This is a mechanism module, not a specific disease. It sits downstream of, and specializes, the lysosomal_substrate_accumulation module: the hub node "Lysosomal GAG Accumulation" is the GAG-specific instance of "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation". Disorder entries reference individual nodes via conforms_to (e.g., "mps_gag_storage#Heparan Sulfate-Driven Neuroinflammation" for a neuronopathic type, or "mps_gag_storage#Chondrocyte Keratan Sulfate Storage and Impaired Endochondral Ossification" for Morquio). The coherence rule the module encodes is that an MPS type switches whole arms ON or OFF according to its stored-GAG profile but never assigns contradictory modifiers within an arm; this is why lumping all MPS into one graph is incoherent (the central-neurodegeneration node would have to be both present and absent) and why splitting per gene is redundant (MPS IIIA-D, or IVA-B, share an identical arm set). Evidence is drawn from MPS reviews and primary studies documenting the GAG-specific arms; evidence_source is OTHER for cross-MPS reviews, MODEL_ORGANISM for the MPS III mouse-model studies, and IN_VITRO for the cultured neuron synaptic study. Key conformance targets: the hub "Lysosomal GAG Accumulation" and the three arm-entry nodes named above.
Lysosomal GAG Accumulation
central effector
Deficiency of a specific GAG-degrading lysosomal enzyme leaves a partially degraded glycosaminoglycan undegraded, so it accumulates within the lysosome. This is the GAG-specific instance of the central lysosomal-storage effector, and it is the branch point of the module: the chemical identity of the stored GAG (heparan sulfate, dermatan sulfate, or keratan sulfate) determines which cell types store substrate and therefore which downstream arm is engaged. Undegraded GAG is not inert — it acts as a danger signal that engages the Toll-like receptor 4 innate-immune pathway, providing the molecular link from storage to the inflammatory and neuroinflammatory effectors of the arms below.
Downstream
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Heparan Sulfate-Driven Neuroinflammation
When heparan sulfate is the stored GAG (MPS I, II, III, VII), it accumulates in neurons and microglia and engages the neuronopathic arm.
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Dermatan Sulfate-Driven Connective-Tissue and ECM Storage
When dermatan sulfate is the stored GAG (MPS I, II, VI, VII), it accumulates in connective-tissue fibroblasts and ECM and engages the somatic arm.
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Chondrocyte Keratan Sulfate Storage and Impaired Endochondral Ossification
When keratan sulfate is the stored GAG (MPS IV), it accumulates in chondrocytes and engages the skeletal-dysplasia arm.
Heparan Sulfate-Driven Neuroinflammation
effector
Undegraded heparan sulfate accumulates in neurons and microglia and triggers a neuroinflammatory cascade. This arm is engaged only by heparan sulfate-storing types; it is the entry node of the neuronopathic arm and the mechanistic reason heparan sulfate accumulation, uniquely among the GAGs, produces central nervous system disease.
Downstream
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Synaptic Dysfunction and Secondary Storage
Neuroinflammation and accumulating heparan-sulfate oligosaccharides disrupt synaptic components and drive secondary metabolite storage.
Synaptic Dysfunction and Secondary Storage
amplifier
Heparan-sulfate oligosaccharides and the neuroinflammatory milieu disrupt synaptic vesicle proteins and synaptic signalling, and drive secondary accumulation of gangliosides (GM2/GM3) in neurons. This amplifies primary storage into functional neuronal failure.
Downstream
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Progressive Central Neurodegeneration
Sustained neuroinflammation and synaptic failure culminate in progressive neuronal loss.
Progressive Central Neurodegeneration
consequence
Sustained heparan-sulfate storage, neuroinflammation and synaptic failure produce progressive neuronal loss, presenting clinically as developmental regression, intellectual disability and dementia. This is the terminal node of the neuronopathic arm and is absent in types that do not store heparan sulfate (MPS IV, VI, IX).
Dermatan Sulfate-Driven Connective-Tissue and ECM Storage
effector
Undegraded dermatan sulfate accumulates in connective-tissue fibroblasts and the extracellular matrix of bone, heart valve, cornea and viscera. This is the entry node of the somatic arm and produces the connective-tissue phenotype shared by the somatic MPS types: dysostosis multiplex, valvular thickening, corneal clouding and hepatosplenomegaly. It is engaged by dermatan sulfate-storing types and does not by itself produce central neurodegeneration.
Used by disorders
Sly syndrome
as Dermatan sulfate-driven connective-tissue storage
Downstream
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Multisystem Somatic Disease
Progressive connective-tissue and ECM storage culminates in multi-organ and airway disease.
Multisystem Somatic Disease
consequence
Accumulated connective-tissue and ECM storage produces progressive multisystem somatic disease: musculoskeletal abnormalities, cardiac valve and respiratory/airway disease, and organomegaly. This is the terminal node of the somatic arm.
Chondrocyte Keratan Sulfate Storage and Impaired Endochondral Ossification
effector
Undegraded keratan sulfate (with chondroitin-6-sulfate) accumulates preferentially in chondrocytes and cartilage extracellular matrix, impairing endochondral ossification and chondrogenesis. This is the entry node of the skeletal-dysplasia arm, engaged specifically by keratan sulfate-storing types (MPS IV / Morquio). Critically, this arm produces a different storage cell and a different outlet from the somatic arm and carries no primary neurodegeneration.
Used by disorders
Morquio syndrome
as Cartilage matrix dysfunction and impaired endochondral ossification
Downstream
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Skeletal Dysplasia and Craniovertebral Instability
Impaired endochondral ossification produces a generalized skeletal dysplasia with mechanical craniovertebral instability.
Skeletal Dysplasia and Craniovertebral Instability
consequence
Impaired endochondral ossification produces a generalized skeletal dysplasia (disproportionate short stature, kyphoscoliosis, pectus carinatum, genu valgum, joint laxity) and odontoid hypoplasia with C1-C2 craniovertebral instability. Resulting cervical cord compression is mechanical and secondary, not a primary storage neurodegeneration — distinguishing this arm's neurological signs from the neuronopathic arm. This is the terminal node of the skeletal-dysplasia arm.