Allopurinol Treatment Improves Cognitive Skills, Adaptive Behavior, and Biochemical Markers in Young Patients With Adenylosuccinate Lyase Deficiency

ABSTRACT

Adenylosuccinate lyase deficiency (ADSLD) is a rare neurological disorder characterized by psychomotor retardation, autistic behaviors, and seizures, with no specific treatment available. ADSL catalyzes the transformation of succinylaminoimidazole carboxamide ribotide (SAICAr) to AICAR, and succinyl‐AMP (S‐AMP) to AMP. The pathogenesis of the disease is primarily attributed to the toxicity of elevated SAICAr concentrations. Allopurinol, used primarily for hyperuricemia, inhibits purine synthesis and may reduce SAICAr levels. We hypothesized that administering allopurinol could decrease SAICAr levels and lead to clinical improvement. A Phase II, prospective trial evaluated the efficacy of allopurinol in patients with ADSLD over 12 months. Eight participants (four children, four young adults) with developmental delay and high SAICAr levels received Zyloric (10–20 mg/kg/day, maximum 400 mg/day for children and 900 mg/day for adults). The study assessed changes in adaptive and cognitive functioning, behavior, and urinary levels of SAICAr and succinyl‐adenosine (S‐Ado). Results showed clinical improvements in younger, less cognitively impaired patients, indicated by better Vineland Adaptive Behavior Scale (VABS II) scores and reduced hyperactivity on the Aberrant Behavior Checklist (ABC) and Conners Rating Scale‐Revised (CRSR). These improvements correlated with significant decreases in urinary SAICAr levels and an increased S‐Ado/SAICAr ratio. No changes were observed in older or noncompliant patients. Allopurinol had no effect on epilepsy but was well tolerated. Allopurinol showed behavioral and developmental benefits in younger ADSLD patients, suggesting that it may be a viable treatment option.

1. Introduction

Adenylosuccinate lyase deficiency (ADSLD) (OMIM 103050) is a rare autosomal recessive disorder caused by pathogenic variants in the ADSL gene [1]. It presents with a spectrum of neurological symptoms, including psychomotor retardation, autism, and seizures [2, 3, 4, 5, 6], with variable severity [4, 7]. Over 100 patients have been reported globally [4], and no specific treatment exists for ADSLD.

ADSL is a bifunctional enzyme involved in de novo purine synthesis, converting succinylaminoimidazole carboxamide ribotide (SAICAr) to AICAR, and succinyl‐AMP (S‐AMP) to AMP [8, 9] (Figure S1). Diagnosis of ADSLD requires measuring elevated levels of SAICAr, S‐AMP, and their dephosphorylated forms SAICAr and succinyl‐adenosine (S‐Ado) in biological fluids [10]. The Bratton–Marshall test was initially used for screening, but its high false‐negative rate prompted the use of selective assays such as liquid chromatography–tandem mass spectrometry [11] and ADSL gene sequencing. Over 50 pathogenic variants have been identified in the ADSL gene [4, 5, 12], impacting protein biogenesis, stability, and activity [12, 13, 14]. Clinical severity correlates with residual enzyme activity and thermal stability [14, 15, 16, 17, 18]. The use of next‐generation sequencing (NGS) is expected to increase the number of diagnosed cases [19].

The pathogenesis of the disease is mainly due to the toxicity of high SAICAr concentrations in the brain and muscles, rather than a deficit in nucleoside and nucleotide production. Patients typically have elevated plasma and urine SAICAr levels, while purine nucleotide levels remain normal [4, 10, 20, 21]. Succinylpurines, particularly SAICAr, are toxic at the neuronal level [20], and the S‐Ado/SAICAr ratio in cerebrospinal fluid correlates with clinical severity: < 1 in severe neonatal cases, 0.9–1.8 in severe infantile cases, and > 2 in milder cases [2, 7, 21], indicating that SAICAr likely drives part of the pathophysiological process. Previous treatment attempts for ADSLD, including d‐ribose, uridine, and S‐adenosyl‐l‐methionine (SAMe) [22, 23], showed no clinical benefit in patients and inconsistent outcomes in enhancing nucleotide synthesis.

Allopurinol (1,2‐dihydro‐4H‐pyrazolo[3,4‐d]pyrimidin‐4‐one) is a medication used as a xanthine oxidase inhibitor in the treatment of hyperuricemia. Allopurinol is also a structural analog of hypoxanthine. As such, it is a substrate of hypoxanthine phosphoribosyltransferase (HPRT) and produces allopurinol ribonucleotides that inhibit the first step of de novo purine synthesis by blocking PRPP amidotransferase activity, thereby reducing the production of metabolites such as SAICAr and S‐Ado (Figure S1). Interestingly, the mechanism of action of purine supplementation is also based on the inhibition of PRPP amidotransferase.

We hypothesized that allopurinol's inhibition of the initial step in de novo purine synthesis would decrease SAICAr levels. Considering its safety profile, aside from the risk of hypersensitivity due to its metabolite oxypurinol [8], we initiated a clinical study to evaluate the effects of allopurinol treatment on neurocognitive functions and urinary levels of SAICAr and S‐Ado in patients with ADSLD.

2. Methods

2.1. Study Design and Participants

A Phase II, prospective, noncomparative trial (ClinicalTrials.gov ID NCT03776656) was initiated to assess the efficacy of allopurinol treatment over 12 months on adaptive and cognitive functioning in patients with ADSLD. Standardized psychiatric assessments were performed at baseline, 6 months, and 12 months after treatment initiation.

Eligible participants included children (minimum age 18 months) and adults with confirmed ADSLD through urinary SAICAr and S‐Ado quantification, following informed consent. Female participants of childbearing potential needed a negative urine pregnancy test before inclusion and effective contraception until the last dose.

Exclusion criteria included patient or representative refusal, known allergies to allopurinol or its components (especially lactose), concomitant antipurine medications, renal impairment (creatinine clearance < 80 mL/min), hepatic or bone marrow failure, and pregnancy in females of childbearing age.

Patients were recruited from the Metabolomics and Proteomics Biochemistry Laboratory at Necker and French rare disease networks. Twenty‐two patients with ADSLD were identified in France, but some were lost to follow‐up or were deceased.

2.2. Role of Funding Source

The trial was sponsored by the Assistance Publique‐Hôpitaux de Paris Clinical Research and Development Department and was funded by a grant from Programme Hospitalier de Recherche Clinique—PHRC 2016 (AOR16005, French Ministry of Health).

2.3. Procedures

The study aimed to treat participants with Zyloric (Aspen Pharma Trading Ltd.) orally for 12 months (M), in one to three doses, not exceeding 400 mg/day for children and 900 mg/day for adults.

The target dose of 10 mg/kg/day was to be gradually reached by month 3 to minimize allergic reactions, starting at 100 mg/day in the first month and escalating to 10 mg/kg/day. From M3 to M6, the dose was increased to 20 mg/kg/day, adjusted based on urinary and plasma levels of SAICAr and S‐Ado measured at M3. If these metabolites in urine and plasma decreased by at least 70%, the dosage would be reduced to 10 mg/kg/day; otherwise, it would remain at 20 mg/kg/day.

For participants with renal impairment and creatinine clearance between 80 and 100 mL/min, the dosage was adjusted per marketing guidelines, with a maximum of 300 mg/day at M3, maintained until M12, regardless of metabolite levels.

Treatment was to be discontinued immediately in case of cutaneous side effects.

2.4. Outcomes

The primary outcome measure was the improvement in adaptive and cognitive functioning over 12 months, assessed using the Vineland Adaptive Behavior Scales, Second Edition (VABS II), which evaluates communication, motor skills, socialization, and daily living skills for both children and adults. The VABS II scoring yields three subscale scores (each 20–160) and a composite score (mean 100, standard deviation 15), with higher scores indicating improved adaptive functioning.

Secondary outcomes included (i) autism symptom assessment at M0 and M12 via semi‐structured interviews using the Autism Diagnostic Interview‐Revised (ADI‐R) and the Autism Diagnostic Observation Schedule (ADOS); (ii) adaptive functioning, developmental, and cognitive assessments via the Vineland VABS‐II (adaptive functioning scoring) at M0, M6, and M12, Psycho‐Educational Profile, Third Edition (PEP‐3) or Wechsler assessments (developmental and cognitive evaluation) at M0 and M12, the CRSR (attention‐deficit/hyperactivity disorder [ADHD] symptom evaluation) at M0, M6, and M12, and the Aberrant Behavior Checklist (ABC) (aberrant behavior evaluation) at M0, M6, and M12. The ABC includes 58 items across subscales for irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech, with scores ranging from 0 (no problem) to 4 (severe problem).

Quantification of urinary and plasma metabolites SAICAr and S‐Ado was conducted using an LC‐MS/MS assay at baseline (M0) and during treatment at M3, M6, and M12.

Electroencephalogram (EEG) was assessed at M0 for all patients and at M6, M12 for patients presenting epileptic seizures. For these patients, seizure frequency and antiepileptic treatments were collected.

Adverse event of allopurinol was assessed at each visit, that is, crystalluria (presence of xanthine crystals in urine) and renal ultrasound results.

Compliance was evaluated through family interviews, pill counts, and measurements of xanthinuria and uric acid levels at each visit.

2.5. Statistical Analysis

Given the small number of patients, analyses were descriptive. Data were expressed as median (min–max), or numbers (percentages). Statistical analyses were performed using version 4.2.2 of R statistical software.

3. Results

3.1. Patient Characteristics

Eight patients (P2–P9) with ADSLD were enrolled in the trial from October 2019 to July 2021, consisting of four children (P4–P7) and four young adults (P2, P3, P8, P9) from six families, aged 5.8–24.8 years (median age 17.5 years) at inclusion (Table 1). Patients received symptomatic treatments for behavioral disorders and epilepsy, when applicable, along with rehabilitation therapies. The patients maintained a routine diet without excessive uric acid consumption or intake of purine‐rich foods. ADSLD was confirmed by genetic analysis in six patients (Table 1): P2, P3, and P6 through ADSL gene sequencing, while P7–P9 were diagnosed via whole‐exome sequencing. P4 and P5 were diagnosed solely through biochemical analysis.

TABLE 1.

Patient characteristics at baseline.

Patient	Sex	Age (years)	Age of diagnosis (years)	Mutation ADSL NM‐000026.3 DNA variants, protein variants	S_ADO/SAICAr in urine	S‐Ado (μmol/mmol creatinine) in urine	SAICAr (μmol/mmol creatinine) in urine	Global development disabilities	Autism	Epilepsy (treatment(s))
2	M	24.8	16.0	c.1267C>G/c.1277G>A p.L423V/p.R426H	1.10	43.8	39.8	Yes	Yes	Yes (Sodium valproate, clobazam lamotrigine, clonazepam)
3	F	21.8	9.0	c.1277G>A/c.802G>A p.R426H/p.D268N	1.23	30.5	24.8	Yes	No	Yes (lamotrigine, keppra, clobazam, sodium valproate)
4	M	7.2	2.3	n.d.	1.61	55.3	34.3	Yes	No	no
5	M	11.1	4.6	n.d.	2.20	37.9	17.2	Yes	Yes	no
6	F	15.2	6.7	c.340 T>C/c.1253G>C p.Y114H/p.G418A	1.26	22.8	18.1	Yes	Yes	no
7	F	5.8	5.8	c.1187G>A/c.1277G>A p.R396Hi/p.R426H	2.33	77.5	33.2	Yes	No	no
8	M	21.4	16.0	c.1288G>A/c.1288G>A p.D430N/p.D430N	1.63	19.4	11.9	Yes	Yes	Yes (Clonazepam, Sodium valproate)
9	F	19.8	14.5	c.1288G>A/c.1288G>A p.D430N/p.D430N	1.59	23.0	14.5	Yes	Yes	Yes (Sodium valproate)

Abbreviations: F, female; M, male; n.d., not determined.

3.2. Clinical Characteristics at the Time of Inclusion

All patients exhibited moderate (P4–P6) to severe (P2, P3, P7–P9) global developmental disabilities since diagnosis (Table 1). Autistic features were noted in five patients (P2, P5, P6, P8, P9).

Four patients (P2, P3, P8, P9) presented pre‐existing epilepsy diagnosis (Table 1) and were undergoing treatment; among them, three experienced 1–4 seizures in the month before trial inclusion. An EEG was performed for all patients at the time of screening, revealing numerous atypical absence episodes for two patients (P4, P5).

Regarding comorbidities, two patients reported sleep disorders (P2, P8), and P2 (aged 24.8 years) had right hip dislocation and scoliosis.

3.3. Biological Assessment at Baseline

The urinary and plasma profiles of SAICAr and S‐Ado were generally similar; however, only urinary results are presented for simplicity. As shown in Table 1 and Figure 1D,E, all eight patients had significantly elevated urinary levels of SAICAr (11.9–39.8 μmol/mmol creatinine, normal < 1.0 μmol/mmol creatinine) and S‐Ado (19.4–77.5 μmol/mmol creatinine, normal < 7.0 μmol/mmol creatinine). Six patients (P2–P4, P6, P8, P9) had an S‐Ado/SAICAr ratio of less than 1.8, indicating a severe infantile form of the condition, while P5 and P7 exhibited ratios greater than 2.0, corresponding to a milder form of the disorder. Interestingly, the S‐Ado/SAICAr ratio was inversely correlated with patient age, suggesting greater clinical severity with increasing age. This underscores the importance of early screening and treatment for these patients.

FIGURE 1.

Clinical and metabolic evolution of patients treated with allopurinol. (A) Evolution of the results obtained from the Vineland (VABS‐II) at M0, M6, and M12. The VABS II scoring yields three subscale scores (each 20–160) and a composite score (mean 100, standard deviation 15), with higher scores indicating improved adaptive functioning. (B) Evolution of the results obtained from the Aberrant Behavior Checklist (ABC) at M0, M6, and M12. The ABC includes 58 items across subscales for irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech, with scores ranging from 0 (no problem) to 4 (severe problem). (C) Quantification of urinary xanthine levels at M0, M3, M6, and M12 to monitor allopurinol compliance and tolerance. (D) Quantification of urinary S‐Ado/SAICAr at M0, M3, M6, and M12 using LC‐MS/MS. (E) Quantification of urinary SAICAr and S‐Ado at M0, M3, M6, and M12 using LC‐MS/MS. SAICAr, succinylaminoimidazole carboxamide ribotide; S‐Ado, succinyl‐adenosine.

Urinary xanthine levels were normal for all patients (< 28 μmol/mmol creatinine, Figure 1C). Crystalluria was noted before treatment in P2, P3, and P6. P2's morning urine contained amorphous carbonated calcium phosphate (PACC) granules. P3 had struvite crystals along with PACC granulations, while P6's sample revealed calcium oxalate monohydrate (n = 4) and dihydrate (n = 15) crystals, linked to hypercalciuria (10.3 mmol/L).

Renal ultrasounds conducted during screening showed no significant abnormalities.

3.4. Investigational Treatment With Allopurinol

The eight patients were treated with oral allopurinol (Zyloric) for 12 months (Table S1). They started with an initial dose of 10 mg/kg/day for the first 3 months, gradually increasing. Since no patient achieved sufficient metabolite reduction, the dose was maintained at 20 mg/kg/day from M6 to M12.

P8 and P9 exhibited moderate compliance with the investigational treatment, especially in the first 3 months, as assessed through family interviews, pill counts, and xanthinuria (Figure 1C) and uric acid measurements (data not shown). P8 did not reach the full allopurinol dosage per protocol, while P9 received 20 mg/kg/day from M6 onwards (Table S1).

An increase in xanthine concentrations of at least 10‐fold (Figure 1C) and a reduction in uric acid levels of at least 50% (data not shown) were observed in nearly all patients, except for P8 and during the first 3 months for P9.

3.5. Clinical Response to Allopurinol

The clinical examination remained stable for all patients, with no new neurological signs. Regarding the primary outcome, the total composite score on the VABS II showed clinically improvement in four out of eight patients between M0 and M12: P4 (70–80), P5 (5666), P7 (64–84), and P9 (43–49) (Figure 1A). All subdomains of the VABS II improved in these four patients; P4, P5, and P7 exhibited progressive improvement from inclusion, while P9 improved from M6, coinciding with better treatment compliance. P7 demonstrated the most consistent linear progression.

Improvements in hyperactivity scores on the ABC were noted between M0 and M12 in four patients: P3 (22 to 9), P4 (37 to 28), P5 (10 to 8), and P7 (19 to 3). Additionally, irritability decreased in P2 (11 to 6), P7 (5 to 0), and P9 (8 to 4) (Figure 1B). P2 also showed reduced lethargy (14 to 7), while P5 experienced an increase in lethargy (2 to 8) and irritability (4 to 12), coinciding with the diagnosis and treatment of epilepsy. The variable “stereotypic behaviors” and “inappropriate speech” did not show tangible changes.

Three patients showed improved impulsivity on the CRSR parent rating scale at M0 and M12 (P6, P7, and P9).

The initial ADI‐R at M0 identified autism traits in five patients (P2, P5, P6, P8, P9) that had emerged in early childhood, with no changes noted during the study.

Allopurinol had no effect on the seizure frequency and did not modify the EEG. Patients with atypical absences showed improvement at M12 after adjunction of anti‐seizure treatment. Only one patient (P7) presented normal EEG; for the other patients, the slow EEG pattern was not improved by allopurinol treatment.

3.6. Biological Response to Allopurinol

As shown in Figure 1E, urinary SAICAr concentrations significantly decreased by the third month of allopurinol treatment for P3–P5 and P7 (−31%, −21.6%, −16.9%, and −30.7%, respectively) and were maintained throughout the study, except for P5, which showed a slight rise at M12 but remained below baseline level (−5.2%). P9's level decreased at M6 (−27.6%) but returned to baseline level at M12 (0%). P6 remained stable at M6 (−4.4%) but decreased at M12 (−35.4%). No decrease was observed in P2 and poorly compliant P8, whose concentration increased by +25% at M12.

S‐Ado concentrations in urine decreased by M3 for P3 and P7 (−18.7% and −18.1%, respectively) and were maintained for P7 (Figure 1E). However, P3 showed a slight rise at M6 but remained below baseline level until M12 (−8.5%). Decreases were also noted at M6 for P4 and P5 (−17.4% and −14.5%) and at M12 for P6 (−24.1%). No decrease occurred in P2, P8, and P9, whose levels increased by −1.8%, 14.9%, and 26.1% at M12, respectively.

A significant increase in the S‐Ado/SAICAr ratio was observed at M3 for P3, P4, P5, P6, P7, and P9 (17.9%, 23.1%, 16.2%, 14.7%, 18.3%, and 14.1%, respectively), maintained throughout the study except for P5, which decreased at M12 (−7.3%) but remained above 2 (Figure 1D). No increase in the ratio was seen in P2 and P8.

P2, P3, and P6 had the lowest S‐Ado/SAICAr ratios at inclusion (1.10, 1.23, and 1.26) and remained below 1.8 throughout (1.05, 1.42, and 1.48 at M12). In contrast, P4, P5, P7, P8, and P9 had higher initial ratios (1.61, 2.20, 2.33, 1.63, and 1.59) and reached values above 1.8 by study's end, except for P8 (1.93, 2.04, 2.87, 1.50, and 2.00).

3.7. Clinical‐Biological Correlation

P7, the youngest patient (5.8 years old), not only exhibited the best clinical response but also showed the greatest reduction in urinary SAICAr concentration and the highest increase in the S‐Ado/SAICAr ratio, which exceeded 1.8 (Figure 1).

Similarly, P4 (7.2 years old) and P5 (11.1 years old), the two youngest patients after P7, also responded very well clinically to allopurinol treatment. Urinary SAICAr concentrations decreased until M6 and either stabilized for P4 until M12 or slightly increased for P5 by M12. The S‐Ado/SAICAr ratio for both patients rose sharply at M3, subsequently declined, but remained above 1.8 at M12.

P9, who had shown poor compliance during the first 3 months of the study, improved clinically, though less significantly than P7, P4, and P5. Her urinary SAICAr concentration decreased between M3 and M6 but rose slightly by M12. Her S‐Ado/SAICAr ratio increased sharply at M6, then declined at M12 but remained above 1.8.

In contrast, P2, P3, P6, and P8 did not exhibit clinical improvement. However, for P3 and P6, urinary SAICAr concentrations were slightly reduced at M12, and their S‐Ado/SAICAr ratios were slightly increased at M12, though they remained well below 1.8 throughout the study. For P2 and P8, urinary SAICAr concentrations tended to increase, and their S‐Ado/SAICAr ratios decreased. P8 showed poor compliance throughout the study.

3.8. Crystalluria

No xanthine crystals were detected in any analyzed samples, and renal ultrasounds during and at the end of the study showed no significant abnormalities.

3.9. Safety

The treatment was well tolerated by all patients throughout the 12‐month study. Three serious adverse events occurred in two patients: P3 suffered a nasal bone fracture and trauma to the upper lip and tongue due to a fall during an epileptic seizure, while P8 experienced an exacerbation of clonic seizures, loss of balance, and insomnia. These events were attributed to the disease rather than the treatment. At the study end, six patients opted to continue treatment based on satisfactory tolerance and positive outcomes.

4. Discussion

This study presents the first in vivo data on allopurinol over 12 months in patients with ADSLD, a severe condition with no specific treatment. We hypothesized that allopurinol would reduce the toxic SAICAr metabolite accumulated in these patients, as supported by previous literature [2, 4, 7, 10, 20, 21]. This biochemical aspect of allopurinol, noted in the introduction, was initially described by Kelley and Wyngaarden and Gertrude Elion (Nobel Prize in Medicine in 1988) [24]. Notably, allopurinol has shown anticonvulsant and antipsychotic properties, likely due to significant cerebrospinal fluid concentrations following peripheral administration [25, 26].

Our finding indicates a positive clinical and biological response to allopurinol in younger, less cognitively impaired ADSLD patients (P7, P4, P5, and P9), particularly patient P7, who made substantial advancements in psychomotor development. The youngest four patients improved their composite scores on the Vineland II scale from baseline to M12, especially in the ABC hyperactivity score and Vineland II communication and social skills scores. The reduction in hyperactivity may have facilitated better focus and interaction. Clinical improvements correlated with significant reductions in urinary SAICAr levels and increased S‐Ado/SAICAr ratios, aligning with values seen in less severely affected patients.

In contrast, P3 and P6, who did not show improvement in the total composite score on the VABS II with allopurinol treatment, exhibited only slight reductions in urinary SAICAr levels and modest increases in the S‐Ado/SAICAr ratio, remaining well below 1.8, indicative of the most severely affected patients. P2 and P8 demonstrated neither clinical improvement nor changes in succinylpurines after allopurinol treatment, with S‐Ado/SAICAr ratios remaining below 1.8 at both inclusion and the study's end.

Prior to this clinical trial, we provided compassionate allopurinol treatment to five additional patients. The results showed progress in neurodevelopmental skills and behavior, but no improvement in epilepsy (Table S2).

Although the incidence of ADSLD remains undetermined, it is likely underestimated and should be considered in patients with unclassified neurological conditions. Our findings support that early treatment is likely beneficial in patients with ADSL, which may open the way to neonatal screening. A method for measuring succinylpurines from dried blood spots using tandem mass spectrometry has been developed [27].

This study has several limitations. First, it is an open label study. Second, the sample size is limited due to the scarcity of the disease. Third, some neuropsychological assessments were not performed in all subjects. Four patients completed the ADOS, as those without autistic traits on the Autism Diagnostic Interview (ADI) were exempt due to the labor‐intensive nature of the ADOS. Assessments with the PEP‐3, and Wechsler scales were also challenging due to patients' low developmental levels and lack of cooperation, with most exhibiting developmental ages below 24 months.

Two factors may explain the lack of response in some patients. First, since ADSLD is a developmental and antenatal condition, allopurinol may be ineffective in the most severe cases [3, 7]. In human cells, administration of SAICAr or loss of ADSL results in DNA damage and impaired primary ciliogenesis [28]. Second, while SAICAr accumulation may be more toxic than purine deficiency in ADSLD [4, 10, 20, 21], nucleotide synthesis deficits may also contribute, as shown in Caenorhabditis elegans [29]. However, normal nucleotide concentrations have been observed in various tissues of ADSL deficiency patients [30, 31], suggesting that the purine salvage pathway may compensate for impaired nucleotide synthesis [2, 10] (Figure S1).

Prior to this study, no treatment trial for ADSLD, including d‐ribose, uridine [22], and SAMe [23], demonstrated effective results in humans, with inconsistent outcomes in enhancing nucleotide synthesis. Interestingly, Park et al. recently reported a novel therapeutic approach for ATIC deficiency, a disorder of the purine synthesis pathway. This approach involves inhibiting the first step of de novo purine synthesis by targeting PRPP amidotransferase, a mechanism of action similar to that of allopurinol. The therapy includes purine supplementation, which decreases the accumulation of AICA‐riboside and S‐Ado [32]. Moreover, allopurinol treatment has been tested in Lesch–Nyhan syndrome [33]. In this setting, variability in responsiveness was observed, reflecting differences in underlying pathophysiology and uric acid turnover rather than inherent pharmacological heterogeneity.

In conclusion, our findings suggest behavioral and developmental benefits from allopurinol treatment in younger patients with ADSLD. In the absence of alternative therapies, allopurinol may be considered a viable treatment option.

Author Contributions

I.C.‐P. started the preclinical investigation on allopurinol in ADSL patients. P.L., L.R., B.R.‐P., and C.E. designed the study. P.L., M.S., and F.M. provided patient and family care, and monitored the patients. P.L., L.R., B.R.‐P., M.S., C.E., F.M., and S.S. collected and analyzed the data. L.R. and B.R.‐P. performed the neurodevelopmental investigation and analysis. C.G., F.M., and A.K. performed the neurological investigations. S.S. and C.H. performed laboratory analyses and interpretations. P.L., M.S., B.R.‐P., C.E., and S.S. wrote the manuscript and prepared figures and tables. All co‐authors critically reviewed the study.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Figure S1: Metabolic pathway diagram of purine biosynthesis.

Table S1: Allopurinol dosages received (mg/day).

Table S2: Compassionate cohort for allopurinol treatment (unpublished data).

Rousselot‐Pailley B., Semeraro M., Marquant F., et al., “Allopurinol Treatment Improves Cognitive Skills, Adaptive Behavior, and Biochemical Markers in Young Patients With Adenylosuccinate Lyase Deficiency,” Journal of Inherited Metabolic Disease 48, no. 6 (2025): e70092, 10.1002/jimd.70092.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.