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)

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:

1. 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)
2. 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

1. Upstream genetic lesion: biallelic VPS33A missense variant.
2. Protein-level defect: p.Arg498Trp destabilizes VPS33A folding and promotes proteasomal degradation.
3. Complex instability: reduced VPS33A lowers HOPS/CORVET components such as VPS18 and VPS41.
4. Cellular trafficking dysfunction: late endosomal/lysosomal compartment organization and lipid cargo trafficking become abnormal; patient fibroblasts show vacuolation and defective lactosylceramide trafficking.
5. 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.
6. 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

1. Clinical suspicion: early MPS-like facies, dysostosis, hepatosplenomegaly, developmental delay, and recurrent respiratory disease combined with congenital heart disease, nephrotic syndrome/proteinuria, or cytopenias.
2. 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)
3. 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)
4. 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.
5. 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

1. 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)
2. 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)
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)
4. 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

1. (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.

2. (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.

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