Parkinson Disease and Complex Parkinsonism

Gene: ARSA

I don't know

Comment on list classification: 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.

Created: 8 Jul 2026, 9:49 a.m. | Last Modified: 8 Jul 2026, 9:49 a.m.

Panel Version: 1.128

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.

Created: 7 Jul 2026, 5:15 p.m. | Last Modified: 8 Jul 2026, 9:39 a.m.

Panel Version: 1.128

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Metachromatic leukodystrophy, OMIM:250100; metachromatic leukodystrophy, MONDO:0018868; arylsulfatase A deficiency

Publications

• 31312839
• 37381728

I don't know

Association bertween these gene and Parkinson's has been controversial, however a recent publication adds to the supportive evidence for this gene (PMID: 37381728). Gene for Metachromatic leukodystrophy (MIM 250100 AR)
Sources: Expert list

Created: 26 Jun 2024, 3:57 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• PMID: 37381728 PMID: 31312839 PMID: 31312839