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Condition report · Neurological

Hereditary Spastic Paraplegia

Whole genome sequencing evaluates all 80+ HSP genes simultaneously, including SPG4 (SPAST), SPG3A (ATL1), and SPG7 (paraplegin), replacing the sequential single-gene testing that delays diagnosis by years.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

A group of inherited neurological disorders characterized by progressive spasticity and weakness, predominantly affecting the lower limbs, due to degeneration of the longest axons in the spinal cord.

Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by progressive length-dependent degeneration of the corticospinal tract, producing lower limb spasticity and weakness. Over 80 genetic loci (SPG1 through SPG80+) and their corresponding genes have been identified, with autosomal dominant, autosomal recessive, and X-linked inheritance patterns. The most common form is SPG4 (SPAST gene, encoding spastin), accounting for approximately 40% of autosomal dominant HSP cases. Combined prevalence of all HSP forms is approximately 2-10 per 100,000.

HSP is classified as 'pure' (uncomplicated, with spasticity and weakness limited to the lower limbs, with or without urinary urgency and mild sensory loss) or 'complex' (complicated, with spasticity plus additional neurological features such as ataxia, peripheral neuropathy, cognitive impairment, thin corpus callosum, epilepsy, or optic atrophy). The distinction between pure and complex HSP has major prognostic implications: pure HSP typically allows independent ambulation for decades, while complex HSP may include progressive cognitive decline, wheelchair dependence, and shortened life expectancy.

HSP is frequently misdiagnosed. The differential includes primary progressive multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), vitamin B12 deficiency, copper deficiency, spinal cord compression, dopa-responsive dystonia, and structural myelopathy. Many HSP patients undergo years of investigation (MRI brain and spine, lumbar puncture, evoked potentials, NCS/EMG) without a definitive diagnosis. Molecular confirmation through comprehensive genetic testing ends the diagnostic odyssey, provides accurate prognosis (pure vs. complex trajectory), enables genetic counseling for family members, and excludes treatable mimics.

SPG7 (paraplegin) is a common cause of recessive HSP that frequently presents with cerebellar ataxia; it is increasingly recognized as one of the most common genetic ataxias and should be considered in any adult with progressive spastic ataxia.

The 20 conditions we analyse

Hereditary Spastic Paraplegia (All Types)

Umbrella term covering all hereditary spastic paraplegias, including SPG4 (SPAST), the most common dominant form, and SPG5A, SPG6, SPG10, SPG18, SPG30 and SPG31.

Genes analysed

Also known as

familial spastic paraparesis; familial spastic paraplegia; FSP; hereditary spastic paraparesis; HSP; spastic paraplegia; SPG; Strümpell-Lorrain disease

Specific forms also covered

  • Hereditary Spastic Paraplegia 52

    Autosomal recessive

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the AP4S1 gene.

    AP4S1

  • Hereditary Spastic Paraplegia 17

    Autosomal dominant

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the BSCL2 gene.

    BSCL2

  • Hereditary Spastic Paraplegia 49

    Autosomal recessive

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the TECPR2 gene.

    TECPR2

  • Hereditary Spastic Paraplegia 47

    Autosomal recessive

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the AP4B1 gene.

    AP4B1

  • Hereditary Spastic Paraplegia 3a

    Autosomal dominant

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the ATL1 gene.

    ATL1

  • Hereditary Spastic Paraplegia 8

    Autosomal dominant

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the WASHC5 gene.

    WASHC5

  • Hereditary Spastic Paraplegia 13

    Autosomal dominant

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the HSPD1 gene.

    HSPD1

  • Hereditary Spastic Paraplegia 7

    Autosomal recessive spastic paraplegia type 7 is a form of hereditary spastic paraplegia characterized by an onset usually in adulthood (but ranging from 10-72 years) of progressive bilateral lower limb weakness and spasticity, sphincter dysfunction, decreased vibratory sense at the ankles and with additional manifestations including optical neuropathy, nystagmus, strabismus, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, amyotrophy, blepharoptosis and ophthalmoplegia.

    SPG7

  • Hereditary Spastic Paraplegia 56

    Autosomal recessive

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the CYP2U1 gene.

    CYP2U1

  • Hereditary Spastic Paraplegia 75

    Autosomal recessive

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the MAG gene.

    MAG

  • Hereditary Spastic Paraplegia 50

    Autosomal recessive

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the AP4M1 gene.

    AP4M1

  • Hereditary Spastic Paraplegia 33

    Autosomal dominant

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the ZFYVE27 gene.

  • Hereditary Spastic Paraplegia 72

    Any pure hereditary spastic paraplegia in which the cause of the disease is a mutation in the REEP2 gene.

    REEP2

  • Hereditary Spastic Paraplegia 51

    Autosomal recessive

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the AP4E1 gene.

    AP4E1

  • Hereditary Spastic Paraplegia 11

    Autosomal recessive

    Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the SPG11 gene.

    SPG11

  • Hereditary Spastic Paraplegia 12

    Autosomal dominant

    Autosomal dominant spastic paraplegia type 12 is a pure form of hereditary spastic paraplegia characterized by a childhood- to adulthood-onset of slowly progressive lower limb spasticity and hyperreflexia of lower extremities, extensor plantar reflexes, distal sensory impairment, variable urinary dysfunction and pes cavus.

    RTN2

  • Hereditary Spastic Paraplegia 39

    Autosomal recessive

    This syndrome is characterized by progressive spastic paraplegia and distal muscle wasting.

    PNPLA6

  • Hereditary Spastic Paraplegia 15

    Autosomal recessive

    Autosomal recessive spastic paraplegia type 15 is a complex form of hereditary spastic paraplegia characterized by a childhood to adulthood onset of slowly progressive lower limb spasticity (resulting in gait disturbance, extensor plantar responses and decreased vibration sense) associated with mild intellectual disability, mild cerebellar ataxia, peripheral neuropathy (with distal upper limb amyotrophy) and retinal degeneration. Thin corpus callosum is a common imaging finding.

    ZFYVE26

  • Hereditary Spastic Paraplegia 2

    X-linked recessive

    Spastic paraplegia type 2 (SPG2) is an X-linked leukodystrophy characterized primarily by spastic gait and autonomic dysfunction. When additional central nervous system (CNS) signs, such as intellectual deficit, ataxia, or extrapyramidal signs, are present, the syndrome is referred to as complicated SPG.

    PLP1

Includes 126 related subtypes ↓
  • ADAR-related hereditary spastic paraplegia
  • autosomal dominant complex spastic paraplegia
  • autosomal dominant complex spastic paraplegia type 9B
  • autosomal dominant spastic paraplegia type 9
  • autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction
  • autosomal recessive complex spastic paraplegia type 9B
  • autosomal recessive spastic paraplegia type 59
  • autosomal recessive spastic paraplegia type 60
  • autosomal recessive spastic paraplegia type 66
  • autosomal recessive spastic paraplegia type 67
  • autosomal recessive spastic paraplegia type 68
  • autosomal recessive spastic paraplegia type 69
  • autosomal recessive spastic paraplegia type 70
  • autosomal recessive spastic paraplegia type 71
  • autosomal recessive spastic paraplegia type 76
  • autosomal recessive spastic paraplegia type 78
  • Charcot-Marie-Tooth disease type 5
  • complex hereditary spastic paraplegia
  • early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome
  • fatty acid hydroxylase-associated neurodegeneration
  • glutamate pyruvate transaminase 2 deficiency
  • hereditary sensory and autonomic neuropathy with spastic paraplegia
  • hereditary spastic paraplegia 10
  • hereditary spastic paraplegia 11
  • hereditary spastic paraplegia 12
  • hereditary spastic paraplegia 13
  • hereditary spastic paraplegia 14
  • hereditary spastic paraplegia 15
  • hereditary spastic paraplegia 16
  • hereditary spastic paraplegia 17
  • hereditary spastic paraplegia 18
  • hereditary spastic paraplegia 19
  • hereditary spastic paraplegia 2
  • hereditary spastic paraplegia 23
  • hereditary spastic paraplegia 24
  • hereditary spastic paraplegia 25
  • hereditary spastic paraplegia 26
  • hereditary spastic paraplegia 27
  • hereditary spastic paraplegia 28
  • hereditary spastic paraplegia 29
  • hereditary spastic paraplegia 30
  • hereditary spastic paraplegia 31
  • hereditary spastic paraplegia 32
  • hereditary spastic paraplegia 33
  • hereditary spastic paraplegia 34
  • hereditary spastic paraplegia 35
  • hereditary spastic paraplegia 36
  • hereditary spastic paraplegia 37
  • hereditary spastic paraplegia 38
  • hereditary spastic paraplegia 39
  • hereditary spastic paraplegia 3A
  • hereditary spastic paraplegia 4
  • hereditary spastic paraplegia 41
  • hereditary spastic paraplegia 42
  • hereditary spastic paraplegia 43
  • hereditary spastic paraplegia 44
  • hereditary spastic paraplegia 45
  • hereditary spastic paraplegia 46
  • hereditary spastic paraplegia 47
  • hereditary spastic paraplegia 48
  • hereditary spastic paraplegia 49
  • hereditary spastic paraplegia 50
  • hereditary spastic paraplegia 51
  • hereditary spastic paraplegia 52
  • hereditary spastic paraplegia 53
  • hereditary spastic paraplegia 54
  • hereditary spastic paraplegia 55
  • hereditary spastic paraplegia 56
  • hereditary spastic paraplegia 57
  • hereditary spastic paraplegia 5A
  • hereditary spastic paraplegia 6
  • hereditary spastic paraplegia 61
  • hereditary spastic paraplegia 62
  • hereditary spastic paraplegia 63
  • hereditary spastic paraplegia 64
  • hereditary spastic paraplegia 7
  • hereditary spastic paraplegia 72
  • hereditary spastic paraplegia 73
  • hereditary spastic paraplegia 74
  • hereditary spastic paraplegia 75
  • hereditary spastic paraplegia 77
  • hereditary spastic paraplegia 8
  • hereditary spastic paraplegia 9A
  • IFIH1-related hereditary spastic paraplegia
  • kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome
  • macrocephaly-spastic paraplegia-dysmorphism syndrome
  • MASA syndrome
  • mast syndrome
  • maternally-inherited spastic paraplegia
  • PNPLA6-related spastic paraplegia with or without ataxia
  • pure hereditary spastic paraplegia
  • pure or complex hereditary spastic paraplegia
  • RNASEH2B-related hereditary spastic paraplegia
  • spastic ataxia 2
  • spastic paraplegia 18a, autosomal dominant
  • spastic paraplegia 18b, autosomal recessive
  • spastic paraplegia 30A, autosomal dominant
  • spastic paraplegia 30B, autosomal recessive
  • spastic paraplegia 72b, autosomal recessive
  • spastic paraplegia 79A, autosomal dominant, with ataxia
  • spastic paraplegia 80, autosomal dominant
  • spastic paraplegia 81, autosomal recessive
  • spastic paraplegia 82, autosomal recessive
  • spastic paraplegia 83, autosomal recessive
  • spastic paraplegia 84, autosomal recessive
  • spastic paraplegia 85, autosomal recessive
  • spastic paraplegia 86, autosomal recessive
  • spastic paraplegia 87, autosomal recessive
  • spastic paraplegia 88, autosomal dominant
  • spastic paraplegia 89, autosomal recessive
  • spastic paraplegia 90A, autosomal dominant
  • spastic paraplegia 90B, autosomal recessive
  • spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia
  • spastic paraplegia 92, autosomal recessive
  • spastic paraplegia 93, autosomal recessive
  • spastic paraplegia-epilepsy-intellectual disability syndrome
  • spastic paraplegia-facial-cutaneous lesions syndrome
  • spastic paraplegia-glaucoma-intellectual disability syndrome
  • spastic paraplegia-nephritis-deafness syndrome
  • spastic paraplegia-neuropathy-poikiloderma syndrome
  • spastic paraplegia-Paget disease of bone syndrome
  • spastic paraplegia-precocious puberty syndrome
  • spastic paraplegia-severe developmental delay-epilepsy syndrome
  • spastic paraplegia, intellectual disability, nystagmus, and obesity
  • spastic paraplegia, optic atropy, and neuropathy
  • Troyer syndrome
MONDO:0019064Orphanet 685MedGen 20844

Why whole genome sequencing

With 80+ causative genes, sequential single-gene testing is impractical. WGS evaluates the complete HSP genetic landscape in one test, ending diagnostic odysseys that average 5-10 years for rare HSP subtypes.

Ending the diagnostic odyssey: average HSP diagnostic delay is 5-10 years, during which treatable mimics may be missed

HSP patients typically undergo years of neurological investigation before receiving a molecular diagnosis. During this period, treatable conditions that mimic HSP may be under-investigated because the clinical picture is attributed to 'possible HSP.' These include dopa-responsive dystonia (GCH1), B12 or copper deficiency, structural myelopathy, and primary progressive MS. Whole genome sequencing either confirms HSP with a specific gene identification (providing prognosis and reproductive counseling) or excludes HSP, redirecting investigation toward potentially treatable conditions.

SPG4 (SPAST) exon deletions account for 20% of SPG4 cases and are invisible to standard sequencing

Approximately 20% of SPG4 pathogenic alleles are multi-exon deletions or duplications in SPAST, structural variants that are not detectable by standard exon sequencing or Sanger sequencing. A patient with autosomal dominant pure HSP who tests negative on SPAST sequencing may actually carry a SPAST deletion. Whole genome sequencing detects both sequence variants and copy number variants from the same data, identifying the complete spectrum of SPAST pathogenic alleles in a single test without requiring separate MLPA analysis.

Other neurological conditions

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