Leukodystrophy, adult onset

Gene: PSAP

Red List (low evidence)

Comment on list classification: While there are numerous individuals reported in literature with biallelic PSAP variants and Metachromatic leukodystrophy, there is only one patient with symptom onset after 18 years of age. Most individuals present in infancy or during the early years of childhood. Thus, this gene is not in scope of the 'Leukodystrophy, adult onset', and should be demoted to Red rating, until more evidence emerges. An expert-review tag was added to ensure GMS agreement on this demotion.

Created: 30 Sep 2026, 1:01 p.m. | Last Modified: 30 Sep 2026, 1:03 p.m.

Panel Version: 7.12

PMID: 31289144 Fenu et al., 2019
Case report of a 29yo female patient with Metachromatic leukodystrophy and comp het PSAP variants: c.645C>A, p.Asn215Lys and c.665T>C, p.Leu222Ser. Variant p.Leu222Ser suggested to have a milder effect on protein function. Age of disease onset was after age 22yrs. She presented with behavioural and cognitive decline. She was also treated for postpartum depression since early 20s. No motor disturbance except a mild tremor in her hands. Brain MRI showed diffuse leukoencephalopathy, and ENMG revealed a severe demyelinating polyneuropathy. Sural nerve biopsy showed characteristic MLD inclusions. High levels of urinary sulfatides noted. Study specifically says that 'this is the first adult-onset case' reported for this association.

PMID: 37404680 Sheth et al., 2023
Case 2 - 19yo male Indian patient who presented with gait ataxia, difficulty in walking and nystagmus - labelled 'adult‐onset', however his symptoms had started at age 13 years. His MRI brain revealed confluent and symmetrical areas of T2W/FLAIR hyperintensities in the periventricular and deep white matter of bilateral cerebral hemispheres, centrum semiovale and corpus callosum. Mild thinning of the corpus callosum was also seen. He was homozygous for PSAP c.593G > A, p.Cys198Tyr. Method: targeted seq panel of 23 genes.

ClinGen classified the association between PSAP and AR "metachromatic leukodystrophy due to saposin B deficiency" as Definitive (Lysosomal Diseases GCEP, 07/20/2023). All of the 9 probands included in this curation were under the age of 8 years at time of report.

Created: 30 Sep 2026, 12:27 p.m. | Last Modified: 30 Sep 2026, 1 p.m.

Panel Version: 7.12

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Metachromatic leukodystrophy due to SAP-b deficiency, OMIM:249900; metachromatic leukodystrophy due to saposin B deficiency, MONDO:0009590

Publications

• 31289144
• 37404680

Green List (high evidence)

I don't know

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Krabbe disease, atypical, 611722, Metachromatic leukodystrophy due to SAP-b deficiency, 249900

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