Clinical and molecular characterization of patients with adenylosuccinate lyase deficiency

Orphanet J Rare Dis. 2021 Mar 1;16(1):112. doi: 10.1186/s13023-021-01731-6.


Background: Adenylosuccinate lyase deficiency (ADSLD) is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the ADSL gene. The disease is characterized by wide clinical variability. Here we provide an updated clinical profiling of the disorder and discuss genotype-phenotype correlations.

Results: Data were collected through "Our Journey with ADSL deficiency Association" by using a dedicated web survey filled-in by parents. Clinical and molecular data were collected from 18 patients (12 males, median age 10.9 years ± 7.3), from 13 unrelated families. The age at onset ranged from birth to the first three years (median age 0.63 years ± 0.84 SD), and age at diagnosis varied from 2 months to 17 years, (median age 6.4 years ± 6.1 SD). The first sign was a psychomotor delay in 8/18 patients, epilepsy in 3/18, psychomotor delay and epilepsy in 3/18, and apneas, hypotonia, nystagmus in single cases. One patient (sibling of a previously diagnosed child) had a presymptomatic diagnosis. The diagnosis was made by exome sequencing in 7/18 patients. All patients were definitively diagnosed with ADSL deficiency based on pathogenic variants and/or biochemical assessment. One patient had a fatal neonatal form of ADSL deficiency, seven showed features fitting type I, and nine were characterized by a milder condition (type II), with two showing a very mild phenotype. Eighteen different variants were distributed along the entire ADSL coding sequence and were predicted to have a variable structural impact by impairing proper homotetramerization or catalytic activity of the enzyme. Six variants had not previously been reported. All but two variants were missense.

Conclusions: The study adds more details on the spectrum of ADSLD patients' phenotypes and molecular data.

Keywords: Adenylosuccinate lyase deficiency; Epilepsy; Exome sequencing; Intellectual disability; Neurometabolic disease; Purine nucleotide cycle defect.

MeSH terms

  • Adenylosuccinate Lyase* / deficiency
  • Adenylosuccinate Lyase* / genetics
  • Adolescent
  • Autistic Disorder*
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Phenotype
  • Purine-Pyrimidine Metabolism, Inborn Errors* / diagnosis
  • Purine-Pyrimidine Metabolism, Inborn Errors* / genetics


  • Adenylosuccinate Lyase

Supplementary concepts

  • Adenylosuccinate lyase deficiency