Gene Behind Hereditary Spastic Paraplegia Linked to Rare Plaque-Only Dementia

A sweeping international study of more than 700 patients has uncovered a striking and unexpected connection between a well-known hereditary movement disorder and an unusual form of early-onset dementia. Researchers analyzing families from Italy, Brazil, and Japan report that certain mutations in the SPG4/SPAST gene, the most common cause of autosomal dominant hereditary spastic paraplegia, appear to predispose carriers to a rare pathological subtype of dementia characterized by abundant amyloid plaques but a striking absence of the tau tangles that define classic Alzheimer’s disease. The findings, published in Annals of Clinical and Translational Neurology, substantially expand the known clinical spectrum of one of neurology’s most heterogeneous inherited conditions.

Hereditary spastic paraplegias, or HSPs, are a genetically diverse group of neurological disorders in which degeneration of the central nervous system’s corticospinal tracts produces progressive stiffness and weakness of the lower limbs. Clinicians distinguish pure forms, in which pyramidal signs dominate the picture, from complicated forms accompanied by additional neurological or systemic features such as cognitive impairment, thinning of the corpus callosum, epilepsy, peripheral neuropathy, or skeletal anomalies. More than 87 distinct genetic loci have been linked to the disease, and 73 causative genes have been cloned to date. Despite this heterogeneity, mutations in SPG4/SPAST, which encodes the spastin protein, remain the single most frequent cause of the autosomal dominant forms, accounting for a substantial share of all diagnosed families worldwide.

Spastin belongs to the AAA family of ATPases, enzymes that harness the energy of ATP hydrolysis to remodel cellular structures. Its best-characterized roles involve membrane trafficking and the regulation of microtubule reorganization, processes critical to the long axons of motor neurons. More than 300 different pathogenic variants in the gene have been described, and symptoms typically emerge between the second and fourth decades of life, though onset can range from early childhood to beyond age 70. Recognizing the gene’s dominance and the variability of its presentation, an international team set out to map the SPG4/SPAST mutation profile across three continents and to correlate specific variants with the clinical features they produce.

Between 2001 and 2025, the researchers recruited 726 patients diagnosed with HSP, including 628 familial and 98 sporadic cases, drawn from Italy, Brazil, and Japan. The cohort comprised 313 probands from families with pure or complicated disease, and clinical assessments were performed by movement disorder specialists using standardized instruments including the Spastic Paraplegia Rating Scale. Genetic analysis combined Sanger sequencing of all 17 coding exons of SPG4/SPAST with whole-exome or whole-genome sequencing in selected patients and multiplex ligation-dependent probe amplification to detect large genomic rearrangements that shorter-read methods can miss. Healthy control groups from all three countries provided comparison data.

The genetic results were revealing. Overall, 60.9 percent of patients carried no pathogenic SPAST variant, underscoring the extensive genetic heterogeneity of HSP. Among the rest, sequencing identified 52 different heterozygous mutations in 263 autosomal dominant and 21 sporadic cases. Missense mutations were the largest class at 39.2 percent, followed by splice-site mutations, small deletions, nonsense mutations, insertions, and large rearrangements detected by MLPA, which accounted for 15.7 percent. Four novel variants were identified, absent from population databases and from nearly 400 controls, and all co-segregated with disease in their families. Notably, patients carrying missense mutations experienced an earlier median onset, at 36 years, compared with 42 years for carriers of other mutational classes.

Two of the novel variants carried particular weight. A missense change designated c.1382T>G, producing a p.Leu461Arg substitution within the protein’s AAA domain, was found in 18 unrelated patients from seven Italian families who all shared a common haplotype, pointing to a founder effect. Meanwhile, a small deletion of exon 13 appeared in ten unrelated patients from one Brazilian and two Japanese pedigrees, though haplotype analysis suggested these represented independent mutational events. Multivariate regression confirmed that SPG4 mutation status was independently predicted by later age at onset, a predominantly pure phenotype, lower disability stage, and a familial inheritance pattern, consistent with the gene’s established profile.

The most dramatic discovery emerged from the complicated cases. Among 72 SPG4 patients with complicated disease, foot deformities and cognitive deficits were the leading complications. Remarkably, all 18 affected individuals from the seven Italian families carrying the novel p.Leu461Arg variant had developed features compatible with early-onset dementia, and the same association held in the Brazilian and Japanese families carrying the exon 13 deletion. In every family member diagnosed with early-onset dementia, cerebrospinal fluid analysis showed a decreased Aβ42/Aβ40 ratio, consistent with cerebral amyloid plaque accumulation, while p-tau181 levels remained normal or low, indicating an absence of significant tau pathology or neurofibrillary tangle formation.

Autopsy studies on four patients cemented the pathological picture. Brain examination of a 64-year-old Italian patient carrying the novel variant revealed severe atrophy of the frontal, temporal, and parietal lobes, the hippocampus, amygdala, and entorhinal cortex, alongside a spinal cord thinner than normal with degeneration of the corticospinal tracts. Microscopically, the cortex was laden with senile plaques with congophilic cores and neuritic pathology, yet cotton wool plaques, neurofibrillary tangles, and Lewy bodies were entirely absent, and no abnormal α-synuclein or TDP-43 aggregates were detected. The case was classified as plaque-only dementia, scoring A3-B0-C3 on the National Institute on Aging–Alzheimer’s Association ABC system, with frequent neuritic plaque density by CERAD criteria. Comparable findings were confirmed in the other autopsied patients from Brazil and Japan.

Neuroimaging reinforced the clinical observations. Brain MRI in SPG4 patients with cognitive issues showed cerebral atrophy, particularly of the temporal lobes, while patients with intellectual disability displayed a thin corpus callosum without cerebellar involvement or white matter abnormalities. Amyloid PET imaging with 18F-flutemetamol in patients with early-onset dementia revealed cortical tracer binding consistent with substantial β-amyloid deposition, with Centiloid scores exceeding 50, even in individuals lacking overt neuropathological confirmation. Intriguingly, all autopsy-confirmed cases were homozygous for the APOE ε4 allele, a genotype known to foster a biological environment permissive to amyloid-rich, plaque-dominated dementia, and among all cognitively impaired patients, two-thirds were ε4 homozygotes.

The authors propose that these SPG4 variants may define a new disease manifestation: a form of hereditary spastic paraplegia complicated by an atypical, plaque-only pathological subtype of dementia. Because whole-exome and whole-genome sequencing excluded mutations in other dementia-related genes, including those classically associated with Alzheimer’s disease, the mutated spastin protein itself appears to be the likely culprit, though the precise mechanism linking microtubule dysfunction to amyloid accumulation remains unknown. The study also found that 21 percent of ostensibly sporadic cases carried SPG4 mutations, a rate higher than in small families with two affected members, suggesting that the boundary between familial and sporadic HSP is blurrier than previously assumed, with de novo mutations, incomplete penetrance, and misclassified family histories all contributing. The researchers caution that larger haplotype studies and archival research are needed to confirm the founder hypothesis, but the work opens a compelling new frontier in understanding how a single gene can shape both motor degeneration and dementia vulnerability.

Subject of Research: SPG4/SPAST mutations and their association with hereditary spastic paraplegia and plaque-only dementia

Article Title: SPG4 and Dementia: Expanding the Clinical Spectrum

Article References: SPG4 and Dementia: Expanding the Clinical Spectrum. (n.d.). https://doi.org/10.1002/acn3.70371

Image Credits: AI Generated

DOI: 10.1002/acn3.70371

Keywords: hereditary spastic paraplegia, SPG4, SPAST, spastin, dementia, amyloid plaques, plaque-only dementia, APOE ε4, genetics, neurodegeneration, amyloid PET, founder effect