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Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview

Synonyms: Strumpell-Lorrain Syndrome, Uncomplicated Hereditary Spastic Paraparesis

, MD, PhD, FACMG.

Author Information and Affiliations

Initial Posting: ; Last Update: June 5, 2025.

Estimated reading time: 22 minutes

Summary

The purpose of this overview is to:

1.

Briefly describe the clinical characteristics of uncomplicated (pure) hereditary spastic paraplegia;

2.

Review the genetic causes of uncomplicated hereditary spastic paraplegia;

3.

Review the differential diagnosis of uncomplicated hereditary spastic paraplegia, which includes complicated hereditary spastic paraplegia with a focus on treatable genetic disorders;

4.

Provide an evaluation strategy to identify the genetic cause of uncomplicated hereditary spastic paraplegia in a proband (when possible);

5.

Review management of uncomplicated hereditary spastic paraplegia;

6.

Inform genetic counseling of family members of an individual with uncomplicated hereditary spastic paraplegia.

1. Clinical Characteristics of Uncomplicated Hereditary Spastic Paraplegia

The predominant manifestations of uncomplicated (pure) hereditary spastic paraplegia (HSP) are progressive 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; while some individuals have spasticity and no demonstrable weakness, others have spasticity and weakness in approximately the same proportions. Onset may occur in very early childhood with (typically) non-progressive manifestations that resemble spastic diplegic cerebral palsy, or later in childhood or older with (typically) slowly progressive manifestations. Though manifestations may be disabling, life span is not shortened.

Individuals with uncomplicated HSP experience the following:

  • Difficulty walking that may be non-progressive or may worsen insidiously (affected individuals often present with stumbling due to difficulties with foot dorsiflexion). After several years, individuals with progressively worsening gait may experience a "functional plateau" (i.e., the rate of further worsening of gait impairment is like that attributable to age).
  • Often, the need for canes, walkers, or wheelchairs
  • Possible urinary urgency (hypertonic urinary bladder disturbance) and lower-extremity paresthesias (mild diminution of distal lower-extremity vibration sensation)
  • Typically, normal strength and dexterity of the upper extremities
  • No involvement of speech, chewing, or swallowing

Lower-extremity hyperreflexia and extensor plantar responses may be demonstrated on neurologic examination.

The combination of progressive gait abnormality and frank, symmetrical corticospinal tract deficit is a clinical hallmark of uncomplicated HSP.

2. Causes of Uncomplicated Hereditary Spastic Paraplegia

To date, more than 20 genes associated with uncomplicated (pure) hereditary spastic paraplegia (HSP) have been identified. Inheritance can be autosomal dominant or autosomal recessive.

It has been emphasized that because the phenotypic spectrum within a given genetic disorder can be broad and intrafamilial variability and interfamilial variability are typical, knowledge of the causative gene does not inform the phenotype in an individual or a family [Darios et al 2022].

Autosomal dominant uncomplicated HSP accounts for 75%-80% of all uncomplicated HSP (see Table 1). Of the autosomal dominant uncomplicated HSPs:

  • SPG4 (caused by a pathogenic variant in SPAST) is the most common, accounting for approximately 40%;
  • SPG3A (caused by a pathogenic variant in ATL1) is the second most common, accounting for approximately 10%-15% overall and >75% of early-onset autosomal dominant uncomplicated HSP;
  • SPG30 (caused by a pathogenic variant in KIF1A) and SPG31 (caused by a pathogenic variant in REEP1) each account for about 5%;
  • Other types of autosomal dominant uncomplicated HSP with a predominantly adult onset are relatively rare, accounting for 1% or less.

Note: Many of the genes included in Table 1 are associated with a phenotypic spectrum encompassing uncomplicated HSP phenotypes as well as HSP phenotypes with variable additional neurologic and/or organ involvement (i.e., complicated HSP). Genes associated exclusively with complicated HSP are not included in Table 1.

Table 1.

Autosomal Dominant Uncomplicated Hereditary Spastic Paraplegia: Genes and Selected Clinical Features

Gene 1SPG DesignationOnsetHSP Phenotype(s)Other
ADAR Not assignedEarly childhoodUncomplicated HSP 2Reported in a single Hispanic person
ALDH18A1 SPG9AAdolescence to adulthood (1 person w/infantile onset)
  • Uncomplicated HSP 3
  • Cataracts
  • Gastroesophageal reflux
  • Motor neuronopathy
  • Variably present: dysarthria, ataxia, cognitive impairment
  • Rare
  • Also assoc w/AR complicated HSP (SPG9B)
ATL1 SPG3A Infantile to childhood (rarely, adult onset)
  • Uncomplicated HSP characterized by minimal progression w/status course; may present as spastic diplegic cerebral palsy
  • Complicated HSP w/axonal motor neuropathy &/or distal amyotrophy w/lower motor neuron involvement (Silver syndrome phenotype)
  • 80% of early-onset AD HSP
  • 10%-15% of all AD HSP
  • AR inheritance reported in 2 families.
ATP2B4 Not assignedAdulthoodUncomplicated HSP 4Single family
BSCL2 SPG17 (See BSCL2-Related Neurologic Disorders / Seipinopathy.)Adulthood
  • Uncomplicated HSP (foot deformity may be present)
  • Complicated HSP w/amyotrophy of leg muscles &/or pathologic nerve conduction velocities; can be indistinguishable from ALS
Rare
CPT1C SPG73 (OMIM 616282)Early adulthoodUncomplicated HSP (foot deformity may be present)Single family
DNM2 Not assignedBefore age 20 yrsPredominantly uncomplicated HSP w/variable axonal polyneuropathy & mild distal amyotrophy in feet 5Single family
ERLIN2 SPG18AJuvenile to adulthood
  • Uncomplicated HSP 6
  • Amyotrophy w/ALS-like phenotype can develop in later stages of disease
Most pathogenic variants are assoc w/AR HSP (see Table 2).
HSPD1 SPG13 (OMIM 605280)AdulthoodPredominantly uncomplicated HSP w/mild distal amyotrophyRare
KIF1A SPG30A 7Juvenile to adulthood
  • Uncomplicated HSP
  • Complicated HSP ± mild ID, optic nerve atrophy, & rarely epilepsy 7
  • 5%-6% of all AD HSP
  • Also assoc w/AR hereditary sensory & motor neuropathy type 2 8
KIF5A SPG10 (OMIM 604187)Juvenile or adulthood
  • Uncomplicated HSP or predominantly uncomplicated HSP
  • Complicated HSP w/polyneuropathy, pes cavus, &/or ataxia
  • 1%-2% of all AD HSP
  • 5%-8% of all complicated AD HSP
NIPA1 SPG6 9Adulthood (infantile onset rare)
  • Uncomplicated HSP characterized by severe weakness & spasticity; rapidly progressive
  • Complicated HSP w/epilepsy or variable peripheral neuropathy
Rare (~1% of AD HSP)
REEP1 SPG31 (OMIM 610250)2nd to 7th decadesUncomplicated HSP or predominantly uncomplicated HSP w/mild amyotrophyCommon; 4%-6% of all AD HSP
REEP2 SPG72A (OMIM 615625)Very early; average age 4 yrsPredominantly uncomplicated HSP w/musculoskeletal problems & mild postural tremor
  • Rare
  • Inheritance can be AD or AR.
RTN2 SPG12 (OMIM 604805)Before age 20 yrsUncomplicated HSP5% of early-onset AD HSP, but overall rare
SLC33A1 SPG42 (OMIM 612539)Early adulthood
  • Uncomplicated HSP w/mild pes cavus; slowly progressive
  • Complicated HSP
SPAST SPG4 Infancy to 7th decade
  • Uncomplicated HSP. Subtle cognitive impairment has been documented but its relation to the disease remains undetermined (deficits appear late in disease course & are not present in all affected members of a given family).
  • Complicated HSP w/variable distal amyotrophy &/or ataxia
40% of AD HSP
SPG7 SPG7 Juvenile or adulthood
  • Uncomplicated HSP
  • Complicated HSP w/dysarthria, ataxia, optic atrophy, &/or supranuclear palsy
AD inheritance suggested for some pathogenic variants, but rare
WASHC5 SPG8 Adulthood (rarely, infantile onset)Uncomplicated HSP w/severe motor deficit in some personsRare (~1% of AD HSP)

AD = autosomal dominant; AR = autosomal recessive; ALS = amyotrophic lateral sclerosis; HSP = hereditary spastic paraplegia; ID = intellectual disability;

1.

Genes are listed alphabetically.

2.
3.
4.
5.
6.
7.
8.
9.

Autosomal recessive HSP accounts for 25%-30% of all HSP (see Table 2). Autosomal recessive HSP is very heterogeneous with an ever-growing list of newly identified genes. Many new causes of autosomal recessive HSP are very rare and may be limited to a single family or even a single individual. The frequency is increased in populations with a higher degree of consanguinity.

The most common types of autosomal recessive HSP in the general population are:

  • SPG5 (caused by pathogenic variants in CYP7B1), which accounts for 7.3% of all autosomal recessive HSP and 3% of simplex nonsyndromic spastic paraplegia (i.e., a single occurrence in a family);
  • SPG7 (caused by pathogenic variants in SPG7), which may account for approximately 5% of all autosomal recessive HSP;
  • SPG11 (caused by pathogenic variants in SPG11), which accounts for 3%-5% of all autosomal recessive HSP and 75% of individuals with either uncomplicated HSP and complicated HSP who have thin or absent corpus callosum on brain imaging.

Note: Most of the genes included in Table 2 are associated with a phenotypic spectrum encompassing uncomplicated HSP phenotypes and HSP phenotypes with variable additional neurologic and/or organ involvement (i.e., complicated HSP). Genes associated exclusively with complicated HSP are not included in Table 2.

Table 2.

Autosomal Recessive Uncomplicated Hereditary Spastic Paraplegia: Genes and Selected Clinical Features

Gene 1SPG DesignationOnsetHSP Phenotype(s)Other
AP5Z1 SPG48 (OMIM 613647)Typically adulthood (rarely, infantile onset)
  • Uncomplicated HSP w/urinary incontinence
  • Complicated HSP w/parkinsonism, dystonia, thin corpus callosum, & leukodystrophy; severe DD in infantile onset
ATL1 SPG3A Infantile to childhood (rarely, adult onset)
  • Uncomplicated HSP w/minimal progression & static course; may present as spastic diplegic cerebral palsy
  • Complicated HSP w/peripheral neuropathy; autonomic failure reported
AR inheritance is very rare; almost exclusively inherited in an AD manner
CYP7B1 SPG5 (OMIM 270800)Juvenile to early adulthood
  • Uncomplicated HSP
  • Complicated HSP w/ataxia, polyneuropathy, extrapyramidal signs, & MRI signs of leukodystrophy
SPG5A was diagnosed in 9/172 families w/histories consistent w/AR inheritance of HSP. 2
DDHD1 SPG28 (OMIM 609340)Childhood
  • Uncomplicated HSP
  • Complicated HSP w/scoliosis, axonal neuropathy, & cerebellar ataxia
Rare
ERLIN2 SPG18 3Childhood
  • Uncomplicated HSP
  • Complicated HSP w/DD, seizures, & contractures; juvenile primary lateral sclerosis phenotype reported
  • Rare
  • Typically assoc w/complicated HSP (uncomplicated AR HSP reported rarely)
  • Also assoc w/AD uncomplicated HSP
REEP2 SPG72B (OMIM 620606)Early childhoodPredominantly uncomplicated HSP w/musculoskeletal problems & mild postural tremor
  • Rare
  • Inheritance can be AD or AR.
SPG7 SPG7 Juvenile or adulthood
  • Uncomplicated HSP
  • Complicated HSP incl optic neuropathy, progressive external ophthalmoplegia/ptosis, slowed speech, swallowing difficulties, palatal tremor, & subtle cognitive impairment
  • 5%-12% of AR HSP
  • AD inheritance suggested for some pathogenic variants; this remains controversial
SPG11 SPG11 Infancy to early adolescence
  • Uncomplicated HSP
  • Complicated HSP w/ID, polyneuropathy, & ataxia; can also present as juvenile ALS.
Typically assoc w/complicated HSP (uncomplicated AR HSP reported rarely)
USP8 SPG59 4ChildhoodUncomplicated HSPRare

AD = autosomal dominant; AR = autosomal recessive; ALS = amyotrophic lateral sclerosis; DD = developmental delay; HSP = hereditary spastic paraplegia; ID = intellectual disability

1.

Genes are listed alphabetically.

2.
3.
4.

3. Differential Diagnosis of Uncomplicated Hereditary Spastic Paraplegia

The differential diagnosis of uncomplicated (pure) hereditary spastic paraplegia (HSP) includes complicated HSP (characterized by the impairments present in uncomplicated HSP plus other system involvement or other neurologic findings such as ataxia, seizures, intellectual disability, dementia, muscle atrophy, extrapyramidal disturbance, and/or peripheral neuropathy), other genetic disorders, and acquired conditions.

Treatable genetic disorders of interest in the differential diagnosis of uncomplicated HSP include:

Other genetic disorders in the differential diagnosis of uncomplicated HSP include the following (see also Hedera [2018]):

Non-genetic disorders to be considered in the differential diagnosis of uncomplicated HSP include the following:

  • Steadily progressive multiple sclerosis
  • Diplegic form of cerebral palsy (CP) with corresponding MR imaging abnormalities. However, several individuals with presumed CP have had pathogenic variants in genes associated with HSP identified on molecular genetic testing associated with either autosomal dominant or autosomal recessive inheritance [Rainier et al 2006, Hedera 2013].
  • Infection including human immunodeficiency virus (HIV/AIDs), tropical spastic paraplegia (also known as human T-cell leukemia virus 1 [HTLV1]-associated myelopathy), and neurosyphilis
  • Structural abnormalities involving the brain or spinal cord (e.g., tethered cord syndrome and spinal cord compression)
  • Vascular abnormalities including arteriovenous abnormalities or fibrocartilaginous embolism
  • Demyelinating disorders including primary progressive multiple sclerosis or Devi's disease (neuromyelitis optica)
  • Paraneoplastic myelopathies including those associated with anti-GAD65 antibodies
  • Nutritional disorders (reviewed in Hedera [2016]) including copper deficiency and vitamin B12 and E deficiencies

Note: A complete list of non-genetic disorders in the differential diagnosis of uncomplicated HSP is out the scope of this chapter; see Hedera [2016].

4. Evaluation Strategies to Identify the Genetic Cause of Uncomplicated Hereditary Spastic Paraplegia in a Proband

Establishing a specific genetic cause of uncomplicated (pure) hereditary spastic paraplegia (HSP):

  • Can aid in discussions of prognosis (which are beyond the scope of this GeneReview) and genetic counseling;
  • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.

Family history. A three-generation family history should be taken, with attention to relatives with manifestations of uncomplicated HSP and documentation of relevant findings through direct examination or review of medical records, including results of genomic/genetic testing.

Genomic/Genetic Testing

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.

  • A multigene panel that includes some or all the genes listed in Tables 1 and 2 is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered. Exome sequencing is most commonly used; genome sequencing is also possible.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

5. Management

No clinical practice guidelines for uncomplicated (pure) hereditary spastic paraplegia (HSP) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder and information provided by Spastic Paraplegia Foundation.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with uncomplicated HSP, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Uncomplicated Hereditary Spastic Paraplegia: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Spasticity Neurologic examAssess degree of spasticity. 1
Motor & sensory
neuropathy 		NCV, EMG
Musculoskeletal Physical medicine & rehab / PT evalTo include assessment of:
  • Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
  • Need for adaptive devices
  • Footwear needs
  • PT needs
OrthopedicsTo assess for scoliosis & foot deformities
OT
  • To assess small motor function, e.g., hands, feet, face, fingers, & toes
  • To assess ADL
Bladder function
  • Referral to urologist
  • Consider urodynamic eval.
To address spastic bladder symptoms: urgency, frequency, difficulty voiding
Bowel function Referral to gastroenterologistTo assess constipation & fecal incontinence 1
Bulbar muscle
weakness 		Assessment by SLPAssess for speech disorder (dysarthria) &/or swallowing disorder (dysphagia).
Genetic counseling By genetics professionals 2To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of uncomplicated HSP to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:
  • Community or online resources such as Parent to Parent
  • Social work involvement for parental support

ADL = activities of daily living; EMG = electromyography; HSP = hereditary spastic paraplegia; MOI = mode of inheritance; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist

1.

Spastic Paraplegia Rating Scale (SPRS) [Schüle et al 2006]

2.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

At present, no specific treatments can prevent or reverse nerve degeneration in uncomplicated HSP. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Table 4.

Uncomplicated Hereditary Spastic Paraplegia: Treatment of Manifestations

Manifestation/ConcernTreatment/ReferralConsiderations/Other
Spasticity/
Distal weakness 		Individualized PT program
  • Stretching exercises to improve flexibility, ↓ spasticity, & maintain or improve joint range of motion & prevent joint contractures 1
  • Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination, & balance
  • Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL
Reduction of spasticity
  • Massage, ultrasound, electrical stimulation, whirlpool
  • Anodal spinal direct current stimulation 2
Antispasmodic drugsBaclofen, botulinum toxin, dantrolene, tizanidine (used 1 at a time), 3 esp early in disease course to ↓ cramps, make leg muscles less tight, & facilitate walking
Musculoskeletal Correction & stabilization of scoliosisOrthopedic consult for mgmt of scoliosis: bracing, possible spinal surgery
Correction of pes cavusPT for pes cavus, orthotics, botulinum toxin therapy, possible corrective surgery by orthopedic surgery
Bladder dysfunction Treatment can incl anticholinergics such as oxybutynin, solifenacin, & mirabegron.For spastic bladder symptoms: urgency, frequency, difficulty voiding, incontinence
Dysphagia Treatment by gastroenterologist / nutritionist / feeding team
  • Determine exact cause of swallowing malfunction.
  • Modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.
Dysarthria Treatment by SLPTo help maintain vocal control & improve speech, breathing techniques, & communication in general
Bowel function Stool softenersFor constipation & fecal incontinence
Mobility & ADL PT
  • Appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores
  • Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
  • Transfers (e.g., from bed to wheelchair, wheelchair to car)
  • Training how to fall to minimize risk of injury
OT
  • To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming
  • To assist w/household modifications to meet special needs
Psychological By psychologist / social workerPsychological support, social support

ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist; SLP = speech-language pathologist

1.

The role of surgical hamstring and heel cord lengthening and release of the adductor longus remains unknown but should be considered if contractures appear.

2.

Demonstrated by Ardolino et al [2021] in a randomized controlled trial

3.

Baclofen can be tried first and can be used with an intrathecal pump in some individuals. The entire therapeutic range of doses in all four drugs is used. The drugs are administered before sleep if nocturnal cramps are problematic; otherwise, three to four times per day. It usually takes a few days for their effects to become evident. No significant toxicity limits their use.

Surveillance

There is no consensus regarding the frequency of clinical follow up visits; however, routine reevaluations for individuals with uncomplicated HSP are warranted (see Table 5).

Table 5.

Uncomplicated Hereditary Spastic Paraplegia: Recommended Surveillance

System/ConcernEvaluationFrequency
Spasticity Neurologic exam re disease progression & response to current treatment1-2x/yr
Bladder function Per treating urologist, incl monitoring for urinary tract infection
Dysphagia Gastroenterologist / nutritionist / feeding team re nutrition & risk for aspiration
Dysarthria Per neurologic assessment & speech-language assessment
Scoliosis General medical exam of musculoskeletal system
Bowel function Per clinical manifestations
Mobility & ADL Per rehab medicine & PT/OT team
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit

ADL = activities of daily living; OT = occupational therapist; PT = physical therapist

Agents/Circumstances to Avoid

Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness that can adversely affect overall mobility.

6. Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Uncomplicated (pure) hereditary spastic paraplegia (HSP) can be inherited in an autosomal dominant or autosomal recessive manner. Genetic counseling and risk assessment depend on determination of the specific genetic cause of uncomplicated HSP in an individual.

Several genes involved in uncomplicated HSP are associated with both autosomal dominant and autosomal recessive HSP (see Causes of Uncomplicated Hereditary Spastic Paraplegia).

Autosomal Dominant Uncomplicated HSP – Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with autosomal dominant uncomplicated HSP have an affected parent.
  • Some individuals diagnosed with autosomal dominant uncomplicated HSP have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with autosomal dominant uncomplicated HSP caused by a de novo pathogenic variant is unknown.
  • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, de novo occurrence of an HSP-related pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the pathogenic variant.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • The age of onset and degree of disability are highly variable among heterozygous members of the same family.
  • If the HSP-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
  • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the HSP-related pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Uncomplicated HSP – Risk to Family Members

Parents of a proband

Sibs of a proband

  • If both parents are known to be heterozygous for an autosomal recessive uncomplicated HSP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
  • Heterozygous sibs are typically asymptomatic provided the family history is consistent with autosomal recessive inheritance and affected individuals have biallelic pathogenic variants.

Offspring of a proband. The offspring of an individual with autosomal recessive uncomplicated HSP are obligate heterozygotes (carriers) for an HSP-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an HSP-related pathogenic variant.

Related Genetic Counseling Issues

Caution must be exercised when counseling an individual who has all the signs and symptoms of uncomplicated HSP but no similarly affected relatives and in whom a molecular diagnosis has not been established. Without a molecular diagnosis of HSP, the possibility of a diagnosis other than uncomplicated HSP (e.g., primary lateral sclerosis or an acquired disorder) cannot be ruled out and a mode of inheritance cannot be definitively established.

Knowledge of the causative gene does not inform the phenotype in an individual or a family because the phenotypic spectrum within a given genetic disorder can be broad and intrafamilial variability is typical [Darios et al 2022].

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having an HSP-related pathogenic variant; however, it is not possible to make specific predictions about the potential severity of disease in offspring.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

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.

Chapter Notes

Author Notes

Dr Peter Hedera (ude.ellivsiuol@aredeh.retep) is actively involved in clinical research regarding individuals with hereditary spastic paraplegia. He would be happy to communicate with persons who have any questions regarding diagnosis of HSP or other considerations.

Web page: www.uoflhealth.org/provider/peter-hedera-neurology

Author History

John K Fink, MD; University of Michigan (2000-2018)
Peter Hedera, MD, PhD, FACMG (2018-present)

Revision History

  • 5 June 2025 (bp) Comprehensive update posted live
  • 27 September 2018 (ha) Comprehensive update posted live
  • 6 February 2014 (me) Comprehensive update posted live
  • 11 July 2007 (me) Comprehensive update posted live
  • 22 September 2003 (me) Comprehensive update posted live
  • 15 August 2000 (me) Overview posted live
  • 21 March 2000 (jf) Original submission

References

Literature Cited

  • Ardolino G, Bocci T, Nigro M, Vergari M, Di Fonzo A, Bonato S, Cogiamanian F, Cortese F, Cova I, Barbieri S, Priori A. Spinal direct current stimulation (tsDCS) in hereditary spastic paraplegias (HSP): A sham-controlled crossover study. J Spinal Cord Med. 2021;44:46-53. [PMC free article: PMC7919872] [PubMed: 30508408]
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