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Classifications

ICIMD (Inherited Metabolic Disorders)

ISDS Skeletal Nosology

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Mappings

MONDO

MONDO:0015012 mucopolysaccharidosis-plus syndrome

MONDO:0015012 is the dedicated MPSPS class (OMIM:617303, Orphanet:505248), with RO:0004003 to HGNC:18179 (VPS33A). Verified by OAK NEC preflight before curation.

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Inheritance

1

Autosomal recessive inheritance HP:0000007

MPSPS is inherited in an autosomal recessive manner. Affected individuals are homozygous for a VPS33A missense variant; in the Yakut founder population, parents are typically healthy heterozygous carriers and consanguinity is not required.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"MPSPS, whose pathophysiology is not elucidated, is an autosomal recessive multisystem disorder caused by a specific mutation p.R498W in the VPS33A gene."

States the autosomal recessive mode of inheritance and the causal VPS33A p.R498W variant.

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Subtypes

2

Severe infantile MPSPS (p.Arg498Trp founder form)

The classical and by far the commonest form, caused by homozygous VPS33A c.1492C>T (p.Arg498Trp). Presentation is in the first months of life with MPS-like facies and dysostosis together with congenital heart disease, renal and haematopoietic involvement; death from cardiorespiratory failure typically occurs at 10-20 months. 39 of the first 41 reported patients carried this variant.

Show evidence (1 reference)

PMID:36232726 SUPPORT Human Clinical

"Up to now, a total number of 39 patients have been reported; in all of them, the c.1492C>T (p.Arg498Trp) variant of the VPS33A gene was detected."

Establishes p.Arg498Trp as the recurrent variant accounting for essentially all reported MPSPS patients at that time.

Attenuated juvenile MPSPS (p.Arg200Pro)

An attenuated, longer-surviving form described in two unrelated patients homozygous for VPS33A c.599G>C (p.Arg200Pro), with appreciable residual endosomal-lysosomal trafficking. Reported features include normal growth, fetal ascites that resolved spontaneously, recurrent joint effusion and peripheral oedema.

Show evidence (1 reference)

PMID:36153662 SUPPORT Human Clinical

"To our knowledge this is the first report of an attenuated juvenile form of VPS33A insufficiency characterized by appreciable residual endosomal-lysosomal trafficking and a milder mucopolysaccharidosis plus than the disease in infants."

Defines the attenuated juvenile subtype and attributes its milder course to residual endosomal-lysosomal trafficking capacity.

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Discussions and Knowledge Gaps

3

Should MPSPS be classified as a type of mucopolysaccharidosis, or as a distinct vesicular-trafficking metabolic disease that phenocopies one?

KNOWLEDGE GAP OPEN mpsps_nosology

Attached to

pathophysiology#Glycosaminoglycan Accumulation With Normal Lysosomal Hydrolase Activity

GAG storage and MPS-like clinical features argue for inclusion among the mucopolysaccharidoses; normal lysosomal GAG-hydrolase activity and a primary membrane-tethering/trafficking lesion argue for a separate entity. The question is not merely terminological: it determines whether MPSPS belongs in the Mucopolysaccharidoses grouping (whose rationale requires deficiency of a GAG-degrading enzyme) and whether newborn screening by enzyme assay could ever detect it. This entry takes the position that MPSPS is a lysosomal storage disorder reached by a trafficking route, hence downstream-only conformance to lysosomal_substrate_accumulation and no MPS-grouping membership on the criteria as currently written.

Show evidence (1 reference)

PMID:39273517 SUPPORT Other

"Moreover, we asked the question whether MPSPS should be classified as a type of MPS or a separate disease, as contrary to 'classical' MPS types, despite GAG accumulation, no defects in lysosomal enzymes responsible for degradation of these compounds could be detected in MPSPS."

The 2024 review poses exactly this nosological question and states the reason it is unresolved.

Is autophagic flux genuinely impaired in MPSPS, or is the reported autophagy abnormality specific to the p.Arg200Pro variant or to assay conditions?

KNOWLEDGE GAP OPEN mpsps_autophagy_discrepancy

Attached to

pathophysiology#Endolysosomal Compartment Expansion and Over-Acidification

The original p.Arg498Trp study explicitly reported that the mutation did NOT affect the endocytic or autophagic pathways in patient skin fibroblasts, whereas a later study of p.Arg200Pro fibroblasts found elevated LC3-II and p62, indicating a block in autophagic flux. Because HOPS is required for autophagosome-lysosome fusion, an autophagy defect is mechanistically expected, making the negative result surprising. Resolving this matters for whether the Autophagic-Lysosomal Dysfunction conformance asserted here is correct for both variants, and for whether autophagy-modulating therapy is rational.

Proposed experiments

Head-to-head autophagic flux assay across both VPS33A genotypes

mpsps_autophagic_flux_headtohead

Side-by-side autophagic-flux assay (LC3-II turnover with and without bafilomycin A1, plus p62 and tandem mRFP-GFP-LC3 reporter) in p.Arg498Trp and p.Arg200Pro patient fibroblasts and isogenic knock-in controls, under identical starvation and basal conditions.

Live-cell imaging of autophagosome-lysosome fusion

mpsps_autophagosome_lysosome_fusion_imaging

Quantify autophagosome-lysosome fusion directly by live-cell imaging of LC3 and LAMP1 colocalisation in both genotypes, to distinguish a fusion block from altered autophagosome biogenesis.

Show evidence (2 references)

PMID:28013294 SUPPORT In Vitro

"VPS33A is involved in endocytic and autophagic pathways, but the identified mutation did not affect either of these pathways."

The negative finding in p.Arg498Trp fibroblasts that generates the discrepancy.

PMID:40758165 SUPPORT In Vitro

"elevated levels of the LC3-II and p62 proteins (autophagy markers)"

The positive autophagy-marker finding in p.Arg200Pro fibroblasts that conflicts with the earlier negative result.

Every mechanistic result in MPSPS comes from patient skin fibroblasts or transfected HeLa cells - can findings in these systems be assumed to explain the cardiac, renal, marrow and neurodevelopmental disease that actually kills affected children, when no knock-in animal or organ-level human model exists?

HUMAN MODEL MISMATCH OPEN mpsps_no_organ_level_model

Attached to

pathophysiology#Progressive Multisystem Disease With Plus Features

Patient-derived skin fibroblasts and HeLa cells reproduce VPS33A depletion, HOPS/CORVET loss, endolysosomal disorganisation and trafficking defects, but they cannot model the cardiorespiratory, renal-podocyte, marrow-hypoplasia or neurodevelopmental phenotypes. In particular the causal edge from GAG storage to congenital heart disease is asserted clinically but has never been demonstrated experimentally in any system, and the in vitro drug rescues (bortezomib, eliglustat, genistein/ambroxol) are all fibroblast readouts of uncertain organ-level relevance. No validated VPS33A p.Arg498Trp knock-in mouse, zebrafish, organoid or iPSC model recapitulating the human syndrome has been reported.

Proposed experiments

Vps33a p.Arg498Trp knock-in mouse phenotyping

mpsps_knockin_mouse

Generate and phenotype a Vps33a p.Arg498Trp knock-in mouse, with longitudinal echocardiography, urinary protein quantification, renal histology for foamy podocytes, and marrow cellularity, to test whether the plus features are cell-autonomous consequences of the tethering defect.

Patient iPSC-derived cardiac, kidney and haematopoietic models

mpsps_ipsc_organ_models

Differentiate patient iPSCs to cardiomyocytes, kidney organoids and haematopoietic progenitors to determine which plus features arise cell-autonomously versus secondarily to systemic storage, and to retest the candidate drugs in a disease-relevant cell type.

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Pathophysiology

8

VPS33A Missense Variant Destabilisation and Proteasomal Degradation

Biallelic missense variants in VPS33A destabilise the folded protein and target it for proteasomal degradation, so the steady-state intracellular abundance of intact full-length VPS33A falls. The 3D crystal structure of human VPS33A predicts that replacement of arginine 498 by tryptophan de-stabilises folding; the same instability-plus-degradation mechanism is documented for the juvenile p.Arg200Pro variant. The functional consequence is hypomorphic loss of function through protein instability, not gain of function or dominant-negative activity, and mutant protein can be rescued by proteasome inhibition.

VPS33A hgnc:18179

Downstream

HOPS and CORVET Tethering Complex Depletion Loss of intact VPS33A, a core subunit of both complexes, secondarily lowers the abundance of the other HOPS and CORVET components.

Show evidence (3 references)

PMID:31070736 SUPPORT In Vitro

"The 3D crystal structure of human VPS33A predicts that replacement of arginine 498 by tryptophan will de-stabilize VPS33A folding."

Structural basis for destabilisation of VPS33A by the founder p.Arg498Trp substitution.

PMID:31070736 SUPPORT In Vitro

"We propose that the disease is due to diminished intracellular abundance of intact VPS33A."

States the proposed proximal disease mechanism: reduced abundance of intact VPS33A rather than an altered catalytic activity.

PMID:36153662 SUPPORT In Vitro

"We showed decreased abundance of VPS33A in patient derived fibroblasts and provided evidence that the p.Arg200Pro mutation leads to destablization of the protein and proteasomal degradation."

Confirms the same destabilisation-and-proteasomal-degradation mechanism for the second, juvenile-associated VPS33A variant.

HOPS and CORVET Tethering Complex Depletion

VPS33A is a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway. Because VPS33A is shared by both complexes, its depletion is not isolated: patient cells show reduced abundance of the other HOPS and CORVET components as well, so both the early-endosome (CORVET) and late-endosome/lysosome (HOPS) tethering arms are simultaneously compromised.

HOPS complex GO:0030897 CORVET complex GO:0033263

Downstream

Impaired Endosome-Lysosome Tethering and Fusion Depletion of the tethering complexes impairs the membrane tethering and fusion steps of the endocytic route to the lysosome.

Show evidence (3 references)

PMID:31070736 SUPPORT In Vitro

"VPS33A is a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway."

Establishes VPS33A as a shared core subunit of both HOPS and CORVET, the structural reason a single-gene lesion depletes two tethering complexes.

PMID:31070736 SUPPORT In Vitro

"We observed that the missense mutation reduced the abundance of full-length VPS33A and other components of the HOPS and CORVET complexes."

Directly documents secondary depletion of the other HOPS/CORVET components in cells carrying the mutant VPS33A.

PMID:36153662 SUPPORT Other

"A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components of the intracellular membrane-tethering protein complexes, HOPS, and CORVET."

Frames the disease itself as a deficiency of HOPS/CORVET core components causing impaired endocytic trafficking. Evidence source is OTHER because this is the paper's framing/background sentence rather than a report of its own patient or experimental data.

Impaired Endosome-Lysosome Tethering and Fusion

With HOPS and CORVET depleted, the tethering and fusion events that carry endocytic cargo from early through late endosomes into the lysosome become inefficient. Patient fibroblasts show vacuolation with disordered endosomal/lysosomal compartments, elevated EEA1 (required at early/late endosome fusion and early-endosome sorting), altered Golgi morphology, and abnormal endocytic trafficking of lactosylceramide and other glycosphingolipids. This node is the mechanistic pivot of MPSPS: it is a delivery failure upstream of catabolism, not a catabolic block, and it is what distinguishes MPSPS from every classical mucopolysaccharidosis.

endosome to lysosome transport GO:0008333 ↓ DECREASED vesicle fusion GO:0006906 ↓ DECREASED endosome organization GO:0007032 ↕ DYSREGULATED

late endosome GO:0005770 lysosome GO:0005764

Downstream

Glycosaminoglycan Accumulation With Normal Lysosomal Hydrolase Activity GAGs that are not efficiently delivered to the lysosome are not turned over and accumulate in cells, despite intact degradative enzymes.

Endolysosomal Compartment Expansion and Over-Acidification Failed fusion leaves an expanded, abnormally acidified endolysosomal compartment.

Show evidence (3 references)

PMID:31070736 SUPPORT In Vitro

"Here we show that cultured fibroblasts from patients with this disorder have morphological changes: vacuolation with disordered endosomal/lysosomal compartments"

Documents the disordered endosomal/lysosomal compartments and vacuolation in patient-derived cells.

PMID:40758165 SUPPORT In Vitro

"indicated specific changes in cellular vacuoles, elevated levels of the EEA1 protein"

Independent cell-biological confirmation of a disturbed endosomal compartment, with elevated EEA1 marking the early/late endosome fusion and sorting step.

PMID:41310305 SUPPORT Other

"Recent works demonstrated that low abundance of mutated VPS33A causes defective endosomal trafficking, resulting in poor delivery of GAGs (and perhaps also other compounds) to lysosomes, preventing their effective turnover."

States the pivotal causal step explicitly: low VPS33A causes defective endosomal trafficking and poor delivery of GAGs to lysosomes, preventing turnover - a delivery failure rather than a catabolic block. Evidence source is OTHER because this sentence is the paper's background synthesis of prior work, not a result of its own experiments.

Glycosaminoglycan Accumulation With Normal Lysosomal Hydrolase Activity

Heparan, dermatan and (variably) chondroitin sulphate accumulate and are excreted in excess in the urine, and plasma heparan sulphate is extraordinarily elevated - around 60 times the normal reference range and six times the level seen in classical MPS patients. Sialylated conjugates, sialooligosaccharides, elevated beta-D-galactosylsphingosine and cholesterol and sphingolipid abnormalities are also reported. The defining biochemical signature of MPSPS is that all of this occurs with entirely normal activity of the cognate lysosomal hydrolases: it is substrate accumulation without an enzyme deficiency.

glycosaminoglycan catabolic process GO:0006027 ↓ DECREASED

Downstream

Progressive Multisystem Disease With Plus Features Progressive intracellular storage across many tissues produces the MPS-like plus multisystem clinical picture.

Show evidence (6 references)

PMID:39273517 SUPPORT Other

"Patients with MPSPS exhibited excessive excretion of glycosaminoglycans (GAGs) in the urine and exceptionally high levels of heparan sulfate in the plasma, but the accumulation of substrates is not caused by a decrease in the activity of any lysosomal enzymes."

The single most important statement for this entry: GAG storage occurs without any decrease in lysosomal enzyme activity. Evidence source is OTHER because this is a focused review synthesising several study types.

PMID:28013294 SUPPORT Human Clinical

"They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients."

Quantifies the magnitude of heparan sulphate accumulation in MPSPS, which exceeds that of classical MPS.

PMID:28013294 SUPPORT Human Clinical

"We hence propose a new type of MPS that is not caused by an enzymatic deficiency."

The original description explicitly frames MPSPS as an MPS-like storage disease that is not caused by an enzymatic deficiency.

+ 3 more references

Endolysosomal Compartment Expansion and Over-Acidification

Failed tethering and fusion leave an expanded endocytic compartment that is abnormally acidified. Lysosomal over-acidification was detected in patient-derived and VPS33A-depleted cells in the original description, and increased endolysosomal acidification with an expanded endocytic compartment was independently confirmed in the juvenile p.Arg200Pro form. Autophagy markers LC3-II and p62 are elevated in p.Arg200Pro fibroblasts, indicating a block in autophagic flux, though the original p.Arg498Trp study did not detect an autophagic defect (see the autophagy-discrepancy discussion below).

lysosomal lumen acidification GO:0007042 ↑ INCREASED autophagy GO:0006914 ↕ DYSREGULATED

Downstream

Progressive Multisystem Disease With Plus Features Sustained endolysosomal dysfunction drives cell-type-specific injury and progressive organ disease.

Show evidence (4 references)

PMID:28013294 SUPPORT In Vitro

"Lysosomal over-acidification and HS accumulation were detected in patient-derived and VPS33A-depleted cells, suggesting a novel role of this gene in lysosomal functions."

Establishes lysosomal over-acidification together with heparan sulphate accumulation as the cellular readout in MPSPS cells.

PMID:36153662 SUPPORT In Vitro

"As in the infantile form of mucopolysaccharidosis plus, the endocytic compartment in the fibroblasts also expanded-a phenomenon accompanied by increased endolysosomal acidification and impaired intracellular glycosphingolipid trafficking."

Independently replicates endocytic compartment expansion and increased endolysosomal acidification in the second VPS33A variant.

PMID:40758165 SUPPORT In Vitro

"elevated levels of the LC3-II and p62 proteins (autophagy markers)"

Supports an autophagic-flux abnormality in MPSPS fibroblasts. Marked PARTIAL because this is a single p.Arg200Pro cell line and the original p.Arg498Trp study reported no autophagic defect.

+ 1 more reference

Renal Podocyte Storage and Glomerular Destruction

The kidney is one of the two most discriminating "plus" targets. Storage in podocytes converts them to foam cells and destroys glomerular architecture, producing nephrotic-range proteinuria, hypoalbuminaemia, and rising creatinine, cholesterol and uric acid. Histology shows extensive destruction of glomerular structures by foamy podocytes, with periglomerular fibrosis and interstitial inflammation.

podocyte CL:0000653

renal glomerulus UBERON:0000074 kidney UBERON:0002113

Downstream

Progressive Multisystem Disease With Plus Features Glomerular destruction contributes the renal arm of the plus phenotype.

Show evidence (3 references)

PMID:35628659 SUPPORT Human Clinical

"Histological analyses of MPSPS kidneys similarly suggest the extensive destruction of glomerular structures by foamy podocytes."

Directly documents foamy (storage-laden) podocytes destroying glomerular structures in MPSPS kidneys.

PMID:35628659 SUPPORT Human Clinical

"High urinary excretion of protein (caused by impairments in renal filtration), hypoalbuminemia, and elevated levels of creatinine, cholesterol, and uric acid indicate renal dysfunction."

Links the podocyte/glomerular lesion to the measured renal phenotype: proteinuria from impaired filtration, hypoalbuminaemia and azotaemia.

PMID:31936524 SUPPORT Human Clinical

"Renal biopsy showed segmental sclerosis, periglomerular fibrosis and inflammatory cell infiltration."

Provides the biopsy evidence for the periglomerular fibrosis and interstitial inflammation described on this node.

Bone Marrow Hypoplasia and Peripheral Cytopenias

The haematopoietic system is the second discriminating "plus" target. Progressive anaemia and thrombocytopenia develop and correlate with histologically hypoplastic bone marrow; neutropenia/leukopenia, coagulation abnormalities and platelet dysfunction are also reported. Secondary haemophagocytic lymphohistiocytosis has occurred in at least one longer-surviving patient.

bone marrow UBERON:0002371

Downstream

Progressive Multisystem Disease With Plus Features Marrow failure contributes the haematopoietic arm of the plus phenotype.

Show evidence (3 references)

PMID:31936524 SUPPORT Human Clinical

"Bone marrow aspiration analysis showed hypoplastic bone marrow without any storage cells."

Key negative finding: the marrow is hypoplastic yet free of storage cells, which is why this node is deliberately not mapped to the module's storage-cell node and why the mechanism of the cytopenias is unresolved.

PMID:35628659 SUPPORT Human Clinical

"A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow."

Connects the peripheral cytopenias to a hypoplastic marrow, establishing the marrow as the site of the haematopoietic lesion.

PMID:31070736 SUPPORT Human Clinical

"A rare lysosomal disease resembling a mucopolysaccharidosis with unusual systemic features, including renal disease and platelet dysfunction, caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts"

Identifies renal disease and platelet dysfunction as the unusual systemic features distinguishing this disorder from a conventional MPS. Marked PARTIAL because platelet dysfunction is a qualitative platelet defect, not the marrow hypoplasia and quantitative cytopenias this node models.

Progressive Multisystem Disease With Plus Features

The clinical endpoint is a rapidly progressive multisystem disease that looks like a mucopolysaccharidosis - coarse facial features, skeletal abnormalities/dysostosis multiplex, hepatosplenomegaly, respiratory problems, developmental delay and excess urinary GAG - with, superimposed on it, congenital heart defects and renal and haematopoietic disease that are not typical of conventional MPS. For the p.Arg498Trp founder form the outcome is fatal cardiorespiratory failure at 10-20 months.

Show evidence (3 references)

PMID:28013294 SUPPORT Human Clinical

"We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."

Enumerates the MPS-like arm of the multisystem phenotype.

PMID:28013294 SUPPORT Human Clinical

"Additionally, most patients developed heart, kidney, and hematopoietic disorders, which are not typical symptoms for conventional MPS, leading to a fatal outcome between 1 and 2-years old."

Enumerates the "plus" arm - cardiac, renal and haematopoietic disease - and the fatal infantile outcome.

PMID:31936524 SUPPORT Human Clinical

"Disease is very severe, prognosis is unfavorable and most of patients died at age of 10-20 months."

Quantifies the natural history endpoint for the severe founder form.

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Histopathology

2

Glomerular destruction by foamy podocytes

Renal histology in MPSPS shows extensive destruction of glomerular structures by foamy (storage-laden) podocytes, with segmental sclerosis, periglomerular fibrosis and inflammatory cell infiltration. The foamy podocyte is the one unambiguous storage cell described in MPSPS.

Show evidence (2 references)

PMID:35628659 SUPPORT Human Clinical

"Histological analyses of MPSPS kidneys similarly suggest the extensive destruction of glomerular structures by foamy podocytes."

Primary histological description of the renal lesion.

PMID:31936524 SUPPORT Human Clinical

"Renal biopsy showed segmental sclerosis, periglomerular fibrosis and inflammatory cell infiltration."

Adds the sclerotic, fibrotic and inflammatory components of the renal biopsy picture.

Hypoplastic bone marrow without storage cells

Marrow histology shows hypoplasia but, notably, NO storage cells - a key negative that distinguishes the MPSPS cytopenias from a storage-cell infiltration mechanism and leaves them mechanistically unexplained.

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Bone marrow aspiration analysis showed hypoplastic bone marrow without any storage cells."

Documents marrow hypoplasia together with the explicit absence of storage cells.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

34

Blood 4

Decreased total leukocyte count FREQUENT HP:0001882

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Most patients develop hematopoietic disorders including anemia, thrombocytopenia and leukocytopenia."

Names leukocytopenia as one of the haematopoietic disorders present in most patients, supporting both the phenotype and the FREQUENT band.

Anemia FREQUENT HP:0001903

Course: PROGRESSIVE

Show evidence (2 references)

PMID:31936524 SUPPORT Human Clinical

"Most patients develop hematopoietic disorders including anemia, thrombocytopenia and leukocytopenia."

Frequency evidence. "Most patients" maps to FREQUENT per docs/frequency-evidence-guidelines.md.

PMID:35628659 SUPPORT Human Clinical

"A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow."

Directly reports progressive anaemia in MPSPS patients.

Thrombocytopenia FREQUENT HP:0001873

Course: PROGRESSIVE

Show evidence (2 references)

PMID:31936524 SUPPORT Human Clinical

"Most patients develop hematopoietic disorders including anemia, thrombocytopenia and leukocytopenia."

Frequency evidence. "Most patients" maps to FREQUENT per docs/frequency-evidence-guidelines.md.

PMID:35628659 SUPPORT Human Clinical

"A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow."

Directly reports progressive thrombocytopenia in MPSPS patients.

Decreased circulating IgG concentration HP:0004315

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"An increase in serum IgM and decrease of IgG levels were found in MPSPS patients"

Reports decreased serum IgG in MPSPS patients. Note the same sentence reports IgM moving in the OPPOSITE direction, curated separately below so the discordant pattern is not collapsed into a single "low immunoglobulin" claim.

Cardiovascular 5

Hepatosplenomegaly HP:0001433

Show evidence (1 reference)

PMID:28013294 SUPPORT Human Clinical

"We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."

Lists hepatosplenomegaly among the typical MPS manifestations of MPSPS.

Congenital heart defect FREQUENT Abnormal heart morphology HP:0001627

TERM BINDING - do not re-litigate. HP:0001627 is retained deliberately, and the preferred_term/label divergence is correct, not an error: "Congenital heart defect" and "Congenital heart defects" are both EXACT synonyms of HP:0001627 (verified with OAK), so the term does carry congenital semantics even though its primary label does not say so. A review pass suggested re-binding on the grounds that HP:0001627 is a bare morphology parent "with no congenital semantics"; that premise is factually wrong and was rejected. What the review got right was a separate SPECIFICITY point, which has been acted on: wherever the cited source names an individual lesion, a specific HPO term is now curated for it. This umbrella is kept only for the generic statements ("Most patients developed congenital heart defects"), because descending to a specific lesion there would assert something the paper does not report.

Show evidence (3 references)

PMID:31936524 SUPPORT Human Clinical

"Most patients developed congenital heart defects."

Frequency evidence. "Most patients" maps to FREQUENT per docs/frequency-evidence-guidelines.md.

PMID:31936524 SUPPORT Human Clinical

"In addition to typical symptoms for conventional MPS, MPSPS patients developed other features such as congenital heart defects, renal and hematopoietic disorders."

Identifies congenital heart defects as one of the MPSPS-specific "plus" features beyond conventional MPS.

PMID:35327996 SUPPORT Human Clinical

"This syndrome presents with typical symptoms of mucopolysaccharidosis, as well as congenital heart defects, renal, and hematopoietic system disorders."

Independent confirmation of congenital heart defects as part of the MPSPS triad of plus features.

Atrial septal defect HP:0001631

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"congenital heart defects (patent ductus arteriosus (PDA) and atrial septal defect (ASD), pulmonary hypertension"

Names atrial septal defect as one of the congenital heart defects in the MPSPS cardiovascular organ-system list.

Patent ductus arteriosus HP:0001643

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"congenital heart defects (patent ductus arteriosus (PDA) and atrial septal defect (ASD), pulmonary hypertension"

Names patent ductus arteriosus as one of the congenital heart defects in the MPSPS cardiovascular organ-system list.

Pulmonary arterial hypertension HP:0002092

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Mitral and tricuspid valve defects and pulmonary hypertension progressed from moderate to severe within 3"

Documents pulmonary hypertension alongside valve defects and quantifies the strikingly rapid 3-4 month progression noted in the cardiac description.

Eye 1

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Neurology: hydrocephalus syndrome, hypotonia, poor tendon reflexes, nystagmus"

Names nystagmus in the MPSPS neurological organ-system list.

Genitourinary 1

Enlarged kidney HP:0000105

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Abdominal ultrasound revealed hepatosplenomegaly, nephromegaly and renal ectasia."

Documents nephromegaly on imaging. No frequency is asserted because this is a single reported proband.

Head and Neck 2

Coarse facial features HP:0000280

Show evidence (1 reference)

PMID:28013294 SUPPORT Human Clinical

"We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."

Lists coarse facial features among the typical MPS manifestations of MPSPS patients.

Macroglossia HP:0000158

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Coarse facial features: short nose and neck, prominent forehead, epicanthal folds, telecanthus, thick hair, excessive hair growth, periorbital puffiness, long eyelashes, large rounded cheeks, full lips, macroglossia"

Names macroglossia in the MPSPS craniofacial organ-system list.

Immune 1

Recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:28013294 SUPPORT Human Clinical

"We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."

Supports respiratory involvement in MPSPS. Marked PARTIAL because the abstract states "respiratory problems" without specifying the recurrent infective pattern.

Metabolism 1

Hypoalbuminemia HP:0003073

Show evidence (1 reference)

PMID:35628659 SUPPORT Human Clinical

"High urinary excretion of protein (caused by impairments in renal filtration), hypoalbuminemia, and elevated levels of creatinine, cholesterol, and uric acid indicate renal dysfunction."

Directly reports hypoalbuminaemia as part of the MPSPS renal picture.

Musculoskeletal 4

Dysostosis multiplex HP:0000943

Show evidence (1 reference)

PMID:28013294 SUPPORT Human Clinical

"We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."

Supports skeletal involvement as a typical MPS manifestation in MPSPS. Marked PARTIAL because the abstract says "skeletal abnormalities" rather than naming the dysostosis multiplex pattern specifically.

Joint stiffness HP:0001387

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Usually they had a complaint of frequent cough, shortness of breath, noisy breathing and stiffness of joints."

Establishes joint stiffness as a usual presenting complaint in MPSPS infants.

Kyphosis HP:0002808

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Skeletal: barrel-shaped chest, pectus carinatum, kyphosis (thoracic, lumbar)"

Names thoracic and lumbar kyphosis in the MPSPS skeletal organ-system list.

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Neurology: hydrocephalus syndrome, hypotonia, poor tendon reflexes, nystagmus"

Names hypotonia and poor tendon reflexes in the MPSPS neurological organ-system list.

Nervous System 1

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:28013294 SUPPORT Human Clinical

"We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."

Supports cognitive/developmental involvement. Marked PARTIAL because the abstract uses the older term "mental retardation" rather than describing the global developmental delay pattern.

Other 14

Multiple joint contractures HP:0002828

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"joints contracture, stiffness of the elbow, wrist, hip, knee and ankle joints, finger phalangeal swelling, limitation of motion of fingers, claw-hand deformities"

Documents contractures across multiple named joints, supporting the multiple-joint term rather than a single-joint contracture term.

Nephrotic range proteinuria FREQUENT HP:0012593

Show evidence (2 references)

PMID:31936524 SUPPORT Human Clinical

"The majority of MPSPS patients had a nephrotic syndrome."

Frequency evidence. "The majority" maps to FREQUENT per docs/frequency-evidence-guidelines.md.

PMID:35628659 SUPPORT Human Clinical

"High urinary excretion of protein (caused by impairments in renal filtration), hypoalbuminemia, and elevated levels of creatinine, cholesterol, and uric acid indicate renal dysfunction."

Documents heavy proteinuria with hypoalbuminaemia and azotaemia, the nephrotic-range renal phenotype of MPSPS.

Nephrotic syndrome FREQUENT HP:0000100

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"The majority of MPSPS patients had a nephrotic syndrome."

Directly reports nephrotic syndrome in the majority of patients, supporting both the phenotype and the FREQUENT band.

Tricuspid regurgitation HP:0005180

Show evidence (2 references)

PMID:31936524 SUPPORT Human Clinical

"valve insufficiency (tricuspid, mitral)"

Names tricuspid valve insufficiency in the MPSPS cardiovascular organ-system list.

PMID:31936524 SUPPORT Human Clinical

"insufficiency of aortic valve, mitral and tricuspid valve regurgitation, pulmonary hypertension"

Echocardiographic confirmation of tricuspid regurgitation in the reported proband.

Mitral regurgitation HP:0001653

Show evidence (2 references)

PMID:31936524 SUPPORT Human Clinical

"valve insufficiency (tricuspid, mitral)"

Names mitral valve insufficiency in the MPSPS cardiovascular organ-system list.

PMID:31936524 SUPPORT Human Clinical

"insufficiency of aortic valve, mitral and tricuspid valve regurgitation, pulmonary hypertension"

Echocardiographic confirmation of mitral regurgitation in the reported proband.

Ventricular hypertrophy HP:0001714

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"cardiomegaly (ventricular hypertrophy)"

Names cardiomegaly with ventricular hypertrophy in the MPSPS cardiovascular organ-system list.

Delayed CNS myelination HP:0002188

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Magnetic resonance imaging (MRI) and CT of the brain showed apparent delayed myelination in the peripheral white matter and calcification in the basal ganglia."

Reports delayed peripheral white-matter myelination on brain MRI/CT in MPSPS.

Basal ganglia calcification HP:0002135

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Magnetic resonance imaging (MRI) and CT of the brain showed apparent delayed myelination in the peripheral white matter and calcification in the basal ganglia."

Reports basal ganglia calcification on brain MRI/CT in MPSPS.

Fundus hypopigmentation HP:0007894

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Retinal hypopigmentation was seen on the fundus photograph"

Documents the retinal finding. No frequency is asserted because the observation is reported without a denominator.

Bone marrow hypocellularity HP:0005528

Show evidence (1 reference)

PMID:35628659 SUPPORT Human Clinical

"A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow."

Reports hypoplastic bone marrow on histology as the marrow correlate of the cytopenias.

Increased circulating IgM level HP:0003496

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"An increase in serum IgM and decrease of IgG levels were found in MPSPS patients"

Reports increased serum IgM in MPSPS patients, the raised arm of the discordant IgM-high/IgG-low pattern.

Hemophagocytosis HP:0012156

Show evidence (1 reference)

PMID:35327996 SUPPORT Human Clinical

"When he was two years old, he developed secondary hemophagocytic lymphohistiocytosis (HLH), which was successfully treated with steroids."

Single-patient report of secondary HLH complicating MPSPS. No frequency is asserted because this is an isolated case.

Mucopolysacchariduria HP:0008155

Show evidence (1 reference)

PMID:39273517 SUPPORT Other

"Patients with MPSPS exhibited excessive excretion of glycosaminoglycans (GAGs) in the urine and exceptionally high levels of heparan sulfate in the plasma, but the accumulation of substrates is not caused by a decrease in the activity of any lysosomal enzymes."

Documents excessive urinary GAG excretion as a defining MPSPS feature. Evidence source is OTHER because this is a review synthesising reported cases.

Fetal ascites HP:0001791

Show evidence (1 reference)

PMID:36232726 SUPPORT Human Clinical

"Here, we describe the first Polish MPS-PS patient with a novel homozygous c.599G>C (p.Arg200Pro) VPS33A variant presenting over 12 years of follow-up with some novel clinical features, including fetal ascites (resolved spontaneously), recurrent joint effusion and peripheral edemas, normal..."

Reports fetal ascites among the novel clinical features of the juvenile p.Arg200Pro patient.

🧬

Genetic Associations

1

VPS33A (Biallelic missense variants in VPS33A (12q24.31), encoding a core Sec1/Munc18-family subunit of the HOPS and CORVET membrane-tethering complexes, cause MPSPS. Two variants are established: the recurrent founder allele c.1492C>T (p.Arg498Trp), homozygous in essentially all reported patients and associated with the severe infantile form, and c.599G>C (p.Arg200Pro), reported homozygous in two patients with an attenuated juvenile course. Both act as hypomorphic loss of function via protein destabilisation and proteasomal degradation.)

Gene: VPS33A hgnc:18179 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (5 references)

PMID:31070736 SUPPORT In Vitro

"We observed that the missense mutation reduced the abundance of full-length VPS33A and other components of the HOPS and CORVET complexes."

Supports the statement that the missense allele depletes not only VPS33A but the other HOPS/CORVET components, the molecular basis for the disproportionate effect of a single missense change.

PMID:36153662 SUPPORT Human Clinical

"To our knowledge this is the first report of an attenuated juvenile form of VPS33A insufficiency characterized by appreciable residual endosomal-lysosomal trafficking and a milder mucopolysaccharidosis plus than the disease in infants."

Supports the genotype-phenotype correlation: residual trafficking capacity distinguishes the attenuated p.Arg200Pro course from the lethal infantile p.Arg498Trp disease.

PMID:28013294 SUPPORT Human Clinical

"Using whole exome and Sanger sequencing, we identified homozygous c.1492C > T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients."

Original gene discovery: homozygous VPS33A p.Arg498Trp in 13 patients by exome and Sanger sequencing.

+ 2 more references

💊

Medical Actions

6

Supportive and symptomatic care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

There is no approved disease-modifying therapy for MPSPS, and enzyme replacement is not a logical strategy because no single hydrolase is deficient. Management is multidisciplinary and supportive: airway clearance, oxygen and ventilatory support, prompt antibiotics for respiratory infection, nutritional and developmental support, standard cardiac and renal management, transfusion for significant cytopenia, and surveillance of cardiac, renal, respiratory, haematologic, hearing and vision status.

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Currently there is no specific therapy for this disease and clinical management is limited to supportive and symptomatic treatment."

States that no specific therapy exists and management is supportive and symptomatic.

Respiratory support and anti-infective therapy

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Airway clearance and bronchial drainage, supplemental oxygen and ventilatory support as required, and prompt antibiotics for bacterial respiratory infection. This is the highest-yield supportive axis because recurrent respiratory infection from 2-6 months of age is the usual presenting problem and cardiorespiratory failure is the usual mode of death.

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Currently there is no specific therapy for this disease and clinical management is limited to supportive and symptomatic treatment."

Supports supportive/symptomatic management as the standard of care. Marked PARTIAL because the quoted sentence establishes the supportive-care principle without itemising the specific respiratory interventions.

Transfusion support for cytopenias

Action: blood transfusion Ontology label: Blood Transfusion NCIT:C15192

Red-cell or platelet transfusion for clinically significant anaemia or thrombocytopenia arising from the hypoplastic marrow. Purely supportive: it does not address the underlying marrow hypoplasia, whose mechanism is unexplained given the documented absence of marrow storage cells.

Show evidence (1 reference)

PMID:35628659 SUPPORT Human Clinical

"A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow."

Establishes the progressive anaemia and thrombocytopenia that create the transfusion requirement. Marked PARTIAL because it documents the indication rather than reporting transfusion outcomes.

Prolonged corticosteroid therapy for secondary HLH

Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858

In a single unusually long-surviving child who developed secondary haemophagocytic lymphohistiocytosis at two years of age, steroids treated the HLH successfully and a very prolonged course was associated with stabilisation of general and haematological status. This is a single case report; corticosteroids are NOT established MPSPS therapy and the authors themselves state the approach deserves further investigation.

Show evidence (1 reference)

PMID:35327996 SUPPORT Human Clinical

"The prolonged steroid treatment allowed a stabilization of his general and hematological conditions and probably determined an improvement of his psychomotor milestones and new neurological acquisitions with an improvement of quality of life."

Reports the observed benefit. Marked PARTIAL because this is a single uncontrolled case and the authors describe the effect as probable.

Genetic counselling and prenatal diagnosis

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Because MPSPS is autosomal recessive with a defined founder allele, cascade carrier testing, nondirective counselling and targeted prenatal diagnosis (chorionic villus/placental biopsy DNA when the familial variant is known) are the principal preventive options. Increased prenasal thickness on second-trimester ultrasonography can prompt testing in families with no known history.

Show evidence (2 references)

PMID:37628632 SUPPORT Human Clinical

"Consequently, a placental biopsy was performed, leading to an early diagnosis of MPSPS."

Demonstrates feasibility of targeted prenatal molecular diagnosis once parental carrier status is known.

PMID:37628632 SUPPORT Human Clinical

"During their pregnancies, both women underwent prenatal ultrasonography, which revealed increased prenasal thickness during the second trimester."

Identifies the sonographic marker that can trigger prenatal genetic testing.

Proteasome and protein-degradation modulation (experimental)

Action: Pharmacotherapy NCIT:C15986

Because the disease mechanism is destabilisation and degradation of a partially functional VPS33A protein rather than absence of catalytic activity, raising the steady-state level of the mutant protein is a rational strategy. In patient-derived fibroblasts the proteasome inhibitor bortezomib (and, separately, the glucosylceramide-synthase inhibitor eliglustat) partially corrected the lactosylceramide trafficking defect, and the proteasome inhibitor genistein combined with the ERAD inhibitor ambroxol raised mutant VPS33A levels and corrected GAG, endosomal-marker and cytoskeletal defects. All of this is IN VITRO only. No clinical trial exists, and bortezomib's toxicity makes off-label use unsupported outside formal research.

Show evidence (2 references)

PMID:31070736 SUPPORT In Vitro

"Exposure of patient-derived fibroblasts to the clinically approved proteasome inhibitor, bortezomib, or inhibition of glucosylceramide synthesis with eliglustat, partially corrected the impaired lactosylceramide trafficking defect and immediately suggest therapeutic avenues to explore in this..."

Reports partial in vitro correction of a trafficking defect. Marked PARTIAL because this is a cell-culture result with no clinical evidence of benefit.

PMID:41310305 SUPPORT In Vitro

"we demonstrated that treatment with genistein and ambroxol resulted in elevation of the mutant VPS33A protein level, as well as in improvement or correction of various previously reported cellular defects, including GAG levels, endosomal markers, and cytoskeleton elements"

Reports in vitro rescue of mutant VPS33A abundance and multiple downstream cellular defects. Marked PARTIAL because the evidence is a single patient-derived fibroblast line with no clinical data.

🔬

Biochemical Markers

3

Plasma heparan sulphate (INCREASED)

Show evidence (1 reference)

PMID:28013294 SUPPORT Human Clinical

"They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients."

Quantifies the plasma heparan sulphate elevation relative to both the normal range and classical MPS.

Lysosomal hydrolase activity panel (NORMAL)

Show evidence (3 references)

PMID:39273517 SUPPORT Other

"the accumulation of substrates is not caused by a decrease in the activity of any lysosomal enzymes"

States that no lysosomal enzyme activity is decreased in MPSPS. Evidence source is OTHER because this is a review synthesising the reported cases.

PMID:36232726 SUPPORT Human Clinical

"normal results of lysosomal enzymes activity and lysosphingolipids concentration in dried blood spot"

Patient-level confirmation that lysosomal enzyme activities and lysosphingolipid concentrations are normal.

PMID:28013294 SUPPORT Human Clinical

"However, these patients could not be diagnosed enzymatically as MPS."

The original description records that MPSPS patients cannot be diagnosed by enzyme assay, the clinical corollary of normal hydrolase activity.

Urinary glycosaminoglycan fractionation (INCREASED)

Show evidence (2 references)

PMID:31070736 SUPPORT Human Clinical

"Urine glycosaminoglycan studies revealed a pathological excess of sialylated conjugates as well as dermatan and heparan sulphate."

Characterises the urinary GAG profile including the atypical sialylated conjugates.

PMID:36153662 SUPPORT Human Clinical

"Urinary glycosaminoglycan (GAG) analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid."

Documents the urinary GAG species in the attenuated juvenile form.

🔬

Diagnosis

2

Clinical and biochemical suspicion of MPSPS

MPSPS is suspected when an infant has an MPS-like phenotype (coarse facies, dysostosis multiplex, hepatosplenomegaly, developmental delay) with excessive urinary GAG excretion BUT normal activity of the lysosomal enzymes. The negative enzyme panel is the discriminator, and it is also why MPSPS cannot be detected by any enzyme-based newborn screen: there is no deficient hydrolase to assay.

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Finding of MPS-like phenotype and excess secretion of urinary GAGs without deficiency in the activity of lysosomal enzymes is the basis for suspicion of MPSPS."

States the diagnostic triad that raises suspicion of MPSPS, including the pivotal normal-enzyme finding.

Molecular confirmation by VPS33A sequencing

Diagnosis is confirmed by molecular testing of VPS33A - targeted testing for p.Arg498Trp in Yakut families or where the familial variant is known, otherwise a lysosomal-storage/vesicular-trafficking panel or exome sequencing. Whole exome sequencing is what originally identified the gene.

Show evidence (2 references)

PMID:31936524 SUPPORT Human Clinical

"Diagnosis generally requires evidence of clinical picture similar to MPS and molecular genetic testing."

Establishes molecular genetic testing as the confirmatory diagnostic step.

PMID:28013294 SUPPORT Human Clinical

"Using whole exome and Sanger sequencing, we identified homozygous c.1492C > T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients."

Documents the sequencing approaches by which the causal variant is identified.

📈

Progression

4

Prenatal

Prenatal findings can include ascites and increased prenasal, nasal or nuchal thickness on second-trimester ultrasonography, and congenital cardiac valve abnormalities. Many affected newborns are delivered at term with normal Apgar scores.

Show evidence (1 reference)

PMID:37628632 SUPPORT Human Clinical

"During their pregnancies, both women underwent prenatal ultrasonography, which revealed increased prenasal thickness during the second trimester."

Documents the second-trimester sonographic marker.

Early infantile onset

Infantile Age: 2-6 months

Respiratory symptoms typically emerge at 2-6 months of age, with recurrent infections and bronchial obstruction, followed by the MPS-like facies and dysostosis. Growth begins to decline in some patients at around six months to one year.

Show evidence (1 reference)

PMID:35628659 SUPPORT Human Clinical

"Height and weight did not significantly deviate from the average, but in some cases, growth began to decline at around six months or one year of age."

Documents the timing of growth decline, and notes that growth is otherwise largely preserved.

Rapid multisystem progression

Infantile

Cardiac disease can progress from moderate to severe within only 3-4 months, in parallel with worsening renal and haematopoietic involvement.

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Mitral and tricuspid valve defects and pulmonary hypertension progressed from moderate to severe within 3"

Quantifies the pace of cardiac deterioration.

Terminal

Infantile Age: 10-20 months

Death from cardiorespiratory failure typically occurs at 10-20 months in the p.Arg498Trp founder form. The p.Arg200Pro juvenile form survives far longer (one patient followed over 12 years).

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"Disease is very severe, prognosis is unfavorable and most of patients died at age of 10-20 months."

Reports the typical age at death for the severe founder form.

📊

Prevalence

3

Worldwide

Cases In Literature Ultra Rare

MPSPS is ultra-rare. Reported patient counts have risen from 19 (2020) to 24 (2022) to 39-41 (2022-2024) as the entity has become recognised. Orphanet prevalence was not cited here because the local Orphadata snapshot could not be refreshed at curation time (known repo issue); a qualitative band is used instead.

Show evidence (1 reference)

PMID:39273517 SUPPORT Other

"To date, it has been described in 41 patients."

Total reported patient count as of the 2024 review, supporting the ultra-rare band.

Yakut (Sakha) population, Siberia

Birth Prevalence 8.3 per 100,000 1–9 per 100,000

Strong founder effect for c.1492C>T (p.Arg498Trp) in the Yakut population of the Sakha Republic. The reported incidence of 1 per 12,100 births normalises to 8.3 per 100,000. Cases outside Yakutia have been reported from Turkey, Poland and Israel, so MPSPS is not exclusively a Yakut disease.

Show evidence (3 references)

PMID:31936524 SUPPORT Human Clinical

"Incidence rate of MPSPS in Yakuts population is predicted as 1 per 12,100 birth."

Source for the Yakut birth-prevalence figure; 1/12,100 = 8.3 per 100,000.

PMID:31936524 SUPPORT Human Clinical

"Nineteen patients with MPSPS have been identified: seventeen patients were found among the Yakut population (Russia) and two patients from Turkey."

Documents the marked Yakut concentration alongside unrelated Turkish patients.

PMID:31070736 SUPPORT Human Clinical

"caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts-a nomadic Turkic ethnic group of Southern Siberia"

Identifies the founder population in which the disorder was first recognised.

Yakut (Sakha) population, Siberia

Carrier Frequency 1234.6 per 100,000 >1 in 1,000

Carrier (heterozygote) allele frequency of the p.Arg498Trp founder variant in the Yakut population is reported as 1:81, i.e. about 1,235 per 100,000. This is the population-genetic basis for targeted cascade and community carrier screening in Yakut families, and is a population-specific figure with no bearing on global frequency.

Show evidence (1 reference)

PMID:31936524 SUPPORT Human Clinical

"identified extremely high allele frequency in this population (1:81)"

Source for the Yakut founder-allele carrier frequency.

{ }

Source YAML

click to show

name: Mucopolysaccharidosis-Plus Syndrome
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
description: >-
  Mucopolysaccharidosis-plus syndrome (MPSPS) is an ultra-rare autosomal
  recessive multisystem disorder caused by biallelic variants in VPS33A, a core
  Sec1/Munc18-family subunit of both the HOPS (homotypic fusion and protein
  sorting) and CORVET (class C core vacuole/endosome tethering) membrane
  tethering complexes that mediate endosome-lysosome fusion. Clinically it
  phenocopies a mucopolysaccharidosis — coarse facial features, dysostosis
  multiplex, hepatosplenomegaly, developmental delay and excessive urinary
  glycosaminoglycan (GAG) excretion, with plasma heparan sulphate reaching
  roughly 60 times the normal reference range — yet the activities of every
  known GAG-degrading lysosomal hydrolase are normal. MPSPS is therefore
  storage disease without an enzyme deficiency: a membrane-tethering and
  trafficking failure rather than a catabolic block. Superimposed on the
  MPS-like picture are the "plus" features atypical for classical MPS: severe
  congenital heart disease, renal involvement with nephrotic-range proteinuria
  and foamy podocytes, and haematopoietic abnormalities (anaemia,
  thrombocytopenia, hypoplastic marrow). The severe infantile form is caused by
  the recurrent founder variant c.1492C>T (p.Arg498Trp), which is strongly
  enriched in the Yakut (Sakha) population of Siberia but has also been
  reported in Turkish and other unrelated families; affected children usually
  die of cardiorespiratory failure at 10-20 months. A second, attenuated
  juvenile form is associated with the homozygous c.599G>C (p.Arg200Pro)
  variant. No disease-modifying therapy exists.
classifications:
  icimd_category:
  - classification_value: vesicular_trafficking
    notes: >-
      ICIMD "Disorders of vesicular trafficking" is the mechanistically honest
      assignment: the primary lesion is loss of a HOPS/CORVET membrane-tethering
      subunit, not loss of a degradative enzyme. Deliberately NOT classified
      under the ICIMD "glycosaminoglycan degradation" group, despite the GAG
      storage phenotype, because no GAG-degrading hydrolase is deficient.
  isds_skeletal_category:
  - classification_value: lysosomal_storage_with_skeletal_involvement
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 27 "Lysosomal
      storage diseases with skeletal involvement (dysostosis multiplex group)";
      listed as "Mucopolysaccharidosis-plus syndrome (VPS33A deficiency)".
disease_term:
  preferred_term: Mucopolysaccharidosis-plus syndrome
  term:
    id: MONDO:0015012
    label: mucopolysaccharidosis-plus syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015012
      label: mucopolysaccharidosis-plus syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0015012 is the dedicated MPSPS class (OMIM:617303, Orphanet:505248),
      with RO:0004003 to HGNC:18179 (VPS33A). Verified by OAK NEC preflight
      before curation.
parents:
- Lysosomal Storage Disorder
synonyms:
- MPSPS
- MPS-PS
- MPS-plus syndrome
- mucopolysaccharidosis-like plus disease
- mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders
- VPS33A-related mucopolysaccharidosis-plus syndrome
- Mucopolysaccharidosis-plus syndrome, VPS33A-related
notes: >-
  NOSOLOGY AND MODULE CONFORMANCE. MPSPS is the KB's worked example of "storage
  without a catabolic block", and the conforms_to annotations here are
  deliberately PARTIAL and DOWNSTREAM-ONLY against
  lysosomal_substrate_accumulation. The module's trigger node ("Lysosomal
  Hydrolase or Cofactor Deficiency") models loss of a catabolic step, and its
  trigger-to-accumulation edge reads "Loss of the catabolic step leaves the
  substrate undegraded". That is NOT what happens in MPSPS: every cognate
  lysosomal hydrolase retains normal activity (PMID:31070736, PMID:39273517,
  PMID:36232726). Instead, low abundance of destabilised VPS33A depletes the
  HOPS/CORVET tethering complexes, so endosome-lysosome fusion fails and GAGs
  are inefficiently DELIVERED to the compartment where their intact enzymes
  reside (PMID:40758165, PMID:41310305). The three upstream nodes here (VPS33A
  destabilisation; HOPS/CORVET tethering complex depletion; impaired
  endosome-lysosome tethering and fusion) therefore carry no conforms_to — the
  disease reaches the shared cascade by a genuinely different route. Conformance
  is asserted from the GAG-accumulation node onward, on four nodes: the
  accumulation node, the endolysosomal dysfunction node, the renal
  podocyte-storage node (the module's storage-cell arm) and the terminal
  multisystem node. Of the two organ-level "plus" nodes, only the renal one
  conforms: MPSPS marrow is hypoplastic but explicitly contains no storage cells
  (PMID:31936524), so the marrow node is deliberately NOT mapped to the module's
  storage-cell node — the cytopenias are not a storage-cell phenomenon.
  GROUPING MEMBERSHIP. Both groupings are boundary cases, and this entry asserts
  membership in neither. Against kb/groupings/Lysosomal_Storage_Disorders.yaml
  (NECESSARY_AND_SUFFICIENT on lysosomal_substrate_accumulation#Lysosomal
  Substrate Accumulation) MPSPS satisfies the criterion as the checker evaluates
  it, via the accumulation node declared below, and does surface as a candidate
  member — consistent with MONDO placing MPSPS under MONDO:0800088 "lysosomal
  storage disease with skeletal involvement". But that criterion's own wording
  requires accumulation "within the lysosome", and the best current cell biology
  says MPSPS storage is pre-lysosomal: heparan sulphate shows only weak
  colocalisation with LysoTracker and appears to be trapped in endosomes rather
  than delivered to lysosomes (PMID:40758165). The candidate flag should
  therefore be reviewed by a human curator rather than auto-accepted. Against
  kb/groupings/Mucopolysaccharidoses.yaml MPSPS is a genuine boundary case: it
  satisfies the module criterion and the coarse-facies/dysostosis phenotype
  criterion, but the grouping's own rationale states that "every member is
  caused by deficiency of a lysosomal GAG-degrading enzyme", which MPSPS is not.
  On the criteria as currently written MPSPS should NOT be added to the MPS
  grouping without an explicit rationale amendment. Neither grouping file was
  edited by this curation. The same debate is live in the primary literature —
  PMID:39273517 is titled "Is This a Type of Mucopolysaccharidosis or a Separate
  Kind of Metabolic Disease?" — and is recorded as a discussion below.
  For the same reason, classifications.lysosomal_storage_category is left
  unset: the closest enum value, mucopolysaccharidosis, presupposes the
  GAG-hydrolase deficiency that MPSPS lacks.
  DISAMBIGUATION. VPS33A (HGNC:18179, 12q24.31) is NOT VPS33B, whose biallelic
  variants cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome.
  Biallelic VPS16 and VPS41 disorders are mechanistically related HOPS/CORVET
  diseases and are relevant differentials, but they are separate entities and no
  VPS16/VPS41 evidence is used in this entry.
  No GeneReviews chapter exists for MPSPS or VPS33A (PubMed searched
  2026-08-01), so the GeneReviews phenotype baseline step was not applicable.
  In its place, the Vasilev/Sukhomyasova/Otomo 2020 review (PMID:31936524,
  tagged in the top-level references block) was used as the systematic
  phenotype baseline: its organ-system tables are the source of the
  craniofacial, skeletal, cardiovascular, neurological, renal and
  immunological features curated below.
  SUBTYPE IDENTIFIERS. The Infantile and Juvenile subtypes carry no
  disease_term. Neither has a distinct MONDO, OMIM or Orphanet identifier -
  MONDO:0015012 / OMIM:617303 / ORPHA:505248 all denote MPSPS as a single
  entity, and the juvenile form rests on only two reported patients. The
  subtypes are therefore curated as allele-defined clinical forms
  (p.Arg498Trp vs p.Arg200Pro), not as separately coded diseases.
  DECLINED PHENOTYPE: hearing impairment. It was considered and rejected. The
  sentence naming hearing loss in PMID:35628659 describes CONVENTIONAL MPS
  ("Conventional MPS ... display various multisystemic symptoms-including ...
  hearing loss"), explicitly as the contrast class to MPSPS; and the "hearing
  loss" mention in PMID:31936524 belongs to a paragraph about VPS33B ARC/ARKID
  syndromes, a different gene. Neither supports hearing impairment IN MPSPS, so
  no such phenotype is asserted.
  Early death (10-20 months in the founder form) is captured in the description,
  the Infantile subtype and the terminal pathophysiology node rather than as a
  phenotype entry, because HP:0001522 "Death in infancy" sits under HP:0011420
  "Age of death" and is outside the PhenotypeTerm enum used by this schema.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    MPSPS is inherited in an autosomal recessive manner. Affected individuals
    are homozygous for a VPS33A missense variant; in the Yakut founder
    population, parents are typically healthy heterozygous carriers and
    consanguinity is not required.
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MPSPS, whose pathophysiology is not elucidated, is an autosomal recessive multisystem disorder caused by a specific mutation p.R498W in the VPS33A gene."
    explanation: >-
      States the autosomal recessive mode of inheritance and the causal VPS33A
      p.R498W variant.
has_subtypes:
- name: Infantile
  display_name: Severe infantile MPSPS (p.Arg498Trp founder form)
  description: >-
    The classical and by far the commonest form, caused by homozygous VPS33A
    c.1492C>T (p.Arg498Trp). Presentation is in the first months of life with
    MPS-like facies and dysostosis together with congenital heart disease,
    renal and haematopoietic involvement; death from cardiorespiratory failure
    typically occurs at 10-20 months. 39 of the first 41 reported patients
    carried this variant.
  evidence:
  - reference: PMID:36232726
    reference_title: "Mucopolysaccharidosis-Plus Syndrome: Report on a Polish Patient with a Novel VPS33A Variant with Comparison with Other Described Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Up to now, a total number of 39 patients have been reported; in all of them, the c.1492C>T (p.Arg498Trp) variant of the VPS33A gene was detected."
    explanation: >-
      Establishes p.Arg498Trp as the recurrent variant accounting for essentially
      all reported MPSPS patients at that time.
- name: Juvenile
  display_name: Attenuated juvenile MPSPS (p.Arg200Pro)
  description: >-
    An attenuated, longer-surviving form described in two unrelated patients
    homozygous for VPS33A c.599G>C (p.Arg200Pro), with appreciable residual
    endosomal-lysosomal trafficking. Reported features include normal growth,
    fetal ascites that resolved spontaneously, recurrent joint effusion and
    peripheral oedema.
  evidence:
  - reference: PMID:36153662
    reference_title: "Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge this is the first report of an attenuated juvenile form of VPS33A insufficiency characterized by appreciable residual endosomal-lysosomal trafficking and a milder mucopolysaccharidosis plus than the disease in infants."
    explanation: >-
      Defines the attenuated juvenile subtype and attributes its milder course to
      residual endosomal-lysosomal trafficking capacity.
pathophysiology:
- name: VPS33A Missense Variant Destabilisation and Proteasomal Degradation
  description: >-
    Biallelic missense variants in VPS33A destabilise the folded protein and
    target it for proteasomal degradation, so the steady-state intracellular
    abundance of intact full-length VPS33A falls. The 3D crystal structure of
    human VPS33A predicts that replacement of arginine 498 by tryptophan
    de-stabilises folding; the same instability-plus-degradation mechanism is
    documented for the juvenile p.Arg200Pro variant. The functional consequence
    is hypomorphic loss of function through protein instability, not gain of
    function or dominant-negative activity, and mutant protein can be rescued
    by proteasome inhibition.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: VPS33A
    term:
      id: hgnc:18179
      label: VPS33A
  notes: >-
    Deliberately carries no conforms_to. This trigger is a chaperone/tethering
    protein-stability defect, not the hydrolase-or-cofactor catabolic deficiency
    that the lysosomal_substrate_accumulation module's trigger node models.
  evidence:
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The 3D crystal structure of human VPS33A predicts that replacement of arginine 498 by tryptophan will de-stabilize VPS33A folding."
    explanation: >-
      Structural basis for destabilisation of VPS33A by the founder p.Arg498Trp
      substitution.
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We propose that the disease is due to diminished intracellular abundance of intact VPS33A."
    explanation: >-
      States the proposed proximal disease mechanism: reduced abundance of intact
      VPS33A rather than an altered catalytic activity.
  - reference: PMID:36153662
    reference_title: "Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We showed decreased abundance of VPS33A in patient derived fibroblasts and provided evidence that the p.Arg200Pro mutation leads to destablization of the protein and proteasomal degradation."
    explanation: >-
      Confirms the same destabilisation-and-proteasomal-degradation mechanism for
      the second, juvenile-associated VPS33A variant.
  downstream:
  - target: HOPS and CORVET Tethering Complex Depletion
    causal_link_type: DIRECT
    description: >-
      Loss of intact VPS33A, a core subunit of both complexes, secondarily
      lowers the abundance of the other HOPS and CORVET components.

- name: HOPS and CORVET Tethering Complex Depletion
  description: >-
    VPS33A is a core component of the class C core vacuole/endosome tethering
    (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes,
    which have essential functions in the endocytic pathway. Because VPS33A is
    shared by both complexes, its depletion is not isolated: patient cells show
    reduced abundance of the other HOPS and CORVET components as well, so both
    the early-endosome (CORVET) and late-endosome/lysosome (HOPS) tethering
    arms are simultaneously compromised.
  role: amplifier
  biological_scale: MOLECULAR
  protein_complexes:
  - preferred_term: HOPS complex
    term:
      id: GO:0030897
      label: HOPS complex
    modifier: DECREASED
  - preferred_term: CORVET complex
    term:
      id: GO:0033263
      label: CORVET complex
    modifier: DECREASED
  evidence:
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "VPS33A is a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway."
    explanation: >-
      Establishes VPS33A as a shared core subunit of both HOPS and CORVET, the
      structural reason a single-gene lesion depletes two tethering complexes.
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed that the missense mutation reduced the abundance of full-length VPS33A and other components of the HOPS and CORVET complexes."
    explanation: >-
      Directly documents secondary depletion of the other HOPS/CORVET components
      in cells carrying the mutant VPS33A.
  - reference: PMID:36153662
    reference_title: "Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components of the intracellular membrane-tethering protein complexes, HOPS, and CORVET."
    explanation: >-
      Frames the disease itself as a deficiency of HOPS/CORVET core components
      causing impaired endocytic trafficking. Evidence source is OTHER because
      this is the paper's framing/background sentence rather than a report of its
      own patient or experimental data.
  downstream:
  - target: Impaired Endosome-Lysosome Tethering and Fusion
    causal_link_type: DIRECT
    description: >-
      Depletion of the tethering complexes impairs the membrane tethering and
      fusion steps of the endocytic route to the lysosome.

- name: Impaired Endosome-Lysosome Tethering and Fusion
  description: >-
    With HOPS and CORVET depleted, the tethering and fusion events that carry
    endocytic cargo from early through late endosomes into the lysosome become
    inefficient. Patient fibroblasts show vacuolation with disordered
    endosomal/lysosomal compartments, elevated EEA1 (required at early/late
    endosome fusion and early-endosome sorting), altered Golgi morphology, and
    abnormal endocytic trafficking of lactosylceramide and other
    glycosphingolipids. This node is the mechanistic pivot of MPSPS: it is a
    delivery failure upstream of catabolism, not a catabolic block, and it is
    what distinguishes MPSPS from every classical mucopolysaccharidosis.
  role: central_effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: endosome to lysosome transport
    term:
      id: GO:0008333
      label: endosome to lysosome transport
    modifier: DECREASED
  - preferred_term: vesicle fusion
    term:
      id: GO:0006906
      label: vesicle fusion
    modifier: DECREASED
  - preferred_term: endosome organization
    term:
      id: GO:0007032
      label: endosome organization
    modifier: DYSREGULATED
  cellular_components:
  - preferred_term: late endosome
    term:
      id: GO:0005770
      label: late endosome
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  notes: >-
    Deliberately carries no conforms_to. This is the distinctive upstream route
    by which MPSPS reaches lysosomal-storage biology, and it has no counterpart
    in the lysosomal_substrate_accumulation module chain.
  evidence:
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that cultured fibroblasts from patients with this disorder have morphological changes: vacuolation with disordered endosomal/lysosomal compartments"
    explanation: >-
      Documents the disordered endosomal/lysosomal compartments and vacuolation
      in patient-derived cells.
  - reference: PMID:40758165
    reference_title: "Cellular and molecular changes in mucopolysaccharidosis-plus syndrome caused by a homozygous c.599G > C (p.Arg200Pro) variant of the VPS33A gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "indicated specific changes in cellular vacuoles, elevated levels of the EEA1 protein"
    explanation: >-
      Independent cell-biological confirmation of a disturbed endosomal
      compartment, with elevated EEA1 marking the early/late endosome fusion and
      sorting step.
  - reference: PMID:41310305
    reference_title: "The use of genistein and ambroxol may be an effective approach in correcting cellular dysfunctions of mucopolysaccharidosis-plus syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recent works demonstrated that low abundance of mutated VPS33A causes defective endosomal trafficking, resulting in poor delivery of GAGs (and perhaps also other compounds) to lysosomes, preventing their effective turnover."
    explanation: >-
      States the pivotal causal step explicitly: low VPS33A causes defective
      endosomal trafficking and poor delivery of GAGs to lysosomes, preventing
      turnover - a delivery failure rather than a catabolic block. Evidence
      source is OTHER because this sentence is the paper's background synthesis
      of prior work, not a result of its own experiments.
  downstream:
  - target: Glycosaminoglycan Accumulation With Normal Lysosomal Hydrolase Activity
    causal_link_type: DIRECT
    description: >-
      GAGs that are not efficiently delivered to the lysosome are not turned
      over and accumulate in cells, despite intact degradative enzymes.
  - target: Endolysosomal Compartment Expansion and Over-Acidification
    causal_link_type: DIRECT
    description: >-
      Failed fusion leaves an expanded, abnormally acidified endolysosomal
      compartment.

- name: Glycosaminoglycan Accumulation With Normal Lysosomal Hydrolase Activity
  description: >-
    Heparan, dermatan and (variably) chondroitin sulphate accumulate and are
    excreted in excess in the urine, and plasma heparan sulphate is
    extraordinarily elevated - around 60 times the normal reference range and
    six times the level seen in classical MPS patients. Sialylated conjugates,
    sialooligosaccharides, elevated beta-D-galactosylsphingosine and cholesterol
    and sphingolipid abnormalities are also reported. The defining biochemical
    signature of MPSPS is that all of this occurs with entirely normal activity
    of the cognate lysosomal hydrolases: it is substrate accumulation without an
    enzyme deficiency.
  role: central_effector
  biological_scale: CELLULAR
  conforms_to: "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation"
  biological_processes:
  - preferred_term: glycosaminoglycan catabolic process
    term:
      id: GO:0006027
      label: glycosaminoglycan catabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: glycosaminoglycan
    term:
      id: CHEBI:18085
      label: glycosaminoglycan
    modifier: INCREASED
  notes: >-
    This is the one node where MPSPS genuinely converges on the
    lysosomal_substrate_accumulation module, and it is the reason conforms_to
    is asserted here but not on the three upstream nodes. Two departures from
    the module must be read alongside the conformance. First, the cause: the
    module's accumulation node presumes the substrate arrived at the lysosome
    and could not be degraded, whereas in MPSPS the substrate is poorly
    delivered. Second - and more consequentially - the COMPARTMENT may differ.
    The module (and the Lysosomal_Storage_Disorders grouping criterion) specify
    accumulation "within the lysosomal lumen", but in MPSPS fibroblasts heparan
    sulphate shows only weak colocalisation with LysoTracker and is interpreted
    as trapped in endosomes rather than delivered to lysosomes (PMID:40758165).
    Conformance is asserted because the disease-level endpoint - progressive
    intracellular storage of an undegraded macromolecule driving secondary
    endolysosomal dysfunction and multisystem disease - is the same, but it
    should NOT be read as asserting classical intralysosomal storage. This is
    the single most interesting unresolved detail in MPSPS cell biology and is
    the reason the grouping membership question stays open.
  evidence:
  - reference: PMID:39273517
    reference_title: "Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients with MPSPS exhibited excessive excretion of glycosaminoglycans (GAGs) in the urine and exceptionally high levels of heparan sulfate in the plasma, but the accumulation of substrates is not caused by a decrease in the activity of any lysosomal enzymes."
    explanation: >-
      The single most important statement for this entry: GAG storage occurs
      without any decrease in lysosomal enzyme activity. Evidence source is OTHER
      because this is a focused review synthesising several study types.
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients."
    explanation: >-
      Quantifies the magnitude of heparan sulphate accumulation in MPSPS, which
      exceeds that of classical MPS.
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We hence propose a new type of MPS that is not caused by an enzymatic deficiency."
    explanation: >-
      The original description explicitly frames MPSPS as an MPS-like storage
      disease that is not caused by an enzymatic deficiency.
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urine glycosaminoglycan studies revealed a pathological excess of sialylated conjugates as well as dermatan and heparan sulphate."
    explanation: >-
      Characterises the stored/excreted species as dermatan and heparan sulphate
      plus sialylated conjugates.
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Lipidomic screening showed elevated β-D-galactosylsphingosine with unimpaired activity of cognate lysosomal hydrolases."
    explanation: >-
      Documents accumulation of a lipid species alongside explicitly unimpaired
      cognate lysosomal hydrolase activity.
  - reference: PMID:40758165
    reference_title: "Cellular and molecular changes in mucopolysaccharidosis-plus syndrome caused by a homozygous c.599G > C (p.Arg200Pro) variant of the VPS33A gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a weak HS colocalisation with LysoTracker Red"
    explanation: >-
      Qualifies the conformance asserted on this node: heparan sulphate shows
      only weak colocalisation with an acidic-lysosome marker in MPSPS
      fibroblasts, so the storage compartment may be endosomal rather than the
      lysosomal lumen the module's accumulation node presumes. Marked PARTIAL
      because it supports storage while contradicting its classical localisation.
  downstream:
  - target: Progressive Multisystem Disease With Plus Features
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Progressive intracellular storage across many tissues produces the
      MPS-like plus multisystem clinical picture.

- name: Endolysosomal Compartment Expansion and Over-Acidification
  description: >-
    Failed tethering and fusion leave an expanded endocytic compartment that is
    abnormally acidified. Lysosomal over-acidification was detected in
    patient-derived and VPS33A-depleted cells in the original description, and
    increased endolysosomal acidification with an expanded endocytic compartment
    was independently confirmed in the juvenile p.Arg200Pro form. Autophagy
    markers LC3-II and p62 are elevated in p.Arg200Pro fibroblasts, indicating a
    block in autophagic flux, though the original p.Arg498Trp study did not
    detect an autophagic defect (see the autophagy-discrepancy discussion below).
  role: amplifier
  biological_scale: CELLULAR
  conforms_to: "lysosomal_substrate_accumulation#Autophagic-Lysosomal Dysfunction and Secondary Cascade"
  biological_processes:
  - preferred_term: lysosomal lumen acidification
    term:
      id: GO:0007042
      label: lysosomal lumen acidification
    modifier: INCREASED
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DYSREGULATED
  notes: >-
    This is the weakest of the four asserted conformances and is qualified in
    two ways. (1) It rests on the lysosomal-dysfunction half of the module node:
    endolysosomal expansion and over-acidification are solidly replicated across
    both VPS33A variants, whereas the autophagy half is contested - see the
    mpsps_autophagy_discrepancy discussion and the REFUTE evidence item retained
    below. (2) The edge topology differs from the module: the module places
    autophagic-lysosomal dysfunction strictly downstream of substrate
    accumulation, whereas here over-acidification and accumulation are parallel
    consequences of the same tethering failure, and PMID:40758165 explicitly
    entertains over-acidification as a candidate primary mechanism rather than a
    storage consequence.
  evidence:
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Lysosomal over-acidification and HS accumulation were detected in patient-derived and VPS33A-depleted cells, suggesting a novel role of this gene in lysosomal functions."
    explanation: >-
      Establishes lysosomal over-acidification together with heparan sulphate
      accumulation as the cellular readout in MPSPS cells.
  - reference: PMID:36153662
    reference_title: "Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "As in the infantile form of mucopolysaccharidosis plus, the endocytic compartment in the fibroblasts also expanded-a phenomenon accompanied by increased endolysosomal acidification and impaired intracellular glycosphingolipid trafficking."
    explanation: >-
      Independently replicates endocytic compartment expansion and increased
      endolysosomal acidification in the second VPS33A variant.
  - reference: PMID:40758165
    reference_title: "Cellular and molecular changes in mucopolysaccharidosis-plus syndrome caused by a homozygous c.599G > C (p.Arg200Pro) variant of the VPS33A gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "elevated levels of the LC3-II and p62 proteins (autophagy markers)"
    explanation: >-
      Supports an autophagic-flux abnormality in MPSPS fibroblasts. Marked
      PARTIAL because this is a single p.Arg200Pro cell line and the original
      p.Arg498Trp study reported no autophagic defect.
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "VPS33A is involved in endocytic and autophagic pathways, but the identified mutation did not affect either of these pathways."
    explanation: >-
      Retained deliberately as counter-evidence: the original p.Arg498Trp study
      found no measurable effect on the endocytic or autophagic pathways in
      patient skin fibroblasts, which is in tension with the later p.Arg200Pro
      autophagy-marker findings. The disagreement is recorded as an open
      knowledge gap rather than silently resolved.
  downstream:
  - target: Progressive Multisystem Disease With Plus Features
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Sustained endolysosomal dysfunction drives cell-type-specific injury and
      progressive organ disease.

- name: Renal Podocyte Storage and Glomerular Destruction
  description: >-
    The kidney is one of the two most discriminating "plus" targets. Storage in
    podocytes converts them to foam cells and destroys glomerular architecture,
    producing nephrotic-range proteinuria, hypoalbuminaemia, and rising
    creatinine, cholesterol and uric acid. Histology shows extensive destruction
    of glomerular structures by foamy podocytes, with periglomerular fibrosis
    and interstitial inflammation.
  role: effector
  biological_scale: TISSUE
  conforms_to: "lysosomal_substrate_accumulation#Storage-Cell Cytotoxicity and Neuroinflammation"
  notes: >-
    Conforms to the module's storage-cell node, substituting the podocyte
    (CL:0000653) for the module's generic macrophage/neuron storage cells - the
    module explicitly states that the specific storage cell varies by disorder.
    The foamy podocyte is the one unambiguous storage cell in MPSPS. Note the
    deliberate asymmetry with the marrow node, which does NOT conform because
    MPSPS marrow is hypoplastic without storage cells. Neuroinflammation, the
    other half of the module node's title, is not asserted here: no MPSPS
    microglial or astrocyte activation data exist.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histological analyses of MPSPS kidneys similarly suggest the extensive destruction of glomerular structures by foamy podocytes."
    explanation: >-
      Directly documents foamy (storage-laden) podocytes destroying glomerular
      structures in MPSPS kidneys.
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High urinary excretion of protein (caused by impairments in renal filtration), hypoalbuminemia, and elevated levels of creatinine, cholesterol, and uric acid indicate renal dysfunction."
    explanation: >-
      Links the podocyte/glomerular lesion to the measured renal phenotype:
      proteinuria from impaired filtration, hypoalbuminaemia and azotaemia.
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal biopsy showed segmental sclerosis, periglomerular fibrosis and inflammatory cell infiltration."
    explanation: >-
      Provides the biopsy evidence for the periglomerular fibrosis and
      interstitial inflammation described on this node.
  downstream:
  - target: Progressive Multisystem Disease With Plus Features
    causal_link_type: DIRECT
    description: >-
      Glomerular destruction contributes the renal arm of the plus phenotype.

- name: Bone Marrow Hypoplasia and Peripheral Cytopenias
  description: >-
    The haematopoietic system is the second discriminating "plus" target.
    Progressive anaemia and thrombocytopenia develop and correlate with
    histologically hypoplastic bone marrow; neutropenia/leukopenia, coagulation
    abnormalities and platelet dysfunction are also reported. Secondary
    haemophagocytic lymphohistiocytosis has occurred in at least one
    longer-surviving patient.
  role: effector
  biological_scale: TISSUE
  notes: >-
    Deliberately carries no conforms_to, in explicit contrast to the renal
    podocyte node. MPSPS marrow is hypoplastic but contains NO storage cells
    (PMID:31936524), so mapping it to the module's storage-cell cytotoxicity
    node would be wrong: the cytopenias are not a storage-cell phenomenon and
    their mechanism remains unexplained.
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone marrow aspiration analysis showed hypoplastic bone marrow without any storage cells."
    explanation: >-
      Key negative finding: the marrow is hypoplastic yet free of storage cells,
      which is why this node is deliberately not mapped to the module's
      storage-cell node and why the mechanism of the cytopenias is unresolved.
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow."
    explanation: >-
      Connects the peripheral cytopenias to a hypoplastic marrow, establishing
      the marrow as the site of the haematopoietic lesion.
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A rare lysosomal disease resembling a mucopolysaccharidosis with unusual systemic features, including renal disease and platelet dysfunction, caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts"
    explanation: >-
      Identifies renal disease and platelet dysfunction as the unusual systemic
      features distinguishing this disorder from a conventional MPS. Marked
      PARTIAL because platelet dysfunction is a qualitative platelet defect, not
      the marrow hypoplasia and quantitative cytopenias this node models.
  downstream:
  - target: Progressive Multisystem Disease With Plus Features
    causal_link_type: DIRECT
    description: >-
      Marrow failure contributes the haematopoietic arm of the plus phenotype.

- name: Progressive Multisystem Disease With Plus Features
  description: >-
    The clinical endpoint is a rapidly progressive multisystem disease that
    looks like a mucopolysaccharidosis - coarse facial features, skeletal
    abnormalities/dysostosis multiplex, hepatosplenomegaly, respiratory problems,
    developmental delay and excess urinary GAG - with, superimposed on it,
    congenital heart defects and renal and haematopoietic disease that are not
    typical of conventional MPS. For the p.Arg498Trp founder form the outcome is
    fatal cardiorespiratory failure at 10-20 months.
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "lysosomal_substrate_accumulation#Progressive Multisystem and Neurodegenerative Disease"
  evidence:
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."
    explanation: >-
      Enumerates the MPS-like arm of the multisystem phenotype.
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, most patients developed heart, kidney, and hematopoietic disorders, which are not typical symptoms for conventional MPS, leading to a fatal outcome between 1 and 2-years old."
    explanation: >-
      Enumerates the "plus" arm - cardiac, renal and haematopoietic disease - and
      the fatal infantile outcome.
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease is very severe, prognosis is unfavorable and most of patients died at age of 10-20 months."
    explanation: >-
      Quantifies the natural history endpoint for the severe founder form.
phenotypes:
- name: Coarse facial features
  category: Craniofacial
  description: >-
    Coarse facies is one of the MPS-like presenting features of MPSPS, together
    with a short nose and neck, periorbital puffiness and macroglossia.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."
    explanation: >-
      Lists coarse facial features among the typical MPS manifestations of MPSPS
      patients.
- name: Dysostosis multiplex
  category: Skeletal
  description: >-
    Skeletal abnormalities of the dysostosis multiplex pattern, with barrel
    chest, kyphosis/lordosis, bullet-shaped phalanges and joint stiffness.
  phenotype_term:
    preferred_term: Dysostosis multiplex
    term:
      id: HP:0000943
      label: Dysostosis multiplex
  evidence:
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."
    explanation: >-
      Supports skeletal involvement as a typical MPS manifestation in MPSPS.
      Marked PARTIAL because the abstract says "skeletal abnormalities" rather
      than naming the dysostosis multiplex pattern specifically.
- name: Macroglossia
  category: Craniofacial
  description: >-
    Macroglossia is part of the coarse-facies complex, alongside short nose and
    neck, prominent forehead, epicanthal folds, telecanthus, periorbital
    puffiness, long eyelashes, full lips and excessive hair growth.
  phenotype_term:
    preferred_term: Macroglossia
    term:
      id: HP:0000158
      label: Macroglossia
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coarse facial features: short nose and neck, prominent forehead, epicanthal folds, telecanthus, thick hair, excessive hair growth, periorbital puffiness, long eyelashes, large rounded cheeks, full lips, macroglossia"
    explanation: >-
      Names macroglossia in the MPSPS craniofacial organ-system list.
- name: Multiple joint contractures
  category: Skeletal
  description: >-
    Contractures and stiffness affecting the elbow, wrist, hip, knee and ankle
    joints, with limitation of finger motion and claw-hand deformities.
  phenotype_term:
    preferred_term: Multiple joint contractures
    term:
      id: HP:0002828
      label: Multiple joint contractures
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "joints contracture, stiffness of the elbow, wrist, hip, knee and ankle joints, finger phalangeal swelling, limitation of motion of fingers, claw-hand deformities"
    explanation: >-
      Documents contractures across multiple named joints, supporting the
      multiple-joint term rather than a single-joint contracture term.
- name: Joint stiffness
  category: Skeletal
  description: >-
    Joint stiffness is one of the presenting complaints, noted from the first
    hospital contact at 2-6 months of age.
  phenotype_term:
    preferred_term: Joint stiffness
    term:
      id: HP:0001387
      label: Joint stiffness
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usually they had a complaint of frequent cough, shortness of breath, noisy breathing and stiffness of joints."
    explanation: >-
      Establishes joint stiffness as a usual presenting complaint in MPSPS
      infants.
- name: Kyphosis
  category: Skeletal
  description: >-
    Thoracic and lumbar kyphosis with lumbar lordosis, barrel-shaped chest and
    pectus carinatum, as part of the dysostosis multiplex pattern.
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal: barrel-shaped chest, pectus carinatum, kyphosis (thoracic, lumbar)"
    explanation: >-
      Names thoracic and lumbar kyphosis in the MPSPS skeletal organ-system list.
- name: Hepatosplenomegaly
  category: Gastrointestinal
  description: >-
    Enlargement of both liver and spleen, an MPS-like visceral storage feature.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."
    explanation: >-
      Lists hepatosplenomegaly among the typical MPS manifestations of MPSPS.
- name: Global developmental delay
  category: Neurological
  description: >-
    Psychomotor retardation and developmental delay or regression, with
    hypotonia and delayed speech. Longer-surviving children sat at 10-13 months
    and walked at 22-28 months.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."
    explanation: >-
      Supports cognitive/developmental involvement. Marked PARTIAL because the
      abstract uses the older term "mental retardation" rather than describing
      the global developmental delay pattern.
- name: Recurrent respiratory infections
  category: Respiratory
  description: >-
    Recurrent upper and lower respiratory infections with bronchial obstruction
    and progressive respiratory insufficiency; respiratory symptoms commonly
    emerge at 2-6 months of age and cardiorespiratory failure is the usual mode
    of death.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG."
    explanation: >-
      Supports respiratory involvement in MPSPS. Marked PARTIAL because the
      abstract states "respiratory problems" without specifying the recurrent
      infective pattern.
- name: Congenital heart defect
  category: Cardiovascular
  description: >-
    Congenital heart disease is one of the defining "plus" features of MPSPS and
    is not typical of conventional mucopolysaccharidosis. Cardiac disease can
    progress from moderate to severe within 3-4 months and contributes to early
    mortality. This entry is the umbrella covering the sources' generic
    "congenital heart defects" statements, where no individual lesion is
    specified; the specifically named lesions (PDA, ASD, tricuspid and mitral
    insufficiency, ventricular hypertrophy, pulmonary hypertension) are each
    curated as their own phenotype below.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  notes: >-
    TERM BINDING - do not re-litigate. HP:0001627 is retained deliberately, and
    the preferred_term/label divergence is correct, not an error: "Congenital
    heart defect" and "Congenital heart defects" are both EXACT synonyms of
    HP:0001627 (verified with OAK), so the term does carry congenital semantics
    even though its primary label does not say so. A review pass suggested
    re-binding on the grounds that HP:0001627 is a bare morphology parent
    "with no congenital semantics"; that premise is factually wrong and was
    rejected. What the review got right was a separate SPECIFICITY point, which
    has been acted on: wherever the cited source names an individual lesion, a
    specific HPO term is now curated for it. This umbrella is kept only for the
    generic statements ("Most patients developed congenital heart defects"),
    because descending to a specific lesion there would assert something the
    paper does not report.
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients developed congenital heart defects."
    explanation: >-
      Frequency evidence. "Most patients" maps to FREQUENT per
      docs/frequency-evidence-guidelines.md.
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to typical symptoms for conventional MPS, MPSPS patients developed other features such as congenital heart defects, renal and hematopoietic disorders."
    explanation: >-
      Identifies congenital heart defects as one of the MPSPS-specific "plus"
      features beyond conventional MPS.
  - reference: PMID:35327996
    reference_title: "Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This syndrome presents with typical symptoms of mucopolysaccharidosis, as well as congenital heart defects, renal, and hematopoietic system disorders."
    explanation: >-
      Independent confirmation of congenital heart defects as part of the MPSPS
      triad of plus features.
- name: Nephrotic range proteinuria
  category: Renal
  description: >-
    Heavy proteinuria from impaired glomerular filtration, with hypoalbuminaemia
    and rising creatinine, cholesterol and uric acid. Renal disease is one of the
    most discriminating "plus" features of MPSPS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nephrotic range proteinuria
    term:
      id: HP:0012593
      label: Nephrotic range proteinuria
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of MPSPS patients had a nephrotic syndrome."
    explanation: >-
      Frequency evidence. "The majority" maps to FREQUENT per
      docs/frequency-evidence-guidelines.md.
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High urinary excretion of protein (caused by impairments in renal filtration), hypoalbuminemia, and elevated levels of creatinine, cholesterol, and uric acid indicate renal dysfunction."
    explanation: >-
      Documents heavy proteinuria with hypoalbuminaemia and azotaemia, the
      nephrotic-range renal phenotype of MPSPS.
- name: Nephrotic syndrome
  category: Renal
  description: >-
    Frank nephrotic syndrome - heavy proteinuria with hypoalbuminaemia and
    oedema - develops in the majority of MPSPS patients, with nephromegaly and
    rising creatinine and uric acid.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of MPSPS patients had a nephrotic syndrome."
    explanation: >-
      Directly reports nephrotic syndrome in the majority of patients,
      supporting both the phenotype and the FREQUENT band.
- name: Atrial septal defect
  category: Cardiovascular
  description: >-
    Atrial septal defect is one of the two specifically named congenital heart
    defects in MPSPS.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital heart defects (patent ductus arteriosus (PDA) and atrial septal defect (ASD), pulmonary hypertension"
    explanation: >-
      Names atrial septal defect as one of the congenital heart defects in the
      MPSPS cardiovascular organ-system list.
- name: Patent ductus arteriosus
  category: Cardiovascular
  description: >-
    Patent ductus arteriosus is the other specifically named congenital heart
    defect in MPSPS.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital heart defects (patent ductus arteriosus (PDA) and atrial septal defect (ASD), pulmonary hypertension"
    explanation: >-
      Names patent ductus arteriosus as one of the congenital heart defects in
      the MPSPS cardiovascular organ-system list.
- name: Tricuspid regurgitation
  category: Cardiovascular
  description: >-
    Tricuspid valve insufficiency/regurgitation, which together with mitral
    involvement can progress from moderate to severe within 3-4 months.
  phenotype_term:
    preferred_term: Tricuspid valve insufficiency
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "valve insufficiency (tricuspid, mitral)"
    explanation: >-
      Names tricuspid valve insufficiency in the MPSPS cardiovascular
      organ-system list.
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "insufficiency of aortic valve, mitral and tricuspid valve regurgitation, pulmonary hypertension"
    explanation: >-
      Echocardiographic confirmation of tricuspid regurgitation in the reported
      proband.
- name: Mitral regurgitation
  category: Cardiovascular
  description: >-
    Mitral valve insufficiency/regurgitation, reported alongside tricuspid
    involvement.
  phenotype_term:
    preferred_term: Mitral valve insufficiency
    term:
      id: HP:0001653
      label: Mitral regurgitation
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "valve insufficiency (tricuspid, mitral)"
    explanation: >-
      Names mitral valve insufficiency in the MPSPS cardiovascular organ-system
      list.
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "insufficiency of aortic valve, mitral and tricuspid valve regurgitation, pulmonary hypertension"
    explanation: >-
      Echocardiographic confirmation of mitral regurgitation in the reported
      proband.
- name: Ventricular hypertrophy
  category: Cardiovascular
  description: >-
    Cardiomegaly with ventricular hypertrophy, accompanied by tachycardia,
    hypertension and a systolic murmur.
  phenotype_term:
    preferred_term: Ventricular hypertrophy
    term:
      id: HP:0001714
      label: Ventricular hypertrophy
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiomegaly (ventricular hypertrophy)"
    explanation: >-
      Names cardiomegaly with ventricular hypertrophy in the MPSPS
      cardiovascular organ-system list.
- name: Pulmonary arterial hypertension
  category: Cardiovascular
  description: >-
    Pulmonary hypertension accompanies the mitral and tricuspid valve lesions
    and can progress from moderate to severe within only 3-4 months,
    contributing to the fatal cardiorespiratory outcome.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mitral and tricuspid valve defects and pulmonary hypertension progressed from moderate to severe within 3"
    explanation: >-
      Documents pulmonary hypertension alongside valve defects and quantifies the
      strikingly rapid 3-4 month progression noted in the cardiac description.
- name: Decreased total leukocyte count
  category: Hematological
  description: >-
    Leukocytopenia accompanies the anaemia and thrombocytopenia as part of the
    multilineage cytopenia of MPSPS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Leukocytopenia
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients develop hematopoietic disorders including anemia, thrombocytopenia and leukocytopenia."
    explanation: >-
      Names leukocytopenia as one of the haematopoietic disorders present in most
      patients, supporting both the phenotype and the FREQUENT band.
- name: Hypotonia
  category: Neurological
  description: >-
    Hypotonia with poor tendon reflexes, part of the neurological organ-system
    involvement. Note that hypertonia of the legs was the presenting sign in one
    reported proband, so tone abnormality in MPSPS is not uniformly low.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurology: hydrocephalus syndrome, hypotonia, poor tendon reflexes, nystagmus"
    explanation: >-
      Names hypotonia and poor tendon reflexes in the MPSPS neurological
      organ-system list.
- name: Nystagmus
  category: Neurological
  description: >-
    Nystagmus is reported among the neurological features of MPSPS.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurology: hydrocephalus syndrome, hypotonia, poor tendon reflexes, nystagmus"
    explanation: >-
      Names nystagmus in the MPSPS neurological organ-system list.
- name: Delayed CNS myelination
  category: Neurological
  description: >-
    Brain MRI and CT show apparent delayed myelination in the peripheral white
    matter, a structural correlate of the developmental delay.
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging (MRI) and CT of the brain showed apparent delayed myelination in the peripheral white matter and calcification in the basal ganglia."
    explanation: >-
      Reports delayed peripheral white-matter myelination on brain MRI/CT in
      MPSPS.
- name: Basal ganglia calcification
  category: Neurological
  description: >-
    Intracranial calcification in the basal ganglia is reported on brain imaging.
  phenotype_term:
    preferred_term: Basal ganglia calcification
    term:
      id: HP:0002135
      label: Basal ganglia calcification
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging (MRI) and CT of the brain showed apparent delayed myelination in the peripheral white matter and calcification in the basal ganglia."
    explanation: >-
      Reports basal ganglia calcification on brain MRI/CT in MPSPS.
- name: Fundus hypopigmentation
  category: Ophthalmological
  description: >-
    Retinal hypopigmentation has been observed on fundus photography.
  phenotype_term:
    preferred_term: Retinal hypopigmentation
    term:
      id: HP:0007894
      label: Fundus hypopigmentation
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Retinal hypopigmentation was seen on the fundus photograph"
    explanation: >-
      Documents the retinal finding. No frequency is asserted because the
      observation is reported without a denominator.
- name: Enlarged kidney
  category: Renal
  description: >-
    Nephromegaly with renal ectasia on abdominal ultrasound, alongside
    hepatosplenomegaly.
  phenotype_term:
    preferred_term: Nephromegaly
    term:
      id: HP:0000105
      label: Enlarged kidney
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abdominal ultrasound revealed hepatosplenomegaly, nephromegaly and renal ectasia."
    explanation: >-
      Documents nephromegaly on imaging. No frequency is asserted because this is
      a single reported proband.
- name: Hypoalbuminemia
  category: Renal
  description: >-
    Low serum albumin accompanying the heavy urinary protein loss.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High urinary excretion of protein (caused by impairments in renal filtration), hypoalbuminemia, and elevated levels of creatinine, cholesterol, and uric acid indicate renal dysfunction."
    explanation: >-
      Directly reports hypoalbuminaemia as part of the MPSPS renal picture.
- name: Anemia
  category: Hematological
  description: >-
    Progressive, typically normocytic anaemia correlating with hypoplastic bone
    marrow.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients develop hematopoietic disorders including anemia, thrombocytopenia and leukocytopenia."
    explanation: >-
      Frequency evidence. "Most patients" maps to FREQUENT per
      docs/frequency-evidence-guidelines.md.
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow."
    explanation: >-
      Directly reports progressive anaemia in MPSPS patients.
- name: Thrombocytopenia
  category: Hematological
  description: >-
    Progressive thrombocytopenia; platelet dysfunction has also been described
    as an unusual systemic feature of the disorder.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients develop hematopoietic disorders including anemia, thrombocytopenia and leukocytopenia."
    explanation: >-
      Frequency evidence. "Most patients" maps to FREQUENT per
      docs/frequency-evidence-guidelines.md.
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow."
    explanation: >-
      Directly reports progressive thrombocytopenia in MPSPS patients.
- name: Bone marrow hypocellularity
  category: Hematological
  description: >-
    Histologically hypoplastic bone marrow underlying the peripheral cytopenias.
  phenotype_term:
    preferred_term: Bone marrow hypocellularity
    term:
      id: HP:0005528
      label: Bone marrow hypocellularity
  evidence:
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow."
    explanation: >-
      Reports hypoplastic bone marrow on histology as the marrow correlate of the
      cytopenias.
- name: Decreased circulating IgG concentration
  category: Immunological
  description: >-
    Serum IgG is decreased in MPSPS patients, part of a dysimmunoglobulinaemia
    pattern in which IgM moves in the opposite direction.
  phenotype_term:
    preferred_term: Decreased circulating IgG concentration
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An increase in serum IgM and decrease of IgG levels were found in MPSPS patients"
    explanation: >-
      Reports decreased serum IgG in MPSPS patients. Note the same sentence
      reports IgM moving in the OPPOSITE direction, curated separately below so
      the discordant pattern is not collapsed into a single "low immunoglobulin"
      claim.
- name: Increased circulating IgM level
  category: Immunological
  description: >-
    Serum IgM is increased in MPSPS patients, discordant with the decreased IgG.
  phenotype_term:
    preferred_term: Increased circulating IgM level
    term:
      id: HP:0003496
      label: Increased circulating IgM level
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An increase in serum IgM and decrease of IgG levels were found in MPSPS patients"
    explanation: >-
      Reports increased serum IgM in MPSPS patients, the raised arm of the
      discordant IgM-high/IgG-low pattern.
- name: Hemophagocytosis
  category: Hematological
  description: >-
    Secondary haemophagocytic lymphohistiocytosis has been reported in an
    unusually long-surviving MPSPS patient at two years of age and was
    successfully treated with corticosteroids. HLH should be suspected in MPSPS
    patients with suggestive symptoms.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:35327996
    reference_title: "Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When he was two years old, he developed secondary hemophagocytic lymphohistiocytosis (HLH), which was successfully treated with steroids."
    explanation: >-
      Single-patient report of secondary HLH complicating MPSPS. No frequency is
      asserted because this is an isolated case.
- name: Mucopolysacchariduria
  category: Metabolic
  description: >-
    Excessive urinary excretion of glycosaminoglycans - heparan and dermatan
    sulphate, with chondroitin sulphate in some patients - is a constant feature
    and the finding that first suggests a mucopolysaccharidosis.
  phenotype_term:
    preferred_term: Mucopolysacchariduria
    term:
      id: HP:0008155
      label: Mucopolysacchariduria
  evidence:
  - reference: PMID:39273517
    reference_title: "Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients with MPSPS exhibited excessive excretion of glycosaminoglycans (GAGs) in the urine and exceptionally high levels of heparan sulfate in the plasma, but the accumulation of substrates is not caused by a decrease in the activity of any lysosomal enzymes."
    explanation: >-
      Documents excessive urinary GAG excretion as a defining MPSPS feature.
      Evidence source is OTHER because this is a review synthesising reported
      cases.
- name: Fetal ascites
  category: Prenatal
  description: >-
    Fetal ascites has been reported prenatally, in one juvenile-form patient
    resolving spontaneously. Increased prenasal thickness on second-trimester
    ultrasonography is another reported prenatal marker.
  subtype: Juvenile
  phenotype_term:
    preferred_term: Fetal ascites
    term:
      id: HP:0001791
      label: Fetal ascites
  evidence:
  - reference: PMID:36232726
    reference_title: "Mucopolysaccharidosis-Plus Syndrome: Report on a Polish Patient with a Novel VPS33A Variant with Comparison with Other Described Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe the first Polish MPS-PS patient with a novel homozygous c.599G>C (p.Arg200Pro) VPS33A variant presenting over 12 years of follow-up with some novel clinical features, including fetal ascites (resolved spontaneously), recurrent joint effusion and peripheral edemas, normal growth, and visceral obesity."
    explanation: >-
      Reports fetal ascites among the novel clinical features of the juvenile
      p.Arg200Pro patient.
biochemical:
- name: Plasma heparan sulphate
  notes: >-
    Plasma heparan sulphate is extraordinarily elevated in MPSPS - about 60
    times the normal reference range and six times the level found in classical
    MPS patients - making it the most discriminating single biochemical marker.
  presence: INCREASED
  evidence:
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients."
    explanation: >-
      Quantifies the plasma heparan sulphate elevation relative to both the normal
      range and classical MPS.
- name: Lysosomal hydrolase activity panel
  notes: >-
    The activities of the known GAG-degrading lysosomal enzymes are NORMAL in
    MPSPS. This is the pivotal negative finding that separates MPSPS from every
    classical mucopolysaccharidosis and the reason affected children cannot be
    diagnosed enzymatically. Lysosphingolipid concentrations in dried blood spot
    are likewise normal.
  presence: NORMAL
  evidence:
  - reference: PMID:39273517
    reference_title: "Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the accumulation of substrates is not caused by a decrease in the activity of any lysosomal enzymes"
    explanation: >-
      States that no lysosomal enzyme activity is decreased in MPSPS. Evidence
      source is OTHER because this is a review synthesising the reported cases.
  - reference: PMID:36232726
    reference_title: "Mucopolysaccharidosis-Plus Syndrome: Report on a Polish Patient with a Novel VPS33A Variant with Comparison with Other Described Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal results of lysosomal enzymes activity and lysosphingolipids concentration in dried blood spot"
    explanation: >-
      Patient-level confirmation that lysosomal enzyme activities and
      lysosphingolipid concentrations are normal.
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, these patients could not be diagnosed enzymatically as MPS."
    explanation: >-
      The original description records that MPSPS patients cannot be diagnosed by
      enzyme assay, the clinical corollary of normal hydrolase activity.
- name: Urinary glycosaminoglycan fractionation
  notes: >-
    Urinary GAG electrophoresis or LC-MS/MS shows excess heparan and dermatan
    sulphate; hyaluronic acid was increased in the juvenile p.Arg200Pro patient
    and chondroitin sulphate only in another. Sialylated conjugates and urinary
    sialooligosaccharides are additionally reported, a pattern not seen in
    classical MPS.
  presence: INCREASED
  evidence:
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urine glycosaminoglycan studies revealed a pathological excess of sialylated conjugates as well as dermatan and heparan sulphate."
    explanation: >-
      Characterises the urinary GAG profile including the atypical sialylated
      conjugates.
  - reference: PMID:36153662
    reference_title: "Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urinary glycosaminoglycan (GAG) analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid."
    explanation: >-
      Documents the urinary GAG species in the attenuated juvenile form.
genetic:
- name: VPS33A
  gene_term:
    preferred_term: VPS33A
    term:
      id: hgnc:18179
      label: VPS33A
  relationship_type: CAUSATIVE
  association: >-
    Biallelic missense variants in VPS33A (12q24.31), encoding a core
    Sec1/Munc18-family subunit of the HOPS and CORVET membrane-tethering
    complexes, cause MPSPS. Two variants are established: the recurrent founder
    allele c.1492C>T (p.Arg498Trp), homozygous in essentially all reported
    patients and associated with the severe infantile form, and c.599G>C
    (p.Arg200Pro), reported homozygous in two patients with an attenuated
    juvenile course. Both act as hypomorphic loss of function via protein
    destabilisation and proteasomal degradation.
  variant_origin: GERMLINE
  notes: >-
    Variant class and mechanism: both known alleles are germline homozygous
    MISSENSE substitutions in conserved regions, acting as hypomorphic loss of
    function through protein instability - NOT nonsense, frameshift, whole-gene
    deletion, gain of function or dominant negative. No CNV, structural,
    somatic or mosaic mechanism has been implicated, and no modifier gene is
    known. Because VPS33A is a shared core subunit, the molecular consequence
    extends beyond VPS33A itself: patient cells show secondary reduction of the
    other HOPS/CORVET components (VPS18, VPS41), so a single missense allele
    depletes two multi-subunit complexes.
    Penetrance and genotype-phenotype: penetrance of homozygous p.Arg498Trp
    appears complete in reported families, with no formal age-dependent
    penetrance estimate published. The genotype-phenotype correlation is the
    clearest feature of the MPSPS genetics - p.Arg498Trp gives the lethal
    infantile disease while p.Arg200Pro gives an attenuated juvenile course,
    attributed to appreciable RESIDUAL endosomal-lysosomal trafficking rather
    than to any qualitative difference in mechanism. Caveat: the p.Arg200Pro
    correlation rests on only two reported patients.
    Founder allele: p.Arg498Trp is a Yakut founder allele with a carrier
    frequency of 1:81 and a birth incidence of about 1 per 12,100 in that
    population (see prevalence). Consanguinity is not required - the original
    Yakut series comprised children of healthy, non-consanguineous parents -
    although the two Turkish patients were born to first cousins.
  evidence:
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed that the missense mutation reduced the abundance of full-length VPS33A and other components of the HOPS and CORVET complexes."
    explanation: >-
      Supports the statement that the missense allele depletes not only VPS33A
      but the other HOPS/CORVET components, the molecular basis for the
      disproportionate effect of a single missense change.
  - reference: PMID:36153662
    reference_title: "Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge this is the first report of an attenuated juvenile form of VPS33A insufficiency characterized by appreciable residual endosomal-lysosomal trafficking and a milder mucopolysaccharidosis plus than the disease in infants."
    explanation: >-
      Supports the genotype-phenotype correlation: residual trafficking capacity
      distinguishes the attenuated p.Arg200Pro course from the lethal infantile
      p.Arg498Trp disease.
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using whole exome and Sanger sequencing, we identified homozygous c.1492C > T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients."
    explanation: >-
      Original gene discovery: homozygous VPS33A p.Arg498Trp in 13 patients by
      exome and Sanger sequencing.
  - reference: PMID:36232726
    reference_title: "Mucopolysaccharidosis-Plus Syndrome: Report on a Polish Patient with a Novel VPS33A Variant with Comparison with Other Described Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Up to now, a total number of 39 patients have been reported; in all of them, the c.1492C>T (p.Arg498Trp) variant of the VPS33A gene was detected."
    explanation: >-
      Confirms p.Arg498Trp as the recurrent allele across the whole reported
      cohort at that time.
  - reference: PMID:36153662
    reference_title: "Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe an attenuated juvenile form of VPS33A-related syndrome-mucopolysaccharidosis plus in a man who is homozygous for a hitherto unknown missense mutation (NM_022916.4: c.599 G>C; NP_075067.2:p. Arg200Pro) in a conserved region of the VPS33A gene."
    explanation: >-
      Establishes the second pathogenic VPS33A allele and its association with the
      attenuated juvenile phenotype.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    MPSPS is ultra-rare. Reported patient counts have risen from 19 (2020) to 24
    (2022) to 39-41 (2022-2024) as the entity has become recognised. Orphanet
    prevalence was not cited here because the local Orphadata snapshot could not
    be refreshed at curation time (known repo issue); a qualitative band is used
    instead.
  evidence:
  - reference: PMID:39273517
    reference_title: "Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To date, it has been described in 41 patients."
    explanation: >-
      Total reported patient count as of the 2024 review, supporting the
      ultra-rare band.
- population: Yakut (Sakha) population, Siberia
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 8.3
  notes: >-
    Strong founder effect for c.1492C>T (p.Arg498Trp) in the Yakut population of
    the Sakha Republic. The reported incidence of 1 per 12,100 births normalises
    to 8.3 per 100,000. Cases outside Yakutia have been reported from Turkey,
    Poland and Israel, so MPSPS is not exclusively a Yakut disease.
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Incidence rate of MPSPS in Yakuts population is predicted as 1 per 12,100 birth."
    explanation: >-
      Source for the Yakut birth-prevalence figure; 1/12,100 = 8.3 per 100,000.
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nineteen patients with MPSPS have been identified: seventeen patients were found among the Yakut population (Russia) and two patients from Turkey."
    explanation: >-
      Documents the marked Yakut concentration alongside unrelated Turkish
      patients.
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts-a nomadic Turkic ethnic group of Southern Siberia"
    explanation: >-
      Identifies the founder population in which the disorder was first
      recognised.
- population: Yakut (Sakha) population, Siberia
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1234.6
  notes: >-
    Carrier (heterozygote) allele frequency of the p.Arg498Trp founder variant
    in the Yakut population is reported as 1:81, i.e. about 1,235 per 100,000.
    This is the population-genetic basis for targeted cascade and community
    carrier screening in Yakut families, and is a population-specific figure
    with no bearing on global frequency.
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified extremely high allele frequency in this population (1:81)"
    explanation: >-
      Source for the Yakut founder-allele carrier frequency.
diagnosis:
- name: Clinical and biochemical suspicion of MPSPS
  description: >-
    MPSPS is suspected when an infant has an MPS-like phenotype (coarse facies,
    dysostosis multiplex, hepatosplenomegaly, developmental delay) with
    excessive urinary GAG excretion BUT normal activity of the lysosomal
    enzymes. The negative enzyme panel is the discriminator, and it is also why
    MPSPS cannot be detected by any enzyme-based newborn screen: there is no
    deficient hydrolase to assay.
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finding of MPS-like phenotype and excess secretion of urinary GAGs without deficiency in the activity of lysosomal enzymes is the basis for suspicion of MPSPS."
    explanation: >-
      States the diagnostic triad that raises suspicion of MPSPS, including the
      pivotal normal-enzyme finding.
- name: Molecular confirmation by VPS33A sequencing
  description: >-
    Diagnosis is confirmed by molecular testing of VPS33A - targeted testing for
    p.Arg498Trp in Yakut families or where the familial variant is known,
    otherwise a lysosomal-storage/vesicular-trafficking panel or exome
    sequencing. Whole exome sequencing is what originally identified the gene.
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis generally requires evidence of clinical picture similar to MPS and molecular genetic testing."
    explanation: >-
      Establishes molecular genetic testing as the confirmatory diagnostic step.
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using whole exome and Sanger sequencing, we identified homozygous c.1492C > T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients."
    explanation: >-
      Documents the sequencing approaches by which the causal variant is
      identified.
histopathology:
- name: Glomerular destruction by foamy podocytes
  description: >-
    Renal histology in MPSPS shows extensive destruction of glomerular
    structures by foamy (storage-laden) podocytes, with segmental sclerosis,
    periglomerular fibrosis and inflammatory cell infiltration. The foamy
    podocyte is the one unambiguous storage cell described in MPSPS.
  evidence:
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histological analyses of MPSPS kidneys similarly suggest the extensive destruction of glomerular structures by foamy podocytes."
    explanation: >-
      Primary histological description of the renal lesion.
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal biopsy showed segmental sclerosis, periglomerular fibrosis and inflammatory cell infiltration."
    explanation: >-
      Adds the sclerotic, fibrotic and inflammatory components of the renal
      biopsy picture.
- name: Hypoplastic bone marrow without storage cells
  description: >-
    Marrow histology shows hypoplasia but, notably, NO storage cells - a key
    negative that distinguishes the MPSPS cytopenias from a storage-cell
    infiltration mechanism and leaves them mechanistically unexplained.
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone marrow aspiration analysis showed hypoplastic bone marrow without any storage cells."
    explanation: >-
      Documents marrow hypoplasia together with the explicit absence of storage
      cells.
progression:
- phase: Prenatal
  notes: >-
    Prenatal findings can include ascites and increased prenasal, nasal or
    nuchal thickness on second-trimester ultrasonography, and congenital cardiac
    valve abnormalities. Many affected newborns are delivered at term with
    normal Apgar scores.
  evidence:
  - reference: PMID:37628632
    reference_title: "Prenatal Diagnosis of Mucopolysaccharidosis-Plus Syndrome (MPSPS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During their pregnancies, both women underwent prenatal ultrasonography, which revealed increased prenasal thickness during the second trimester."
    explanation: >-
      Documents the second-trimester sonographic marker.
- phase: Early infantile onset
  subtype: Infantile
  age_range: 2-6 months
  notes: >-
    Respiratory symptoms typically emerge at 2-6 months of age, with recurrent
    infections and bronchial obstruction, followed by the MPS-like facies and
    dysostosis. Growth begins to decline in some patients at around six months
    to one year.
  evidence:
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Height and weight did not significantly deviate from the average, but in some cases, growth began to decline at around six months or one year of age."
    explanation: >-
      Documents the timing of growth decline, and notes that growth is otherwise
      largely preserved.
- phase: Rapid multisystem progression
  subtype: Infantile
  notes: >-
    Cardiac disease can progress from moderate to severe within only 3-4 months,
    in parallel with worsening renal and haematopoietic involvement.
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mitral and tricuspid valve defects and pulmonary hypertension progressed from moderate to severe within 3"
    explanation: >-
      Quantifies the pace of cardiac deterioration.
- phase: Terminal
  subtype: Infantile
  age_range: 10-20 months
  notes: >-
    Death from cardiorespiratory failure typically occurs at 10-20 months in the
    p.Arg498Trp founder form. The p.Arg200Pro juvenile form survives far longer
    (one patient followed over 12 years).
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease is very severe, prognosis is unfavorable and most of patients died at age of 10-20 months."
    explanation: >-
      Reports the typical age at death for the severe founder form.
treatments:
- name: Supportive and symptomatic care
  description: >-
    There is no approved disease-modifying therapy for MPSPS, and enzyme
    replacement is not a logical strategy because no single hydrolase is
    deficient. Management is multidisciplinary and supportive: airway clearance,
    oxygen and ventilatory support, prompt antibiotics for respiratory
    infection, nutritional and developmental support, standard cardiac and renal
    management, transfusion for significant cytopenia, and surveillance of
    cardiac, renal, respiratory, haematologic, hearing and vision status.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently there is no specific therapy for this disease and clinical management is limited to supportive and symptomatic treatment."
    explanation: >-
      States that no specific therapy exists and management is supportive and
      symptomatic.
- name: Respiratory support and anti-infective therapy
  description: >-
    Airway clearance and bronchial drainage, supplemental oxygen and ventilatory
    support as required, and prompt antibiotics for bacterial respiratory
    infection. This is the highest-yield supportive axis because recurrent
    respiratory infection from 2-6 months of age is the usual presenting problem
    and cardiorespiratory failure is the usual mode of death.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31936524
    reference_title: "Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently there is no specific therapy for this disease and clinical management is limited to supportive and symptomatic treatment."
    explanation: >-
      Supports supportive/symptomatic management as the standard of care. Marked
      PARTIAL because the quoted sentence establishes the supportive-care
      principle without itemising the specific respiratory interventions.
- name: Transfusion support for cytopenias
  description: >-
    Red-cell or platelet transfusion for clinically significant anaemia or
    thrombocytopenia arising from the hypoplastic marrow. Purely supportive: it
    does not address the underlying marrow hypoplasia, whose mechanism is
    unexplained given the documented absence of marrow storage cells.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: blood transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  evidence:
  - reference: PMID:35628659
    reference_title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow."
    explanation: >-
      Establishes the progressive anaemia and thrombocytopenia that create the
      transfusion requirement. Marked PARTIAL because it documents the
      indication rather than reporting transfusion outcomes.
- name: Prolonged corticosteroid therapy for secondary HLH
  description: >-
    In a single unusually long-surviving child who developed secondary
    haemophagocytic lymphohistiocytosis at two years of age, steroids treated the
    HLH successfully and a very prolonged course was associated with
    stabilisation of general and haematological status. This is a single case
    report; corticosteroids are NOT established MPSPS therapy and the authors
    themselves state the approach deserves further investigation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  evidence:
  - reference: PMID:35327996
    reference_title: "Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prolonged steroid treatment allowed a stabilization of his general and hematological conditions and probably determined an improvement of his psychomotor milestones and new neurological acquisitions with an improvement of quality of life."
    explanation: >-
      Reports the observed benefit. Marked PARTIAL because this is a single
      uncontrolled case and the authors describe the effect as probable.
- name: Genetic counselling and prenatal diagnosis
  description: >-
    Because MPSPS is autosomal recessive with a defined founder allele, cascade
    carrier testing, nondirective counselling and targeted prenatal diagnosis
    (chorionic villus/placental biopsy DNA when the familial variant is known)
    are the principal preventive options. Increased prenasal thickness on
    second-trimester ultrasonography can prompt testing in families with no known
    history.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37628632
    reference_title: "Prenatal Diagnosis of Mucopolysaccharidosis-Plus Syndrome (MPSPS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consequently, a placental biopsy was performed, leading to an early diagnosis of MPSPS."
    explanation: >-
      Demonstrates feasibility of targeted prenatal molecular diagnosis once
      parental carrier status is known.
  - reference: PMID:37628632
    reference_title: "Prenatal Diagnosis of Mucopolysaccharidosis-Plus Syndrome (MPSPS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During their pregnancies, both women underwent prenatal ultrasonography, which revealed increased prenasal thickness during the second trimester."
    explanation: >-
      Identifies the sonographic marker that can trigger prenatal genetic testing.
- name: Proteasome and protein-degradation modulation (experimental)
  description: >-
    Because the disease mechanism is destabilisation and degradation of a
    partially functional VPS33A protein rather than absence of catalytic
    activity, raising the steady-state level of the mutant protein is a rational
    strategy. In patient-derived fibroblasts the proteasome inhibitor bortezomib
    (and, separately, the glucosylceramide-synthase inhibitor eliglustat)
    partially corrected the lactosylceramide trafficking defect, and the
    proteasome inhibitor genistein combined with the ERAD inhibitor ambroxol
    raised mutant VPS33A levels and corrected GAG, endosomal-marker and
    cytoskeletal defects. All of this is IN VITRO only. No clinical trial exists,
    and bortezomib's toxicity makes off-label use unsupported outside formal
    research.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:31070736
    reference_title: "The lysosomal disease caused by mutant VPS33A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Exposure of patient-derived fibroblasts to the clinically approved proteasome inhibitor, bortezomib, or inhibition of glucosylceramide synthesis with eliglustat, partially corrected the impaired lactosylceramide trafficking defect and immediately suggest therapeutic avenues to explore in this fatal orphan disease."
    explanation: >-
      Reports partial in vitro correction of a trafficking defect. Marked PARTIAL
      because this is a cell-culture result with no clinical evidence of benefit.
  - reference: PMID:41310305
    reference_title: "The use of genistein and ambroxol may be an effective approach in correcting cellular dysfunctions of mucopolysaccharidosis-plus syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrated that treatment with genistein and ambroxol resulted in elevation of the mutant VPS33A protein level, as well as in improvement or correction of various previously reported cellular defects, including GAG levels, endosomal markers, and cytoskeleton elements"
    explanation: >-
      Reports in vitro rescue of mutant VPS33A abundance and multiple downstream
      cellular defects. Marked PARTIAL because the evidence is a single
      patient-derived fibroblast line with no clinical data.
discussions:
- discussion_id: mpsps_nosology
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Should MPSPS be classified as a type of mucopolysaccharidosis, or as a
    distinct vesicular-trafficking metabolic disease that phenocopies one?
  attaches_to:
  - "pathophysiology#Glycosaminoglycan Accumulation With Normal Lysosomal Hydrolase Activity"
  rationale: >-
    GAG storage and MPS-like clinical features argue for inclusion among the
    mucopolysaccharidoses; normal lysosomal GAG-hydrolase activity and a primary
    membrane-tethering/trafficking lesion argue for a separate entity. The
    question is not merely terminological: it determines whether MPSPS belongs in
    the Mucopolysaccharidoses grouping (whose rationale requires deficiency of
    a GAG-degrading enzyme) and whether newborn screening by enzyme assay could
    ever detect it. This entry takes the position that MPSPS is a lysosomal
    storage disorder reached by a trafficking route, hence downstream-only
    conformance to lysosomal_substrate_accumulation and no MPS-grouping
    membership on the criteria as currently written.
  evidence:
  - reference: PMID:39273517
    reference_title: "Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Moreover, we asked the question whether MPSPS should be classified as a type of MPS or a separate disease, as contrary to 'classical' MPS types, despite GAG accumulation, no defects in lysosomal enzymes responsible for degradation of these compounds could be detected in MPSPS."
    explanation: >-
      The 2024 review poses exactly this nosological question and states the
      reason it is unresolved.
- discussion_id: mpsps_autophagy_discrepancy
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is autophagic flux genuinely impaired in MPSPS, or is the reported autophagy
    abnormality specific to the p.Arg200Pro variant or to assay conditions?
  attaches_to:
  - "pathophysiology#Endolysosomal Compartment Expansion and Over-Acidification"
  rationale: >-
    The original p.Arg498Trp study explicitly reported that the mutation did NOT
    affect the endocytic or autophagic pathways in patient skin fibroblasts,
    whereas a later study of p.Arg200Pro fibroblasts found elevated LC3-II and
    p62, indicating a block in autophagic flux. Because HOPS is required for
    autophagosome-lysosome fusion, an autophagy defect is mechanistically
    expected, making the negative result surprising. Resolving this matters for
    whether the Autophagic-Lysosomal Dysfunction conformance asserted here is
    correct for both variants, and for whether autophagy-modulating therapy is
    rational.
  proposed_experiments:
  - experiment_id: mpsps_autophagic_flux_headtohead
    name: Head-to-head autophagic flux assay across both VPS33A genotypes
    description: >-
      Side-by-side autophagic-flux assay (LC3-II turnover with and without
      bafilomycin A1, plus p62 and tandem mRFP-GFP-LC3 reporter) in p.Arg498Trp
      and p.Arg200Pro patient fibroblasts and isogenic knock-in controls, under
      identical starvation and basal conditions.
  - experiment_id: mpsps_autophagosome_lysosome_fusion_imaging
    name: Live-cell imaging of autophagosome-lysosome fusion
    description: >-
      Quantify autophagosome-lysosome fusion directly by live-cell imaging of
      LC3 and LAMP1 colocalisation in both genotypes, to distinguish a fusion
      block from altered autophagosome biogenesis.
  evidence:
  - reference: PMID:28013294
    reference_title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "VPS33A is involved in endocytic and autophagic pathways, but the identified mutation did not affect either of these pathways."
    explanation: >-
      The negative finding in p.Arg498Trp fibroblasts that generates the
      discrepancy.
  - reference: PMID:40758165
    reference_title: "Cellular and molecular changes in mucopolysaccharidosis-plus syndrome caused by a homozygous c.599G > C (p.Arg200Pro) variant of the VPS33A gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "elevated levels of the LC3-II and p62 proteins (autophagy markers)"
    explanation: >-
      The positive autophagy-marker finding in p.Arg200Pro fibroblasts that
      conflicts with the earlier negative result.
- discussion_id: mpsps_no_organ_level_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Every mechanistic result in MPSPS comes from patient skin fibroblasts or
    transfected HeLa cells - can findings in these systems be assumed to explain
    the cardiac, renal, marrow and neurodevelopmental disease that actually kills
    affected children, when no knock-in animal or organ-level human model exists?
  attaches_to:
  - "pathophysiology#Progressive Multisystem Disease With Plus Features"
  rationale: >-
    Patient-derived skin fibroblasts and HeLa cells reproduce VPS33A depletion,
    HOPS/CORVET loss, endolysosomal disorganisation and trafficking defects, but
    they cannot model the cardiorespiratory, renal-podocyte, marrow-hypoplasia or
    neurodevelopmental phenotypes. In particular the causal edge from GAG storage
    to congenital heart disease is asserted clinically but has never been
    demonstrated experimentally in any system, and the in vitro drug rescues
    (bortezomib, eliglustat, genistein/ambroxol) are all fibroblast readouts of
    uncertain organ-level relevance. No validated VPS33A p.Arg498Trp knock-in
    mouse, zebrafish, organoid or iPSC model recapitulating the human syndrome
    has been reported.
  proposed_experiments:
  - experiment_id: mpsps_knockin_mouse
    name: Vps33a p.Arg498Trp knock-in mouse phenotyping
    description: >-
      Generate and phenotype a Vps33a p.Arg498Trp knock-in mouse, with
      longitudinal echocardiography, urinary protein quantification, renal
      histology for foamy podocytes, and marrow cellularity, to test whether the
      plus features are cell-autonomous consequences of the tethering defect.
  - experiment_id: mpsps_ipsc_organ_models
    name: Patient iPSC-derived cardiac, kidney and haematopoietic models
    description: >-
      Differentiate patient iPSCs to cardiomyocytes, kidney organoids and
      haematopoietic progenitors to determine which plus features arise
      cell-autonomously versus secondarily to systemic storage, and to retest the
      candidate drugs in a disease-relevant cell type.
references:
- reference: PMID:28013294
  title: "Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms."
- reference: PMID:31070736
  title: "The lysosomal disease caused by mutant VPS33A."
- reference: PMID:31936524
  title: "Mucopolysaccharidosis-Plus Syndrome."
- reference: PMID:35628659
  title: "Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome."
- reference: PMID:39273517
  title: "Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease?"

📚

References & Deep Research

References

5

PMID:28013294

Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms.

No top-level findings curated for this source.

PMID:31070736

The lysosomal disease caused by mutant VPS33A.

No top-level findings curated for this source.

PMID:31936524

Mucopolysaccharidosis-Plus Syndrome.

No top-level findings curated for this source.

PMID:35628659

Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome.

No top-level findings curated for this source.

PMID:39273517

Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease?

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Mucopolysaccharidosis-Plus Syndrome (MPSPS): Disease Characteristics Report

Edison Scientific Literature 18 citations 2026-08-01T18:33:29.840748

Mucopolysaccharidosis-Plus Syndrome (MPSPS): Disease Characteristics Report

Executive summary

Mucopolysaccharidosis-plus syndrome (MPSPS) is an ultra-rare, autosomal-recessive lysosomal/endolysosomal trafficking disorder caused by biallelic VPS33A variants. It resembles classical mucopolysaccharidoses because glycosaminoglycans (GAGs) accumulate and are excessively excreted, but differs fundamentally because activities of the known GAG-degrading lysosomal enzymes remain normal. The “plus” phenotype comprises particularly prominent congenital cardiac disease, nephrotic/renal disease, and hematologic abnormalities. The severe founder form, caused by VPS33A c.1492C>T (p.Arg498Trp; R498W), usually begins in infancy and historically caused death from cardiorespiratory failure at approximately 10–20 months. A 2024 review counted 41 reported patients and described two patients with c.599G>C (p.Arg200Pro) and a milder juvenile phenotype. Evidence remains dominated by small case series, patient fibroblasts, and reviews; there is no approved disease-modifying treatment or validated population-screening program. (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9, cyske2024mucopolysaccharidosisplussyndromeis pages 1-2, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3, pavlova2019thelysosomaldisease pages 7-10)

domain	established finding	evidence type/strength	key ontology suggestions
Definition / classification	Mucopolysaccharidosis-plus syndrome (MPSPS) is an ultra-rare autosomal-recessive lysosomal/endolysosomal trafficking disorder with MPS-like glycosaminoglycan accumulation but without deficiency of known lysosomal GAG-degrading enzymes; reviews note debate over whether it is a true MPS subtype or a distinct metabolic disease (vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, cyske2024mucopolysaccharidosisplussyndromeis pages 1-2)	Human disease review + mechanistic primary study; moderate-strong for disease definition, moderate for classification debate (vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, cyske2024mucopolysaccharidosisplussyndromeis pages 1-2, pavlova2019thelysosomaldisease pages 7-10)	Lysosomal storage disease; endolysosomal transport disorder; possible MONDO term search: “mucopolysaccharidosis-plus syndrome”; GO: lysosomal transport, endosome organization
VPS33A variants and inheritance	Established severe infantile form is caused by homozygous VPS33A c.1492C>T (p.Arg498Trp / p.R498W); 2024 review additionally reports VPS33A c.599G>C (p.Arg200Pro) in 2 juvenile milder cases. Inheritance is autosomal recessive (vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)	Human case series/reviews; strong for p.Arg498Trp, moderate for p.Arg200Pro pending broader replication (vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)	HGNC: VPS33A; SO: missense_variant; inheritance: autosomal recessive inheritance
Epidemiology	By 2024, 41 patients had been described; strong founder effect in the Yakut population is reported, with most early cases from Yakutia and a birth incidence estimate of ~1 in 12,100 in Yakuts for p.Arg498Trp. Sex distribution in one 16-patient Yakut cohort was 8 female / 8 male (cyske2024mucopolysaccharidosisplussyndromeis pages 1-2, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3, vasilev2020mucopolysaccharidosisplussyndrome pages 5-9)	Human cohort/review; moderate because numbers are small and literature is rapidly evolving (cyske2024mucopolysaccharidosisplussyndromeis pages 1-2, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3, vasilev2020mucopolysaccharidosisplussyndrome pages 5-9)	Founder effect; rare disease; population of interest: Yakut/Sakha
Core phenotypes	Multisystem phenotype includes coarse facial features, short neck/nose, periorbital puffiness, macroglossia, growth deficiency, hepatosplenomegaly, dysostosis multiplex, kyphosis/lordosis, barrel chest, joint contractures/stiffness, clawed fingers, developmental delay/regression, hypotonia, nystagmus, recurrent respiratory infections, congenital heart disease, renal disease/nephrotic syndrome, and hematologic abnormalities including anemia, thrombocytopenia, neutropenia/coagulation defects (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9, vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, cyske2024mucopolysaccharidosisplussyndromeis pages 3-5, cyske2024mucopolysaccharidosisplussyndromeis pages 5-7)	Human case series and focused review; strong for infantile p.Arg498Trp phenotype (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9, vasilev2020mucopolysaccharidosisplussyndrome pages 9-11)	HPO suggestions: Coarse facial features; Macroglossia; Dysostosis multiplex; Joint contracture; Hepatosplenomegaly; Developmental delay; Hypotonia; Nystagmus; Recurrent respiratory infections; Congenital heart defect; Nephrotic syndrome; Anemia; Thrombocytopenia; Neutropenia
Biomarkers / diagnosis	Characteristic laboratory pattern: elevated urinary GAGs, especially heparan sulfate and dermatan sulfate, with very high plasma heparan sulfate; additional reports note increased sialooligosaccharides/sialic acid. A key distinguishing feature is normal activities of known lysosomal enzymes for GAG degradation. Diagnosis is based on MPS-like clinical presentation plus biochemical findings and confirmatory molecular testing for VPS33A; prenatal diagnosis is reported as available (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)	Human clinical/biochemical evidence; strong for elevated GAGs with normal lysosomal enzyme assays (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)	HPO: Elevated urinary glycosaminoglycan; Proteinuria; Hypoalbuminemia; Delayed myelination. Diagnostic concepts: urine GAG analysis, plasma HS quantification, VPS33A sequencing
Mechanism	VPS33A is a core HOPS/CORVET subunit. p.Arg498Trp is predicted to destabilize VPS33A, reducing full-length VPS33A and other HOPS/CORVET components, causing disordered endolysosomal compartments, abnormal lactosylceramide trafficking, cholesterol/sphingolipid abnormalities, autophagy-endosomal dysfunction, and impaired intracellular handling of GAGs despite normal enzyme activities. Some mechanistic details remain uncertain (pavlova2019thelysosomaldisease pages 7-10, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3, cyske2024mucopolysaccharidosisplussyndromeis pages 3-5)	Primary human fibroblast mechanistic study + focused review; strong for VPS33A instability/HOPS-CORVET depletion and trafficking defects, moderate for full causal chain to GAG accumulation (pavlova2019thelysosomaldisease pages 7-10, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3, cyske2024mucopolysaccharidosisplussyndromeis pages 3-5)	GO suggestions: endocytic vesicle fusion; lysosomal transport; autophagosome-lysosome fusion; endosome organization. Cellular compartment: lysosome, late endosome, autophagosome
Prognosis / natural history	Typical severe p.Arg498Trp disease begins in early infancy with recurrent respiratory problems around 2–6 months and progresses rapidly; most reported patients died from cardiorespiratory failure at about 10–20 months. Juvenile cases linked to p.Arg200Pro appear milder/longer-surviving but remain very limited (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9, vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)	Human cohort/review; strong for poor prognosis of infantile founder variant, weak-moderate for variant-specific milder prognosis due to only 2 cases (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9, vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)	HPO suggestions: Infantile onset; Progressive course; Early death
Treatment	No approved disease-modifying therapy or relevant clinical trial was identified in retrieved evidence. Current management is supportive/symptomatic: respiratory support, antibiotics, oxygen, vitamins, ACE inhibitors, transfusions, and selected cardiac surgery. Experimental in vitro rescue of patient fibroblast defects has been reported with bortezomib and eliglustat; these findings are preclinical and should not be interpreted as established clinical therapy (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, pavlova2019thelysosomaldisease pages 7-10)	Human supportive-care evidence + preclinical cell data; strong that no specific established therapy exists, weak-moderate for translational promise of bortezomib/eliglustat because evidence is in vitro only (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, pavlova2019thelysosomaldisease pages 7-10)	NCIT-style intervention suggestions: Supportive care; Oxygen therapy; Anti-infective therapy; Blood transfusion; Cardiac surgical procedure; Proteasome inhibitor (experimental); Glucosylceramide synthase inhibitor (experimental)

Table: This table condenses the strongest available evidence for key disease-characteristic domains in mucopolysaccharidosis-plus syndrome. It separates established human findings from experimental or still-uncertain observations and suggests ontology mappings useful for knowledge-base curation.

1. Disease information

Definition and classification

MPSPS is a Mendelian, multisystem lysosomal storage/vesicular-trafficking disease. Unlike classical MPS, its primary defect is not a hydrolase deficiency but impaired intracellular membrane trafficking associated with deficient or unstable VPS33A and disturbed HOPS/CORVET function. Whether MPSPS should be classified as an MPS subtype or as a separate metabolic trafficking disorder remains debated. The most defensible current knowledge-base classification is VPS33A-related lysosomal/endolysosomal trafficking disorder with MPS-like GAG storage. (cyske2024mucopolysaccharidosisplussyndromeis pages 1-2, vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, pavlova2019thelysosomaldisease pages 7-10)

A direct abstract statement from the 2024 focused review is: “Patients with MPSPS exhibited excessive excretion of glycosaminoglycans (GAGs) in the urine and exceptionally high levels of heparan sulfate in the plasma, but the accumulation of substrates is not caused by a decrease in the activity of any lysosomal enzymes.” (cyske2024mucopolysaccharidosisplussyndromeis pages 1-2)

Names and identifiers

Preferred name: Mucopolysaccharidosis-plus syndrome.
Synonyms: MPS-plus syndrome, MPSPS, MPS-PS, VPS33A-related mucopolysaccharidosis-plus syndrome, and lysosomal disease caused by mutant VPS33A.
OMIM: the focused 2020 review identifies the disease as OMIM #617303. One retrieved passage from the 2019 paper was indexed as #610034, which likely reflects a gene/disease-record conflation; #617303 should therefore be used provisionally and independently verified in OMIM before production ingestion. (vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, pavlova2019thelysosomaldisease pages 7-10)
Gene location: VPS33A, chromosome 12q24.31; the founder variant is in exon 12. (vasilev2020mucopolysaccharidosisplussyndrome pages 1-3)
MONDO, Orphanet, MeSH, ICD-10/ICD-11: no reliable disease-specific identifiers were recovered from the accessed primary literature. Do not infer them. Generic coding may fall under mucopolysaccharidosis or other lysosomal storage disorders, but that lacks MPSPS specificity.

The evidence is principally aggregated disease-level literature, derived from published case reports/series and experimental studies of patient-derived fibroblasts—not longitudinal EHR-scale cohorts.

2. Etiology

MPSPS is caused by biallelic germline VPS33A variants and follows autosomal-recessive inheritance. The best-established severe allele is NM_022916.4:c.1492C>T, p.(Arg498Trp); transcript version should be verified in the reporting laboratory. The 2024 review states that this variant occurred in 39 of 41 reported patients and that two milder juvenile patients carried c.599G>C, p.(Arg200Pro). Evidence for p.Arg498Trp is strong; p.Arg200Pro remains based on only two reported patients. (vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)

The Yakut/Sakha enrichment is consistent with a founder effect and geographic isolation. The 2020 review reported an allele frequency of approximately 1:81 in the Yakut population; this should be interpreted as a population-specific estimate, not a global frequency. A 2024 review estimated incidence at approximately 1 per 12,100 births in Yakuts. (vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)

No environmental, infectious, dietary, occupational, sex-specific, or lifestyle cause is established. No protective genetic variants, environmental protective factors, modifier genes, or reproducible gene–environment interactions have been demonstrated. Viral or respiratory infections may precipitate clinical deterioration in affected children but are complications/triggers, not primary causes. Consanguinity is not required: the early 16-patient Yakut cohort included children of healthy, reportedly non-consanguineous parents. (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9)

3. Phenotypes

The phenotype is progressive and multisystemic. Frequencies below are qualitative unless a denominator is explicitly available; publication bias and repeated reporting of the same patients preclude reliable pooled percentages.

Craniofacial, skeletal, and growth manifestations

Coarse facial features, prominent forehead, short nose/neck, periorbital puffiness, macroglossia, facial/limb edema, and loose skin.
Growth deficiency/short stature.
Dysostosis multiplex, barrel chest, kyphosis/lordosis, bullet-shaped phalanges, joint stiffness or contractures, clawed fingers, and frequent falls.
Suggested HPO: Coarse facial features (HP:0000280), Macroglossia (HP:0000158), Short stature (HP:0004322), Dysostosis multiplex (HP:0000943), Kyphosis (HP:0002808), Joint contracture (HP:0001371). (cyske2024mucopolysaccharidosisplussyndromeis pages 3-5, cyske2024mucopolysaccharidosisplussyndromeis pages 5-7, vasilev2020mucopolysaccharidosisplussyndrome pages 5-9)

Neurologic and developmental manifestations

Developmental delay or regression, psychomotor retardation, hypotonia, cognitive impairment, poor memory/concentration, autistic features, nystagmus, hydrocephalus, and delayed speech have been reported. Milestones in longer-surviving cases included sitting at 10–13 months, walking at 22–28 months, and delayed speech. MRI/CT findings include delayed myelination, cerebral/cerebellar abnormalities, global atrophy, and basal-ganglia or other intracranial calcification. Suggested HPO: Global developmental delay (HP:0001263), Developmental regression (HP:0002376), Hypotonia (HP:0001252), Delayed CNS myelination (HP:0002188), Brain atrophy (HP:0012444), Nystagmus (HP:0000639). (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, cyske2024mucopolysaccharidosisplussyndromeis pages 5-7, vasilev2020mucopolysaccharidosisplussyndrome pages 5-9)

Respiratory and infectious manifestations

Recurrent upper/lower respiratory infections, bronchial obstruction, dyspnea, and progressive respiratory failure are prominent. In the early cohort, respiratory symptoms commonly emerged at 2–6 months. Suggested HPO: Recurrent respiratory infections (HP:0002205), Dyspnea (HP:0002094), Bronchial obstruction, and Respiratory failure (HP:0002878). (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9)

Cardiovascular manifestations

Congenital heart disease includes atrial septal defect, patent foramen ovale, valve regurgitation/insufficiency, and pulmonary hypertension. Cardiac disease may progress substantially over only 3–4 months and contributes to early mortality. Suggested HPO: Congenital heart defect (HP:0001627), Atrial septal defect (HP:0001631), Pulmonary hypertension (HP:0002092), and valve-regurgitation terms. (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, vasilev2020mucopolysaccharidosisplussyndrome pages 5-9)

Renal manifestations

Renal disease is one of the most discriminating “plus” features. Reports describe nephromegaly, nephrotic syndrome, marked proteinuria, hypoalbuminemia, elevated creatinine and uric acid, calcium deficiency, and occasional tubular disease. Histopathology includes glomerular destruction, periglomerular fibrosis, interstitial inflammation, and foam cells in podocytes. Suggested HPO: Nephrotic syndrome (HP:0000100), Proteinuria (HP:0000093), Hypoalbuminemia (HP:0003073), Nephromegaly (HP:0000105), and Renal insufficiency (HP:0000083). (pavlova2019thelysosomaldisease pages 7-10, cyske2024mucopolysaccharidosisplussyndromeis pages 8-10)

Hematologic and immune manifestations

Normocytic anemia, thrombocytopenia, neutropenia/leukopenia, coagulation abnormalities, hypogammaglobulinemia, and hypoplastic marrow have been reported. Suggested HPO: Anemia (HP:0001903), Thrombocytopenia (HP:0001873), Neutropenia (HP:0001875), Abnormality of coagulation (HP:0001928), and Hypogammaglobulinemia (HP:0004313). (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, cyske2024mucopolysaccharidosisplussyndromeis pages 3-5, cyske2024mucopolysaccharidosisplussyndromeis pages 5-7)

Other manifestations and functional impact

Hepatomegaly/hepatosplenomegaly, subclinical hypothyroidism, retinal hypopigmentation, and peripheral or retrocochlear hearing impairment occur. Suggested HPO: Hepatomegaly (HP:0002240), Splenomegaly (HP:0001744), Hypothyroidism (HP:0000821), and Hearing impairment (HP:0000365). (cyske2024mucopolysaccharidosisplussyndromeis pages 8-10, cyske2024mucopolysaccharidosisplussyndromeis pages 5-7)

No validated MPSPS-specific EQ-5D, SF-36, PROMIS, caregiver-burden, or health-utility data were found. Nevertheless, developmental impairment, severe cardiorespiratory disease, recurrent hospitalization/infection, mobility limitation, transfusion requirements, and very early mortality imply profound effects on child and family quality of life.

4. Genetic and molecular information

Causal gene: VPS33A, encoding a 596-amino-acid, approximately 67-kDa Sec1/Munc18-family protein and core component of both HOPS and CORVET tethering complexes. (cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)

Pathogenic variants:

c.1492C>T; p.Arg498Trp (R498W)—homozygous missense, germline, severe infantile phenotype. Structural modeling predicts destabilized folding; patient cells show reduced full-length VPS33A and secondary reduction of VPS18/VPS41 and other complex components. Functional consequence is best described as hypomorphic loss of function through protein instability/proteasomal degradation, rather than gain of function or dominant-negative activity. (vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, pavlova2019thelysosomaldisease pages 7-10)
c.599G>C; p.Arg200Pro—homozygous missense reported in two juvenile patients with milder, longer-surviving disease. Classification and population frequency should be checked directly in ClinVar/gnomAD before clinical use. (cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)

Global gnomAD/TOPMed/1000 Genomes frequencies, ClinVar review status, HGNC numerical identifier, and ACMG evidence codes were not recoverable from the accessed literature. Both are constitutional/germline variants; no somatic etiology is implicated. No established modifier genes, epigenetic signature, methylation abnormality, chromosomal rearrangement, CNV, anticipation, or germline mosaicism has been documented.

5. Environmental information

MPSPS is monogenic. There is no evidence that toxins, radiation, air pollution, smoking, alcohol, diet, exercise, occupation, or infectious agents cause the disorder. Respiratory infections are frequent complications and can worsen cardiorespiratory status. Routine vaccination and infection avoidance are reasonable supportive measures, but neither prevents the inherited molecular defect.

6. Mechanism and pathophysiology

Causal chain

Upstream genetic lesion: biallelic VPS33A missense variant.
Protein-level defect: p.Arg498Trp destabilizes VPS33A folding and promotes proteasomal degradation.
Complex instability: reduced VPS33A lowers HOPS/CORVET components such as VPS18 and VPS41.
Cellular trafficking dysfunction: late endosomal/lysosomal compartment organization and lipid cargo trafficking become abnormal; patient fibroblasts show vacuolation and defective lactosylceramide trafficking.
Metabolic storage: heparan, dermatan, and chondroitin sulfates accumulate despite normal cognate lysosomal hydrolases; sialylated conjugates, cholesterol, sphingolipids, β-D-galactosylsphingosine/psychosine, and deacylated galactosylceramide abnormalities have also been reported.
Downstream injury: lysosomal/endosomal stress, altered lipid/GAG homeostasis, probable autophagic dysfunction, inflammation/fibrosis, and cell-type-specific injury produce dysostosis, myelin/neurologic injury, nephrotic disease, cytopenias, cardiac disease, and respiratory failure. The precise link between trafficking failure and GAG accumulation remains incompletely resolved. (cyske2024mucopolysaccharidosisplussyndromeis pages 2-3, pavlova2019thelysosomaldisease pages 7-10, cyske2024mucopolysaccharidosisplussyndromeis pages 3-5, cyske2024mucopolysaccharidosisplussyndromeis pages 8-10)

The 2019 primary-study abstract states that patient fibroblasts showed “vacuolation with disordered endosomal/lysosomal compartments”, while the p.Arg498Trp replacement was predicted to “de-stabilize VPS33A folding.” It further proposed that disease results from “diminished intracellular abundance of intact VPS33A.” (pavlova2019thelysosomaldisease pages 7-10)

Suggested GO terms include vesicle-mediated transport (GO:0016192), endosome organization (GO:0007032), lysosomal transport (GO:0007041), endosome-to-lysosome transport (GO:0008333), autophagosome–lysosome fusion, and regulation of macroautophagy (GO:0016241). Relevant compartments include lysosome (GO:0005764), late endosome (GO:0005770), autophagosome (GO:0005776), HOPS, and CORVET complexes.

Evidence boundaries

The strongest MPSPS-specific mechanistic evidence comes from structural modeling, biochemical assays, lipidomics, microscopy, and trafficking assays in patient fibroblasts. Broad transcriptomic, single-cell, spatial-transcriptomic, proteomic, epigenomic, CRISPR-screen, and multi-omics maps specific to MPSPS were not found. General MPS transcriptomic findings should not be automatically transferred to MPSPS.

7. Anatomical structures affected

Primary systems include:

Kidney: glomeruli, podocytes, tubulointerstitium; UBERON suggestions: kidney (UBERON:0002113), renal glomerulus (UBERON:0000074). Candidate CL terms: podocyte (CL:0000653) and renal tubular epithelial cell.
Heart and pulmonary vasculature: valves, septa, myocardium, pulmonary arteries; heart (UBERON:0000948).
Respiratory tract/lung: bronchi and lungs; lung (UBERON:0002048).
Skeleton/connective tissue: vertebral column, ribs, long bones, hands, joints, cartilage; bone tissue (UBERON:0002481) and articular cartilage.
CNS and peripheral nervous system: cerebral white matter, basal ganglia, cerebellum, peripheral nerves; brain (UBERON:0000955), cerebral white matter (UBERON:0002437). Candidate cells include oligodendrocytes (CL:0000128) and neurons, although direct MPSPS cell-specific proof is limited.
Liver/spleen and hematopoietic tissues: liver (UBERON:0002107), spleen (UBERON:0002106), bone marrow (UBERON:0002371); erythroid, megakaryocytic, and neutrophil lineages.

Subcellular localization centers on endosomes, lysosomes, autophagosomes, and HOPS/CORVET-associated membrane-fusion machinery. Findings are generally bilateral/systemic rather than lateralized. (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, cyske2024mucopolysaccharidosisplussyndromeis pages 8-10, cyske2024mucopolysaccharidosisplussyndromeis pages 5-7)

8. Temporal development

Prenatal findings can include ascites from approximately 11–24 weeks, congenital cardiac abnormalities/valve regurgitation, and increased nuchal, nasal, or prenasal thickness. Many affected newborns are delivered at term with normal Apgar scores, followed by an insidious but rapidly progressive infantile course. (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9, cyske2024mucopolysaccharidosisplussyndromeis pages 5-7)

For p.Arg498Trp disease, respiratory and systemic manifestations generally become evident in the first months, often at 2–6 months. Cardiac, renal, skeletal, hematologic, and neurodevelopmental disease then progresses, with death commonly at 10–20 months. Disease is lifelong and progressive; spontaneous remission is not established. p.Arg200Pro may produce a juvenile, slower phenotype, but evidence is too sparse to define stages reliably. (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)

The critical intervention window is likely prenatal or very early infancy because irreversible organ injury develops rapidly. This is a biologically plausible expert inference, not a demonstrated treatment-window statistic.

9. Inheritance and population

Inheritance is autosomal recessive. For two heterozygous parents, each pregnancy has the standard Mendelian probabilities of 25% affected, 50% carrier, and 25% unaffected/non-carrier, assuming no unusual reproductive mechanism. Penetrance of homozygous p.Arg498Trp appears high in reported families, but formal age-dependent penetrance estimates do not exist. Expressivity varies, especially between p.Arg498Trp and p.Arg200Pro. Anticipation is not expected and has not been observed. Germline mosaicism has not been reported but cannot be excluded as a general counseling possibility.

By September 2024, 41 patients had been described. Earlier data included 17 Yakut and two Turkish patients, while the foundational 16-patient Yakut series had an equal sex distribution—eight girls and eight boys—consistent with autosomal inheritance. There is a marked Yakut/Sakha founder concentration, with additional Turkish, Mediterranean, and Polish-origin cases. Global prevalence, annual incidence, carrier frequency, and sex ratio are unknown. (cyske2024mucopolysaccharidosisplussyndromeis pages 1-2, vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3, vasilev2020mucopolysaccharidosisplussyndrome pages 5-9)

10. Diagnostics

Recommended diagnostic workflow

Clinical suspicion: early MPS-like facies, dysostosis, hepatosplenomegaly, developmental delay, and recurrent respiratory disease combined with congenital heart disease, nephrotic syndrome/proteinuria, or cytopenias.
Urine/plasma biochemistry: quantify urinary total GAGs and characterize fractions by electrophoresis or LC-MS/MS. Elevated urinary heparan and dermatan sulfate—and sometimes chondroitin sulfate—plus exceptionally elevated plasma heparan sulfate support MPSPS. Sialooligosaccharides/sialic acid may also be increased. (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3, cyske2024mucopolysaccharidosisplussyndromeis pages 3-5)
Lysosomal enzyme panel: demonstrate normal activities of known GAG-degrading enzymes. This is a defining discriminator from classical MPS but does not independently establish MPSPS. (cyske2024mucopolysaccharidosisplussyndromeis pages 1-2, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)
Molecular confirmation: sequence VPS33A, initially by targeted testing for p.Arg498Trp in Yakut families or known familial variants. Otherwise use a lysosomal-storage/vesicular-trafficking panel or WES/WGS, with deletion/duplication analysis if sequencing is nondiagnostic.
Functional assessment when necessary: VPS33A abundance, HOPS/CORVET proteins, trafficking assays, or RNA/protein studies in fibroblasts may help resolve a VUS, but these are research-level tests.

WES identified the disorder historically and is appropriate when the phenotype is atypical. WGS may detect noncoding or structural lesions but has no demonstrated MPSPS-specific yield advantage. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line unless another diagnosis is suspected.

Organ evaluation

Recommended baseline studies, guided by reported manifestations, include CBC/differential, coagulation profile, immunoglobulins, creatinine/electrolytes, albumin, urinalysis and urine protein quantification; ECG and echocardiography; chest/airway and pulmonary assessment; skeletal survey; brain MRI and hearing/ophthalmologic evaluation; abdominal and renal ultrasonography. Renal biopsy is not required for genetic diagnosis but can characterize unexplained nephrotic disease.

Differential diagnosis

Classical MPS I, II, III, IV, VI, VII, IX/X; mucolipidoses; oligosaccharidoses/sialidosis; Niemann–Pick disease; Gaucher disease; Krabbe disease; and other HOPS/CORVET-subunit disorders—especially biallelic VPS16 disease—should be considered. The combination of MPS-like storage, normal lysosomal hydrolase activities, severe renal/hematologic disease, and biallelic VPS33A variants is distinguishing. (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, cyske2024mucopolysaccharidosisplussyndromeis pages 8-10, sofou2021bi‐allelicvps16variants pages 2-3)

Prenatal and screening applications

Targeted prenatal diagnosis through chorionic-villus or amniotic-fluid DNA is feasible when familial variants are known. A 2023 publication specifically reported prenatal diagnosis of MPSPS, although its full text was unavailable in the retrieved corpus. Preimplantation genetic testing for monogenic disease is conceptually available. There is no established universal newborn-screening program or validated DBS enzyme assay, because the defining defect is not a missing GAG hydrolase. Cascade testing and targeted carrier screening are most relevant in Yakut families and communities with known founder ancestry. (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11, lipinski2025mucopolysaccharidoses—whatcliniciansneed pages 12-13)

11. Outcome and prognosis

The p.Arg498Trp infantile phenotype has a very poor prognosis. In early series, most children died from cardiorespiratory failure at 10–20 months. No valid five- or ten-year survival curves, mortality rates per person-year, or treatment-stratified life-expectancy estimates exist. (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9, vasilev2020mucopolysaccharidosisplussyndrome pages 9-11)

Major morbidity includes developmental disability/regression, impaired mobility, skeletal deformity, recurrent infections, respiratory insufficiency, congenital/progressive cardiac disease, nephrotic syndrome/renal failure, and cytopenias. Recovery is not expected without correction of the molecular defect; supportive interventions can transiently stabilize complications. Likely adverse prognostic factors include p.Arg498Trp genotype, early cardiorespiratory involvement, pulmonary hypertension, nephrotic disease, and severe hematologic dysfunction, but no validated prognostic model or biomarker exists. Plasma/urine GAGs and proteinuria are candidate monitoring biomarkers, not validated surrogate endpoints.

12. Treatment

Current real-world management

There is no approved disease-modifying therapy. Care is multidisciplinary and supportive:

airway clearance/bronchial drainage, oxygen and ventilatory support where required;
prompt antibiotics for bacterial respiratory infections;
nutritional and developmental support;
ACE inhibitors or other standard cardiac/renal management when indicated;
red-cell or platelet transfusion for clinically significant cytopenia;
selected corrective/palliative cardiac surgery;
physical, occupational, speech, and respiratory therapy;
hearing, vision, renal, cardiac, pulmonary, and hematologic surveillance. (vasilev2020mucopolysaccharidosisplussyndrome pages 9-11)

Suggested NCIT intervention concepts include Supportive Care, Oxygen Therapy, Antibiotic Therapy, Blood Transfusion, Physical Therapy, Occupational Therapy, Speech Therapy, and Cardiac Surgical Procedure. Exact NCIT codes should be resolved against the current NCIt release rather than inferred.

A prolonged corticosteroid course was reported in a single child in 2022 with a claimed favorable clinical impact, but the full article was not retrievable here and this does not establish efficacy. Steroids should not be represented as standard therapy.

Experimental approaches

In patient-derived fibroblasts, the proteasome inhibitor bortezomib increased/rescued mutant protein and the glucosylceramide-synthase inhibitor eliglustat partially corrected abnormal lactosylceramide trafficking; the reported eliglustat concentration was 50 nM. These are in vitro observations only, not evidence of clinical safety or benefit in infants with MPSPS. Bortezomib’s toxicity and eliglustat’s indication-specific pharmacology make off-label use unsupported outside formal research. (pavlova2019thelysosomaldisease pages 7-10)

The primary paper’s abstract states: “Exposure of patient-derived fibroblasts to the clinically approved proteasome inhibitor, bortezomib, or inhibition of glucosylceramide synthesis with eliglustat, partially corrected the impaired lactosylceramide trafficking defect.” (pavlova2019thelysosomaldisease pages 7-10)

No MPSPS-specific enzyme-replacement therapy is logical at present because no single hydrolase is deficient. No clinical evidence supports hematopoietic stem-cell transplantation, AAV gene therapy, lentiviral therapy, CRISPR editing, ASOs, siRNA, or mRNA therapy. These remain conceptual strategies. The clinical-trial search found no relevant registered MPSPS interventional trial.

13. Prevention

Primary lifestyle or environmental prevention is not possible. Prevention is reproductive/genetic:

identify carriers through cascade testing and targeted founder-variant testing;
provide nondirective genetic counseling;
offer prenatal diagnosis or PGT-M when parental variants are known;
consider community-tailored carrier screening in high-risk Yakut/Sakha populations, subject to local consent, ethics, and health-system validation.

Secondary prevention consists of early molecular diagnosis and rapid surveillance for cardiac, renal, respiratory, and hematologic complications. Tertiary prevention includes vaccination according to routine schedules, prompt infection treatment, respiratory support, renal/cardiac management, transfusion support, rehabilitation, and avoidance of nephrotoxic or respiratory-depressant exposures when possible. No vaccine or prophylactic drug prevents MPSPS itself.

14. Other species and natural disease

No naturally occurring VPS33A-related MPSPS was identified in companion animals, livestock, or wildlife. Therefore, no veterinary breed association, VBO term, zoonotic potential, or cross-species transmission applies. VPS33A is evolutionarily conserved and HOPS/CORVET membrane-fusion biology is conserved across eukaryotes, but conservation alone is not evidence of natural animal disease.

15. Model organisms and experimental systems

MPSPS-specific systems

The principal disease model is patient-derived skin fibroblasts, which reproduce VPS33A depletion, reduction of HOPS/CORVET components, vacuolated/disordered endolysosomal compartments, abnormal lactosylceramide trafficking, and lipid/GAG abnormalities. HeLa cells expressing mutant VPS33A have been used to show proteasomal degradation and pharmacologic rescue. These systems are valuable for trafficking, protein-stability, lipidomic, and drug-screen studies but do not reproduce organ-level cardiopulmonary, renal, skeletal, or neurodevelopmental disease. (pavlova2019thelysosomaldisease pages 7-10)

Related—not equivalent—models

A biallelic VPS16 MPS-like disorder provides mechanistically related evidence: patient fibroblasts had reduced HOPS/CORVET subunits, defective transferrin uptake, and lysosome/autophagosome accumulation, rescued by VPS16 re-expression. Disrupted vps16 in zebrafish caused impaired development/myelination and lysosome/autophagosome accumulation, especially in glia. This supports HOPS/CORVET biology but is not a VPS33A MPSPS model. (sofou2021bi‐allelicvps16variants pages 2-3)

No well-validated VPS33A p.Arg498Trp knock-in mouse, rat, zebrafish, Drosophila, organoid, or iPSC model that recapitulates the full human syndrome was identified in the retrieved literature. Developing knock-in and patient-iPSC models is a high research priority.

Evidence appraisal and recent developments

The most important 2023–2024 development is expansion from 19 known patients in the 2020 review to 41 by 2024, together with recognition of p.Arg200Pro-associated juvenile disease, prenatal-diagnosis implementation, and a sharper mechanistic distinction between enzyme-deficient classical MPS and a trafficking-deficient MPS-like disorder. (cyske2024mucopolysaccharidosisplussyndromeis pages 1-2, vasilev2020mucopolysaccharidosisplussyndrome pages 1-3, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)

Authoritative expert interpretation in the 2024 review is that the nosology remains unsettled: GAG storage argues for inclusion among MPS, whereas normal lysosomal GAG-hydrolase activity and primary vesicle-trafficking dysfunction argue for a separate metabolic disease. For knowledge-base purposes, both relationships should be represented rather than forcing a single unqualified parent class. (cyske2024mucopolysaccharidosisplussyndromeis pages 1-2)

Key sources and publication details

Cyske Z, et al. “Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease?” International Journal of Molecular Sciences. Published September 2024. DOI/URL: https://doi.org/10.3390/ijms25179570. Focused current review; patient count, second variant, phenotype and mechanistic synthesis. (cyske2024mucopolysaccharidosisplussyndromeis pages 1-2, cyske2024mucopolysaccharidosisplussyndromeis pages 2-3)
Vasilev F, Sukhomyasova A, Otomo T. “Mucopolysaccharidosis-Plus Syndrome.” International Journal of Molecular Sciences. Published January 9, 2020. DOI/URL: https://doi.org/10.3390/ijms21020421. Foundational disease review and clinical summary. (vasilev2020mucopolysaccharidosisplussyndrome pages 5-9, vasilev2020mucopolysaccharidosisplussyndrome pages 1-3)
Pavlova EV, et al. “The lysosomal disease caused by mutant VPS33A.” Human Molecular Genetics. Published online April 2019; 28:2514–2530. DOI/URL: https://doi.org/10.1093/hmg/ddz077. Primary human-fibroblast, structural, lipidomic, and pharmacologic study. (pavlova2019thelysosomaldisease pages 7-10)
Sofou K, et al. “Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease.” EMBO Molecular Medicine. Published May 2021. DOI/URL: https://doi.org/10.15252/emmm.202013376. Related HOPS/CORVET disease and zebrafish evidence, not MPSPS itself. (sofou2021bi‐allelicvps16variants pages 2-3)

Important limitations: The literature is very small, reported cohorts overlap, phenotype frequencies are not consistently denominated, and several recent reports were unavailable in full text. PMID values were not exposed by the retrieved records and therefore are not fabricated here; DOI URLs are supplied instead. Database identifiers, ClinVar classifications, transcript accessions, allele frequencies, and ontology codes should undergo direct database validation before production release.

References

(vasilev2020mucopolysaccharidosisplussyndrome pages 5-9): Filipp Vasilev, Aitalina Sukhomyasova, and Takanobu Otomo. Mucopolysaccharidosis-plus syndrome. International Journal of Molecular Sciences, 21:421, Jan 2020. URL: https://doi.org/10.3390/ijms21020421, doi:10.3390/ijms21020421. This article has 47 citations.
(cyske2024mucopolysaccharidosisplussyndromeis pages 1-2): Zuzanna Cyske, Lidia Gaffke, Karolina Pierzynowska, and Grzegorz Węgrzyn. Mucopolysaccharidosis-plus syndrome: is this a type of mucopolysaccharidosis or a separate kind of metabolic disease? International Journal of Molecular Sciences, 25:9570, Sep 2024. URL: https://doi.org/10.3390/ijms25179570, doi:10.3390/ijms25179570. This article has 13 citations.
(cyske2024mucopolysaccharidosisplussyndromeis pages 2-3): Zuzanna Cyske, Lidia Gaffke, Karolina Pierzynowska, and Grzegorz Węgrzyn. Mucopolysaccharidosis-plus syndrome: is this a type of mucopolysaccharidosis or a separate kind of metabolic disease? International Journal of Molecular Sciences, 25:9570, Sep 2024. URL: https://doi.org/10.3390/ijms25179570, doi:10.3390/ijms25179570. This article has 13 citations.
(pavlova2019thelysosomaldisease pages 7-10): Elena V Pavlova, Aleksey Shatunov, Lena Wartosch, Alena I Moskvina, Lena E Nikolaeva, Nicholas A Bright, Karen L Tylee, Heather J Church, Andrea Ballabio, J Paul Luzio, and Timothy M Cox. The lysosomal disease caused by mutant vps33a. Human Molecular Genetics, 28:2514-2530, Apr 2019. URL: https://doi.org/10.1093/hmg/ddz077, doi:10.1093/hmg/ddz077. This article has 42 citations and is from a domain leading peer-reviewed journal.
(vasilev2020mucopolysaccharidosisplussyndrome pages 1-3): Filipp Vasilev, Aitalina Sukhomyasova, and Takanobu Otomo. Mucopolysaccharidosis-plus syndrome. International Journal of Molecular Sciences, 21:421, Jan 2020. URL: https://doi.org/10.3390/ijms21020421, doi:10.3390/ijms21020421. This article has 47 citations.
(vasilev2020mucopolysaccharidosisplussyndrome pages 9-11): Filipp Vasilev, Aitalina Sukhomyasova, and Takanobu Otomo. Mucopolysaccharidosis-plus syndrome. International Journal of Molecular Sciences, 21:421, Jan 2020. URL: https://doi.org/10.3390/ijms21020421, doi:10.3390/ijms21020421. This article has 47 citations.
(cyske2024mucopolysaccharidosisplussyndromeis pages 3-5): Zuzanna Cyske, Lidia Gaffke, Karolina Pierzynowska, and Grzegorz Węgrzyn. Mucopolysaccharidosis-plus syndrome: is this a type of mucopolysaccharidosis or a separate kind of metabolic disease? International Journal of Molecular Sciences, 25:9570, Sep 2024. URL: https://doi.org/10.3390/ijms25179570, doi:10.3390/ijms25179570. This article has 13 citations.
(cyske2024mucopolysaccharidosisplussyndromeis pages 5-7): Zuzanna Cyske, Lidia Gaffke, Karolina Pierzynowska, and Grzegorz Węgrzyn. Mucopolysaccharidosis-plus syndrome: is this a type of mucopolysaccharidosis or a separate kind of metabolic disease? International Journal of Molecular Sciences, 25:9570, Sep 2024. URL: https://doi.org/10.3390/ijms25179570, doi:10.3390/ijms25179570. This article has 13 citations.
(cyske2024mucopolysaccharidosisplussyndromeis pages 8-10): Zuzanna Cyske, Lidia Gaffke, Karolina Pierzynowska, and Grzegorz Węgrzyn. Mucopolysaccharidosis-plus syndrome: is this a type of mucopolysaccharidosis or a separate kind of metabolic disease? International Journal of Molecular Sciences, 25:9570, Sep 2024. URL: https://doi.org/10.3390/ijms25179570, doi:10.3390/ijms25179570. This article has 13 citations.
(sofou2021bi‐allelicvps16variants pages 2-3): Kalliopi Sofou, Kolja Meier, Leslie E Sanderson, Debora Kaminski, Laia Montoliu‐Gaya, Emma Samuelsson, Maria Blomqvist, Lotta Agholme, Jutta Gärtner, Chris Mühlhausen, Niklas Darin, Tahsin Stefan Barakat, Lars Schlotawa, Tjakko van Ham, Jorge Asin Cayuela, and Fredrik H Sterky. Bi‐allelic vps16 variants limit hops/corvet levels and cause a mucopolysaccharidosis‐like disease. EMBO Molecular Medicine, May 2021. URL: https://doi.org/10.15252/emmm.202013376, doi:10.15252/emmm.202013376. This article has 36 citations and is from a highest quality peer-reviewed journal.
(lipinski2025mucopolysaccharidoses—whatcliniciansneed pages 12-13): Patryk Lipiński, Agnieszka Różdżyńska-Świątkowska, Karolina Wiśniewska, Joanna Rusecka, Agnieszka Ługowska, Zbigniew Żuber, Aleksandra Jezela-Stanek, Zuzanna Cyske, Lidia Gaffke, Karolina Pierzynowska, Grzegorz Węgrzyn, and Anna Tylki-Szymańska. Mucopolysaccharidoses—what clinicians need to know: a clinical, biochemical, and molecular overview. Biomolecules, 15:1448, Oct 2025. URL: https://doi.org/10.3390/biom15101448, doi:10.3390/biom15101448. This article has 9 citations.

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Mucopolysaccharidosis-Plus Syndrome (MPSPS): Disease Characteristics Report

Executive summary

1. Disease information

Definition and classification

Names and identifiers

2. Etiology

3. Phenotypes

Craniofacial, skeletal, and growth manifestations

Neurologic and developmental manifestations

Respiratory and infectious manifestations

Cardiovascular manifestations

Renal manifestations

Hematologic and immune manifestations

Other manifestations and functional impact

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

Evidence boundaries

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended diagnostic workflow

Organ evaluation

Differential diagnosis

Prenatal and screening applications

11. Outcome and prognosis

12. Treatment

Current real-world management

Experimental approaches

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

MPSPS-specific systems

Related—not equivalent—models

Evidence appraisal and recent developments

Key sources and publication details

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