| Category | Summary |
|---|---|
| Disease / identifiers | **Combined saposin deficiency**; **MONDO:** MONDO:0012719 (combined PSAP deficiency); **OMIM:** 611721 (pqac-00000008, pqac-00000001) |
| Common synonyms | **Prosaposin deficiency**, **PSAP deficiency**, **combined PSAP deficiency**, **combined saposin A/B/C/D deficiency**, **complete prosaposin deficiency** (pqac-00000002, pqac-00000003, pqac-00000005) |
| Causal gene | **PSAP** (prosaposin), encoding the precursor cleaved into saposins **A–D**; loss of both null alleles causes absence of all four saposins (pqac-00000000, pqac-00000001, pqac-00000002) |
| Inheritance | **Autosomal recessive**; reported affected individuals are typically **biallelic/homozygous** or compound heterozygous for pathogenic PSAP variants (pqac-00000000, pqac-00000001, pqac-00000003, pqac-00000005) |
| Typical onset | Usually **neonatal/early infantile** with severe presentation; literature describes it as a relatively uniform neonatal disease, though rare later childhood presentations have been reported (pqac-00000001, pqac-00000003, pqac-00000005, pqac-00000000) |
| Key neurologic phenotypes | Severe neurologic disease with **hypotonia**, **seizures/myoclonus**, **poor suck/swallow**, **apnea/respiratory distress**, **developmental delay/regression**, **ataxia/extrapyramidal signs**, and profound neurodegeneration/demyelination (pqac-00000001, pqac-00000003, pqac-00000005, pqac-00000002, pqac-00000009) |
| Key visceral / hematologic phenotypes | **Hepatosplenomegaly**, elevated liver enzymes, **thrombocytopenia**, anemia; neurovisceral dystrophy is characteristic in classic neonatal cases (pqac-00000001, pqac-00000003, pqac-00000005) |
| Skin / eye / other phenotypes | **Ichthyosis** reported in at least one neonatal case; **cherry-red spots** and optic disc atrophy reported in PSAP-related severe infantile presentations (pqac-00000001, pqac-00000003) |
| Imaging / pathology | Brain MRI/neuropathology may show **cortical atrophy**, **white-matter abnormalities/demyelination**, **gray-matter heterotopias**, **abnormal gyration**, **thin corpus callosum**, paucity of myelin, active demyelination, neuronal loss, and astrocytosis (pqac-00000000, pqac-00000001, pqac-00000002, pqac-00000005) |
| Core mechanism | Loss of saposins A–D disrupts lysosomal sphingolipid degradation, causing accumulation of multiple sphingolipids (notably **lactosylceramide**, **glucosylceramide**, **globotriaosylceramide**, **sulfatides**, **ceramides**) with downstream neuroinflammation and myelin loss (pqac-00000002, pqac-00000011, pqac-00000012) |
| Enzyme assays / biochemical clues | Reduced lysosomal enzyme activities can be seen despite intact enzyme genes, e.g. low **β-glucosidase/GCase** and **β-galactocerebrosidase**; PSAP-linked GCase deficiency may show elevated **chitotriosidase** (pqac-00000001, pqac-00000012) |
| Urinary sphingolipid findings | **Urinary sphingolipid analysis** (TLC or ESI-MS/MS) is a key real-world diagnostic tool; multiple sphingolipids are elevated, with **globotriaosylceramide (Gb3)** reported as markedly increased in one neonatal pSap-d case (pqac-00000003, pqac-00000005) |
| Plasma lyso-lipid / biomarker findings | **Plasma glucosylsphingosine (lyso-GL1)** and **chitotriosidase** can be elevated in PSAP deficiency; experimental/cellular work also implicates **Lyso-Gb3** as elevated in PSAP-knockout models (pqac-00000012, pqac-00000001) |
| Example pathogenic variants | Reported case variants include **c.803delG** (frameshift, premature stop) (pqac-00000002); **splice acceptor mutation upstream of exon 10** causing premature stop/low transcript (pqac-00000003); **c.1419_1422delCTTC, p.Phe474fs** null allele (pqac-00000000); **c.G1228T, p.Glu410Ter** (pqac-00000003) |
| Reported outcomes / prognosis | Prognosis is generally **poor** in classic combined deficiency: several neonatal/infantile cases died in the **neonatal period**, at **55 days**, by **4 months**, or by **5 months** from respiratory failure, infections, sepsis, or multiorgan failure (pqac-00000001, pqac-00000003, pqac-00000005, pqac-00000000) |
| Current treatment / implementation | No disease-specific approved therapy identified; management is largely **supportive** (antiepileptics, respiratory support, tube/gastrostomy feeding, skin care). A 2023 zebrafish model suggested **acid sphingomyelinase/SMPD1 modulation** as a potential therapeutic target, while **monomethyl fumarate** did not improve survival in that model (pqac-00000001, pqac-00000009, pqac-00000010, pqac-00000014) |


*Table: This table condenses the most useful clinical, molecular, diagnostic, and prognostic facts about combined saposin deficiency/combined PSAP deficiency from case reports and recent mechanistic studies. It is designed as a quick-reference artifact for a disease knowledge base entry.*