different fatty acids and amino acids, leading to a buildup of various organic acids, not just glutaric acid. So while glutaric acid may be elevated, it's only one component of a much broader metabolic dysfunction.
Symptoms: GA2 has variable severity, ranging from mild adult-onset forms to severe, life-threatening neonatal forms. Symptoms can include:
Hypoglycemia: low blood sugar
Metabolic acidosis: buildup of acid in the blood
Hepatomegaly: enlarged liver
Cardiomyopathy: heart muscle disease
"Sweaty feet" odor (due to excretion of isovaleric acid)
Muscle weakness
Lethargy
Vomiting
Diagnosis: GA2 is diagnosed based on clinical presentation, elevated levels of various organic acids (including glutaric acid, but also others) in urine, elevated acylcarnitines in blood, and enzyme testing or genetic testing of the *ETFA*, *ETFB*, or *ETFDH* genes.
Treatment:
Dietary management: A low-fat, low-protein diet.
Riboflavin supplementation: Many individuals with GA2 respond dramatically to high doses of riboflavin.
Carnitine supplementation: To help remove excess organic acids.
Management of metabolic crises: Similar to GA1, emergency protocols are crucial during illness.

Key Differences Summarized:

| Feature | Glutaric Acidemia Type 1 (GA1) | Glutaric Acidemia Type 2 (GA2/MADD) |
|-------------------|---------------------------------------|------------------------------------------|
| Enzyme Deficiency | Glutaryl-CoA Dehydrogenase (GCDH) | ETF or ETFDH (Multiple Acyl-CoA Dehydrogenase) |
| Primary Metabolites Affected | Lysine, Hydroxylysine, Tryptophan | Multiple fatty acids and amino acids |
| Key Accumulated Compound | Glutaric acid, 3-hydroxyglutaric acid | Variety of organic acids (including glutaric) |
| Treatment | Low-lysine diet, carnitine, emergency protocols | Low-fat/low-protein diet, riboflavin, carnitine |
| Common Features | Macrocephaly, dystonia, encephalopathic crises | Hypoglycemia, metabolic acidosis, "sweaty feet" odor |

Important Considerations:

Both GA1 and GA2 are inherited in an autosomal recessive pattern, meaning that both parents must carry a copy of the mutated gene for their child to be affected.
Early diagnosis and treatment are crucial for both conditions to prevent severe neurological damage and improve long-term outcomes.
Newborn screening has significantly improved the early detection of GA1.
Genetic counseling is recommended for families with a history of either GA1 or GA2.
The severity and presentation of both conditions can vary widely.

This information provides a general overview. It is essential to consult with a qualified healthcare professional for accurate diagnosis, personalized treatment, and management of glutaric acidemia or glutaric aciduria.