Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency

Brief Title

Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency

Official Title

Evaluation of a Treatment With Allopurinol on Autistic Disorders and Epilepsy in Adenylosuccinate Lyase Deficiency (ADSL)

Brief Summary

      The aim of this study is to evaluate the effectiveness of allopurinol treatment at 12 months
      on the adaptive and cognitive functioning of patients with adenylosuccinate lyase deficiency
      (ADSL). The psychiatric evaluation will involve the use of standardized tools prior to
      initiation of treatment, and will be repeated 6 months and 12 months after the start of

      The decrease in the concentration of SAICAR and S-Ado metabolites, which are markers of
      adenylosuccinate lyase (ADSL) deficiency, will also be quantified.

      Similarly, the efficacy of allopurinol on epileptic seizures for epileptic patients and on
      electrocardiogram abnormalities will be evaluated secondarily

Detailed Description

      Adenylosuccinate lyase deficiency (ADSL) is a rare disorder of purine metabolism whose
      symptoms are mental retardation, autistic disorders, epilepsy, related to the accumulation of
      succinylpurines: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine
      (S- Ado). The S-Ado / SAICAr ratio in the cerebrospinal fluid (CSF) is correlated with the
      clinical severity: the cerebral toxicity of SAICAr is incriminated. There is no specific

      Based on the work of Gertrude B. Elion (1988 Nobel Prize in Medicine), who reports that
      allopurinol (a structural analogue of hypoxanthine) can be a substrate for hypoxanthine
      phosphoribosyltransferase (HPRT) and thus produce allopurinol ribonucleotides with as a first
      step in the de novo synthesis of purines, investigators tested the hypothesis that treatment
      with allopurinol in children with ADSL deficiency would reduce the production of the toxic
      metabolite SAICAr.

      This hypothesis was validated in 3 minor patients with biological and clinical improvement.

      So the investigators put the phase II, non-comparative study based on 4 visits to
      Necker-Enfants malades Hospital or La Pitié-Salpêtrière Hospital: Month 0 (before treatment),
      Month 3, Month 6 and Month 12 after the start of treatment.

      After verification of the inclusion criteria and information of the parents or the patient or
      guardian, signature of the consent and inclusion of the patient:

        -  Clinical and neurological evaluation;

        -  Psychiatric assessment with standardized tests;

        -  Biological evaluation: determination of urinary and plasma metabolites (SAICAr, S-Ado,
           ...) Experimental treatment: Allopurinol (Zyloric®) will be administered orally for 12
           months without exceeding 400 mg / day in children and 900 mg / day in adults, with
           dosage adjustment in case of renal failure.

Study Phase

Phase 2

Study Type


Primary Outcome

Measurement of adaptive functional improvement : composite total score for Vineland II adaptive behaviour Scale

Secondary Outcome

 Evolution of the Scores of different subdomains Vineland II scale from baseline


Adenylosuccinate Lyase Deficiency



Study Arms / Comparison Groups

Description:  Oral administration of Allopurinol (Zyloric®) for 12 months without exceeding 400 mg / day in children and 900 mg / day in adults, with dosage adjustment in case of renal failure


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

October 14, 2019

Completion Date

April 2022

Primary Completion Date

April 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Child (minimum age 18 months) or adult with adenylosuccinate lyase; deficiency (ADSL)
             confirmed by quantification of SAICAr and S-Ado urinary;

          -  Girls / women of childbearing age must:

               -  have a negative pregnancy test;

               -  agree to use a reliable method of contraception from the baseline visit to the
                  last dose of study treatment

          -  Consent of the patient, his parents or his legal representative;

          -  Beneficiary of social security (affiliated or entitled).

        Exclusion Criteria:

          -  Refusal of the child, his parents or the patient or his representative;

          -  Allergy known to allopurinol or to one of the constituents of the product (lactose in

          -  Patients treated with Antipurines (azathioprine, mercaptopurine);

          -  Patients treated with vidarabine, cytotoxic drugs (eg cyclophosphamide, doxorubicin,
             bleomycin, procarbazine, alkyl halides), ciclosporin, or didanosine

          -  Renal failure characterized by creatinine clearance <80 ml/mn

          -  Hepatic insufficiency

          -  Medullary insufficiency but possibly serious

          -  Breastfeeding

          -  Pregnancy or wishing to conceive during the study period




18 Months - N/A

Accepts Healthy Volunteers



Pascale De LONLAY, MD, PhD, , 

Location Countries


Location Countries


Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

Assistance Publique - Hôpitaux de Paris


 URC-CIC Paris Descartes Necker Cochin

Study Sponsor

Pascale De LONLAY, MD, PhD, Principal Investigator, Assistance Publique - Hôpitaux de Paris

Verification Date

August 2021