What are the main symptoms of argininosuccinic aciduria (ASA) and who does it affect?
This rare genetic condition can theoretically affect patients at any age but symptoms are more often observed in childhood and even uncommonly during the first days of life.
Acute initial presentation is more frequent. Patients develop feeding difficulties, increasing sleepiness and hypotonia then coma and die if the diagnosis is not done rapidly.
Milder cases may present with non-specific developmental delay, learning difficulties and epilepsy.
Liver dysfunction, which may progress to cirrhosis and occasionally to liver cancer, and high blood pressure are often observed.
Acute decompensations are often triggered by infections and other stresses such as birth.
How common is ASA?
The true prevalence of ASA is not known but could be approximately 1/70 000 live births (Nagamani et al. Genet Med; 2012:14(5):501-507).
This disease is part of a group of disease known as urea cycle defects. The estimated incidence of ASA and UCD could be as high as 5 new patients per year in the UK.
What is currently known about the causes of ASA?
In the body there is a permanent turnover of molecules. Proteins breakdown produce ammonia, a highly diffusible and toxic molecule especially for the brain. A specific pathway in the liver known as “Urea cycle” can detoxify ammonia in urea wasted in urine.
Argininosuccinic aciduria (ASA) is a genetic disease where an enzymatic protein from the urea cycle pathway is defective in liver cells. Patients with ASA develop intoxication due to ammonia accumulation.
A second pathophysiological mechanism arose recently. The deficient protein in ASA is involved in the synthesis of nitric oxide (NO), an important molecule in cell signalling and vasculature relaxation. A lack of nitric oxide could explain part of long term symptoms (learning difficulties, liver impairment, hypertension) observed even when ammonia levels are low and well treated.
Are there currently any treatments available for ASA?
When a patient presents acute symptoms with very high levels of ammonia, patients require urgent haemodialysis (extrarenal removal therapy) in Intensive Care Unit to reduce rapidly the ammonia. Patients suffer from severe brain oedema with a risk of death or severe neurological damage.
In case of recovery, conventional treatment for ASA consists of:
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a strict protein restricted diet to avoid ammonia synthesis. The diet is costly and regular blood tests are required to monitor for enough protein supply to avoid growth failure and potential nutritional deficiencies.
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daily ammonia scavenger drugs intake
To “repair” a genetically damaged liver urea cycle, liver transplantation (LT) can be used as treatment for ASA. However, LT carries a risk of mortality, long term complications, and a life-long immunosuppression. In addition there is worldwide acute shortage of donor organs.
You have recently been awarded £198,473.00 from Action Medical Research in the form of a Research Training Fellowship to study ASA and to investigate gene therapy to treat the condition. Please can you outline how you plan to use this grant?
The aim of this project is to develop an alternative treatment of this disease in correcting in the cells the defective gene encoding the ineffective protein.
I will develop initially a virus enclosing the transgene. The virus is used as a device, “a vector”, to infect the cell with the transgene and allow an integration of this transgene in the defective cell.
I will then study the safety and the efficacy of this vector with the transgene in a murine model.
My aim is to develop a translational therapeutic approach for a human clinical trial in 5 years. I will identify a cohort of ASA patients suitable for a gene therapy trial.
How will your study build on previous research?
Recent research on ASA is mainly scientific approaches studying the importance of nitric oxide in the pathophysiology of ASA. I will study the murine model recently described in the literature (Erez et al. Nature; 2011:17(12): 1619-1626) and face if gene therapy approach is able to correct both ammonia intoxication and lack of nitric oxide and prevent symptoms of ASA.
What hurdles do you expect to face in developing gene therapy to treat ASA?
Gene therapy has pitfalls: insufficient or transient expression of the transgene, difficulty of the transgene to reach the organs mainly involved in the disease, risk of immunisation against the efficient protein.
I will use vectors well-known and try to minimise as much as possible these risks.
What impact would gene therapy for ASA have on patients and their families?
Gene therapy aims to be a curative approach of the disease. I hope restoring a functional enzymatic protein that will restore activity of both urea and nitric oxide cycles. The aim would be to stop medications and diet or at least alleviate it in a large part. This would improve massively the daily quality of life and offer a huge relief to patients and families.
This will completely modify the outcome: from a life-threatening disease with acute risk of decompensation and coma, patients would be able to cope much better with stresses or infections. No risk of progressive health deterioration would be observed.
Do you think it will ever be possible to prevent ASA?
For rare inherited conditions, a full prevention of the disease is unlikely. Most of these diseases are inherited with an autosomic recessive mode. That means that both parents are carriers (they have one abnormal copy of the gene) but they are usually asymptomatic. The disease appears when a child receives 2 parental wrong copies of the gene.
A parental screening of all rare genetic conditions (>5000) seems unlikely to happen in the coming years. However, once the disease is identified in the family, we can detect the carriers and counsel them. In case of a patient affected, successful gene therapy would be an ideal approach to treat him at an early stage to avoid any symptom of the disease happening.
Where can readers find more information?
Action Medical Research is a UK-wide charity saving and changing children’s lives through medical research. It wants to make a difference in:
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tackling premature birth and treating sick and vulnerable babies
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helping children affected by disability, disabling conditions and infections
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targeting rare diseases that together severely affect many forgotten children.
The charity runs a Research Training Fellowship scheme. This supports promising doctors and researchers early in their careers and develops future leaders in children’s research. As Research Training Fellows, these high-fliers carry out a key piece of research to help children and undertake training to develop their research expertise. Over the past 40 years, Action Medical Research has funded 164 fellowships at a total value of over £11 million (almost £17 million in today’s terms).
Other information can be found at:-
About Dr Julien Baruteau
As a Paediatrician specialised in Metabolic Medicine, I was graduated with my Bachelor of Medicine and Surgery and Specialist Diploma In Paediatrics (MRCPCH equivalent) in 2004 and 2008 respectively in France. Then I specialised in Metabolic Medicine working as a Locum Consultant during 4 years in Robert Debré Hospital, Paris and in University Children Hospital, Toulouse, France. I gained valuable clinical experience and decided to move as a Clinical Fellow in the largest unit of Metabolic Medicine in the UK at Great Ormond Street Hospital to improve my knowledges and clinical skills. In order to attend this post, I was registered as a Specialist in Paediatrics with a licence to practise by the General Medical Council.
As I also had a keen interest in research, I started a Masters in Research Degree with a training project about cell therapy. I investigated hepatocyte progenitor cells (HPC) transplantation in phenylketonuria in Pediatric Hepatology and Cell Therapy Laboratory of Professor Etienne Sokal, Catholic University of Louvain, in Brussels, Belgium (2011-2012). In this project I gained significant experience in different laboratory methods (molecular genetics, mass spectrometry, cell culture and biology) and was successful in getting Master’s Research degree from University Toulouse III, France (2012). This work is now included in a wider human clinical trial project of translational medicine using these HPC for human portal injections in Inherited Metabolic Diseases (IMDs). I was strongly motivated by this exciting experience and I have the willingness to increase my training in basic science and experimental research in translational medicine to help in providing new therapeutics from bench to bedside.
My academic interest is mainly in IMD in Paediatrics and particularly liver IMD. I wrote a medical thesis entitled “Perinatal hemochromatosis with antenatal high-dose intravenous immunoglobulins: the French cohort in 2008.” awarded by the Etienne Chabrol Award also awarded this work from National Academy of Medicine, Paris, France, which is for the best work in Paediatric Hepatology in France for the previous 2 years. My last publication described the clinical and biological phenotype of the largest ever-reported cohort of fatty acid oxidation defects from a large French cohort.
My career aim is to become an Academic Paediatrician working in the area of Metabolic Medicine. I intend to establish myself as a scientist in the field of inherited metabolic diseases (IMD) including Urea Cycle Disorders and many others that would benefit from novel treatments and specifically cell or/and gene therapied in a translational approach. This fellowship will allow me to undertake a PhD, the next step in order to reach my goal. As a clinical paediatrician I realise in my daily practice how limited our therapeutics are to prevent further metabolic complications in my patients and especially neurological morbidity. That is why I am strongly motivated to investigate new research areas of regenerative medicine such as cell or gene therapies in IMD.
Genetic diagnosis solves medical mystery for 30 undiagnosed patients