Skip to content
How It Works
Explore
Resources Ask a Question
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Ask a Question
PubMed This is a summary of 17 peer-reviewed journal articles Updated
Neurology

The Biology and Misdiagnosis of HSP

At a Glance

Hereditary Spastic Paraplegia (HSP) is caused by a breakdown in the long nerve cells connecting the brain to the spinal cord. Because its symptoms progress very slowly, HSP is frequently misdiagnosed as Cerebral Palsy, Multiple Sclerosis, or ALS before diagnostic testing confirms it.

Understanding the biology of pure HSP helps explain why getting a correct diagnosis often takes a long time. The problem isn’t with the muscles, but with the “electrical wiring”—the upper motor neurons—that carries signals from your brain to your spinal cord [1][2].

The Logistics of the Longest Nerves

Imagine your nervous system as a giant telecommunications network. The corticospinal tracts are the longest “cables”. Some individual nerve cells (axons) are over three feet long [3][4].
Because these cables are so long, they are incredibly difficult for the cell to maintain. In HSP, these maintenance systems fail, leading to a “dying-back” phenomenon: the nerve doesn’t die all at once; instead, the very end of the cable—the part that controls the legs—starts to wither first [5][3].

What Goes Wrong Inside the Cell?

Mutations disrupt two vital pieces of cellular machinery:

  1. Microtubules (The Highway System): Long tubes that transport supplies down the nerve. Proteins like spastin (SPG4) act like track maintenance crews. When they fail, the supply chain breaks [6][7].
  2. Endoplasmic Reticulum or ER (The Factory): Manufactures proteins and fats. In HSP, the ER becomes stressed, failing to produce materials needed for healthy nerves [8][9].

The Diagnostic “Labyrinth”

Misdiagnosis is common because symptoms overlap with other conditions:

  • Cerebral Palsy (CP): A common misdiagnosis for children. CP is non-progressive (often from a birth injury), whereas HSP is progressive [10][11].
  • Multiple Sclerosis (MS): MS usually shows “plaques” or lesions on an MRI, whereas HSP is a steady, slow decline without typical MS lesions [12][13].
  • ALS and PLS: Serious motor neuron diseases. Doctors distinguish pure AD-HSP from these by looking for a relatively normal brain MRI or mild spinal cord atrophy [14][15], or by testing for neurofilament light chain (NfL) in the blood, which is much higher in ALS than in pure HSP [16][17].

Return to Home.

Common questions in this guide

Why is HSP frequently misdiagnosed?
HSP symptoms often overlap with other neurological conditions like Cerebral Palsy, Multiple Sclerosis, or ALS. Because HSP progresses very slowly and lacks the typical brain lesions seen in MS, it can take time for doctors to confirm an accurate diagnosis.
How is HSP different from Cerebral Palsy?
Cerebral Palsy is typically a non-progressive condition that often results from a birth injury. In contrast, HSP is a progressive genetic disorder where symptoms slowly worsen over time as the long nerve cells degenerate.
What happens to the nerve cells in HSP?
In HSP, the longest nerve cells that connect the brain to the spinal cord have trouble maintaining themselves. This causes a 'dying-back' effect, where the furthest ends of the nerves that control your legs slowly wither and lose function.
How do doctors tell the difference between pure HSP and ALS?
Doctors evaluate brain MRIs and may test your blood or spinal fluid for a marker called neurofilament light chain (NfL). NfL levels are typically much higher in ALS than in pure HSP, helping doctors distinguish between the two conditions.
What role does the SPG4 mutation play in HSP?
The SPG4 mutation affects a protein called spastin, which acts like a maintenance crew for the microtubule 'highways' inside your cells. When these break down, nerve cells cannot transport the supplies they need to stay healthy.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Why was it difficult to distinguish my condition from other disorders like CP or MS initially?
  2. 2.Does my specific genetic mutation primarily affect the endoplasmic reticulum or the microtubules?
  3. 3.What markers in my blood or spinal fluid, such as neurofilament light chain, helped rule out ALS or PLS?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (17)
  1. 1

    Hereditary Spastic Paraplegia in Alberta: Lessons from a Well-Defined Cohort Including the Indigenous Population.

    Assaedi E, Ashtiani S, Estiar MA, et al.

    Movement disorders clinical practice 2025; (12(9)):1346-1356 doi:10.1002/mdc3.70115.

    PMID: 40322871
  2. 2

    Anaesthesia and orphan disease: Management of a case of Strumpell-Lorrain disease and review of the literature.

    Ponsonnard S, Damon A, Gueye EM

    European journal of anaesthesiology 2017; (34(8)):562-563 doi:10.1097/EJA.0000000000000615.

    PMID: 28682816
  3. 3

    Ascending Axonal Degeneration of the Corticospinal Tract in Pure Hereditary Spastic Paraplegia: A Cross-Sectional DTI Study.

    List J, Kohl Z, Winkler J, et al.

    Brain sciences 2019; (9(10)) doi:10.3390/brainsci9100268.

    PMID: 31601037
  4. 4

    Hereditary primary lateral sclerosis and progressive nonfluent aphasia.

    Gazulla J, Ferrer I, Izquierdo-Alvarez S, et al.

    Journal of neurology 2019; (266(5)):1079-1090 doi:10.1007/s00415-019-09235-x.

    PMID: 30834979
  5. 5

    SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency.

    Montoro-Gámez C, Nolte H, Molinié T, et al.

    Brain : a journal of neurology 2023; (146(10)):4117-4131 doi:10.1093/brain/awad136.

    PMID: 37086482
  6. 6

    Microtubule-dependent and independent roles of spastin in lipid droplet dispersion and biogenesis.

    Tadepalle N, Robers L, Veronese M, et al.

    Life science alliance 2020; (3(6)) doi:10.26508/lsa.202000715.

    PMID: 32321733
  7. 7

    Spastin mutations impair coordination between lipid droplet dispersion and reticulum.

    Arribat Y, Grepper D, Lagarrigue S, et al.

    PLoS genetics 2020; (16(4)):e1008665 doi:10.1371/journal.pgen.1008665.

    PMID: 32315314
  8. 8

    Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia.

    Allison R, Edgar JR, Pearson G, et al.

    The Journal of cell biology 2017; (216(5)):1337-1355 doi:10.1083/jcb.201609033.

    PMID: 28389476
  9. 9

    Inhibition of ER stress improves progressive motor deficits in a REEP1-null mouse model of hereditary spastic paraplegia.

    Wang B, Yu Y, Wei L, Zhang Y

    Biology open 2020; (9(9)) doi:10.1242/bio.054296.

    PMID: 32878877
  10. 10

    Childhood-onset hereditary spastic paraplegia and its treatable mimics.

    Ebrahimi-Fakhari D, Saffari A, Pearl PL

    Molecular genetics and metabolism 2022; (137(4)):436-444 doi:10.1016/j.ymgme.2021.06.006.

    PMID: 34183250
  11. 11

    Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A.

    Hamamie-Chaar A, Renaud M, Gençpinar P, et al.

    Journal of neurology 2024; (271(9)):6343-6348 doi:10.1007/s00415-024-12565-0.

    PMID: 39003427
  12. 12

    Multiple sclerosis in patients with hereditary spastic paraplegia: a case report and systematic review.

    Giannoccaro MP, Matteo E, Bartiromo F, et al.

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2022; (43(9)):5501-5511 doi:10.1007/s10072-022-06145-1.

    PMID: 35595875
  13. 13

    A new paraplegin mutation in a patient with primary progressive multiple sclerosis.

    Bellinvia A, Pastò L, Niccolai C, et al.

    Multiple sclerosis and related disorders 2020; (44()):102302 doi:10.1016/j.msard.2020.102302.

    PMID: 32570181
  14. 14

    Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4.

    Kessler C, Serna-Higuita LM, Wilke C, et al.

    Annals of clinical and translational neurology 2022; (9(3)):326-338 doi:10.1002/acn3.51518.

    PMID: 35171517
  15. 15

    Gait Patterns in Patients with Hereditary Spastic Paraparesis.

    Serrao M, Rinaldi M, Ranavolo A, et al.

    PloS one 2016; (11(10)):e0164623 doi:10.1371/journal.pone.0164623.

    PMID: 27732632
  16. 16

    "Ears of the Lynx" MRI Sign Is Associated with SPG11 and SPG15 Hereditary Spastic Paraplegia.

    Pascual B, de Bot ST, Daniels MR, et al.

    AJNR. American journal of neuroradiology 2019; (40(1)):199-203 doi:10.3174/ajnr.A5935.

    PMID: 30606727
  17. 17

    Serum NfL, but not GFAP, differentiates primary lateral sclerosis from adrenomyeloneuropathy and hereditary spastic paraplegia type 4.

    Kessler C, Wilke C, Hengel H, et al.

    Amyotrophic lateral sclerosis & frontotemporal degeneration 2026; (27(1-2)):110-117 doi:10.1080/21678421.2025.2557936.

    PMID: 40961460

This page explains the biology and common misdiagnoses of HSP for educational purposes only. Always consult a neurologist for an accurate diagnosis and interpretation of your specific symptoms.

Get notified when new evidence is published on Autosomal dominant pure spastic paraplegia.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.