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Adenylosuccinate lyase deficiency
A disorder of purine metabolism characterized by intellectual disability, psychomotor delay and/or regression, seizures, and autistic features.
ORPHA:46Classification level: Disorder
The prevalence and incidence of ADSL deficiency are unknown. More than 80 cases have been reported to date, mostly from Europe and the Mediterranean region. The disorder may be underdiagnosed as it is probably panethnic.
ADSL covers a continuous clinical spectrum with three major forms: fatal neonatal, severe (type I), and mild to moderate form (type II). Clinical variability is found, even in patients from the same family. Onset is generally between birth and early childhood. Cases ranging from fatal neonatal encephalopathy (presenting with hypokinesia, intractable seizures and respiratory failure) to mild intellectual disability have been reported. Intellectual disability is found in all patients, epilepsy of various types in most, and autistic features in about one third (failure to make eye contact, hypersensitivity to noise and light, repetitive behavior, agitation, temper tantrums, autoaggression and self-mutilation). Other less common manifestations include psychomotor delay, hyperactivity, speech impairment, muscular hypotonia, muscle wasting, and spasticity. Severely affected patients often have microcephaly. Prenatal manifestations are also reported: impaired intrauterine growth, microcephaly, fetal hypokinesia, and loss of fetal heart rate variability.
ADSL is a defect of purine metabolism affecting purinosome assembly and reducing metabolite fluxes through purine de novo synthesis and purine nucleotide recycling pathways. Biochemically, this defect manifests by the presence in the biologic fluids of two dephosphorylated substrates of ADSL enzyme: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). The underlying defect is associated with mutations in the ADSL gene (22q13.1). No strict genotype-phenotype correlations have been found.
Final diagnosis requires demonstration of succinylpurines in extracellular fluids such as plasma, cerebrospinal fluids (CSF) and/or urine using HPLC or HPLC-MS and/or genomic cDNA sequencing of the ADSL gene and characterization of mutant proteins. For selective screening, rapid methods are used (Bratton-Marshall or TLC). Reported findings on brain magnetic resonance imaging (MRI) include white matter anomalies, atrophy of the cerebral cortex, corpus callosum, cerebellar vermis, lack of myelination, delayed myelination, and lissencephaly (see this term).
The differential diagnoses include neurological disorders with intractable seizures and encephalopathy, and other inborn errors of purine and pyrimidine metabolism with neurological manifestations.
Prenatal diagnosis is possible when a disease-causing mutation has been identified in an affected family.
ADSL deficiency follows an autosomal recessive pattern of inheritance.
Management and treatment
There is currently no effective treatment for ADSL deficiency. Treatment is primarily supportive, aimed at controlling seizures. The aim of treating epilepsy is to control or at least decrease seizure frequency with minimal side effects. Treatment with anticonvulsive drugs (e.g. valproic acid, phenobarbital, carbamazepine, topiramate, levetiracetam, phenitoin, clobazam) depends on the type of seizures. Patients often require polypharmacy with the use of two or more anticonvulsants. Drug resistance is common.
Life expectancy in ADSL deficiency is variable. Neonatal forms may lead to early death, whereas onset in early childhood usually entails a stable course.