Leukodystrophy, adult onset

Gene: CTSA

Comment on mode of inheritance: As reviewed by Lauren Turton and Luke Stuart, the MOI should be updated to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' in the next GMS update.

Created: 11 Sep 2026, 10:58 p.m. | Last Modified: 11 Sep 2026, 10:58 p.m.

Panel Version: 7.10

Green List (high evidence)

CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). This variant has been described across a number of CARASAL cohorts from varying backgrounds, though most patients described to-date are of European origin.

Hervé et al., 2012 (PMID 23175731): Identified a chromosome 20q13 region linked to a leukoencephalopathy phenotype in two French sisters. A later publication reported that this family was subsequently confirmed to carry the recurrent CTSA p.Arg325Cys variant (personal communication with the authors; 2026 report).

Bugiani et al., 2016 (PMID 27664989): First description of CARASAL in two Dutch kindreds. Haplotype analysis revealed a shared region of 1,145 kb on chromosome 20q13 suggesting a common ancestral origin, and the c.973C>T p.(Arg325Cys) variant (identified via exome sequencing) segregated with disease. The authors proposed that the introduced cysteine residue may alter protein folding, although SDS-PAGE experiments did not support this. Based on increased cathepsin A precursor protein, astrocytic endothelin-1 (ET-1) accumulation, increased premyelinating oligodendrocyte progenitors, and reduced myelin basic protein in patient white matter, they proposed that impaired ET-1 degradation contributes to vasculopathy and defective oligodendrocyte maturation. This mechanism is inferential and has not been experimentally validated.

Hwang et al., 2017 (PMID 28702507): Reported an additional British patient with CARASAL heterozygous for CTSA c.973C>T p(Arg325Cys). Analysis of the informative marker D20S838 suggested a common genetic ancestry with the previously reported Dutch families.

Budhdeo et al., 2022 (PMID 35904593): Described two further affected individuals, one of Chinese ancestry and one Brazilian individual of Italian origin, in who underwent exome sequencing and targeted Sanger sequencing, respectively. These cases expanded the ethnic distribution of CARASAL beyond the previously reported Dutch, British, and French families. Haplotype data were not available.

Cerfontaine et al., 2026 (PMID 41908989): Reported 21 affected individuals (including 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys), 4 affected obligate carriers) a from three Dutch pedigrees, including some overlap with the original 2016 Bugiani discovery cohort. The recurrent CTSA p.Arg325Cys variant was described as a Dutch founder variant and segregated with disease across multiple large pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI.

Yoon et al., 2023 (case report, accessed at:https://www.jns-journal.com/article/S0022-510X(23)01466-1/fulltext) Reported a Korean patient presenting with cognitive decline and leukodystrophy on brain imaging. Sequencing of a lysosomal disease panel identified heterozygous CTSA c.973C>T (p.Arg325Cys).

Population data:CTSA c.973C>T (p.Arg325Cys) is present in gnomAD v4 in one heterozygous individual (European non-Finnish ancestry), with no homozygotes observed (overall allele frequency 6.2 × 10^-7).
In silico data: AlphaMissense predicts the variant to be likely benign.

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Despite lacking functional evidence supporting variant pathogenicity and a yet-to-be determined disease mechanism, segregation and enrichment in relevant disease cohorts is convincing across multiple ethnic backgrounds. Thus a green rating is reiterated, with monoallelic inheritance.

Created: 9 Sep 2026, 10:47 a.m. | Last Modified: 10 Sep 2026, 4:11 p.m.

Panel Version: 7.9

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394); cathepsin a-related arteriopathy-strokes-leukoencephalopathy (MONDO:0035551)

Publications

• 35904593
• 41908989
• 27664989

Green List (high evidence)

CARASAL is the monoallelic phenotype. This gene is already green in the adult onset neurodegenerative disorders panel for monoallelic. The phenotype is also relevant for adult onset leukodystrophy patients.
Has OMIM phenotype for monoallelic OMIM: 621394

Created: 19 Aug 2026, 8:25 a.m. | Last Modified: 19 Aug 2026, 8:25 a.m.

Panel Version: 7.9

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

I don't know

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Galactosialidosis, 256540

I don't know

Review and rating uploaded from file (Consensus gene list for R62 Adult-Onset Leukodystrophy - Leeds.xlsx) submitted by Ian Berry (Leeds Genetics Laboratory) on behalf of Yorkshire and North East GLH for GMS Neurology specialist test group. Phenotype and MOI not submitted.

Created: 4 Jul 2019, 4:32 p.m. | Last Modified: 4 Jul 2019, 4:32 p.m.

Panel Version: 0.10

Green List (high evidence)

Included all genes listed in clinical cases in Lynch et al 2015 PMID:28334938 and Ayrignac et al. 2015 PMID: 25527826. Included all genes with clear adult onset listed in Vanderver 2017 PMID:27159321 and Ahmed et al. 2017 PMID:24357685. A small number of genes from these resources were omitted, particularly those with limited or single case reports referenced in Ahmed et al, those with a metabolic basis (that could be determined by standard metabolic assays), and recessive diseases where the likelihood of encountering incidental carrier status is far more likely than finding a diagnosis e.g. Cockayne syndrome. Due to variable expressivity and potential later onset of phenotype in hypomorphic cases, peroxisomal biogenesis disorders OMIM phenotypic Series PS214100 and GeneReviews PMID:20301621 included.

Created: 4 Jul 2019, 4:06 p.m. | Last Modified: 4 Jul 2019, 4:06 p.m.

Panel Version: 0.9

Publications

• 28334938
• 25527826
• 27159321
• 24357685
• 20301621

Variants in this GENE are reported as part of current diagnostic practice