Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency

Study Overview
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Brief Summary
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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 treatment. 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
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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 treatment. 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.

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

Conditions
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Adenylosuccinate Lyase Deficiency

Intervention / Treatment
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* Drug: Allopurinol


Participation Criteria
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Eligibility Criteria
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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 particular); 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

Ages Eligible for Study
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Minimum Age: 18 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allopurinol<br>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 | Drug: Allopurinol<br>* Daily oral administration<br>* Other names: Zyloric®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of adaptive functional improvement : composite total score for Vineland II adaptive behaviour Scale | to assess Efficacy of Allopurinol (Zyloric)® treatment from Baseline : For each scale : Mean : 100 SD : 15 Adaptive behaviour composite : Range 20 to 180 -Domains scores : Range 20 to 140 -Communication : Range 20 to 140 -Daily living skills : Range 20 to 140 -Socialization : 20 to 140 -Motor skills : 20 to 140 For each scale values are considered to be better or worse outcome :High 130 to 140 -Moderately High 115 to 129 -Adequate 86 to 114 -Moderately Low 71 to 85 -Low 20 to 70 Total score is obtained by summing the subdomains scores | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution of the Scores of different subdomains Vineland II scale from baseline | Clinical evolution for developmental and cognitive assessment | at 0, 6 months and 12 months | 
| Evolution of the Psycho-Educative Profile (PEP III/R) from baseline | Clinical evolution for developmental and cognitive assessment | at 0, 12 months | 
| Evolution of the Score ADI-R (Autism Diagnostic Interview-Revised) from baseline | Clinical evaluation for autistic symptoms : scale ranges : A : Social interactions: 0 to 30 (significative if >10) B : Communication : 0 to 26 (significative if > 7 or 8) C : Repetitive and restricted interests : 0 to 16 (significative if >3) D : Developmental abnormality present before 36 months : 0 to 5 (significative if >1) better score : 0 (non autistic) - worse score : the higher score is the worst | at 0, 12 months | 
| Evolution of the Score ADOS-2 (Autism Diagnostic Observation Schedule 2) from baseline | Clinical evaluation for autistic symptoms. Scale ranges : A : Socialization : social interactions and communication : 0 to 20 (social interactions : 0 to 6 -communication : 0 to 14) B : Restricted and repetitive interests : 0 to 8 Total : A+B : 0 to 28 Autism : total score>12 - Autism Spectrum Disorder : total score >8 Better score : 0 - Worse score : the highest score is the worst | at 0, 12 months | 
| Evolution of the Score on Conners hyperactivity Scale | Clinical evolution for behavioral disorders and adaptive functioning Conners Scale for Parents : - Subscales : Behavioural difficulties (items 2-8-14-19-20-27-35-39) : 0 to 24 Learning difficulties (items 10-25-31-37) : 0 to 12 Somatisation (items 32-41-43-44) : 0 to 12 Impulsivity, hyperactivity (items 4-5-11-13): 0 to 12 Anxiety (items 12-16-24-47): 0 to 12 -Hyperactivity index : sum of the items (4-7-11-13-14-25-31-33-37-38) divided by 10 : 0 to 3 Conners Scale for teachers : - Subscales : Behavioural difficulties (items 4-5-6-10-11-12-23-27) : 0 to 24 Impulsivity, hyperactivity (items 1-2-3-8-14-15-16) : 0 to 21 Inattention, passivity (items 7-9-18-20-21-22-26-28) : 0 to 24 -Hyperactivity index (sum of the items 1-5-7-8-10-11-14-15-21-26 divided by 10) : 0 to 3 Better score : 0 - Worse score : the highest score is the worst -Hyperactivity index : Significative if> 1,5 | at 0, 6 months and 12 months | 
| Evolution of the Score on ABC scale (Aberrant Behaviour Checklist) | Clinical evolution for behavioral disorders and adaptive functioning scale ranges : Irritability : 0 to 45 Lethargy : 0 to 48 Stereotypy : 0 to 21 Hyperactivity : 0 to 48 Inappropriate speech : 0 to 12 Better score : 0 -Worse score : the highest score is the worst on each scale- there is no total score | at 0, 6 months and 12 months | 
| Evolution of SAICAr levels in the urine | Evolution of the quantity of urinary metabolites from Baseline | at 0, 6 months and 12 months | 
| Evolution of S-Ado levels in the urine | Evolution of the quantity of urinary metabolites from Baseline | at 0, 6 months and 12 months | 
| Evolution of SAICAr levels in the blood | Evolution of the quantity of plasma metabolites from Baseline | at 0, 6 months and 12 months | 
| Evolution of S-Ado levels in the blood | Evolution of the quantity of plasma metabolites from Baseline | at 0, 6 months and 12 months | 
| Evolution of the number of seizures from Baseline for epileptic patients | at baseline, performing neurological examinations and interrogation | at 0 and 12 months | 
| Evolution of antiepileptic treatments from Baseline for epileptic patients | at baseline, performing neurological examinations and interrogation | at 0 and 12 months | 
| Evolution of electroencephalogram tracing from Baseline for epileptic patients | normal/abnormal | at 0 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adenylosuccinate lyase, Deficit, Allopurinol, Autism, Epilepsy