Last updated:
9/25/2025
Years published: 2003, 2004, 2010, 2021, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, 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 (ADSL deficiency) is a rare inherited metabolic disorder characterized by developmental delay, seizures, learning/intellectual disability and autism related behaviors.
Based on the age of onset and the severity of the symptoms it can be classified in three forms:
Signs and symptoms across these forms vary greatly from person to person and may include slowing of thought and physical movement (psychomotor impairment), autism related traits such as repetitive behaviors and failure to make eye contact, seizures, progressive loss of muscle tissue (muscle wasting), difficulty eating and drinking due to the psychomotor problems (secondary feeding problems) and in the most severe cases, weakness in the trunk of the body (axial hypotonia) with increased strength and muscle mass in the limbs (peripheral hypertonia).
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.
ADSL deficiency is caused by changes (pathogenic variants) in the ADSL gene. These variants reduce the activity of the enzyme adenylosuccinate lyase (ADSL enzyme). Inheritance is autosomal recessive.
There is no FDA‑approved, disease‑modifying therapy for ADSL deficiency. Management is supportive and multidisciplinary.
Introduction
ADSL 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 for nucleic acids and are involved 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. In ADSL deficiency, the body’s ability to make these important purines changes. Researchers are still debating how these genetic and molecular mechanisms cause the symptoms seen in people with ADSL deficiency.
According to the onset, the signs and symptoms and the severity of the disease ADSL deficiency can be classified in three forms:
The severity of the signs and symptoms seem to be related to the amount of residual ADSL enzyme activity.
ADSL deficiency 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. ADSL deficiency is caused when the enzyme adenylosuccinate lyase is less functional than normal.
Adenylosuccinate lyase normally converts succinylaminoimidazole carboxamide ribotide into aminoimidazole carboxamide ribotide in this purine pathway. When adenylosuccinate lyase is not functioning well, succinylaminoimidazole carboxamide ribotide gets converted into succinylaminoimidazole carboxamide riboside. Further down in this pathway, adenylosuccinate lyase also converts adenylosuccinate into adenosine monophosphate. When adenylosuccinate 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 (such as cerebrospinal fluid, plasma and urine) that are normally undetectable in healthy people: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S‑Ado). When these are measured in the fluid surrounding the brain and spinal cord (cerebrospinal fluid), the S Ado/SAICAr ratio helps doctors estimate disease severity as lower ratios are linked with more severe disease.
Early research suggests that when SAICAr increases, it may over‑activate part of the body’s innate immune system known as the alternative complement pathway. When this pathway is overly active, it produces small signaling fragments called C3a and C5a (pieces of complement proteins). These signals attract leukocytes (white blood cells) and trigger the release of cytokines, natural chemical messengers that drive inflammation. Together, these changes may make the blood–brain barrier (protective lining that helps shield the brain) more permeable which can set off inflammation within the brain and spinal cord and, over time, lead to neurodegeneration (injury and loss of nerve cells). These findings are emerging and help guide future research, but they have not yet changed standard of care.
Inheritance
Inheritance is autosomal recessive. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
Only around 100 cases of ADSL deficiency have been reported in the medical literature. Prevalence is estimated at ~0.00125 cases per 100,000 individuals. All forms of ADSL 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.
ASLD has been diagnosed in people from many countries (Australia, Belgium, Czech Republic, Colombia, Italy, France, Germany, Malaysia, Morocco, the Netherlands, Norway, Poland, Portugal, Spain, Turkey, the United Kingdom and the United States). Most individuals with this condition are in Belgium and the Netherlands.
A diagnosis of ADSL 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 disease-causing genetic changes (pathogenic variants) that cause ADSL deficiency.
The cerebrospinal‑fluid S‑Ado/SAICAr ratio can support phenotypic stratification (lower ratios correspond to more severe disease).
Imaging can be helpful in supporting a suspicion of ADSL deficiency, as certain brain abnormalities appear with varying severity across different types. In the more severe form (type I), cerebral and cerebellar atrophy as well as white matter abnormalities are typically more pronounced than in children with the milder ADSL type II.
For families where both parents are known to be carriers of an ADSL gene variant, prenatal diagnosis can be performed via chorionic villus sampling or amniotic fluid sampling. These tests can be done 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. The ketogenic diet has been used in a few people with refractory epilepsy and showed some seizure control improvement.
Patients typically require a multidisciplinary approach involving neurologists, metabolic specialists and other healthcare professionals to manage their symptoms and provide comprehensive care.
Studies have been done to identify treatments specific for ADSL deficiency (such as D-ribose, uridine and S-adenosyl-1-methionine) but these experimental treatments have not been proven to be beneficial.
In test-tube studies, adenine or guanine supplementation improved mitochondrial mass, shape and respiration in ADSL‑deficient fibroblasts and lymphoblasts, whereas uridine/cytidine did not; ERK activation partially rescued defects in model organisms. These strategies remain experimental.
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
Magnusen AF, Hopkin RJ, Vorhees C, et al. Emerging role of complement system in the induction of neuroinflammation in adenylosuccinate lyase deficiency disorder. Brain Behav Immun Health. 2025;48:101091. Published 2025 Aug 19. doi:10.1016/j.bbih.2025.101091
Cutillo G, Masnada S, Lesca G, et al. Electroclinical features and phenotypic differences in adenylosuccinate lyase deficiency: Long-term follow-up of seven patients from four families and appraisal of the literature. Epilepsia Open. 2024;9(1):106-121. doi:10.1002/epi4.12837
Mastrogiorgio G, Macchiaiolo M, Buonuomo PS, et al. Clinical and molecular characterization of patients with adenylosuccinate lyase deficiency. Orphanet J Rare Dis. 2021;16:112. https://doi.org/10.1186/s13023-021-01731-6
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-Szymańska A. Adenylosuccinate lyase deficiency. J Inherit Metab Dis. 2015;38(2):231-242. doi:10.1007/s10545-014-9755-y
Pérez-Dueñas 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 – 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
Online Mendelian Inheritance in Man (OMIM). Adenylosuccinase deficiency. Updated: 11/29/2016. Available at: https://omim.org/entry/103050 Accessed Sept 22, 2025.
Lanska DL. Adenylosuccinate lyase deficiency. In: Lewis SL, Editor-in-Chief. MedLink Neurology. San Diego: MedLink, LLC. Updated: February 4, 2025. Available at: https://www.medlink.com/articles/adenylosuccinate-lyase-deficiency Accessed Sept 22, 2025.
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