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Hereditary Spastic Paraplegia Overview

Synonyms: Familial Spastic Paraplegia, Hereditary Spastic Paraparesis, Strumpell-Lorrain Syndrome
, MD
Department of Neurology
University of Michigan
Ann Arbor, Michigan

Initial Posting: ; Last Update: February 6, 2014.


Clinical characteristics.

The hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous disorders characterized by lower extremity spasticity and weakness (occurring in variable proportion). When symptoms begin after childhood, they usually progress slowly and steadily. When symptoms begin in very early childhood, they may be non-progressive and resemble spastic diplegic cerebral palsy.

HSP is classified as "uncomplicated" if neurologic impairment is limited to lower extremity spastic weakness, hypertonic urinary bladder disturbance, and mild diminution of lower extremity vibration sensation. HSP is classified as "complicated" if the impairment present in uncomplicated HSP is accompanied by other systemic or neurologic abnormalities such as ataxia, seizures, cognitive impairment, dementia, amyotrophy, extrapyramidal disturbance, or peripheral neuropathy (in the absence of other causes for these additional features).

Neurologic examination of individuals with uncomplicated HSP demonstrates variable degrees of increased muscle tone (spasticity) particularly in the hamstrings, quadriceps, gastrocnemius-soleus, and adductor muscles; weakness in the iliopsoas, hamstring, and tibialis anterior muscles; hyperreflexia at the patella and ankles; often (though not always) mildly reduced vibration sensation in the toes; extensor plantar responses; and spastic gait.


HSP is diagnosed by:

  • Typical clinical symptoms of spastic gait impairment and neurologic findings of lower extremity spasticity and weakness;
  • Often (though not always) a family history of similarly affected first-degree relative(s); and
  • Exclusion of other disorders.

Magnetic resonance imaging (MRI) of the brain and spinal cord are usually normal; cerebrospinal fluid studies, electromyography, and nerve conduction studies are usually normal in uncomplicated HSP.

Genetic testing is increasingly available and particularly useful to confirm a clinical diagnosis of HSP. Since molecular genetic testing at present does not include all genes known to cause HSP, the absence of an identified pathogenic variant in a gene known to cause HSP does not exclude the diagnosis of HSP.

Genetic counseling.

Genetic types of HSP can be inherited in an autosomal dominant, autosomal recessive, X-linked, or maternally inherited (mitochondrial) manner. When studied, genetic penetrance is high (estimated at 90%). Genetic counseling depends on an accurate diagnosis and determining the mode of inheritance in each family. Genetic testing may be useful in determining the genetic type of HSP. Prenatal testing for some types of spastic paraplegia is possible for pregnancies at increased risk if the pathogenic variant(s) have been identified in the family.


At present, no treatment prevents or reverses nerve degeneration in HSP. Treatment is directed towards reducing symptoms and improving strength and balance through physical therapy and rehabilitation; assistive devices to improve functional gait (e.g., ankle-foot orthotic devices); medications and stretching to reduce spasticity (e.g., oral and intrathecal Lioresal®, intramuscular botulinum toxin [Botox®] injection); and medications to reduce urinary urgency.


Clinical Manifestations of HSP

The predominant symptoms of hereditary spastic paraplegia (HSP) are lower extremity weakness and spasticity. When symptoms begin in very early childhood, they may be non-progressive and resemble spastic diplegic cerebral palsy. When symptoms begin later in childhood or later they usually progress slowly and steadily. After a number of years, it is not usual for individuals with progressively worsening gait to experience a "functional plateau" (i.e., the rate of further worsening of gait impairment is similar to that attributable to age).

Classification. HSP is classified clinically as uncomplicated (nonsyndromic) or complicated (syndromic) and genetically by mode of inheritance, chromosome locus, and/or causative allelic variant. Genetic loci for HSP are designated SPG (for "spastic paraplegia") 1 through 56 in order of their discovery [Fink 2013].

  • "Uncomplicated" ("pure") HSP is characterized by neurologic impairment limited to progressive lower extremity spastic weakness, hypertonic urinary bladder disturbance, and mild diminution of lower extremity vibration sensation [Harding 1983].
    Uncomplicated HSP begins at any age, from early childhood through late adulthood. Symptoms may be non-progressive (when they begin in very early childhood); or worsen slowly over many years (when symptoms begin after childhood). HSP with early-onset symptoms that are non-progressive may resemble spastic diplegic cerebral palsy.
    Affected individuals experience difficulty walking (that may either be non-progressive or worsen insidiously) and often require canes, walkers, or wheelchairs. Urinary urgency and lower extremity paresthesiae may occur.
    Individuals with uncomplicated HSP typically retain normal strength and dexterity of the upper extremities and have no involvement of speech, chewing, or swallowing. Though symptoms may be disabling, uncomplicated HSP does not shorten life span.
  • "Complicated" HSP is characterized by the impairments present in uncomplicated HSP accompanied by other system involvement or other neurologic findings including ataxia, seizures, intellectual disability, dementia, amyotrophy, extrapyramidal disturbance, or peripheral neuropathy, in the absence of other causes for these additional features.

Establishing the Diagnosis of HSP

HSP is diagnosed on the basis of the following:

  • Characteristic clinical symptoms of bilateral lower extremity spastic weakness often accompanied by urinary urgency that may be non-progressive (with early childhood onset symptoms); or slowly progressive (with symptom onset after childhood)
  • Neurologic examination demonstrating corticospinal tract deficits affecting both lower extremities (spastic weakness, hyperreflexia, typically associated with bilateral extensor plantar responses), often accompanied by mildly impaired vibration sensation in the distal lower extremities and symptoms of hypertonic urinary bladder
  • Family history consistent with autosomal dominant, autosomal recessive, or X-linked inheritance or maternal (mitochondrial) inheritance
  • Exclusion of alternate disorders (see Differential Diagnosis)
  • Molecular genetic testing; increasingly available and potentially useful confirming the clinical diagnosis HSP

Neurologic examination. Individuals with uncomplicated HSP demonstrate the following:

  • Bilateral lower extremity spasticity (maximal in hamstrings, quadriceps, adductors, and gastrocnemius-soleus muscles) and weakness (maximal in the iliopsoas, hamstring, and tibialis anterior muscles). Spasticity and weakness are variable. Some individuals have spasticity and no demonstrable weakness, whereas others have spasticity and weakness in approximately the same proportions.
  • Lower extremity hyperreflexia and extensor plantar responses
  • Often, mildly impaired vibration sensation in the distal lower extremities

Neuropathology. The most commonly reported pathology in uncomplicated HSP is axon degeneration that is maximal at the distal ends of the corticospinal tracts and, to a lesser extent, at the distal ends of dorsal column fibers. Mild loss of anterior horn cells may occur. Demyelination, if present, is consistent with the degree of axonal degeneration [Schwarz & Liu 1956, Behan & Maia 1974].

Differential Diagnosis of HSP

The differential diagnosis includes:

Prevalence of HSP

The prevalence of HSP has been estimated to range from 1.3:100,000 (in Ireland) [McMonagle et al 2002], to 9.6: 100,000 (in Spain) [Sedel et al 2007].

Genetic types of hereditary spastic paraplegia (HSP). To date, more than 56 HSP loci and 41HSP-related genes have been identified.

Table 1.

Summary of Hereditary Spastic Paraplegia – Autosomal Dominant Inheritance

Gene / Locus Name
(Chromosome Locus 1)
ProteinClinical SyndromeReferences
ATL1 / SPG3AAtlastin-1Uncomplicated HSP:
  • Typical onset in childhood (may be non-progressive) or adolescence to adulthood (w/insidious progression)
  • Genetic non-penetrance reported
  • De novo pathogenic variant reported presenting as spastic diplegic cerebral palsy
Hazan et al [1993], Paternotte et al [1998], Zhao et al [2001]
SPAST / SPG4SpastinUncomplicated HSP; most common cause of AD HSP (~40%):
  • Onset in infancy to senescence
  • Late-onset cognitive impairment variably present
Hazan et al [1994], Hentati et al [1994b], Charvin et al [2003], Evans et al [2005], Roll-Mecak & Vale [2005]
NIPA1 / SPG6Non-imprinted in Prader-Willi / Angelman syndrome region protein 1 (magnesium transporter NIPA1)Uncomplicated HSP:
  • Prototypic late-adolescent, early-adult onset, slowly progressive
  • Rarely, complicated by epilepsy or variable peripheral neuropathy; in 1 case, ALS
Fink et al [1995a], Fink et al [1995b], Rainier et al [2003], Chen et al [2005], Du et al [2011], Svenstrup et al [2011], Martinez-Lage et al [2012]
WASHC5 (KIAA0196) / SPG8WASH complex subunit 5Uncomplicated HSPHedera et al [1999a], Hedera et al [1999b], Reid et al [2000], Valdmanis et al [2007], Bian et al [2011]
UnknownComplicated HSP:
  • Cataracts
  • Gastroesophageal reflux
  • Motor neuronopathy
Seri et al [1999], Meijer et al [2004]
KIF5A / SPG10Kinesin heavy chain isoform 5AUncomplicated HSP or complicated by distal muscle atrophyReid et al [1999], Fichera et al [2004]
RTN2 / SPG12Reticulon-2Uncomplicated HSPReid et al [2000], Montenegro et al [2012]
HSPD1 / SPG13Chaperonin 60 (heat shock protein 60, HSP60)Uncomplicated HSP: adolescent – adult onsetFontaine et al [2000], Hansen et al [2002], Bross et al [2008]
BSCL2 / SPG17BSCL2 (seipin)Complicated HSP: amyotrophy of hand muscles (Silver syndrome)Patel et al [2001], Windpassinger et al [2004], Auer-Grumbach et al [2005]
UnknownUncomplicated HSPValente et al [2002]
UnknownComplicated HSP:
  • Hearing impairment
  • Persistent vomiting due to hiatal hernia (inherited)
Orlacchio et al 2005
REEP1 / SPG31Receptor expression- enhancing protein 1Uncomplicated HSP or occasionally associated w/peripheral neuropathyZüchner et al [2006a], Züchner et al [2006b], Beetz et al [2008]
ZFYVE27 / SPG33ProtrudinUncomplicated HSPMannan et al [2006]
  • Onset age 14-28 years
  • Motor sensory neuropathy
Schüle et al [2009]
UnknownUncomplicated HSPHanein et al [2007]
UnknownIn 5 members of a single family:
  • Onset age 16-21 years
  • Atrophy of intrinsic hand muscles (severe in 1 subject age 58)
Orlacchio et al [2008]
SPG40 (locus unknown)UnknownUncomplicated HSP:
  • Onset age >35
  • Known AD HSP loci excluded
Subramony et al [2009]
UnknownIn a single Chinese family:
  • Adolescent onset
  • Mild weakness of intrinsic hand muscles
Zhao et al [2008]
SLC33A1 / SPG42Acetyl -coenzyme A transporterUncomplicated HSP in a single kindred:
  • Onset age 4-40 years
  • 1 possible instance of incomplete penetrance
Lin et al [2008], Lin et al [2010], Schlipf et al [2010]

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, from OMIM; protein from UniProt.

See Spastic paraplegia: Phenotypic Series to view genes associated with this phenotype in OMIM.


Chromosome locus included only when the gene is not known

Table 2.

Summary of Hereditary Spastic Paraplegia – Autosomal Recessive Inheritance

Gene / Locus Name
(Chromosome Locus 1)
ProteinClinical SyndromeReferences
CYP7B1 / SPG5ACYP7B1 proteinUncomplicated; or complicated by:
  • Axonal neuropathy
  • Distal or generalized muscle atrophy
  • White-matter abnormalities on MRI
Hentati et al [1994a], Wilkinson et al [2003], Muglia et al [2004], Tang et al [2004], Tsaousidou et al [2008], Biancheri et al [2009], Criscuolo et al [2009]
SPG7 / SPG7ParapleginUncomplicated; or variably complicated by:
  • Mitochondrial abnormalities on skeletal muscle biopsy
  • Dysarthria, dysphagia, optic disc pallor, axonal neuropathy, & evidence of vascular lesions, cerebellar atrophy, or cerebral atrophy on cranial MRI
Garner et al [1990], De Michele et al [1998]
SPG11 / SPG11SpatacsinReported to account for 50% of AR HSP. Uncomplicated; or variably complicated by:
  • Thin corpus callosum, ID, upper-extremity weakness, dysarthria, & nystagmus
  • "Kjellin syndrome" (childhood-onset, progressive SPG w/pigmentary retinopathy, ID, dysarthria, dementia, & distal muscle atrophy)
  • Juvenile, slowly progressive ALS
Martínez Murillo et al [1999], Winner et al [2004]
UnknownComplicated HSP in 3 members of a consanguineous Italian family:
  • Onset age ~30 years
  • ID & distal motor neuropathy (sural nerve biopsy normal)
Vazza et al [2000]
ZFYVE26 / SPG15Zinc finger FYVE domain-containing protein 26Complicated HSP: pigmented maculopathy, distal amyotrophy, dysarthria, ID, & further intellectual deterioration (Kjellin syndrome) variably presentHughes et al [2001], Hanein et al [2008]
ERLIN2 / SPG18Erlin-2Complicated HSP in 2 families:
  • ID & thin corpus callosum
  • ERLIN2 pathogenic variants also identified in subjects w/juvenile primary lateral sclerosis
Al-Yahyaee et al [2006], Alazami et al [2011], Al-Saif et al [2012]
SPART / SPG20SpartinComplicated HSP: distal muscle wasting (Troyer syndrome)Cross & McKusick [1967], Crosby et al [2002], Patel et al [2002], Proukakis et al [2004], Lu et al [2006]
SPG21 / SPG21MaspardinComplicated HSP: dementia, cerebellar & extrapyramidal signs, thin corpus callosum, & white matter abnormalities (Mast syndrome)Simpson et al [2003]
UnknownComplicated HSP:
  • Onset in childhood
  • Skin pigment abnormality (vitiligo), premature graying, characteristic facies; Lison syndrome
Blumen et al [2003]
UnknownComplicated HSP:
  • Childhood onset
  • Spastic dysarthria & pseudobulbar signs variably present
Hodgkinson et al [2002]
UnknownIn 4 members of a consanguineous Italian family:
  • Adult onset (age 30-46 yrs)
  • Back & neck pain related to disk herniation & SPG (Note: Surgical correction of disk herniation ameliorated pain and reduced SPG.)
  • Other: peripheral neuropathy
Zortea et al [2002]
UnknownComplicated HSP in 5 members of a consanguineous Bedouin family:
  • Childhood onset (age 7-8 yrs)
  • Progressive spastic paraparesis w/dysarthria & distal amyotrophy in both upper & lower limbs
  • Nerve conduction studies normal
  • Mild ID, normal brain MRI
Wilkinson et al [2005]
UnknownUncomplicated HSP in 7 members of 1 family:
  • Adult onset (age 25-45 years)
  • Complicated HSP in 3 members of a 2nd family
  • Onset: childhood
  • Ataxia, dysarthria; ID, sensorimotor polyneuropathy, facial dysmorphism, & short stature
Meijer et al [2004], Ribai et al [2006]
DDHD1Complicated or uncomplicated HSP:
  • Infantile, childhood, or adolescent onset
  • Axonal neuropathy, distal sensory loss, & cerebellar eye movement disturbance variably present
Bouslam et al [2005], Tesson et al [2012]
KIF1A / SPG30KIF1AComplicated HSP: distal wasting, saccadic ocular pursuit, peripheral neuropathy, mild cerebellar signsKlebe et al [2006]
UnknownMild ID, brain stem dysraphia, clinically asymptomatic cerebellar atrophy
FA2H / SPG35Fatty acid 2-hydroxylaseComplicated HSP in an Omani & a Pakistani kindred:
  • Childhood onset (age 6-11 years)
  • Extrapyramidal features, progressive dysarthria, dementia, seizures
  • Brain white-matter abnormalities & brain iron accumulation
Dick et al [2008], Dick et al [2010], Kruer et al [2010]
PNPLA6 / SPG39Neuropathy target esterase (NTE)Complicated HSP: wasting of distal upper- & lower-extremity musclesRainier et al [2008]
C19orf12 / SPG43C19orf12In 2 sisters from Mali:
  • Onset ages 7 & 12 years
  • Progressive spastic paraplegia w/atrophy of intrinsic hand muscles; dysarthria (in 1 sister)
Meilleur et al [2010]
GJC2 / SPG44Gap junction protein GJA12/GJC2, also known as connexin 47 (Cx47)Complicated HSP:
  • Onset in1st-2nd decade
  • Mild phenotype w/ID, slowly progressive SPG, dysarthria, & upper-extremity involvement
  • MRI & MR spectroscopy imaging consistent w/a hypomyelinating leukoencephalopathy
  • Allelic w/PMLD1, early-onset dysmyelinating disorder w/nystagmus, psychomotor delay, progressive spasticity, ataxia)
  • Caused by GJA/GJC2 variant p.Ile33Met
Orthmann-Murphy et al [2009]
UnknownComplicated HSP in 5 members of a consanguineous kindred from Turkey:
  • Onset age <1 year
  • ID, lower extremity spasticity & contractures
  • Optic atrophy in 1 individual
  • Pendular nystagmus in 2 individuals
  • Normal MRI in 1 individual
Dursun et al [2009]
GBA2 / SPG46Non-lysosomal glucosylceramidaseDementia, congenital cataract, ataxia, thin corpus callosumBoukhris et al [2010]
AP4B1 / SPG47AP-4 complex subunit beta-1Complicated HSP in 2 sibs from a consanguineous Arab family:
  • Early-childhood onset
  • Slowly progressive spastic paraparesis, ID, & seizures
  • Ventriculomegaly in 1 sib; thin corpus callosum & periventricular white-matter abnormalities in the other
Blumkin et al [2011]
AP5Z1 / SPG48AP-5 complex subunit zeta-1 See footnote 2Słabicki et al [2010]
TECPR2 / SPG49Tectonin beta-propeller repeat-containing protein 2Complicated HSP in 5 individuals from 3 apparently unrelated families of Jewish Bukharian ancestry:
  • Infantile onset
  • Hypotonia, developmental delay w/severe ID, & dysmorphic features (short stature, brady-microcephaly, oral, facial, dental, nuchal abnormalities)
  • Spastic, ataxic, & rigid gait developed in childhood
  • Other: gastroesophageal reflux, recurrent apneic episodes, mild dysmorphic features
  • Epilepsy in 2 individuals
  • Thin corpus callosum & cerebellar atrophy on MRI in 2 individuals
Oz-Levi et al [2012]
AP4M1 / SPG50AP-4 complex subunit mu-1In 5 members of a consanguineous Moroccan family:
  • Infantile onset
  • Non-progressive spastic quadriplegia w/severe ID
  • Adducted thumbs variably present
  • Ventriculomegaly, white-matter abnormalities & variable cerebellar atrophy on neuroimaging
  • Neuroaxonal abnormalities, gliosis, & reduced myelin on post mortem exam
Verkerk et al [2009], Najmabadi et al [2011]
AP4E1 / SPG51AP-4 complex subunit epsilon-1Complicated HSP in 2 sibs from a consanguineous Palestinian Jordanian family & 2 sibs from a consanguineous Syrian family:
  • Microcephaly, hypotonia, psychomotor delay, spastic tetraplegia, marked ID w/severe language impairment, facial dysmorphic features; atrophy & diffuse white matter loss on brain MRI
  • Seizures variably present
Abou Jamra et al [2011], Moreno-De-Luca et al [2011], Najmabadi et al [2011]
AP4S1 / SPG52AP-4 complex subunit sigma-1In 5 members of a consanguineous Syrian family:
  • Neonatal hypotonia & severe ID
  • Progressive early childhood-onset SPG, microcephaly, short stature, & facial dysmorphism
Dell'Angelica et al [1999], Hirst et al [1999], Abou Jamra et al [2011]
VPS37A / SPG53Vacuolar protein sorting-associated protein 37AComplicated HSP in 9 persons from 2 Muslim Arab families: developmental delay, progressive lower-extremity spasticity, & subsequently progressive upper-extremity involvement; skeletal dysmorphism (kyphosis & pectus carinatum); mild-to-moderate ID; variable hypertrichosis & impaired vibration sensationZivony-Elboum et al [2012]
DDHD2 / SPG54DDHD2Complicated HSP in affected persons from 4 unrelated families:
  • Onset age <2 years
  • Psychomotor delay, ID, progressive spasticity (leading to foot contractures), thin corpus callosum, periventricular white-matter abnormalities
  • Dysarthria, dysphagia, strabismus, & optic hypoplasia variably present
Al-Yahyaee et al [2006], Schuurs-Hoeijmakers et al [2012]
C12orf65 / SPG55C12orf65, mitochondrialComplicated HSP in 2 Japanese brothers from consanguineous parents:
  • Childhood onset
  • Reduced visual acuity (w/central scotoma & optic atrophy), reduced upper-extremity strength & dexterity, lower-extremity muscle atrophy, & motor sensory neuropathy variably present
Antonicka et al [2010], Shimazaki et al [2012]
CYP2U1 / SPG56Cytochrome P450 2U1Complicated HSP in 5 unrelated families:
  • Early-childhood onset
  • Upper-extremity involvement, upper-extremity dystonia, ID, thin corpus callosum, brain white-matter disturbance, axonal neuropathy, & basal ganglia calcifications variably present
Tesson et al [2012]
GAD1 / (no SPG designation)Glutamate decarboxylase 1In 4 sibs from a consanguineous Pakistani family: spastic cerebral palsy & moderate-to-severe IDMitchell & Bundey [1997], McHale et al [1999], Lynex et al [2004]
SPOAN syndrome
UnknownComplicated HSP: SPG associated w/optic atrophy, neuropathy (SPOAN)Macedo-Souza et al [2005]
5p15.31-14.1 (no SPG designation)Epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5)Complicated HSP associated w/mutilating sensory neuropathyBouhouche et al [2006a], Bouhouche et al [2006b]

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name from OMIM; protein from UniProt.

See Spastic paraplegia: Phenotypic Series to view genes associated with this phenotype in OMIM.

ID = intellectual disability

SPG = spastic paraplegia


Chromosome locus included when the gene is not known


Based on analysis of KIAA0415 (now known as AP5Z1) in 166 unrelated individuals w/SPG (38 recessive, 64 dominant, 64 apparently sporadic) and controls

Table 3.

Summary of Hereditary Spastic Paraplegia – X-Linked Inheritance

Gene / Locus Name
(Chromosome Locus 1)
ProteinClinical SyndromeReferences
L1CAM / SPG1Neural cell adhesion molecule L1Complicated HSP:
  • ID
  • Hydrocephalus, aphasia, & adducted thumbs variably present
Jouet et al [1994]
PLP1 / SPG2Myelin proteolipid proteinComplicated HSP: CNS white-matter abnormality on MRI & peripheral neuropathy variably presentKobayashi et al [1994], Saugier-Veber et al [1994], Cambi et al [1996], Hudson [2003]
UnknownUncomplicated; or complicated by motor aphasia, reduced vision, nystagmus, mild ID, bowel/bladder dysfunctionSteinmüller et al [1997], Tamagaki et al [2000]
SLC16A2 / SPG22Monocarboxylate transport 8Complicated HSP (Allan-Herndon-Dudley syndrome):
  • Congenital onset
  • Neck muscle hypotonia in infancy, ID, dysarthria, ataxia, SPG, abnormal facies
Allan et al [1944], Marx [1991], Bialer et al [1992]
UnknownUncomplicated: onset age 12-25 yearsMacedo-Souza et al [2008]

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name from OMIM; protein from UniProt.

See Spastic paraplegia: Phenotypic Series to view genes associated with this phenotype in OMIM.

ID = intellectual disability

SPG = spastic paraplegia


Chromosome locus included only when the gene is not known

Table 4.

Summary of Hereditary Spastic Paraplegia – Maternal (Mitochondrial) Inheritance

Gene/Locus Name (Chromosome Locus 1)ProteinClinical SyndromeReferences
No SPG designationMitochondrial gene MT-ATP6Progressive spastic paraplegia:
  • Adult onset
  • Mild-to-severe symptoms
  • Axonal neuropathy, late-onset dementia, & cardiomyopathy variably present
Verny et al [2011]

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name from OMIM; protein from UniProt.

Evaluation Strategy

Evaluation strategy to establish the cause of spastic paraplegia in an affected person includes the following:

  • Clinical evaluation. A thorough medical history, neurologic history, and physical examination
  • Family history. A three-generation family history with attention to other relatives with possible HSP. Documentation of relevant findings in family members can be accomplished either through direct examination of those individuals or through review of their medical records including neuroimaging, neuropathology, neurologic examination, and results of molecular genetic testing.
  • Molecular genetic testing, available clinically for many of the HSPs
    • One genetic testing strategy is serial single gene molecular genetic testing based on some combination of factors that may include (but are not limited to) the following:
      • Mode of inheritance
      • Clinical findings (e.g., age at onset, additional clinical features, MRI findings)
      • Prevalence of the disorder (e.g., mutation of SPG4 (encoding spastin), the single most common cause of dominantly inherited HSP, accounts for approximately 30 to 40% of affected individuals)
      • Patient’s ethnicity
    • An alternative genetic testing strategy is use of a multigene panel that includes a combination of genes mentioned in Table 1, Table 2, Table 3, and Table 4. Note: The genes included and the methods used in multigene panels vary by laboratory and over time.
      For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hereditary spastic paraplegia (HSP) may be transmitted in an autosomal dominant manner, an autosomal recessive manner, or an X-linked manner, depending on the genetic subtype in a family.

Risk to Family Members – Autosomal Dominant HSP

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%.
  • The age of onset and degree of disability are highly variable among members of the same family, in different families with the same pathogenic variant, or between genetic types of HSP.

Offspring of a proband. Each child of an individual with autosomal dominant HSP is at a 50% risk of inheriting the pathogenic variant.

Risk to Family Members – Autosomal Recessive HSP

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes, and therefore carry one mutated allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • The unaffected sibs of an affected individual have a 2/3 chance of being heterozygous.
  • Heterozygotes are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive HSP are obligate heterozygotes (carriers) for a mutated allele causing HSP.

Risk to Family Members – X-Linked HSP

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the genetic status of the proband's mother.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Sons who inherit the variant will be affected; daughters who inherit the variant are carriers and will be unaffected.
  • The age of onset, penetrance, and degree of disability are not predictable in members of the same family, in different families with the same pathogenic variant, or between genetic types of HSP.

Offspring of a proband. All daughters of an affected male are carriers; none of his sons will be affected.

Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being carriers or being affected (depending on their gender, family relationship, and the carrier status of the proband's mother).

Related Genetic Counseling Issues

Caution must be exercised when counseling an individual who has all the signs and symptoms of HSP but who has no other similarly affected relatives. Such individuals may be diagnosed as having primary lateral sclerosis (PLS). While such individuals with no known family history of HSP may have autosomal recessive HSP (and thus low risk of transmitting the disorder to offspring), it is also possible that they have X-linked HSP, autosomal dominant HSP with reduced penetrance, a de novo pathogenic variant, mistaken paternity, or an environmentally acquired disorder.

Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for hereditary spastic paraplegia are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Spastic Paraplegia Foundation, Inc.
    7700 Leesburg Pike
    Ste 123
    Falls Church VA 22043
    Phone: 877-773-4483 (toll-free)
  • A.I. Vi.P.S.
    Associazione Italiana Vivere la Paraparesi Spastica Onlus
    Via Tevere, 7
    20020 Lainate (MI)
    Phone: 39 392 9825622
  • Tom Wahlig-Foundation
    Tom Wahlig Stiftung
    Büro Veghestrasse 22
    Phone: 49 (0) 251 - 20 07 91 20


Treatment of Manifestations

At present, there is no specific treatment to prevent or reverse nerve degeneration in HSP. Treatments are directed at reducing symptoms and improving balance, strength, and agility. Current recommendations:

  • Daily regimen of physical therapy directed toward improving cardiovascular fitness, maintaining and improving muscle strength and gait, and reducing spasticity is recommended.
  • Occupational therapy, assistive walking devices, and ankle-foot orthotics are often used.
  • Drugs to reduce muscle spasticity (e.g., Lioresal® [oral or intrathecal], tizanidine, dantrolene, Botox® injections) and reduce urinary urgency (e.g., oxybutynin)

Prevention of Secondary Complications

Daily regimen of physical therapy is recommended to improve cardiovascular fitness, maintain and improve muscle strength and gait, and reduce spasticity.


Patients should be evaluated periodically (annually or as needed) by a neurologist and physiatrist to assess progression and develop treatment strategies to maximize walking ability and reduce symptoms.

Agents/Circumstances to Avoid

Exposure to medications or chemicals that cause neuropathy should be avoided if possible.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

HSP symptoms generally do not change significantly during pregnancy (although, if medications such as baclofen are reduced or discontinued during pregnancy, spasticity may be increased). In general, uncomplicated HSP does not pose increased risk for pregnancy, labor, or delivery. In general, having uncomplicated HSP does not increase risk associated with obstetric anesthesia.

Therapies Under Investigation

Search in the US and in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.


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Chapter Notes

Revision History

  • 6 February 2014 (me) Comprehensive update posted live
  • 3 February 2009 (cd) Revision: sequence analysis for SPG5A available clinically
  • 21 May 2008 (cd) Revision: mutations in ZFYVE26 identified as causative of SPG15
  • 4 March 2008 (cd) Revision: sequence analysis of entire coding region available for SPG8 and SPG33
  • 4 October 2007 (cd) Revision: sequence analysis for SPG10 available on a clinical basis
  • 11 July 2007 (me) Comprehensive update posted live
  • 21 October 2004 (cd) Revision: arginase deficiency added
  • 26 February 2004 (cd) Revision: testing for SPG6 clinically available
  • 15 October 2003 (cd) Revision: test availability
  • 22 September 2003 (me) Comprehensive update posted live
  • 15 August 2000 (me) Overview posted live
  • 21 March 2000 (jf) Original submission
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