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08 Jul 2026	Neurodegenerative disorders, adult onset v9.2	ARSA	Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023 Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction." Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls. Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD. Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H. Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar. Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD. PMID: 31312839 Lee et al., 2019 Reported a 32yo female proband with MLD, comp het for ARSA variants p.L300S and p.C174Y. Her father and paternal uncle had Parkinson's disease, and were heterozygous for the ARSA p.L300S variant - thought to be a potential risk factor. Also analysed 92 cases with familial dominant Parkinson's disease. ARSA p.N352S was found to be a protective variant (more common in controls than PD cohort). "ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein." In cell lines, authors showed that ARSA deficiency correlates with an increase in α-synuclein aggregation.; to: PMID: 37381728 Senkevich et al., 2023 Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction." Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls. Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD. Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H. Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar. Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD. PMID: 31312839 Lee et al., 2019 Reported a 32yo female proband with MLD, comp het for ARSA variants p.L300S and p.C174Y. Her father and paternal uncle had Parkinson's disease, and were heterozygous for the ARSA p.L300S variant - thought to be a potential risk factor. Also analysed 92 cases with familial dominant Parkinson's disease. ARSA p.N352S was found to be a protective variant (more common in controls than PD cohort). "ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein." In cell lines, authors showed that ARSA deficiency correlates with an increase in α-synuclein aggregation.
08 Jul 2026	Neurodegenerative disorders, adult onset v9.2	ARSA	Ida Ertmanska commented on gene: ARSA: Comment on mode of inheritance: ARSA deficiency is a well-established cause of recessive metachromatic leukodystrophy. There is also some emerging evidence that heterozygous variants in ARSA may be a genetic modifier of Parkinson's disease. However, heterozygous variants act as risk factors, rather than causing familial dominant disease. Hence, the mode of inheritance should remain as 'BIALLELIC, autosomal or pseudoautosomal' on this panel.
08 Jul 2026	Neurodegenerative disorders, adult onset v9.2	ARSA	Ida Ertmanska reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31312839, 37381728; Phenotypes: Metachromatic leukodystrophy, OMIM:250100, metachromatic leukodystrophy, MONDO:0018868, arylsulfatase A deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
29 Mar 2021	Neurodegenerative disorders, adult onset v2.49	ARSA	Ivone Leong Phenotypes for gene: ARSA were changed from Metachromatic leukodystrophy (#250100); Dystonia to Metachromatic leukodystrophy, OMIM:250100; Dystonia
02 Sep 2019	Neurodegenerative disorders, adult onset v1.101	ARSA	Louise Daugherty commented on gene: ARSA: Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group. All the green and amber, except for the genes with triplet repeats, were reviewed.
02 Sep 2019	Neurodegenerative disorders, adult onset v1.100	ARSA	Louise Daugherty Source Wessex and West Midlands GLH was added to ARSA.
02 Sep 2019	Neurodegenerative disorders, adult onset v1.99	ARSA	Tracy Lester reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Metachromatic leukodystrophy (#250100), Dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
23 Jul 2019	Neurodegenerative disorders, adult onset v1.74	ARSA	Louise Daugherty commented on gene: ARSA: Review and rating submitted by Nick Beauchamp (Sheffield Diagnostic genetics Service), on behalf of Yorkshire and North East GLH for GMS Neurology specialist test group.
23 Jul 2019	Neurodegenerative disorders, adult onset v1.72	ARSA	Nick Beauchamp reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Metachromatic leukodystrophy (#250100), Dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
23 Jul 2019	Neurodegenerative disorders, adult onset v1.67	ARSA	Louise Daugherty Source Yorkshire and North East GLH was added to ARSA.
23 Apr 2019	Neurodegenerative disorders, adult onset v1.11	ARSA	Louise Daugherty reviewed gene: ARSA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
23 Apr 2019	Neurodegenerative disorders, adult onset v1.10	ARSA	James Polke reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
23 Apr 2019	Neurodegenerative disorders, adult onset v1.9	ARSA	Louise Daugherty Source NHS GMS was added to ARSA.
23 Apr 2019	Neurodegenerative disorders, adult onset v1.8	ARSA	Louise Daugherty Source London North GLH was added to ARSA.
18 Dec 2018	Neurodegenerative disorders, adult onset v0.2	ARSA	Rebecca Foulger Added phenotypes Dystonia for gene: ARSA
18 Dec 2018	Neurodegenerative disorders, adult onset v0.2	ARSA	Rebecca Foulger gene: ARSA was added gene: ARSA was added to Neurodegenerative disorders - adult onset. Sources: Expert Review Green Mode of inheritance for gene: ARSA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ARSA were set to Metachromatic leukodystrophy (#250100)