Adenylosuccinate lyase deficiency

Abstract

Adenylosuccinate lyase ADSL) deficiency 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). More than 80 individuals with ADSL deficiency have been identified, but incidence of the disease remains unknown. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The fatal neonatal form has onset from birth and presents with fatal neonatal encephalopathy with a lack of spontaneous movement, respiratory failure, and intractable seizures resulting in early death within the first weeks of life. Patients with type I (severe form) present with a purely neurologic clinical picture characterized by severe psychomotor retardation, microcephaly, early onset of seizures, and autistic features. A more slowly progressing form has also been described (type II, moderate or mild form), as having later onset, usually within the first years of life, slight to moderate psychomotor retardation and transient contact disturbances. Diagnosis is facilitated by demonstration of SAICAr and S-Ado in extracellular fluids such as plasma, cerebrospinal fluid and/or followed by genomic and/or cDNA sequencing and characterization of mutant proteins. Over 50 ADSL mutations have been identified and their effects on protein biogenesis, structural stability and activity as well as on purinosome assembly were characterized. To date there is no specific and effective therapy for ADSL deficiency.

Fig. 1

De novo purine biosynthesis pathway. Abbreviations are as follows: PRPP, phosphoribosylpyrophosphate; SAICAR, succinylaminoimidazole carboxamide ribotide; SAICAr, succinylaminoimidazole carboxamide riboside; AICAR, aminoimidazole carbozamide ribotide; FAICAR, formyloaminoimidazole carboxamide ribotide; IMP, inosine monophosphate; S-AMP, adenylosuccinate; S-Ado, succinyladenosine; AMP, adenine monophosphate; XMP, xanthine monophosphate; GMP, guanine monophosphate; ADSL, adenylosuccinate lyase; AICAR TF, aminoimidazole carboxamide riboside transformylase; IMP CH, inosine monophosphate cyclohydrolase; ATIC, bifunctional enzyme AICAR transformylase/IMP cyclohydrolase

Fig. 2

a-c. Axial and sagittal T₂-weighted and T₁-weighted cranial magnetic resonance imaging of a patient with type I ADSL deficiency: arrows indicate myelination of the posterior limbs of the internal capsules, enlarged subarachnoid space in the frontal regions, widened lateral ventricles (especially enlargement of the body and occipital horns), wide Sylvian fissures with hypoplasia operculum, thin corpus callosum and lack of myelination of the white matter volume

Fig. 3

a-b. Axial T₂-weighted and T₁-weighted cranial magnetic resonance of a patient with type I ADSL deficiency: arrows indicate symmetrical widening of the lateral ventricles, enlarged sulci of the brain cortex gyri, especially in the parieto-occipital lobes

Fig. 4

Photos of patients with type II adenylosuccinate lyase deficiency