Citrin Deficiency

Introduction

Citrin deficiency or Citrullinemia type II is an inherited metabolic disorder (IMD). It is caused by mutations in the SLC25A13 gene encoding a mitochondrial transporter, citrin. It has a different presentation regarding to age, with impaired liver function (neonatal cholestasis) in the neonatal period to altered mental state due to high ammonia levels (hyperammonemic encephalopathy) in adults. Often citrin deficiency is characterized by a food preference which is rich in proteins and / or lipids and aversion to carbohydrates. Although citrin deficiency has a pan-ethnic distribution, it is much more common in Asia.

Causes and Risk Factors

Citrin is responsible for transporting important molecules across the powerhouse of our cells – the mitochondria and thus is involved in the following important metabolic functions:

1. Energy production
2. Glucose production
3. Urea cycle which helps to remove ammonia as urea
4. Galactose metabolism

Patients with a faulty SLC25A13 gene which encodes citrin have a citrin deficiency, resulting in energy deficiency in the liver due to inability of the liver cells to efficiently utilize glucose and fatty acids to produce energy.

Mode of Inheritance

Citrin deficiency is an autosomal recessive condition, caused by a faulty SLC25A13 gene. Everybody has two copies of SLC25A13 gene, one from each parent. Individuals with only one faulty copy of SLC25A13 gene are called “citrin deficiency carrier” and do not develop citrin deficiency. When both copies of SLC25A13 gene are faulty, they develop citrin deficiency.

If both parents are carriers of a mutation in the SLC25A13 gene, their child would have 1/4 (i.e. 25%) chance of having citrin deficiency (i.e. two copies of faulty SLC25A13 gene), 1/2 (i.e. 50%) chance to become a carrier (i.e. 1 normal and 1 faulty SLC25A13 gene), and 1/4 (i.e.25%) chance of having two normal copies of SLC25A13 gene.

Signs and Symptoms

The clinical presentation of citrin deficiency may be different in each patient. Patients may have no symptoms to more than one symptom at different stages of their life. They are usually healthy at birth and rarely develop symptoms in the first week of life.

The three clinical phenotypes of Citrin deficiency are as follows (information adapted from the Citrin Foundation website):

*Not all patients may develop these phenotypes and may remain asymptomatic after the NICCD phase.

Diagnosis

Diagnosis is based on clinical and biochemical suspicion. The biochemical analysis may show high ammonia levels, altered blood profile of amino acid with increased concentration of citrulline and arginine as well as threonine / serine ratio. The diagnosis is confirmed by genetic study of the SLC25A13 gene.

In Hong Kong, citrin deficiency is one of the conditions covered by the newborn screening programme offered to all babies born in public hospitals. Citrin deficiency might also be suspected for older children who have certain signs and symptoms (e.g. cholestatic jaundice, failure to thrive).

The HKCH metabolic medicine team provides assessment, counseling, diagnostic workup, and treatment for newborns screened positive for citrin deficiency, and children suspected with citrin deficiency. Special diagnostic and biochemical tests including SLC25A13 gene analysis are available in HKCH.

Treatment

General

Treatments of citrin deficiency is somewhat different depending on the age of onset of the disease:

• In NICCD, a diet supplemented with vitamins and lactose-free formula (in children with increased excretion of galactose) and medium chain triglycerides (MCT) is administered. The restriction of lactose reduces galactosemia / urea and MCT administration improves cholestasis. In rare cases, liver transplant may be needed.
• In the post-NICCD period, all citrin deficiency patients should follow a low carbohydrate, high protein and fat diet.
• In FTTDCD, dietary treatment with MCT has been suggested to be helpful.
• In CTLN2, dietary treatment with low carbohydrate / high protein and MCT, have shown to decrease the concentration of ammonia in the blood and reduce hypertriglyceridemia. Liver transplantation is also an option and prevents high ammonia crisis, corrects the metabolic abnormalities, and eliminates the preference for protein-rich foods.

Special treatment options available in HKCH

HKCH provides expert paediatric metabolic service to treat patients with citrin deficiency and its associated medical problems in a holistic manner. The multi-disciplinary paediatric metabolic medicine team comprises of pediatricians, 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 inform the metabolic medicine team if there is any issue with the special diet.

It is important to attend the nearby accident and emergency department (A&E) for timely in-hospital support and monitoring in case of intolerance to special diet, persistent high fever or illness, or hypoglycemia. The letter or information sheet on the emergency management of citrin deficiency is a helpful quick reference when presenting to the A&E.

Patients with citrin deficiency need to see the metabolic medicine team regularly even when they do not have symptoms. They need regular clinic assessment, blood test monitoring, and update of treatment plans in order to match the body’s need.

Special care options available in HKCH

In HKCH, the paediatric metabolic medicine team offers 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.

Conclusion

Citrin deficiency is an inherited metabolic disorder that can have serious consequences in some patients. Early diagnosis and treatment can improve the quality of life of individuals with the disease.

References and Useful Resources

• Citrin Foundation
• Newborn screening programme for inborn errors of metabolism information leaflet series (No.13) Citrullinaemia Type II - by Department of health and Hospital Authority, Hong Kong.

Acknowledgement

Principal author: Dr Belaramani Kiran Moti on behalf of Metabolic Medicine Team, HKCH
Initial posting: Mar 2024

© 2024 Hong Kong Children’s Hospital. All rights reserved.