Adenylosuccinate lyase deficiency




Adenylosuccinate lyase deficiency is a rare, inherited metabolic disorder. In ASLD, the enzyme adenylosuccinate lyase (ASL) does not work properly anymore. The adenylosuccinate lyase is involved in the synthesis of purines, which are needed for energy metabolism and are also building blocks of DNA. The defect in this enzyme leads to an accumulation of two chemicals, succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine, in cerebrospinal fluid, blood plasma and in urine. It is unclear whether the pathological mechanisms of this disease result from a deficiency of purines, a toxicity of intermediates, or perturbation of another pathway or system. Symptoms of ASLD are highly variable, but the onset of this disease is in general in early infancy. Symptoms include a wide range of neurological features (e.g. epilepsy, autistic features, psychomotor retardation) and can sometimes also include abnormal physical features (e.g. severe growth failure, brachycephaly, low set ears). 


The onset of ASLD is in early infancy. The symptoms and the physical findings associated with ASLD vary greatly from case to case. As a rule, patients with ASLD present with a mix of neurological symptoms that usually will include some of the following:

  • Epilepsy
  • Axial hypotonia with peripheral hypertonia
  • Muscle wasting
  • Secondary feeding problems
  • Psychomotor retardation
  • Autistic features

Although abnormal physical features (dysmorphism) are not common, when they do occur they may include

  • Severe growth failure
  • Small head circumference
  • Brachycephaly (flat head syndrome)
  • Flat occiput (back portion of the head)
  • Prominent metopic suture
  • Intermittent divergent strabismus (diverging eyes)
  • Small nose with anteverted nostrils
  • Long and smooth philtrum
  • Thin upper lip
  • Low set ears


In ASLD, both copies of an important enzyme are damaged and therefore have a strongly reduced function. Thus, it can no longer convert two chemical compounds in the body, which then accumulate in blood plasma, cerebrospinal fluid and urine. If the symptoms of ASLD are caused by the inefficient enzyme activity, or by the high concentrations of the accumulated compounds, is still a matter of debate.

Adenylosuccinate lyase is encoded on chromosome 22. Patients are only affected if they inherit from both of their parents a mutated version of the gene (autosomal recessive disease). Adenylosuccinate lyase deficiency is categorized as a disorder of the manufacture of purine nucleotides from scratch (biosynthesis) in the body. The de novo purine biosynthesis pathway involves 10 steps that lead from 5-phosphoribosylpyrophosphate (PRPP) to inosine monophosphate (IMP), from which the adenine and guanine nucleotides are formed. Purine nucleotides play vital roles in the cells, particularly in the process of building up or breaking down complex body chemicals (intermediary metabolism) and in energy-transforming reactions. Moreover, they serve as building blocks of nucleic acids (DNA) and thus participate in molecular mechanisms by which genetic information is stored. Adenylosuccinate lyase (ADSL, also termed adenylosuccinase) catalyzes 2 steps in the synthesis of purine nucleotides: the conversion of succinylaminoimidazolecarboxamide ribotide (SAICAR) into aminoimidazole-carboxamide ribotide (AICAR), the eighth step of the de novo pathway, and the formation of adenosine monophosphate (AMP) from adenylosuccinate (S-AMP), the second step in the conversion of inosine monophosphate (IMP) into AMP.

ASLD is characterized by the presence of succinyl-5-amino-4-imidazolecarboxamide riboside (SAICA-riboside) and succinyladenosine (S-Ado) in urine and cerebrospinal fluid. Both compounds are dephosphorylated degradation products of the accumulated substrates of the Adenylosuccinate lyase, SAICAR and S-AMP.

It is unclear whether the pathological mechanisms of this disease result from a deficiency of purines, a toxicity of intermediates, or perturbation of another pathway or system.


ASLD is an inheritable, autosomal recessive disease, in which patients are only affected if they inherit from both of their parents a mutated version of the gene. The inheritance of only one damaged version of this gene does not lead to the disease, but makes the corresponding person a “carrier” that can inherit this mutated gene further to its children. If a case of ASLD is known in the history of your family, genetic counseling may be helpful if you are thinking about having children.


The marked clinical heterogeneity of ADSL deficiency, and the absence of pathognomonic signs, justify systematic screening for the disorder in unexplained, profound as well as mild psychomotor retardation, in neurological disease with convulsions and/or hypotonia, and in children with autism.

Diagnostic tests are based on the presence of SAICA-riboside and S-Ado in cerebospinal fluid and/or urine. These can be identified by various techniques. For systematic screening, a modified Bratton-Marshall test performed on urine appears most practical, in which SAICA-riboside and S-Ado are detected in the urine. As a drawback, patients who receive sulphonamides or antiepileptic medication can be detected as false positives. In the laboratory, both compounds can be detected in the body fluids via sophisticated methods like thin-layer chromatography or HPLC with UV detection and spectral analysis.

Interestingly, in the severely affected patients, concentrations of S-Ado in urine, CSF and plasma are in the same range as those of SAICA-riboside. In contrast, in the mildly affected. patients, concentrations of S-Ado are distinctly higher than those of SAICA-riboside. This indicates a protective effect of S-Ado which results in a milder form of the disease progression.


Several patients, particularly those presenting with early epilepsy, have died in infancy. Other patients, particularly those with higher S-Ado/SAICA-riboside ratios, fare relatively well, and have reached adult age. 


Treatment most often involves treating the symptoms patients experience. For example, anti-seizure medications for epileptic seizures or vision correction methods for intermittent divergent strabismus. Autistic disorder treatments may be used as well, such as behavioral therapy or speech therapy. Physical therapy may also be beneficial.

With the aim to replenish hypothetically decreased concentrations of adenine nucleotides in ADSL-deficient tissues, some patients have been treated for several months with oral adenine (10 mg/kg per day), associated with allopurinol (5 to 10 mg/kg per day) to avoid conversion into very poorly soluble 2,8-dihydroxyadenine. No clinical or biochemical improvement was recorded, with the exception of some acceleration of growth.

The oral administration of D-ribose (1.5 g/kg per day) has been reported to reduce seizure frequency and to improve behaviour in a 13-year old patient.


  • Health Key
  • NIH