Activity

Filter

Cancel
Date Panel Item Activity
21 actions
Leukodystrophy, adult onset v7.12 CTSA Achchuthan Shanmugasundram Phenotypes for gene: CTSA were changed from Galactosialidosis, 256540 to Brain small vessel disease 6 with leukoencephalopathy, OMIM:621394; cathepsin a-related arteriopathy-strokes-leukoencephalopathy, MONDO:0035551
Leukodystrophy, adult onset v7.11 CTSA Achchuthan Shanmugasundram Publications for gene: CTSA were set to 27159321; 25527826; 28334938; 20301621; 24357685
Leukodystrophy, adult onset v7.10 CTSA Achchuthan Shanmugasundram Added comment: 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.
Leukodystrophy, adult onset v7.10 CTSA Achchuthan Shanmugasundram Mode of inheritance for gene: CTSA was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy, adult onset v7.9 CTSA Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: CTSA.
Tag Q3_26_MOI tag was added to gene: CTSA.
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart changed review comment from: 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)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from three 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. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: 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.
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart changed review comment from: 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)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from two 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. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: 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)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from three 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. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart changed review comment from: 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). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers, from two 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. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: 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)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from two 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. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart changed review comment from: 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). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers. 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. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: 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). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers, from two 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. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart changed review comment from: 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). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers. 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. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: 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). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers. 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. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 35904593, 41908989, 27664989; Phenotypes: Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394), cathepsin a-related arteriopathy-strokes-leukoencephalopathy (MONDO:0035551); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Leukodystrophy, adult onset v7.9 CTSA Lauren Turton reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v0.19 CTSA David Lynch reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Leukodystrophy, adult onset v0.15 CTSA Catherine Snow Mode of inheritance for gene CTSA was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Galactosialidosis, 256540 for gene: CTSA
Leukodystrophy, adult onset v0.14 CTSA Catherine Snow reviewed gene: CTSA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Galactosialidosis, 256540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy, adult onset v0.10 CTSA Louise Daugherty reviewed gene: CTSA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Leukodystrophy, adult onset v0.9 CTSA Ian Berry reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: ; Publications: 28334938, 25527826, 27159321, 24357685, 20301621; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Leukodystrophy, adult onset v0.8 CTSA Louise Daugherty Publications for gene CTSA were changed from to 27159321; 25527826; 28334938; 20301621; 24357685
Leukodystrophy, adult onset v0.7 CTSA Louise Daugherty Source Expert Review Green was added to CTSA.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Leukodystrophy, adult onset v0.6 CTSA Louise Daugherty Source NHS GMS was added to CTSA.
Leukodystrophy, adult onset v0.5 CTSA Louise Daugherty gene: CTSA was added
gene: CTSA was added to White matter disorders - adult onset. Sources: Yorkshire and North East GLH
Mode of inheritance for gene: CTSA was set to