PLS and Hereditary Spastic Paraplegia — The Genetic Boundary
There is a diagnostic boundary problem at the edge of PLS: some patients who present with progressive spastic paraparesis, upper motor neuron signs, and no lower motor neuron findings — a picture entirely consistent with adult-onset PLS — turn out, on genetic testing, to carry mutations in hereditary spastic paraplegia genes. When that happens, the diagnosis changes. The patient does not have PLS; they have late-onset HSP. Understanding where this boundary lies, and why it matters, is one of the strongest arguments for genetic testing in apparent PLS.
The clinical overlap problem
Primary lateral sclerosis and hereditary spastic paraplegia (HSP) are two distinct disease categories that share a clinical core. Both cause progressive spastic paraparesis — weakness and stiffness of the legs driven by upper motor neuron dysfunction. Both produce hyperreflexia, extensor plantar responses, and slow, effortful gait. In many presentations, the neurological examination looks the same.
The classical teaching is that they can be distinguished clinically: PLS tends to affect arms, speech, and swallowing as it progresses; HSP is often "pure" (limited to the legs) or "complicated" (spastic paraparesis plus cerebellar ataxia, thin corpus callosum, or peripheral neuropathy, depending on the HSP subtype). PLS is typically sporadic with adult onset; HSP runs in families and can present at any age.
In practice, these distinctions are often unreliable in individual patients. Late-onset HSP can appear sporadic if family members have never been evaluated or if the patient is unaware of affected relatives. Some HSP subtypes — particularly late-onset autosomal dominant forms like SPG4 — are phenotypically indistinguishable from PLS on clinical grounds alone. A patient presenting at age 55 with progressive spastic gait and no family history may look clinically identical whether the cause is sporadic PLS or unrecognized autosomal dominant SPG4.
The genetic landscape of HSP
HSP is defined by genetics. Unlike PLS, which is typically sporadic and lacks an identified causal gene in adult patients, HSP is a genetically defined disease category. More than 70 SPG (spastic paraplegia) gene loci have been identified, with inheritance patterns spanning autosomal dominant, autosomal recessive, and X-linked forms. The clinical phenotype — which muscles are affected, what additional features are present, how rapidly it progresses — varies substantially by genetic subtype.
The most common autosomal dominant form is SPG4, caused by mutations in the spastin gene on chromosome 2p22. Spastin is a microtubule-severing ATPase involved in axonal transport. SPG4 accounts for approximately 40% of autosomal dominant HSP in most European populations. Its presentation is often a slowly progressive pure spastic paraparesis with adult onset, mild upper extremity involvement possible, and variable severity even within families. This is exactly the clinical picture that can be mistaken for PLS.
SPG7 (paraplegin mutations) is the most commonly identified autosomal recessive form and is particularly important in the PLS context because it has repeatedly appeared in case series of patients initially presenting with apparent PLS. Paraplegin is a mitochondrial protease involved in mitochondrial quality control. SPG7 mutations can produce a slowly progressive spastic paraparesis that is clinically indistinguishable from adult PLS before genetic testing. The recessive inheritance means a patient can have SPG7 without a positive family history — both parents are carriers but unaffected.
Other SPG loci that have appeared in apparent PLS patients include SPG11 (spatacsin — typically recessive, often with additional features like thin corpus callosum), SPG5A (CYP7B1 — recessive, responsive to dietary cholesterol reduction in some reports), and a range of less common loci. The C9orf72 hexanucleotide expansion has also been reported in some PLS patients, potentially representing C9orf72-associated MND with a UMN-predominant phenotype rather than true PLS.
What the case series show
Multiple case reports and small series have documented SPG gene mutations — most commonly SPG7 — in patients initially diagnosed with PLS. The consistent theme across these reports is diagnostic displacement: a patient receives a clinical diagnosis of PLS based on neurological examination, meets clinical criteria, and then undergoes genetic testing (either targeted SPG panel or whole genome sequencing) that identifies a pathogenic SPG variant. At that point, the diagnosis becomes genetically confirmed HSP, and the clinical label of PLS is withdrawn.
The frequency of this phenomenon is uncertain. Published estimates vary depending on the population studied, the scope of genetic testing performed, and how rigorously PLS criteria were applied before genetic testing. Some series find SPG gene variants in 10–15% of carefully characterized apparent PLS patients; others find lower rates. The Manini et al. 2025 WGS study found SPG hits in a minority of their adult PLS cohort, consistent with this range.
What is clear is that the phenomenon is real, reproducible across multiple independent series and research groups, and clinically significant in the patients it affects. It is not a theoretical concern but a documented diagnostic issue.
Why the distinction matters
For a patient who turns out to have HSP rather than PLS, the diagnostic reclassification has several important consequences.
The most significant is for family members. Adult-onset HSP with autosomal dominant inheritance (SPG4) means a 50% risk for first-degree relatives — each child of an affected parent has a 50% chance of inheriting the mutation. Autosomal recessive forms (SPG7, SPG11) mean siblings of affected individuals have a 25% chance of being affected and a 50% chance of being carriers. These are concrete genetic risks that warrant carrier testing and genetic counseling for the family, none of which apply if the diagnosis remains sporadic PLS.
There are also potential therapeutic implications. Some HSP subtypes have specific management considerations. SPG5A (CYP7B1 mutations) involves abnormal bile acid metabolism, and early reports suggested potential benefit from dietary modification targeting that pathway, though the evidence remains preliminary. SPG7 mutations involve mitochondrial dysfunction, and mitochondrial-targeted approaches are of research interest. These are not established treatments, but they represent disease-specific biological targets that do not exist in sporadic PLS, where no pathomechanistic target has been identified.
Prognostically, some HSP subtypes have well-characterized natural histories that differ from sporadic PLS. The trajectory, the likelihood of needing a wheelchair, and the involvement of systems beyond the motor pathway can all differ between HSP subtypes, and a genetic diagnosis informs these predictions in a way a clinical PLS diagnosis does not.
The Spastic Paraplegia Foundation (SP Foundation) explicitly serves both PLS and HSP patients, recognizing that these populations share clinical experiences, care needs, physical therapy approaches, and advocacy interests despite differing diagnoses. This shared community infrastructure reflects the practical reality that PLS and HSP patients often navigate similar challenges even when the underlying disease is different.
Implications for genetic testing in PLS
The PLS/HSP genetic boundary is the strongest clinical argument for genetic testing in adult PLS — stronger than the argument for testing for ALS-associated genes, which rarely yield actionable findings in PLS. If a patient with apparent PLS undergoes SPG gene panel testing or WGS and is found to carry an SPG variant, the diagnosis changes and the family implications are immediate and concrete.
Current practice varies. Some centers include HSP gene panels as part of the standard PLS diagnostic workup; others rely on clinical features and family history to guide testing. There is no universal consensus guideline, reflecting the rarity of PLS and the limited evidence base. The general principle is that genetic testing for HSP genes is appropriate in any patient with apparent PLS, particularly if family history is uncertain (not definitively negative), if there are additional features suggesting a complicated HSP (cerebellar signs, peripheral neuropathy, cognitive changes), or if genetic counseling is being considered for family members.
A negative result — no SPG variant found — does not rule out HSP: new SPG loci continue to be discovered, and current panels do not cover all HSP genes. But a comprehensive SPG panel or WGS substantially reduces the probability of a genetically diagnosable HSP, and a negative result provides meaningful reassurance even if it is not absolute certainty.
How this connects
The Genetics Research hub covers this issue as part of the broader PLS genetics landscape, including the observation from the Manini 2025 WGS study that SPG hits appear in a minority of adult PLS patients under comprehensive sequencing. For patients considering genetic testing, the Genetics patient guide addresses what to expect from HSP gene panel testing and how to interpret results. The diagnostic challenge is also discussed at Diagnosis in the context of the differential diagnosis workup. For the juvenile PLS story — which involves a different gene and mechanism but similarly demonstrates that some clinical PLS is genetic — see ALS2 and Juvenile PLS.
Citation
Spastic Paraplegia Foundation. PLS and HSP: Overlap and Distinction. spasticparaplegia.org.
Silani V, et al. Genetics of primary lateral sclerosis. PubMed. PMID 33602012. (Review covering SPG gene findings in apparent PLS cohorts.)