Submission Details

PSAP was first reported in relation to “Krabbe disease due to saposin A deficiency” (http://purl.obolibrary.org/obo/MONDO_0012720), an autosomal recessive lysosomal disease, in 2005 (Spiegel et al, PMID: 15773042).

PSAP encodes prosaposin, a highly conserved glycoprotein which is a precursor for 4 cleavage products, the Sphingolipid Activator Proteins, or saposins A, B, C, and D. Saposins localize primarily to the lysosomes where they each have a different role the catabolism of glycosphingolipids (Meyer et al, 2014, PMID: 25130661). Because the location and type of different variants within PSAP determines which specific saposin is impacted, PSAP will be curated separately for four different conditions: Krabbe disease due to saposin A deficiency (this curation), metachromatic leukodystrophy due to saposin B deficiency, Gaucher disease due to saposin C deficiency, and combined PSAP deficiency. These “splits” in curations were made on the basis of the published disease assertions, molecular mechanism (impact of the variant on the different cleavage products of the prosapson protein), and phenotypic differences, based on the ClinGen Lumping and Splitting Guidelines.

Specific to this gene-disease validity curation, Saposin A activates galactocerebrosidase (also known as galactosylceramide beta-galactosidase, galactosylceramidase) which is required for the degradation of galactosylceramide, galactosylsphingosine, and other galactolipids. Deficiency of galactocerebrosidase activity due to biallelic variants in the GALC gene causes Krabbe disease, a neurological condition with a range of age of onset and severity that is associated with rapid deterioration and death in childhood for individuals with the infantile onset form (Orsini et al, 2018, PMID: 20301416). This curation examines the evidence that variants in PSAP, which encodes Sapsoin A, an activator of galactocerebrosidase, can also cause Krabbe disease.

Three published cases with biallelic variants in PSAP and clinical and biochemical features consistent with Krabbe disease were identified (Spiegel et al, 2005, PMID: 15773042; Kose et al, 2018, PMID: 29995202; Calderwood et al, 2020, PMID: 31439510). Each of these individuals was homozygous for either a missense or inframe deletion within the region of the PSAP gene that encodes Saposin A (amino acids 60-143) (Meyer et al, 2014, PMID: 25130661. Another case was mentioned in the text of an article, homozygous for a previously reported missense change, but no clinical details were available (Suzuki et al, 2016, PMID: 27638581). A total of 1.4 points was given for genetic evidence.

This gene-disease relationship is also supported by experimental evidence including the biochemical functional of Saposin A, which is consistent with the biochemical and clinical findings in patients (Harzer et al, 1997, PMID: 9409731; Harzer et al, 2001, PMID: 11707278) and the clinical and biochemical features observed in a Saposin A-deficient knock-in mouse (Matsuda et al, 2001, PMID: 11371512). A total of 5 points was given for experimental evidence.

In summary, there is moderate evidence to support the relationship between PSAP and the autosomal recessive lysosomal disease ““Krabbe disease due to saposin A deficiency”. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was first approved by the ClinGen Lysosomal Diseases GCEP on December 4, 2023 (SOP v10), and was re-evaluated, with no changes, on Sept 12, 2025 (SOP v11).