- Donate
- Understanding Rare Disease
- Living with a Rare Disease
- Community Support
- Advancing Research
- Driving Policy
- Get Involved
- Rare Disease News
- Resource Library
- About Us
- For Clinicians & Researchers
- For Patient Organizations
Last updated: October 19, 2022
Years published: 2003, 2004, 2010, 2021
NORD gratefully acknowledges Gaby Lee, MS, NORD Editorial Intern from the Stanford University MS Program in Human Genetics and Genetic Counseling and MaryAnn Campion, EdD, MS, CGC, Clinical Associate Professor, Director, Stanford University MS Program in Human Genetics and Genetic Counseling, for assistance in the preparation of this report.
Summary
Adenylosuccinate lyase deficiency is an inherited metabolic disorder that is characterized into three categories (fatal neonatal form, type I and type II), each of which has a specific age of onset and severity of symptoms. Individuals with this disorder may have symptoms such as slowing of thought and physical movement, seizures, muscle weakness and may exhibit behaviors associated with autism. This syndrome has been diagnosed in individuals around the world and its incidence is not yet known.
Introduction
Adenylosuccinate lyase deficiency (ASLD) is a rare, inherited metabolic disorder caused by a genetic change which lowers the effectiveness of the enzyme adenylosuccinate lyase (ASL). The disorder causes the buildup of two chemicals in body fluids (such as cerebrospinal fluid, plasma, and urine) that arenโt normally seen in healthy individuals. These two chemicals are succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine. The symptoms and the physical findings associated with ASLD vary greatly from person to person. People with ASLD can have a mix of neurological symptoms such as:
Differences in body structure that are specifically related to this disorder (dysmorphic features) are not common. However, when they do occur, they are usually subtle and may include slowed growth, skull differences such as a small head circumference (microcephaly) or flattened back of the head (flat occiput), occasional deviation of the eye (intermittent divergent strabismus), small nose with anteverted nostrils, long and smooth philtrum, thin upper lip and low set ears.
Adenylosuccinate lyase deficiency is categorized as a purine biosynthesis disorder. Purines are nucleotides that play vital roles in the cells, particularly in the process of building up or breaking down complex chemicals (intermediary metabolism) and in providing energy for cellular activity (energy-transforming reactions). Purines also serve as building blocks of nucleic acids and thus participate in molecular mechanisms by which genetic information is stored. Biosynthesis is how an organism makes different molecules and is often used to describe the synthesis of molecules that are particularly important for the organism to survive. ASLD changes the bodyโs ability to make these important purines. Researchers are still debating how these genetic and molecular mechanisms cause the symptoms seen in people with ASLD.
Three categories of adenylosuccinate lyase deficiency have been recognized. The first is the fatal neonatal form, where babies have encephalopathy with lack of spontaneous movement, respiratory failure and intractable seizures. There may be some prenatal indications such as the fetus being small in size (IUGR), having a small head (microcephaly), a low level of fetal movement (hypokinesia) and a loss of fetal heart rate variability.
Adenylosuccinate lyase deficiency type I (ASLD-I), the severe childhood form, is only associated with neurological differences. These may include severe slowing of thought and movement (psychomotor impairment), epilepsy, low muscle tone in the trunk of the body (axial hypotonia) with normal tendon reflexes and features associated with autism including absent or poor eye contact, stereotypies, tantrums, agitation and a tendency toward turning aggression onto oneself.
Patients with type II adenylosuccinate lyase deficiency (ASLD-II) have mild to moderate clinical features in comparison. They may have slight to moderate psychomotor impairment, show temporary changes in hearing and vision (transient auditory and visual contact disturbance), but do not have epilepsy.
Adenylosuccinate lyase deficiency (ASLD) is a type of metabolic disorder. Metabolism is the process in which organisms take in various organic materials, use them to build cellular structures and for energy, and expel any waste products. Adenylosuccinate lyase is important in the production of purines (guanine and adenine), which are molecules that are important for the structure of genetic information and in providing sources of energy. ASLD is caused when the enzyme adenylosuccinate lyase is less functional than normal.
In particular, adenylosuccinate lyase normally converts succinylaminoimidazole carboxamide ribotide into aminoimidazole carbozamide ribotide in this purine pathway. When adenylosuccinate lyase is not functioning well, succinylaminoimidazole carbozamide ribotide gets converted into succinylaminoimidazole carbozamide riboside. Further down in this pathway, adenylosuccinate lyase also converts adenylosuccinate into adenine monophosphate. When adenosyccinate lyase is not functioning well, adenylosuccinate gets converted into succinyladenosine.
Therefore, in individuals in whom adenylosuccinate lyase is not functioning well, doctors can detect two compounds in body fluids that are normally undetectable: aminoimidazole carbozamide riboside and succinyladenosine. These compounds can be found in different fluids in the body including in plasma (a component of blood) and in cerebral spinal fluid (the fluid that surrounds the nerves in our spine).
ASLD is an autosomal recessive genetic disorder. Autosomal recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All forms of adenylosuccinate lyase deficiency affect males and females in equal numbers. The age of onset and frequency is different between the different types. People with the fatal neonatal form and type I begin showing symptoms within the first few months of life. In type II, people begin showing symptoms within the first few years of life. Of known cases of ASLD, 5-10% of cases are the neonatal form, 70-80% are type I, and 15-20% are type II (Donti, 2016).
ASLD has been diagnosed in individuals from a number of countries (Australia, Belgium, Czech Republic, Colombia, Italy, France, Germany, Malaysia, Morocco, Netherlands, Norway, Poland, Portugal, Spain, Turkey, United Kingdom and the United States of America). The majority of individuals with this condition are in Belgium and Netherlands.
A diagnosis of adenylosuccinate lyase deficiency should be considered in infants with seizures, delayed milestones, muscle weakness and/or autistic features. The diagnosis is based on elevated levels of two compounds in body fluids such as plasma, urine and cerebrospinal fluid (the fluid that surrounds the spinal nerves). These two compounds are called succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine, and they are not usually detectable in these fluids. Sequencing of the ADSL gene can identify the disease-causing genetic change (pathogenic variant).
For families where both parents are known to be carriers of adenylosuccinate lyase deficiency, prenatal diagnosis can be performed via chorionic villus sampling or amniotic fluid sampling. These two tests occur during pregnancy where a doctor uses an ultrasound to guide a needle and extract cells from either the placenta or from the fluid surrounding the fetus. These cells can be analyzed using molecular analysis of the ADSL gene.
Treatment
Current treatments are available to control seizures, although drug resistance can occur. Studies have been done to identify treatments specific for ASLD (such as D-ribose, uridine and S-adenosyl-1-methionine), but these experimental treatments have not been proven to be beneficial.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Donti TR, Cappuccio G, Hubert L, et al. Diagnosis of adenylosuccinate lyase deficiency by metabolomic profiling in plasma reveals a phenotypic spectrum. Mol Genet Metab Rep. 2016;8:61-66. Published 2016 Jul 27. doi:10.1016/j.ymgmr.2016.07.007
Jurecka A, Zikanova M, Kmoch S, Tylki-Szymaลska A. Adenylosuccinate lyase deficiency. J Inherit Metab Dis. 2015;38(2):231-242. doi:10.1007/s10545-014-9755-y
Pรฉrez-Dueรฑas B, Sempere A, Campistol J, et al. Novel features in the evolution of adenylosuccinate lyase deficiency. Eur J Paediatr Neurol. 2012;16(4):343-348. doi:10.1016/j.ejpn.2011.08.008
Zikanova M et al. Biochemical and structural analysis of 14 mutant adsl enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency. Hum Mutat 2010; 31:445-455
Mierzewska H et al. Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinate lyase deficiency โ MRI, clinical, biochemical and neuropathological findings of Polish patients. Folia Neuropathol 2009; 47:314-320
Ariyananda Lde Z et al. Biochemical and biophysical analysis of five disease-associated human adenylosuccinate lyase mutants. Biochemistry 2009; 48:5291-5302
Gitiaux C et al. Misleading behavioural phenotype with adenylosuccinate lyase deficiency. Eur J Hum Genet 2009; 17:133-136
Mouchegh K et al. Lethal fetal and early neonatal presentation of adenylosuccinate lyase deficiency: observation of 6 patients in 4 families. J Pediatr 2007; 150:57-61
Spiegel EK, Colman RF, Patterson D. Adenylosuccinate lyase deficiency. Mol Genet Metab. 2006;89(1-2):19-31. doi:10.1016/j.ymgme.2006.04.018
Edery P et al. Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: a report on three patients. Am J Med Genet 2003; 120A:185-190
Holder-Espinasse M et al. Towards a suggestive facial dysmorphism in adenylosuccinate lyase deficiency? J Med Genet 2002; 39:440-442
Ciardo F et al. Neurologic aspects of adenylosuccinate lyase deficiency. J Child Neurol 2001; 16:301-308
Race V et al. Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency. Hum Mol Genet 2000; 9:2159-2165
Kmoch S et al. Human adenylosuccinate lyase (ADSL), cloning and characterization of full- lengthy cDNA and its isoform, gene structure and molecular basis for ADSL deficiency in six patients. Hum Mol Genet 2000; 9:1501-1513
Marie S et al. Mutation analysis in adenylosuccinate lyase deficiency: eight novel mutations in the reevaluated full ADSL coding sequence. Hum Mutat 1999; 13:197-202
Salerno C et al. Effect of D-ribose on purine synthesis and neurological symptoms in a patient with adenylosuccinase deficiency. Biochim Biophys Acta 1999; 1453:135-140
Verginelli D et al. Identification of new mutations in the adenylosuccinate lyase gene associated with impaired enzyme activity in lymphocytes and red blood cells. Biochim Biophys Acta 1998; 1406: 81-84
Salerno C et al. Failure of muscle energy metabolism in a patient with adenylosuccinate deficiency: an in vivo study by phosphorus NMR spectroscopy. Biochim Biophys Acta 1997; 1360:271-276
Jaeken J et al. Adenylosuccinate lyase: and inborn error of purine nucleotide synthesis. Eur J Pediatr 1988; 148:126-131
Jaeken J, Van den Berghe G. An infantile autistic syndrome characterised by the presence of succinylpurines in body fluids. Lancet 1984; 2:1058-1061
INTERNET
OMIM Online Mendelian Inheritance in Man..https://www.ncbi.nlm.nih.gov/omim/608222; https://www.ncbi.nlm.nih.gov/omim/103050 Accessed May 4, 2021.
NORD strives to open new assistance programs as funding allows. If we donโt have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDโs mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/No patient organizations found related to this disease state.
Your donation will help more than 30 million Americans with a rare disease navigate their diagnosis, receive financial assistance, and access the care and support they deserve. Make your tax-deductible gift today!