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PubMed This is a summary of 17 peer-reviewed journal articles Updated
Neurology

The Diagnostic Journey: Genetics and Imaging

At a Glance

Complex AD-HSP is diagnosed through a combination of clinical exams, brain and spinal cord MRIs, and crucial genetic testing. Identifying specific gene mutations and imaging markers like spinal cord atrophy helps doctors confirm AD-HSP and definitively differentiate it from conditions like ALS.

Finding the correct name for your symptoms often involves a complex puzzle of brain scans, blood tests, and genetic “blueprint” reading [1][2]. Because Complex AD-HSP is rare and shares symptoms with other conditions, the diagnostic journey can be long and sometimes involve initial misdiagnoses [3].

The Diagnostic Pathway

To reach a diagnosis of Complex AD-HSP, doctors typically follow a step-by-step process:

  • Clinical Exam: A neurologist looks for signs of upper motor neuron (UMN) involvement, such as stiff legs, “jumpy” reflexes, and gait changes [4].
  • Imaging (MRI): Scans of the brain and spine are used to look for specific structural “markers” [5].
  • Metabolic Screening: Blood and urine tests are often used to rule out “mimics,” such as vitamin deficiencies or rare metabolic disorders [1][6].
  • Genetic Testing: This is the most crucial step for a definitive diagnosis [1].
    • Targeted Gene Panels: Usually the first step, these tests look at a specific group of genes known to cause HSP [7].
    • Whole Exome/Genome Sequencing (WES/WGS): If a panel is negative, these more advanced tests scan almost all of your DNA to find rare or new mutations [8][7].

Differentiating from ALS and PLS

It is common for patients with HSP to worry about Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig’s disease) or Primary Lateral Sclerosis (PLS) [3]. While they share the symptom of leg stiffness, they are very different conditions:

Feature AD-HSP ALS
Disease Speed Very slow, progressing over decades [4]. Rapid progression, often unfolding over years [9].
Nerve Involvement Predominantly “upper” motor nerves, starting in legs [10]. Both “upper” and “lower” motor nerves; involves muscle twitching/rapid wasting [3][11].
Genetic Markers Specific HSP genes (e.g., SPAST, NIPA1) [12]. ALS-specific genes (e.g., C9orf72, SOD1) [13].
  • Biomarkers: A protein called Neurofilament Light Chain (NfL) is a marker of nerve damage. While it can be elevated in both, levels are typically much higher and rise faster in ALS compared to HSP, helping doctors tell them apart [14][15].

Key Imaging Findings

Radiologists look for specific “clues” on an MRI that point toward a complex form of HSP:

  • Thin Corpus Callosum (TCC): The bridge connecting the two sides of your brain may appear unusually thin. While this is extremely common in recessive forms of HSP, it can sometimes be seen in certain dominant forms [16][5].
  • Spinal Cord Atrophy: The spinal cord may appear thinner than normal, especially in the upper (thoracic) area, reflecting the degeneration of the long nerve tracts [5][17].

Diagnostic Completeness Checklist

If you have recently been diagnosed or are reviewing your diagnostic journey, ensure your team has discussed the following:

  1. [ ] Targeted HSP Genetic Panel (testing for multiple SPG types to confirm the exact mutation).
  2. [ ] Brain and Spinal Cord MRI (to rule out structural mimics and look for spinal cord atrophy).
  3. [ ] Nerve Conduction Studies (EMG) (to check for peripheral nerve involvement, which is common in complex AD-HSP).
  4. [ ] Metabolic Screening (to rule out treatable mimics).
  5. [ ] Multidisciplinary Review (consulting with a neurogenetics specialist to interpret complex genetic results).

Common questions in this guide

How is Complex AD-HSP diagnosed?
Doctors diagnose Complex AD-HSP using a step-by-step process that includes a clinical exam, brain and spinal cord MRIs, metabolic screening, and specific genetic testing. A targeted gene panel is usually the most crucial step for confirming the diagnosis.
How is AD-HSP different from ALS?
While both conditions can cause leg stiffness, AD-HSP progresses very slowly over decades and primarily affects upper motor nerves. ALS progresses much faster, involves both upper and lower motor nerves, and has completely different genetic markers.
What does a thin corpus callosum on my MRI mean?
The corpus callosum is the bridge connecting the two sides of the brain. A thinning of this structure is an imaging clue that radiologists sometimes see on an MRI in certain dominant forms of Hereditary Spastic Paraplegia.
What is the next step if my targeted HSP genetic panel is negative?
If a standard genetic panel does not find a mutation, your doctor may recommend whole exome or whole genome sequencing. These advanced tests scan almost all of your DNA to search for rare or new genetic mutations causing your symptoms.
What does the NfL biomarker test tell doctors?
Neurofilament Light Chain (NfL) is a protein that indicates nerve damage. While NfL levels can be slightly elevated in HSP, they are typically much higher and rise faster in ALS, helping doctors distinguish between the two conditions through a blood test.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Based on my genetic testing, what is the specific 'SPG' number and mutation identified?
  2. 2.Did my MRI show any specific changes, such as spinal cord atrophy or a thin corpus callosum, that align with my diagnosis?
  3. 3.How do we definitively rule out ALS or PLS in my case?
  4. 4.If my targeted genetic panel was negative, is Whole Exome Sequencing (WES) our next step?
  5. 5.What do my Neurofilament Light (NfL) levels tell us about my disease activity compared to other conditions?

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

    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
  2. 2

    Triple A syndrome presenting as complicated hereditary spastic paraplegia.

    Leveille E, Gonorazky HD, Rioux MF, et al.

    Molecular genetics & genomic medicine 2018; (6(6)):1134-1139 doi:10.1002/mgg3.492.

    PMID: 30381913
  3. 3

    Description of combined ARHSP/JALS phenotype in some patients with SPG11 mutations.

    Khani M, Shamshiri H, Fatehi F, et al.

    Molecular genetics & genomic medicine 2020; (8(7)):e1240 doi:10.1002/mgg3.1240.

    PMID: 32383541
  4. 4

    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
  5. 5

    Identification of a novel mutation in ATP13A2 associated with a complicated form of hereditary spastic paraplegia.

    Odake Y, Koh K, Takiyama Y, et al.

    Neurology. Genetics 2020; (6(5)):e514 doi:10.1212/NXG.0000000000000514.

    PMID: 33134512
  6. 6

    Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.

    Coutelier M, Goizet C, Durr A, et al.

    Brain : a journal of neurology 2015; (138(Pt 8)):2191-205 doi:10.1093/brain/awv143.

    PMID: 26026163
  7. 7

    Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia.

    Méreaux JL, Banneau G, Papin M, et al.

    Brain : a journal of neurology 2022; (145(3)):1029-1037 doi:10.1093/brain/awab386.

    PMID: 34983064
  8. 8

    Whole exome sequencing in Serbian patients with hereditary spastic paraplegia.

    Brankovic M, Ivanovic V, Basta I, et al.

    Neurogenetics 2024; (25(3)):165-177 doi:10.1007/s10048-024-00755-x.

    PMID: 38499745
  9. 9

    Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis.

    Thouvenot E, Demattei C, Lehmann S, et al.

    European journal of neurology 2020; (27(2)):251-257 doi:10.1111/ene.14063.

    PMID: 31437330
  10. 10

    Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the KIF1A gene.

    Krenn M, Zulehner G, Hotzy C, et al.

    European journal of neurology 2017; (24(5)):741-747 doi:10.1111/ene.13279.

    PMID: 28332297
  11. 11

    The Upper Motor Neuron-Improved Knowledge from ALS and Related Clinical Disorders.

    Menon P, Vucic S

    Brain sciences 2021; (11(8)) doi:10.3390/brainsci11080958.

    PMID: 34439577
  12. 12

    Is NIPA1-associated hereditary spastic paraplegia always 'pure'? Further evidence of motor neurone disease and epilepsy as rare manifestations.

    Tanti M, Cairns D, Mirza N, et al.

    Neurogenetics 2020; (21(4)):305-308 doi:10.1007/s10048-020-00619-0.

    PMID: 32500351
  13. 13

    The genetic architecture of primary lateral sclerosis in a cohort of Italian patients.

    Schito P, Domi T, Russo T, et al.

    Journal of neurology 2025; (272(12)):780 doi:10.1007/s00415-025-13525-y.

    PMID: 41269363
  14. 14

    Serum neurofilament light chain is increased in hereditary spastic paraplegias.

    Wilke C, Rattay TW, Hengel H, et al.

    Annals of clinical and translational neurology 2018; (5(7)):876-882 doi:10.1002/acn3.583.

    PMID: 30009206
  15. 15

    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
  16. 16

    Review of the Genetic Spectrum of Hereditary Spastic Paraplegias in the Middle East and North Africa Regions.

    Salari M, Hojjatipour F, Etemadifar M, Soleimani S

    Neurology. Genetics 2025; (11(2)):e200250 doi:10.1212/NXG.0000000000200250.

    PMID: 40041249
  17. 17

    Association of spinal cord structure with cognition in hereditary spastic paraplegia type 5.

    Chen X, Lin K, Qiu L, et al.

    Frontiers in neurology 2025; (16()):1639011 doi:10.3389/fneur.2025.1639011.

    PMID: 41551307

This page explains diagnostic tests and imaging for Complex AD-HSP for educational purposes only. Always consult your neurologist or genetic counselor to interpret your specific genetic results and MRI scans.

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