May 2026 Research Update

This month, the clearest progress came from larger human studies showing that hereditary spastic paraplegia (HSP) is often genetically explainable, and that the specific gene change can help frame what the condition may look like over time. In SPG4 (SPAST), researchers reported two main progression patterns, with one linked to earlier and more severe disability and another linked to a later but accelerating course. In a separate national cohort, many different genes were involved, but a handful explained a large share of diagnosed cases, while some people still had no clear genetic answer. [1] [2]

In the SPG4 study, people with de novo (new) SPAST missense variants were more likely to fall into a rapidly progressive, more severe subgroup, which included early developmental delays and earlier loss of walking. People with inherited truncating variants were more common in a moderate subgroup, where progression was slower at first but could speed up later. The study also measured plasma neurofilament light chain (a blood marker linked to nerve cell injury) and found it was higher in both SPG4 subgroups, most noticeably in severe early disease. [1]

In the Iranian cohort of 103 unrelated people evaluated for HSP, whole-exome sequencing identified pathogenic or likely pathogenic variants, or variants of uncertain significance, in most probands, with a high overall rate of genetic solutions. SPG11, SPG4, SPG7, and SPG15 together accounted for about 40% of the group, while variants were spread across 37 genes in total. Twenty-two people still did not receive a genetic diagnosis, which points to additional causes that may not yet be captured by current testing approaches. [2]

For patients and families, these studies add practical clarity about what genetic results can mean. They support that many people with suspected HSP can receive a genetic explanation, but not everyone will, even with advanced testing. For SPG4 specifically, the reported link between certain SPAST variant types and different progression patterns may matter more in the future, such as for designing research studies or for discussing expected ranges of symptoms, but it is not a standalone prediction for any one person. Blood neurofilament results are also an early step toward tracking disease activity in SPG4, but this marker is not yet presented here as something that guides day-to-day decisions for individuals. [1] [2]

This month also included early-stage laboratory studies that map out where cell problems may start in certain HSP subtypes, and which parts of those pathways might be adjustable with drugs. These studies do not show patient benefit, but they help explain the disease process more clearly and narrow down targets that researchers can test next. One focused on how a key cell recycling protein is moved inside neurons in AP-4-related HSP, and another screened approved compounds to shift a mitochondrial process in SPG7 patient cells. [3] [4]

In a human neuron model of AP-4 deficiency, a large CRISPR loss-of-function screen identified genes that changed where ATG9A ended up inside the cell. Knockdown of ANPEP and NPM1 increased ATG9A availability outside the trans-Golgi network, which is one sign that these genes help control ATG9A trafficking. For patients, the main point is that AP-4-related HSP is being linked to specific, testable steps in how neurons handle internal transport and recycling. [3]

In SPG7 patient-derived fibroblasts, researchers screened 2000 FDA/EMA-approved compounds for effects on mitochondrial permeability transition pore (mPTP) flickering, a type of brief pore opening that can be part of normal mitochondrial behavior. Thirteen compounds increased flickering while preserving cell and mitochondrial integrity in this assay, and berberine was the most consistent modulator across both SPG7 and control cells, shifting flickering toward smaller events. This is a proof-of-concept that mitochondrial behaviors measurable in patient cells can be changed pharmacologically, but it does not yet show symptom effects in people with SPG7. [4]

For patients, this group of studies mainly matters as research groundwork rather than something that changes care now. It helps clarify that different HSP genes can lead to different cellular problems, and that scientists are beginning to identify points in those pathways that might be targeted by future treatments. What remains uncertain is whether changing ATG9A trafficking in neurons or mPTP flickering in fibroblasts will translate into meaningful benefits for walking, stiffness, fatigue, or other daily symptoms. These results are best viewed as early signals that guide what should be tested next in more disease-relevant models and, later, in human studies. [3] [4]

This month, several single-patient reports and small family series added detail about how specific genetic forms of HSP can look in real life, including symptoms outside the legs and changes seen on imaging or lab tests. The shared pattern is that careful genetic and functional work can strengthen or refine a diagnosis, and that the same gene can show a wider range of features than some families may expect. Because these are individual reports, they are best understood as examples that expand the known range rather than predictions of what will happen to others. [5] [6] [7]

For SPG56 (CYP2U1), one report used functional testing to show that two missense variants led to loss of enzyme activity and unstable protein, and this evidence supported reclassifying one variant (Arg186His) as pathogenic. This matters because it shows how a genetic change can move from "uncertain" to more clearly disease-causing when additional lab data are added. The paper also discussed possible supportive approaches, but it did not test treatments in a way that shows effectiveness. [5]

For SPG11, a multidisciplinary case report described macular dystrophy (Kjellin syndrome) identified on detailed eye imaging even though vision was largely preserved at the time of evaluation. The main message is that retina changes can be present with minimal symptoms, and specialized eye imaging may detect changes that are not obvious from day-to-day vision. The report does not establish how common this is across SPG11, but it documents what it can look like in an adult patient. [6]

Several reports focused on rarer genes and broader nervous system involvement. An autopsy report of a man with homozygous KIF1A-related disorder (HSP-30B) and coexisting SCA31 found FTLD-TDP-43 with motor neuron disease pathology late in life, raising the possibility of overlap with the FTLD-ALS spectrum through a TDP-43-related pathway in this individual. Other small family reports added genetic evidence for SPG83 due to biallelic HPDL variants, including a newly reported missense change, and described a Mexican family with the same disorder. [7] [8] [9]

Not every genetic diagnosis that overlaps with HSP results in the same symptom pattern. A report of two related individuals with a homozygous PNPLA6 variant presented as isolated cerebellar ataxia on brain MRI without the multisystem features sometimes linked to PNPLA6. A separate pediatric report of SPG84 (PI4KA) described compound heterozygous variants of uncertain significance along with reduced PI4KA expression and lower plasma PI4P/PI levels, offering possible supportive functional evidence while still leaving uncertainty about the exact role of the variants. [10] [11]

For patients and caregivers, these reports mainly add understanding of the range of symptoms and test findings that can come with particular genes, rather than changing what is known to work for treatment. They may matter now when a family is trying to make sense of a genetic result, especially when a variant is uncertain and functional testing can help clarify whether it is likely disease-causing. They also highlight that some HSP-related conditions can involve vision, balance and coordination, swallowing, bladder symptoms, or cognitive changes in some people, depending on the gene and the individual. What remains uncertain is how often these features happen across all people with the same genetic diagnosis, since case reports cannot answer frequency or risk. [5] [6] [7] [8] [9] [10] [11]