Submission Details

PSAP was first reported in relation to “metachromatic leukodystrophy due to saposin B deficiency” (MONDO:0009590), an autosomal recessive lysosomal disease, in 1990 (Rafi et al, PMID: 2302219; Kretz et al, PMID: 2320574).

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, metachromatic leukodystrophy due to saposin B deficiency (this curation), 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 protein), and phenotypic differences, based on the ClinGen Lumping and Splitting Guidelines.

Specific to this gene-disease validity curation, Saposin B activates the hydrolysis of cerebroside sulfate (sulfatide) by arylsulphatase A (ARSA). Both the deficiency of ARSA activity, caused by biallelic pathogenic variants within the ARSA gene, and the deficiency of saposin B, caused by variants in PSAP, can result in metachromatic leukodystrophy (MLD), with ARSA being the more common cause (Cessani et al, 2015, PMID: 26462614). In individuals with this condition, sulfatides accumulate resulting in progressive demyelination and dysfunction of the central and peripheral nervous systems. Symptoms include progressive motor and cognitive decline, ataxia, seizures, spasticity, and vision and hearing loss.

In this curation, data on 11 variants in PSAP (missense, splice site, initiator codon) in 9 patients from 9 publications were collected (Rafi et al, 1990, PMID: 2302219; Kretz et al, 1990, PMID: 2320574; Holtschmidt et al, 1991, PMID: 2019586; Henseler et al, 1996, PMID: 8554069; Wrobe et al, 2000, PMID: 10682309; Deconinck et al, 2008, PMID: 17616409; Kuchar et al, 2009, PMID: 19267410; Siri et al, 2014, PMID: 24478108; Kolnikova et al, 2019, PMID: 31319425; Madaan et al, 2019, PMID: 31319425). The most commonly observed variants are c.645C>A (p.Asn215Lys) and c.722G>C (p.Cys241Ser). Additional evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function.

This gene-disease relationship is also supported by experimental evidence including the biochemical functional of Saposin B, which is consistent with the biochemical and clinical findings in patients (Gieselmann and von Figura, 1990, PMID: 1977956), the results of an experiment in which breakdown of sulfatide in Saposin B-deficient cells was rescued by the addition of Saposin B (Wrobe et al, 2000, PMID: 10682309), and the clinical and biochemical features observed in a Saposin B-deficient knock-in mouse (Sun et al, 2008; PMID: 18480170).

In summary, PSAP is definitely associated with autosomal recessive “metachromatic leukodystrophy due to saposin B deficiency”. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases GCEP on July 20, 2023, SOP v9.