Glutaric Aciduria Type I

Introduction

GA1 is a rare, serious but treatable inherited metabolic disorder (IMD). It belongs to the group of IMD called organic acidemia – patients cannot metabolize certain amino acids (the building blocks of protein) and have harmful substances (organic acids) building up in the body.

Causes and Risk Factors

Our body breaks down protein in food into amino acids when we eat, and breaks down protein in our muscles into amino acids during prolonged fasting and stress. Our body then utilizes the amino acids by processing them with special chemicals called enzymes. Different enzymes target specifically at different amino acids.

Patients with GA1 lack an enzyme called “glutaryl-CoA dehydrogenase” (GCDH). GCDH is responsible to process three amino acids, namely lysine, hydroxylysine, and tryptophan. When these three amino acids cannot be processed, harmful substances including glutaric acid (an organic acid) build up to a harmful level in the body, which damages the body, especially the brain.

Mode of Inheritance

GA1 is an autosomal recessive disease, caused by faulty GCDH gene. Everybody has two copies of GCDH gene, one from each parent, which tell the body how to make GCDH. People with only one faulty copy of GCDH gene are called “GA1 carrier” and they do not develop GA1. When both copies of GCDH gene are faulty, the body cannot make GCDH properly or even cannot make it at all.

If both parents are carriers for GA1, their child would have 1/4 (i.e. 25%) chance of having GA1 (i.e. 2 copies of faulty CGDH gene), 1/2 (i.e. 50%) chance to become a carrier (i.e. 1 normal and 1 faulty GCDH gene), and 1/4 chance of having 2 copies of normal GCDH gene.

Signs and Symptoms

Despite having this inborn genetic condition, babies with GA1 are usually healthy at birth. They may have a relatively big head. They typically develop symptoms at infancy or early childhood. They may even develop metabolic crisis, especially when they have an infection, fever, stomach upset, or prolonged fasting. Metabolic crisis is a period of time when a metabolic disorder makes the patient seriously ill. If the crisis is left untreated, it would be life-threatening.

Symptoms vary from person to person. Some children with GA1 have very mild or no symptoms. Some develop brain damage and intellectual disabilities even if they have never experienced a metabolic crisis.

Signs and symptoms of metabolic crisis include:

• Poor appetite, nausea and vomiting
• Irritability or sleepiness, floppiness (low muscle tone) and weakness
• Muscle spasm, abnormal posture or movements, poor coordination and balance
• Bleeding around the brain (subdural haemorrhage) or in the eyes (retinal haemorrhage)
• Coldness, breathing difficulties, seizures, coma

Diagnosis

In Hong Kong, GA1 is one of the conditions covered by the newborn screening programme offered to all babies born in public hospitals. GA1 might also be suspected for older children who have certain signs and symptoms (e.g. large head plus movement disorder).

The HKCH metabolic medicine team provides assessment, counselling, diagnostic workup, and treatment for newborns screened positive for GA1, and children suspected with GA1. Special gene (GCDH) tests and even enzyme tests with blood, urine and/or skin samples can be done to confirm the condition.

Treatment and Management

General

• GA1 can be treated with special diet and medicine. With early and adequate lifelong treatment, most patients with GA1 can lead a healthy and active life. Otherwise, patients could develop metabolic crisis, especially during illness, and have long-term brain damage.
• To achieve early treatment, patients who are highly suspicious of having GA1 might be put on treatment while awaiting confirmatory test result.
• Special diet is tailored to provide adequate protein and nutrients for normal growth, whilst limiting the amount of certain amino acids especially lysine and tryptophan to reduce the build-up of harmful substances. High protein foods (e.g. meat, fish, eggs, dairy, nuts) need to be limited. Breastfeeding is still encouraged but the amount of breast milk intake needs to be measured and controlled, and a special lysine-free milk formula is often needed to achieve the nutritional requirements.
• A sick day diet is designed to replace protein-containing food with high-sugar drinks and special amino acid formula during illness, in order to minimize the risk of metabolic crisis.
• A medicine called L-carnitine helps the body to clear some of the excess glutaric acid. It needs to be taken regularly, with additional supplementation during intercurrent illness / physical stress, as directed by the doctor.
• A letter or information sheet on the emergency management of GA1 is provided for episodic medical attendance, in case the healthcare professionals have not encountered GA1 before.

Special tests / investigations available in HKCH

HKCH provides expert paediatric metabolic service to treat patients with GA1 and its associated medical problems in a holistic manner. The multi-disciplinary paediatric metabolic medicine team comprises of paediatricians, geneticists, biochemical pathologists, nurses, dietitians, pharmacists, physiotherapists, occupational therapists, speech therapists, clinical psychologists, and medical social workers.

Follow-up Care

General

• It is important to follow the special diet regularly and avoid prolonged fasting. Patients should follow the sick day diet during illness. It is important to inform the metabolic medicine team if there is any issue with the special diet or when sick day diet is started.
• It is important to attend the local accident and emergency department (A&E) immediately for timely in-hospital support and monitoring, in case of intolerance to sick day diet, persistent high fever or illness, or development of symptoms of metabolic crisis. The letter or information sheet on the emergency management of GA1 is a helpful quick reference for presenting to the A&E.
• Patients with GA1 need to see the metabolic medicine team regularly even when they do not have symptom. They need regular clinical assessment, blood test monitoring, and update of treatment plans in order to match the body’s needs.
• Patients may need additional supportive medications and therapies, especially if the brain is affected.

Special care options available in HKCH

We offer in-patient, day-patient, and out-patient assessment and follow-up for patients, as well as tele-support for regional hospitals, clinics, and families. Carers and patients are educated and empowered for home management, whilst staying in contact with the team for advice and support.

References and Useful Resources

• Newborn screening programme for inborn errors of metabolism information leaflet series (No.2) Glutaric Acidemia Type I - by Department of Health and Hospital Authority, Hong Kong.

Acknowledgement

Principal author: Dr Anne Kwok on behalf of Metabolic Medicine Team, HKCH
Initial posting: Mar 2024

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