Table 1.

Description of the most relevant pathologies where an involvement of purines and pyrimidines in neurodevelopmental alterations has been hypothesized or demonstrated.

Disease	Causes and incidence	Symptoms	References
ADA deficiency (ADA-SCID)	Autosomal recessive mutation in the ADA gene (20q13.12). Estimated incidence 1:200,000-1,000,000.	Severe immunodeficiency Seizures Autistic behaviors	Bottini et al., 2001; Micheli et al., 2011
ADSL deficiency	Autosomal recessive mutation in the ADSL gene (22q13.1). Enzyme deficiency leads to accumulation of toxic derivatives of adenosine in body fluids. Rare disorder (80 patients worldwide).	Developmental delay Seizures Hypotonia Autistic features Brain atrophy	Micheli et al., 2011; Jinnah et al., 2013
ATIC deficiency	Autosomal recessive mutation in the ATIC gene (2q35). Accumulation of toxic derivatives of adenosine in body fluids. One single case with complete deficiency of the ATIC enzyme was described.	Intellectual disabilities Blindness Epilepsy	Marie et al., 2004
Autism spectrum disorder	Still to be clarified. The concurrence of genetic and environmental factors has been suggested. It manifests in the first 36 months of life. Estimated incidence 30-60:10,000.	Impairments in social communication and interactions Stereotyped repetitive behaviors Affective instability	Voineagu et al., 2011; Lauritsen, 2013
Dihydropyrimidinase (DHP) deficiency	Autosomal recessive mutation in the DPYS gene (8q22). 11 cases with complete DHP absence have been described. Heterozygous subjects are asymptomatic and show some of the described symptoms upon 5-FU administration (pharmacogenetic syndrome).	Developmental delay Epilepsy	van Kuilenburg et al., 2003, 2010; Micheli et al., 2011
Dihydropyrimidine dehydrogenase (DPD) deficiency	Autosomal recessive mutation in the DPYD gene (1p21.3). Full or partial DPD deficiency is estimated to be present in about 3%-5% of the population. Most of them are asymptomatic. Some of the severe outcomes were observed upon administration of 5-FU (pharmacogenetic syndrome).	Seizures Motor and mental retardation Autistic features Gastroenteric disorders Myelosuppression, myelopathy	van Kuilenburg et al., 2003
Down Syndrome (DS)	Trisomy of chromosome 21 leading to the aberrant overexpression of genes and miRNAs. Incidence: 1:700, 1:1,000 live births.	Broad clinical spectrum Platelet disorders Cardiac alterations Mental retardation Accelerated aging with early deposition of β-amyloid-plaques and Alzheimer's-like features	Dierssen, 2012
Hereditary orotic aciduria (UMPS deficiency)	Autosomal recessive mutation in the UMPS gene (3q21). Rare disorder (20 cases worldwide).	Orotic aciduria, crystalluria, Megaloblastic anemia, immunodeficiency Developmental delay Motor impairment, hypotonia	Wortmann et al., 2017
Hypophosphatasia	Hypomorphic mutations in the ALPL gene, encoding TNAP Estimated incidence: 1/100.000.	Rickets Osteomalacia Seizures	Whyte, 2010; Sebastián-Serrano et al., 2016
Lesch-Nyhan syndrome	X-linked mutation in the HPRT1 gene (Xq26.2-q26.3), producing a defective form of the enzyme. Uric acid precipitates in the body fluids. Alteration in dopamine levels, in particular in basal ganglia. Estimated incidence 1:500,000 (affects only males).	Hyperuricemia, nephrolithiasis, gout Dystonia, choreoathetosis, extrapyramidal symptoms Intellectual disability, self-injurious behavior	Wong et al., 1996; Ceballos-Picot et al., 2009; Jinnah et al., 2013
PRPP synthetase 1 (PRPS1)-deficiency	X-linked point mutation in the PRPS1 gene, with partial or complete loss of enzymatic activity. The most severe outcome is Arts syndrome. Extremely rare.	Developmental delay Hypotonia, ataxia, hearing impairment, optic atrophy, peripheral neuropathy Premature death due to recurrent infections	Duley et al., 2011
PRPS1-superactivation	X-linked point mutation in the PRPS1 gene (Xq22.4), leading to increased enzymatic activity in cells with high RNA/protein turnover. Conversely, the mutated enzyme is unstable in neural cells and erythrocytes, where very low residual activity was found. Rare disorder (30 families worldwide).	Cognitive impairment Ataxia Hypotonia Sensorineural deafness Hyperuricemia, gout, kidney failure	Duley et al., 2011
Schizophrenia	Chronic and severe mental disorder with a typical onset in late adolescence or early adulthood. Caused by a combination of genetic susceptibility and environmental perturbations. Estimated incidence: 1.5:10,000.	Positive symptoms: visual or auditory hallucinations Negative symptoms: apathy, anhedonia and alogia Cognitive symptoms: altered ability to think clearly and to sustain attention	Lewis and Levitt, 2002; McGrath et al., 2008