Clinical and molecular characterization of patients with adenylosuccinate lyase deficiency

Abstract

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.

Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure

“…6c ). LOF mutations in ADSL cause adenylosuccinate lyase deficiency 59 , and the protein is characterized by a notably low EDC value of 0.89. This indicates strong disease variant dispersal throughout the structure.…”

Electroclinical features and phenotypic differences in adenylosuccinate lyase deficiency: Long‐term follow‐up of seven patients from four families and appraisal of the literature

“…6–8 in Mastrogiorgio et al. 8 ), two with type II and one with type I, all having mild developmental delay, and two with epilepsy. Homozygous p.R426H carriers reported in the literature, like our Pts.…”

Child with adenylosuccinate lyase deficiency caused by a novel complex heterozygous mutation in the ADSL gene: A case report

“…Type II is a milder clinical phenotype of ADSL deficiency that involves slow disease progression and no specific symptoms. This phenotype was previously suspected to occur in approximately 15%-20% of patients with ADSL deficiency, but there is some evidence that it may be more common[ 7 ]. Patients with type II ADSL deficiency have only minor neurological involvement and a low incidence of epilepsy; they also have milder brain anomalies and generally do not exhibit microcephaly[ 7 ].…”

“…This phenotype was previously suspected to occur in approximately 15%-20% of patients with ADSL deficiency, but there is some evidence that it may be more common[ 7 ]. Patients with type II ADSL deficiency have only minor neurological involvement and a low incidence of epilepsy; they also have milder brain anomalies and generally do not exhibit microcephaly[ 7 ]. Our patient presented with comprehensive developmental delay and epilepsy, but he lacked autism or microcephaly.…”