| Subtype (SPG#/Gene) | Inheritance (AD/AR/X/mt) | Typical phenotype (pure vs complicated; onset) | Mechanistic theme | Notes/statistics | Key citations |
|---|---|---|---|---|---|
| HSP disease group | AD, AR, X-linked, mitochondrial | Pure forms: progressive lower-limb spasticity/weakness, urinary symptoms, mild dorsal column involvement; complicated forms add ataxia, neuropathy, cognitive impairment, seizures, optic atrophy, extrapyramidal signs; onset ranges from infancy to adulthood | Convergent pathways include axonal transport defects, ER membrane shaping/trafficking, autophagy/lysosome and AP-4 trafficking defects, mitochondrial dysfunction, abnormal myelination, endosomal dysfunction, oxidative stress, and lipid metabolism abnormalities | `>80` loci/genes reported; another review notes `>90` genes/loci; prevalence estimates in recent reviews span `2–6/100,000` and `3–10/100,000` | (pqac-00000000, pqac-00000002, pqac-00000004, pqac-00000007, pqac-00000034) |
| SPG4 / SPAST | AD | Usually pure HSP with slowly progressive lower-limb spasticity/weakness; non-motor features can occur; typical onset from childhood to adulthood | Microtubule severing and axonal transport/cytoskeletal maintenance | Most prevalent AD-HSP; reported as `~40–45%` of familial cases and `~40%` of autosomal dominant cases; most common genotype in several cohorts | (pqac-00000000, pqac-00000002, pqac-00000004, pqac-00000019, pqac-00000034) |
| SPG3A / ATL1 | AD; rare AR forms reported | Usually pure childhood-onset HSP with slow progression and many patients remaining ambulatory; severe very-early-onset complex cases can include axial hypotonia, spastic quadriplegia, dystonia, seizures, and intellectual disability | ER membrane shaping/fusion and axonal network organization | Second most common AD form; one review estimates `~7%` of AD-HSP; 2024 report supports possible autosomal recessive SPG3A in exceptional severe cases | (pqac-00000000, pqac-00000009, pqac-00000034) |
| SPG11 / SPG11 | AR | Commonly complicated HSP; childhood/juvenile onset common; may include cognitive dysfunction, peripheral neuropathy, parkinsonism, dystonia, and seizures | Autophagy/lysosome and endosomal membrane trafficking | Reported as `~18%` of HSP globally in one 2024 review; in HSP with movement disorders, SPG11 accounted for `23.8%`; compared with SPG7 it was more strongly associated with parkinsonism, dystonia, peripheral neuropathy, and cognitive dysfunction | (pqac-00000000, pqac-00000003, pqac-00000034) |
| SPG7 / SPG7 | AR | Often complicated HSP with adult onset; can feature ataxia, extraocular movement abnormalities, seizures, and movement disorders | Mitochondrial dysfunction | In HSP with movement disorders, SPG7 was the most frequent genotype at `31.2%`; compared with SPG11 it was more often adult-onset (`82.9%` vs `8.5%`) and more associated with ataxia and extraocular movement disturbance | (pqac-00000002, pqac-00000003, pqac-00000034) |
| SPG30 / KIF1A | AD and AR reported | Spectrum ranges from mild adult-onset spastic paraplegia to very severe congenital/early-onset complicated disease with developmental delay, neuropathy, optic atrophy, epilepsy, and progressive motor decline | Kinesin-mediated anterograde axonal transport | Motor-domain missense variants are linked to more severe early phenotypes; adult-onset spastic paraplegia can be less severe; KIF1A-associated disease overlaps HSP and broader KAND spectrum | (pqac-00000000) |
| AP-4 deficiency HSPs (e.g., SPG47 / AP4B1; SPG50 / AP4M1) | AR | Typically early-onset complicated HSP/neurodevelopmental disorder with severe motor impairment | AP-4 complex-dependent vesicle trafficking, autophagy/lysosome pathway | Emerging gene-replacement trials are active for AP4B1-related SPG47 and AP4M1-related SPG50, supporting AP-4 trafficking as a translational target | (pqac-00000001, pqac-00000032, pqac-00000033) |
| DDHD2 / SPG54 | AR | Complicated HSP with intellectual disability, speech/gait impairment, hypertonia, and inability to walk in severe cases | Lipid metabolism | 2024 family study identified homozygous nonsense variant `c.985C>T (p.Arg329Ter)` predicted to cause loss of function/nonsense-mediated decay | (pqac-00000012) |
| AP4B1 / SPG47 | AR | Complicated HSP with developmental and motor impairment | AP-4 trafficking, autophagy/lysosome pathway | 2024 family study identified homozygous frameshift `c.965-967delACTinsC p.(Tyr322SerfsTer14)`; current gene-therapy program BFB-101 targets AP4B1 deficiency | (pqac-00000012, pqac-00000033) |
| SPG5 / CYP7B1-associated HSP | AR | HSP with biochemical signature; can be pure or complicated | Lipid/cholesterol metabolism | SPG5 is the clearest subtype with disease-specific fluid biomarker evidence: elevated oxysterols; an interventional trial tested evolocumab with change in `27-hydroxycholesterol` as primary outcome | (pqac-00000002, pqac-00000005, pqac-00000021, pqac-00000031) |


*Table: This table summarizes the principal hereditary spastic paraplegia subtypes highlighted in the retrieved evidence, linking inheritance and phenotype with convergent pathogenic mechanisms. It is useful as a compact map of which genes dominate the current HSP landscape and which pathways are most relevant for diagnosis and therapeutic development.*