Ataxia and cerebellar anomalies - narrow panel
Gene: ASLComment on list classification: Promoting this gene to amber with a recommendation for green rating as there are 5 cases of patients with ataxia and variants identified in the ASL gene (from PMID: 38044746 - Gurung et al 2023 and PMID: 28251416 - Baruteau et al 2017).Created: 4 Jan 2024, 5:09 p.m. | Last Modified: 4 Jan 2024, 10:14 p.m.
Panel Version: 4.46
Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.
The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.
PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries, PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient.
More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.
PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 patients including 2 out of 7 patients with ataxia (patients 25 and 33, c.437G>A; c.446+1G>A and c.348+1G>A; c.532G>A respectively). Genotype data was not available for other patients.
PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective analysis of patients with ASA prior to March 2013 and then prospective analysis of patients until December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant (c.35G>A;p.(Arg12Gln), c.377G>A;p.(Arg126G1n) and c.1138A>G;p.(Lys380Glu) respectively.
(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )Created: 27 Dec 2023, 6:34 p.m. | Last Modified: 7 Jan 2024, 3:57 p.m.
Panel Version: 4.49
Ataxia has been reported in multiple individuals with argininosuccinic aciduria (PMID 38044746, 36994644, 28251416).
Sources: LiteratureCreated: 8 Dec 2023, 12:37 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Ataxia
Publications
Tag Q4_23_promote_green tag was added to gene: ASL. Tag Q4_23_NHS_review tag was added to gene: ASL.
Gene: asl has been classified as Amber List (Moderate Evidence).
Publications for gene: ASL were set to 38044746; 36994644; 28251416
Phenotypes for gene: ASL were changed from Ataxia to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815; Ataxia, HP:0001251
gene: ASL was added gene: ASL was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature Mode of inheritance for gene: ASL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ASL were set to 38044746; 36994644; 28251416 Phenotypes for gene: ASL were set to Ataxia