| SPG designation / subtype | Gene | Protein | Typical inheritance | Key complex HSP clinical features | OMIM / phenotype note |
|---|---|---|---|---|---|
| SPG11 | **SPG11** | Spatacsin | AR | Early-onset progressive spastic paraplegia, thin corpus callosum, cognitive decline/intellectual disability, peripheral neuropathy, dysarthria, bladder dysfunction, ataxia/parkinsonism in some patients (pqac-00000010, pqac-00000012, pqac-00000014, pqac-00000018) | Phenotype OMIM not established here from retrieved evidence; gene-disease association strongly supported (pqac-00000000, pqac-00000010) |
| SPG15 | **ZFYVE26** | Spastizin | AR | Early-childhood developmental delay, adolescent-onset progressive lower-limb spasticity, thin corpus callosum, “ears of the lynx” MRI sign, ataxia, dysarthria, cognitive decline, urinary dysfunction, peripheral neuropathy, dystonia/parkinsonism subset (pqac-00000004, pqac-00000015, pqac-00000017, pqac-00000018) | Phenotype OMIM not established here from retrieved evidence; gene-disease association supported (pqac-00000000) |
| SPG7 | **SPG7** | Paraplegin | AR (occasionally AD/digenic reported in broader literature, not established here) | Adult-onset or variable-onset spastic paraplegia, frequent cerebellar ataxia, optic/extraocular movement abnormalities, seizures or movement disorder features in some patients (pqac-00000008, pqac-00000020) | Gene-disease association supported in Open Targets (pqac-00000000) |
| SPG20 | **SPART** | Spartin | AR | Complex HSP/Troyer syndrome phenotype with spastic paraplegia plus distal amyotrophy, dysarthria, developmental/cognitive involvement; lipid droplet turnover implicated (pqac-00000010) | Gene-disease association supported (pqac-00000000) |
| SPG21 | **SPG21** | Maspardin | AR | Complex spastic paraplegia with cognitive impairment, extrapyramidal features, thin corpus callosum reported in broader HSP spectrum; intracellular trafficking defect (pqac-00000010, pqac-00000012) | Gene-disease association supported (pqac-00000000) |
| SPG35 | **FA2H** | Fatty acid 2-hydroxylase | AR | Complex HSP with spasticity, leukodystrophy/myelin involvement, dystonia/ataxia and cognitive features in some cases; myelin lipid synthesis defect (pqac-00000010, pqac-00000012) | Gene-disease association supported (pqac-00000000) |
| SPG39 | **PNPLA6** | Neuropathy target esterase / patatin-like phospholipase domain-containing protein 6 | AR | Complex HSP with spastic paraplegia plus ataxia, neuropathy, retinal/visual and endocrine/cognitive features across PNPLA6 spectrum; lipid regulation defect (pqac-00000010, pqac-00000020) | Gene-disease association supported (pqac-00000000) |
| SPG47 | **AP4B1** | Adaptor related protein complex 4 subunit beta 1 | AR | Childhood-onset AP-4 deficiency syndrome with spastic paraplegia, global developmental delay, intellectual disability, epilepsy; preclinical gene replacement therapy in development (pqac-00000023, pqac-00000057) | Phenotype OMIM not established here from retrieved evidence |
| SPG50 | **AP4M1** | Adaptor related protein complex 4 subunit mu 1 | AR | Childhood-onset complex HSP with progressive spastic paraplegia, developmental delay, intellectual disability, secondary microcephaly, epilepsy; target of first individualized AAV therapy (pqac-00000055, pqac-00000056) | Phenotype OMIM not established here from retrieved evidence |
| SPG51 | **AP4E1** | Adaptor related protein complex 4 subunit epsilon 1 | AR | AP-4 deficiency syndrome with severe developmental delay, intellectual disability, early hypotonia evolving to spastic paraplegia, epilepsy (pqac-00000023, pqac-00000057) | Phenotype OMIM not established here from retrieved evidence |
| SPG52 | **AP4S1** | Adaptor related protein complex 4 subunit sigma 1 | AR | AP-4 deficiency syndrome with developmental delay, severe intellectual disability, childhood-onset complex spastic paraplegia, epilepsy (pqac-00000023, pqac-00000057) | Phenotype OMIM not established here from retrieved evidence |
| SPG1 | **L1CAM** | L1 cell adhesion molecule | X-linked | Complex spastic paraplegia with intellectual disability, hydrocephalus/corpus callosum abnormalities and other L1 syndrome manifestations; axon guidance/myelination effects (pqac-00000012, pqac-00000023) | Gene-disease association supported (pqac-00000000) |
| SPG2 | **PLP1** | Proteolipid protein 1 | X-linked | Spastic paraplegia with dysmyelination spectrum, variable cognitive/visual features; abnormal myelin maintenance central to disease (pqac-00000010, pqac-00000023) | Gene-disease association supported (pqac-00000000) |
| SPG30 / KIF1A-associated HSP | **KIF1A** | Kinesin family member 1A | AD or AR depending on variant/context | Pediatric complex HSP with spastic paraplegia, developmental delay/intellectual disability, cerebellar signs, optic atrophy/neuropathy in some patients; common pediatric complex HSP gene (pqac-00000000, pqac-00000016) | Gene-disease association supported (pqac-00000000) |
| SPG18 | **ERLIN2** | ER lipid raft associated 2 | AR | Early-onset complicated HSP with spasticity, intellectual disability, joint contractures or seizures reported in spectrum; ER-associated pathway defect (pqac-00000000) | Gene-disease association supported (pqac-00000000) |
| SPG26 | **B4GALNT1** | Beta-1,4-N-acetyl-galactosaminyltransferase 1 | AR | Complex HSP with spasticity, cognitive impairment, cerebellar signs/neuropathy in reported spectrum; ganglioside biosynthesis defect (pqac-00000000) | Gene-disease association supported (pqac-00000000) |
| SPG5A | **CYP7B1** | Cytochrome P450 7B1 | AR | Often pure HSP, but complicated cases can include ataxia/neuropathy; notable because disease-specific biochemical biomarkers (oxysterols) exist (pqac-00000012, pqac-00000030, pqac-00000050) | Gene-disease association supported (pqac-00000000) |
| SPG42 | **SLC33A1** | Acetyl-CoA transporter 1 | AD | Spastic paraplegia with variable complex manifestations; listed among established HSP genes (pqac-00000011, pqac-00000013) | Open Targets association noted for SPG4 locus-related data; phenotype details limited here (pqac-00000000) |
| SPG31 | **REEP1** | Receptor expression-enhancing protein 1 | AD | Usually pure HSP, but complicated phenotypes with neuropathy can occur; ER shaping defect shared with major HSP mechanisms (pqac-00000008, pqac-00000011, pqac-00000025) | Established HSP gene; phenotype details from retrieved evidence are limited |
| SPG3A | **ATL1** | Atlastin-1 | AD | Usually early-onset pure HSP, but part of core mechanistic ER-network genes and occasional complex presentations reported (pqac-00000008, pqac-00000012, pqac-00000025) | Gene-disease association supported (pqac-00000000) |
| SPG4 | **SPAST** | Spastin | AD | Most common AD HSP; generally pure but complex phenotypes exist, especially pediatric or severe cases; microtubule-severing/axonal transport defect (pqac-00000001, pqac-00000012, pqac-00000029) | Gene-disease association supported (pqac-00000000) |
| Novel AR HSP (no SPG number specified here) | **AMFR** | Autocrine motility factor receptor / gp78 | AR | Pure or complex HSP with developmental delay, mild intellectual disability, progressive spasticity; lipid droplet accumulation and ER morphology defects in preclinical models (pqac-00000046) | Newly described AR-HSP gene in retrieved evidence; OMIM phenotype not established here |
| Complex HSP spectrum | **ALDH18A1** | Delta-1-pyrroline-5-carboxylate synthase | AD or AR | Spastic paraplegia with variable developmental/cognitive and neuropathy features across inheritance contexts (pqac-00000000) | Gene-disease association supported (pqac-00000000) |
| Complex HSP spectrum | **ATP13A2** | Lysosomal P5-type ATPase | AR | Complex HSP with parkinsonism/cognitive features and lysosomal-autophagic dysfunction in some patients (pqac-00000000, pqac-00000023) | Gene-disease association supported (pqac-00000000) |


*Table: This table summarizes the major genes implicated in complex hereditary spastic paraplegia, highlighting inheritance, encoded proteins, and distinguishing clinical features. It is useful for comparing the most important SPG subtypes and related complex HSP genes across the heterogeneous disease spectrum.*