Hereditary Spastic Paraplegia

Hereditary Spastic Paraplegia – Introduction

• Group of heterogeneous neurodegenerative disorders caused by monogenic mutations that result in lower limb spasticity and weakness with or without additional clinical findings depending on the specific mutation^(1,2,3)
• Most common neuropathological sign is axonal degeneration involving lateral corticospinal tracts in cervical and thoracic spinal cord⁽¹⁾

Synonyms

• Strumpell-Lorrain disease (SPG4)
• MASA syndrome (SPG1)
• CRASH syndrome (SPG1)
• Gareis-Mason syndrome (SPG1)
• X-linked paraplegia (SPG1)
• X-linked hydrocephalus (SPG1)
• MAST syndrome (SPG21)
• FAHN syndrome (SPG35)

Types

• genetic types of HSP are numerically named by the order in which the genetic loci or gene was discovered^(2,3)
  • > 80 genetic types have been identified
  • many types have only been found in single families
  • complete list of HSP genetic types can be found at National Organization for Rare Disorders (NORD) 2015 Feb PDF or in GeneReviews 2021 Feb 11
  • genetic types are classified by inheritance pattern⁽³⁾
    • autosomal dominant HSP – most common, accounts for reported 75%-80% of individuals with HSP
    • autosomal recessive HSP – heterogeneous group accounts for reported 25%-30% of all individuals with HSP
    • X-linked HSP and mitochondrial HSP – rarest genetic forms account for < 1%-2% of individuals with HSP

Table 1: Relative Prevalence and Characteristic Features of More Common Hereditary Spastic Paraplegia (HSP) Types

Genetic Subtype (Affected Gene, Inheritance Pattern)	Relative Prevalence	Presentation
SPG4 (SPAST, AD)	Most common HSP typeAccounts for reported third of all HSP, 40%-60% of AD HSP, and 15% of sporadic cases	Mean age of onset 32 yearsLower limb spasticity +/- bladder or sensory dysfunction
SPG3A (ATL1, AD)	Second most common AD typeAccounts for reported 75% of AD HSP with early onset and 10%-15% of all AD HSP	Mean age of onset 5.6 yearsLower limb spasticity +/- bladder or sensory dysfunctionAxonal motor neuropathy in reported 25% of cases
SPG31 (REEP1, AD)	Accounts for reported 5% of AD HSP	Age of onset variesLower limb spasticity +/- bladder or sensory dysfunctionAxonal motor neuropathy in reported 50% of cases
SPG30 (KIF1A, AD)	Accounts for reported 5% of AD HSP	Onset in childhood or adulthoodPresentation may include ID
SPG5A (CYP7B1, AR)	Accounts for reported 7.3% of all AR HSP	Onset in childhood or adulthoodClinical features include ataxia, polyneuropathy, extrapyramidal signs, sings of leukodystrophy on MRI
SPG7 (SPG7, AR)	Accounts for reported 5% of all AR HSP	Reported mean age of onset is 41.7 yearsPresents with lower limb spasticity and cerebellar ataxiaProgressive external ophthalmoplegia may be a diagnostic clue
SPG11 (SPG11, AR)	Accounts for reported 8% of all HSP and 75% of HSP cases with radiologic signs of absent or thin CC	Age of onset range is 4-36 yearsPresentation varies and can include cognitive impairment preceding lower limb spasticity

Citation: Abbreviations: AD, autosomal dominant; AR autosomal recessive; CC, corpus callosum; HSP, hereditary spastic paraplegia; ID, intellectual disability; MRI, magnetic resonance imaging. References – Lancet Neurol 2019 Dec;18(12):1136, GeneReviews 2021 Feb 11.

• HSP can alternatively be classified by signs and symptoms (Harding’s classification)^(1,3)
  • uncomplicated HSP (“pure”) characterized by neurologic signs alone
  • complicated HSP characterized by both neurologic and nonneurologic signs

Epidemiology

Incidence/Prevalence

• reported range in prevalence of HSP is 1.8-9.8 cases per 100,000 persons⁽¹⁾
• variation by geographic region⁽¹⁾
  • prevalence in Europe reported to be 3-10/100,000 people
  • prevalence in Japan reported to be 0.2/100,000 people

Risk Factors

• family history of HSP, although 13%-40% of reported cases occur sporadically with no family history⁽²⁾
• autosomal recessive forms commonly seen in consanguineous families^(1,2,3)

Etiology and Pathogenesis

Causes

• pathogenic variant in HSP-related gene^(1,2,3)
• SPG4 is most common HSP type⁽²⁾
  • caused by pathogenic variant in SPAST gene
  • encodes spastin, a protein involved in regulation of microtubule dynamics
  • inheritance is autosomal dominant
• numerous affected genes in HSP, including spastin, are involved in regulation of the endoplasmic reticulum network⁽²⁾
  • pathogenic variants in ATL1 gene that encodes atlastin-1, an integral membrane protein that is enriched in the central nervous system, cause SPG3A; inheritance is autosomal dominant
  • pathogenic variants in REEP1 gene that encodes REEP-1 cause SPG31; inheritance is autosomal dominant
• SPG5 is caused by pathogenic variants in CYP7B1 gene that encodes oxysterol-7alpha-hydroxylase that breaks down cholesterol into primary bile acids⁽²⁾
• complete list of affected genes by HSP type can be found at National Organization for Rare Disorders (NORD) 2015 Feb PDF or in GeneReviews 2021 Feb 11

Pathogenesis

• pathogenesis of HSP is dependent upon specific type and affected gene^(1,2)
• type-specific pathogenesis may include abnormalities in⁽¹⁾
  • cellular membrane and organelle trafficking
  • axonal transport
  • mitochondrial function
  • lipid metabolism
  • myelination
• axonal degeneration in HSP^(1,2)
  • leads to atrophy in cervical and thoracic sections of spinal cord
  • typically affects long sensory and motor axons of corticospinal tract and dorsal column
  • may affect shorter neurons, including those of the cerebellum, basal ganglia, anterior horn cells and Clarke’s column
  • may also involve peripheral nerves leading to motor and sensory neuropathy
• developmental abnormalities of the central nervous system may also be related to HSP⁽¹⁾

History and Physical

Clinical Presentation

Uncomplicated HSP

• slowly progressive gait disturbance is most common initial presentation⁽²⁾
• patients have difficulty walking and may require canes, walkers, or wheelchairs⁽³⁾
• infants and children with early-onset HSP typically present with delayed motor milestones that might be mistaken for cerebral palsy⁽²⁾
• limb spasticity is demonstrable only with walking and is further characterized by⁽²⁾
  • absent limb weakness
  • possible slight asymmetry
• additional findings may include⁽²⁾
  • asymptomatic upper limb hyperreflexia without spasticity (common)
  • brisk jaw jerk
  • urinary symptoms due to detrusor instability or sphincter dyssynergia (common in later stages of disease)
• upper extremities typically have normal dexterity and strength⁽³⁾
• speech, chewing, and swallowing are not affected⁽³⁾

Complicated HSP

• in addition to neurologic impairments seen in uncomplicated HSP, patients with complicated HSP also have either additional neurologic findings or other system involvement^(1,3)
• neurologic signs include⁽²⁾
  • cerebellar abnormalities such as tremor, ataxia, or nystagmus
  • cognitive impairment including dementia and intellectual disability
  • epilepsy
  • peripheral neuropathy causing dysautonomia and sensory abnormalities
  • ptosis and ophthalmoparesis
  • psychiatric disturbances
  • extrapyramidal findings such as chorea, parkinsonism, and dystonia
• nonneurological signs include⁽¹⁾
  • ophthalmologic abnormalities including
    • optic atrophy
    • cataracts
    • optic neuropathy
    • macular degeneration
    • retinitis pigmentosa
  • dysmorphic features including facial dysmorphisms, micro- or macrocephaly, and short stature
  • orthopedic anomalies such as scoliosis, hip dislocation, or foot deformities

Clinical Presentation of Selected HSP Types

• SPG4⁽¹⁾⁽²⁾
  • mean age of onset is 32 years but has been reported to present as late as age 70 years
  • presents with lower limb spasticity with or without bladder or sensory dysfunction
  • ataxia, peripheral motor involvement, cognitive impairment, extrapyramidal abnormalities, dysarthria, and dysphagia have been reported in a small minority of cases
• SPG3A⁽²⁾
  • mean age of onset 5.6 years
  • similar presentation to SPG4 but axonal peripheral motor neuropathy such as loss of stretch reflexes or muscle atrophy more common and reported in up to 25% of cases
• SPG31⁽²⁾
  • bimodal age of presentation with peaks in first and fourth decades of life
  • usually presents as a pure form with lower limb spasticity similar to SPG3A but axonal peripheral neuropathy reported in up to 50% of cases
• SPG11⁽²⁾
  • presents between ages 4-36 years always as complicated HSP
  • phenotype is variable, sometimes even among affected individuals in the same family
  • most present with cognitive impairment that precedes lower limb spasticity
  • lower limb spasticity usually develops in second decade of life
  • dysarthria, ataxia, axonal motor neuropathy, or prominent urinary symptoms develop in more than half of patients
  • upper limb involvement is common as disease progresses
  • levodopa-responsive parkinsonism, oromandibular dystonia, seizures, and visual failure from optic atrophy have also been reported
• SPG7⁽²⁾
  • presents at a mean age of 42 years
  • more common in men than women
  • initially presents with combination of mild lower limb spasticity and cerebellar ataxia
  • progressive waddling gait consistent with associated myopathic weakness
  • external ophthalmoplegia may be seen
• SPG5⁽²⁾
  • median age of onset 13 years with range 1-33 years
  • more common in Chinese population
  • severe dorsal column dysfunction is common as is a sensory ataxia of lower limbs
  • urinary symptoms are prominent and some may have concomitant rectal urgency and incontinence
  • cognition is usually normal

History

History of Present Illness (HPI)

• ask about onset of symptoms⁽²⁾
• obtain detailed and age-appropriate developmental history including⁽²⁾
  • vision or hearing problems
  • delays in achieving gross and fine motor and language-related developmental milestones
  • evidence of regression or loss of previously mastered skills
• ask questions to exclude acquired and treatable conditions for progressive spastic paraplegia⁽²⁾
• ask about presence of urinary symptoms or fecal urgency or incontinence⁽²⁾
• ask about additional symptoms that occur in complicated HSP including⁽¹⁾
  • cognitive impairment or learning difficulties
  • psychiatric symptoms
  • sensory disturbances
  • chorea, dystonia, or parkinsonian symptoms
  • visual disturbances
  • seizures

Past Medical History (PMH)

• ask about birth history and prior illnesses which may suggest an acquired cause of spastic paraplegia such as infections, neoplasia, and nutritional deficiencies⁽²⁾
• ask about history of orthopedic anomalies such as scoliosis, hip dislocation, and foot deformities as they may be related to complex form HSP⁽¹⁾

Family History (FH)

• ask about family history of HSP which may point to specific inheritance pattern, and other neurological diseases which may be allelic variants of HSP^(1,2)

Physical

General Physical

• cognitive and motor developmental milestones may be delayed or intellectual disability may be present^(1,2)
• dysmorphic features may be present including⁽¹⁾
  • macrocephaly
  • microcephaly
  • short stature
  • dysmorphic facial features
  • pectus carinatum
  • other complex deformative syndromes

Skin

• skin findings in select, rare HSP types⁽¹⁾
  • hyperpigmentation of exposed areas and patchy vitiligo (SPG23)
  • hypertrichosis (SPG53)

HEENT

• ocular findings are common and may include⁽¹⁾
  • optic atrophy
  • cataracts
  • optic neuropathy and optic nerve atrophy
  • macular degeneration
  • retinitis pigmentosa
  • ptosis and ophthalmoparesis
  • nystagmus
• hearing loss may occur in specific types⁽¹⁾

Neuro

• assess for length-dependent corticospinal tract and dorsal column degeneration findings including^(1,2)
  • bilateral lower limb spasticity (can be asymmetrical)
  • hyperreflexia in lower limbs and may be present in upper limbs without associated spasticity
  • brisk jaw jerk may be present
  • extensor plantar responses (Babinski sign present)
  • decreased vibration sense
  • abnormal proprioception
• dysarthria and dysphagia may be present in specific types⁽¹⁾

Diagnosis

Making the Diagnosis

• clinical diagnosis of HSP is based on both^(1,3)
  • presence of spastic paraparesis with or without other supporting neurologic or systemic findings
  • exclusion of acquired and other inherited causes of spastic paraplegia
• detailed developmental and family history can help narrow the list of possible HSP types⁽¹⁾
• molecular diagnosis of HSP confirmed with identification of pathogenic variant in HSP-associated gene^(1,2,3)
• reported 51%-71% of suspected cases of HSP, with or without positive family history, are not confirmed with genetic diagnosis despite use of gene panels or whole-exome sequencing⁽²⁾

Differential Diagnosis

Other Genetic Causes of Progressive Spastic Paraplegia

• leukodystrophies (associated genes)^(2,3)
  • adrenoleukodystrophy (ABCD1)
  • adrenomyeloneuropathy, allelic to adrenoleukodystrophy
  • Aicardi-Goutieres syndrome (IFIH1, ADAR, KLC2, RNASEH2B, TREX1)
  • autosomal dominant adult-onset demyelinating leukodystrophy (LMNB1)
  • Alexander disease (GFAP)
  • cerebrotendinous xanthomatosis (CYP27A1)
  • hypomyelinating leukodystrophy with atrophy of basal ganglia and cerebellum (TUBB4A)
  • hypomyelination with brainstem and spinal involvement and leg spasticity (DARS
  • Tay-Sachs disease (HEXA)
  • Sandhoff disease (HEXB)
  • GM2 activator deficiency (GM2A)
  • Krabbe disease (GALC)
  • leukoencephalopathy with brainstem, spinal cord involvement, and lactate elevation (DARS2)
  • metachromatic leukodystrophy (ARSA)
  • Pelizaeus-Merzbacher disease (GJC2), allelic to X-linked HSP-SPG2
• alpha-methyl-acyl-CoA racemase deficiency⁽¹⁾
• Gaucher disease⁽¹⁾
• neurometabolic diseases (involved genes)
  • cobalamin-related remethylation disorders (MMACHC, MMADHC, others)^(2,3)
  • glucose transporter type 1 deficiency syndrome (SLC2A1)⁽²⁾
  • Dopa-responsive dystonia (GCH, TH, others)^(2,3)
  • primary coenzyme Q10 deficiencies (COQ2, APTX, others)⁽²⁾
  • Sjogren-Larsson syndrome (ALDH3A2)⁽¹⁾
  • biotinidase deficiency (BTD)^(2,3)
  • phenylketonuria (PHU)^(2,3)
  • nonketotic hyperglycinemia⁽¹⁾
  • cerebral folate deficiency syndrome⁽¹⁾
  • homocarnosinosis⁽¹⁾
  • urea cycle defects^(1,3)
  • methylene tetrahydrofolate reductase deficiency⁽³⁾
  • cerebrotendinous xanthomatosis⁽³⁾
  • adult polyglucosan body disease (GBE1, allelic to glycogen storage disease type IV)⁽³⁾
  • nucleoside phosphorylase deficiency (PNP)⁽³⁾
• neurodegenerative diseases
  • spastic ataxias – autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and spastic ataxias (SPAX)⁽¹⁾
  • Friedrich ataxia⁽²⁾
  • motor neuron disease- juvenile familial amyotrophic lateral sclerosis⁽¹⁾
  • spinocerebellar ataxias^(1,3)
  • beta-propeller protein-associated neurodegeneration⁽²⁾
  • PLA2G6-associated neurodegeneration⁽²⁾
  • Charcot-Marie-Tooth neuropathy⁽¹⁾
  • centronuclear myopathy⁽¹⁾
  • diplegic cerebral palsy⁽³⁾
  • slowly progressive amyotrophic lateral sclerosis⁽³⁾
• inherited dementias including presenilin-1 or -2 (PSEN1 or PSEN2), amyloid precursor protein, and GRN-related disorders^(1,3)

Acquired Causes of Spastic Paraplegia

• structural abnormalities of brain or spinal cord^(1,2,3)
  • cervical spondylosis
  • spinal or parasagittal neoplasia such as astrocytoma, B-cell lymphoma, ependymoma
  • Chiari malformation
  • atlanto-axial subluxation
  • tethered cord
• demyelinating disorders^(1,3)
  • neuromyelitis optica
  • multiple sclerosis
• vascular abnormalities
  • dural arteriovenous malformation^(2,3)
  • fibrocartilaginous embolism^(1,3)
  • spinal cord infarction⁽¹⁾
  • posterior reversible encephalopathy syndrome with spinal cord involvement⁽¹⁾
• infectious causes
  • human T-lymphotropic virus (HTLV)^(1,2,3)
  • human immunodeficiency virus (HIV)^(1,2,3)
  • neurosyphilis^(1,2,3)
  • cytomegalovirus⁽¹⁾
  • schistosomiasis⁽¹⁾
• nutritional deficiencies
  • vitamin B12 deficiency^(1,2,3)
  • copper deficiency^(1,2,3)
  • vitamin E deficiency⁽³⁾
• toxic or iatrogenic causes⁽²⁾
  • radiation myelopathy
  • lathyrism – irreversible, nonprogressive spastic paraparesis caused by excessive consumption of the chickling pea, Lathyrus sativus (Neurobehav Toxicol Teratol 1983 Nov;5(6):625)
• neurodegenerative – primary lateral sclerosis^(2,3)
• paraneoplastic syndromes associated with following antibodies^(1,3)
  • anti-amphiphysin
  • anti-CRMP-5/CV2
  • anti-Hu
  • anti-GAD65

Testing Overview

• workup focuses on differentiating HSP from other causes of spastic paraplegia and may include⁽¹⁾
  • neuroimaging of brain and spinal cord
  • cerebrospinal fluid analysis
  • neurophysiologic studies
  • complete ophthalmologic exam
  • blood tests for hereditary metabolic disorders and infectious etiologies
• genetic testing used to confirm diagnosis of HSP and identify HSP type, as well as diagnose other inherited disorders that can cause spastic paraplegia, particularly those that are treatable
• in some cases, magnetic resonance imaging may help discern HSP type

Blood Tests

• to rule out acquired and other genetic causes of spastic paraplegia, consider^(1,2)
  • serology for infectious etiologies including
    • human T-lymphotropic virus
    • HIV
    • cytomegalovirus
    • syphilis
    • schistosomiasis antibodies
  • metabolic studies including
    • vitamin B12
    • methylmalonic acid
    • homocysteine
    • serum copper
    • very long chain fatty acids for adrenoleukodystrophy
    • cholestanol for cerebrotendinous xanthomatosis
  • measurement of enzymatic activity including
    • hexosaminidase A and total beta-hexosaminidase for Tay-Sachs disease, Sandhoff disease, and GM2 activator deficiency
    • galactocerebrosidase for Krabbe disease
    • arylsulfatase A for metachromatic leukodystrophy
    • plasma amino acids for arginase deficiency and phenylketonuria (PKU)
    • biotinidase for biotinidase deficiency

Imaging Studies

• although unremarkable for most types of HSP, magnetic resonance imaging (MRI) can help differentiate some SPG types as well as identify other causes of spastic paraplegia⁽²⁾
• MRI findings by HSP type (findings may help guide single gene testing if advanced genetic testing is not available)⁽²⁾
  • SPG2 may show diffuse pattern of hypomyelination of spine
  • SPG7
    • cerebellar atrophy, primarily in vermis, present in reported 39%-95% of affected individuals
    • normally hypointense dentate nucleus appears iso- or hyper-intense compared to pontine white
  • thinning of corpus callosum with T-2 weighted periventricular hyperintensities (ears of lynx sign) seen in SPG11 and SPG15
  • nonspecific white matter lesions seen in about 50% of complex SPG5 cases

Cerebrospinal Fluid (CSF) Analysis

• CSF analysis used to assess for inflammatory and infectious etiologies of spastic paraplegia⁽²⁾
• additionally CSF analysis used to measure⁽²⁾
  • CSF glucose levels to rule out glucose transporter type-1 deficiency syndromes
  • CSF pterins and catecholamines levels to rule out dopamine-responsive dystonia

Genetic Testing

• molecular genetic testing may include⁽³⁾
  • single-gene testing – useful if specific genetic HSP cause is suspected by clinical presentation and/or family history
  • multigene panel – useful if HSP is suspected but likely genetic cause is unknown; specific panel is laboratory-dependent and may include genes not involved in HSP diagnosis
  • comprehensive genomic testing – exome or genomic sequencing is an option when suspected genetic HSP cause is unknown or HSP diagnosis is uncertain
• next generation sequencing panels are used extensively to diagnose genetic HSP types, but limitations include inability to detect⁽¹⁾
  • triplet repeat disorders
  • mutations in intronic or promoter regions
  • copy number variants such as large duplications or exon deletions
• reported 51%-71% of suspected cases of HSP, with or without positive family history, are not confirmed with genetic diagnosis despite use of gene panels or whole-exome sequencing⁽²⁾
• genetic testing may also include other inherited disorders that can cause spastic paraplegia with particular attention to treatable diseases including⁽²⁾
  • adrenoleukodystrophy
  • adult polyglucosan body diseases
  • arginase deficiency
  • biotinidase deficiency
  • phenylketonuria
  • primary coenzyme Q10 deficiencies
• proposed approach to single gene testing if advanced testing is not available⁽²⁾
  • if age of symptom onset < 40 years and there is positive family history, consider testing for SPG4, SPG3A, or SPG31
  • if age of symptom onset < 40 years and there is no family history, testing is based on additional clinical features
    • seizures or cognitive impairment should prompt testing for SPG11 and SPG15
    • sensory ataxia should prompt testing for SPG5
    • cerebellar signs, proximal weakness, or ophthalmoplegia should prompt testing for SPG7
    • absence of these signs or symptoms should prompt testing for SPG4, SP7, and SPG31 (SPG4 or SPG31 may not have been detected earlier in algorithm due to possible de novo variant or insufficient family history)
  • if age of symptom onset > 40 years
    • cerebellar signs, proximal weakness, or ophthalmoplegia should prompt testing for SPG7
    • absence of these signs or symptoms should prompt testing for SPG4, SP7, and SPG31 (SPG4 or SPG31 may not have been detected earlier in algorithm due to possible de novo variant or insufficient family history)
  • suggested testing based on abnormalities on brain imaging
    • cerebral atrophy or thin corpus callosum should prompt testing for SPG11 or SPG15
    • white matter lesions should prompt testing for SPG11, SPG15, and SPG5
    • cerebellar atrophy, or isointense or hyperintense dentate nucleus should prompt testing for SPG7

Neurophysiologic Studies

• neurophysiologic studies are commonly abnormal, but they have limited utility for discriminating between HSP types^(1,2)
  • tests include
    • somatosensory evoked potentials
    • electromyography
    • nerve conduction studies
  • electromyography and nerve conduction studies may detect distal axonal motor neuropathy
  • central motor conduction times measured via transcranial magnetic stimulation in lower limbs reported to be absent or delayed in 31 of 32 patients with SPG4 and SPG11

Management

Management Overview

• no definitive disease-modifying treatment available for HSP; management is supportive^(1,2)
• goals of treatment are to reduce symptoms and improve or maintain balance, strength, and agility⁽³⁾
• multidisciplinary approach to address spasticity-related problems may include^(1,2)
  • physical therapy
  • occupational therapy
  • medical management
• antispasmodic medications and botulinum toxin-A (BoNT-A) therapy are used to treat spasticity associated with HSP despite limited evidence for efficacy
• genetic counseling may be indicated to determine risk to^(1,3)
  • family members following the diagnosis of a proband
  • offspring for family planning purposes

Activity

• Robotic gait training – Teenager exercising with robotic equipment with therapist.Copyright ©2021 EBSCO Information Services.

• physical therapy and neurophysiotherapy
  • supervised exercise programs focused on improving cardiovascular fitness, muscle strength, stretching, and balance are optimal^(2,3)
  • robotic gait training reported to improve measures of balance, ambulation, and quality of life (Front Neurol 2019;10:3full-text)
  • hydrotherapy reported to improve spatiotemporal, kinematic, and kinetic clinical measurements but may worsen compensatory hip rotation (Front Neurol 2019;10:3full-text)
  • functional electrical stimulation reported to improve gait in patients with HSP⁽²⁾
  • 5-week gait adaptability training may not improve gait adaptability in adults with pure HSP(level 2 [mid-level] evidence)
    •  based on small randomized trial
    • 36 patients aged 18-70 years (mean age 47-50 years, 75% male) with pure HSP and ability to walk barefoot on level ground without walking aid were randomized to gait adaptability training vs. waitlist control for 5 weeks and followed for 15 weeks after training
      • gait adaptability training on treadmill equipped with augmented reality included 10 hour-long sessions guided by physical therapist; each session started with 10-minute warm-up, followed by 5 gait-adaptability exercises lasting 8 minutes each, and ended with 5-minute game and 5-minute cool-down period
      • waitlist control group crossed over to gait adaptability training after 5 weeks
    • primary outcome was gait adaptability assessed with obstacle subtask of Emory Functional Ambulation Profile
    • at baseline, mean time required to perform obstacle subtask 10.3 seconds in gait adaptability training group and 9.6 seconds in waitlist control group
    • 56% of gait adaptability training group and 33% of waitlist control group also received physical therapy during intervention period
    • 100% completed treatment and included in analysis
    • comparing gait adaptability training vs. waitlist control after 5-week intervention period
      • mean time required to perform obstacle subtask 8.6 seconds vs. 8.5 seconds (not significant)
      • falls in 33% vs. 39% (no p value reported)
    • no significant differences in clinical or spatiotemporal gait outcomes at week 6 assessed using Mini Balance Evaluation Test, Activities-specific Balance Confidence scale, 10-meter walk test, and 3-dimensional gait analysis
    • Reference – Move-HSP trial (Neurorehabil Neural Repair 2023 Jan;37(1):27full-text)
  • transcutaneous spinal direct current stimulation (tsDCS) might improve spasticity in patients diagnosed with HSP (level 3 [lacking direct] evidence)
    • based on nonclinical outcome in randomized crossover trial
    • 11 patients (mean age 37 years, 55% men) with HSP were randomized to treatment with tsDCS vs. sham procedure in crossover design
    • intervention and evaluation schedule
      • interventions were administered twice daily for 5 days
      • randomized interventions were administered at least 3 months apart
      • assessments were completed following completion of 5 days of intervention, and at 1 week, 1 month, and 2 months following intervention
    • tsDCS consisted of 2 mA administered for 20 minutes in a ramped fashion to achieve blinding
    • sham tsDCS consisted of 2 mA administered for 5 seconds and then turned off in a ramped fashion to achieve blinding
    • Ashworth scale of spasticity score for lower limbs normalized to baseline had significantly greater improvement at 2 months after tsDCS compared to sham (p = 0.0244)
    • no significant improvement in Five Minutes Walking test, Spastic Paraplegia Rating Scale, or electrophysiological measurements
    • Reference – J Spinal Cord Med 2021 Jan;44(1):46full-text
• orthotics such as ankle-foot-orthoses and heel raises may improve mobility^(1,3)

Medications

• antispasmodic medications^(1,2,3)
  • used to treat spasticity associated with HSP despite limited evidence for efficacy
  • agents used include
    • baclofen
    • gabapentin
    • L-dopa
    • dalfampridine
    • progabide (not approved for use in the United States)
    • Reference – Front Neurol 2019;10:3full-text
• botulinum toxin-A (BoNT-A) therapy
  • BoNT-A injections may help target specific problematic muscle groups including ankle, knee, and hip⁽²⁾
  • BoNT-A injections may improve some measures of spasticity but not walking gait velocity or muscle strength in patients with HSP (level 3 [lacking direct] evidence)
    • based on nonclinical outcomes in randomized trial
    • 55 adults (mean age 43 years) with HSP were randomized to treatment with BoNT-A vs. 0.9% saline (placebo) in a cross-over design
    • 75% had uncomplicated HSP
    • intervention and evaluation schedule
      • patients received BoNT-A 100 units intramuscularly divided in 3 injections into the adductor magnus and 100 units intramuscularly divided in 3 injections into the triceps surae
      • baseline evaluation and first randomized intervention was completed at the first visit
      • second randomized intervention was administered at 24-28 weeks
    • 89% completed trial, 93% included in analysis
    • 8 weeks after BoNT-A treatment, patients had significantly greater reduction in adductor tone as measured by Modified Ashworth Scale (MAS) score compared to placebo (p = 0.01)
    • no significant difference 8 weeks after BoNT-A or placebo in
      • maximal gait velocity as measured by 10-meter walking test
      • muscle strength in both hip adductors and triceps surae measured by Medical Research Council scale
      • spasticity in triceps surae measured by MAS
      • measures of pain, fatigue, and self-reporting of quality of gait
    • Reference – SPASTOX trial (Mov Disord 2021 Jul;36(7):1654)
  • BoNT-A injection followed by physical therapy reported to improve spasticity, ambulation, and quality of life in adults with HSP (level 3 [lacking direct] evidence)
    • based on uncontrolled trial
    • 18 adults (mean age 54 years) with HSP had intramuscular BoNT-A injections under electromyographic guidance followed by physical therapy
    • all patients were able to walk with (6 patients) or without walking aids (12 patients) on a level surface
    • specific dose and administration of BoNT-A and physical therapy regimen were individualized
    • injections were repeated twice with ≥ 3 months between injections in 11 of 18 patients
    • patients had intensive physical therapy (2 hours per day for 10 sessions) tailored to individual’s functionality, impairments, and goals
    • significant improvements at 3-month follow-up reported in
      • spasticity as measured by Modified Ashworth Scale
      • 10-meter Walking Test
      • Timed Up and Go test
      •  2-minute Walking Test (2MWT)
      • Walking Handicap Scale
      • quality of life measures
      • Spastic Paraplegia Rating Scale
    • Reference – Front Neurosci 2020;14:111full-text
• other medications
  • oxybutynin for urinary dysfunction^(1,2)
  • cholesterol-lowering medications such as atorvastatin reported to reduce buildup of neurotoxic oxysterols in patients with SPG5 (affected enzyme is involved in degradation of cholesterol into primary bile acids)⁽²⁾

Complications

• progressive weakness and spasticity of lower extremities leading to reliance on walking aids or loss of ambulation^(1,2)
• complex forms of HSP also noted for⁽¹⁾
  • ataxia
  • extrapyramidal signs
  • chorioretinal dystrophy
  • peripheral neuropathy
• in addition to physical limitations of their diagnosis, patients with HSP may experience feelings of
  • shame
  • fear
  • depression
  • frustration
  • Reference – Disabil Rehabil 2020 Dec;42(26):3744
• urinary and bowel dysfunction may present later in disease course⁽²⁾
  • reported to affect 75% of patients with HSP
  • may affect women more than men
  • Reference – Fac Rev 2021;10:27full-text

Prognosis

• overall progression of HSP is slow⁽²⁾
• SPG11 associated with higher disease severity compared to other HSP⁽²⁾
• later onset of disease associated with earlier loss of independent walking⁽²⁾
• independent ambulation reported to decrease with duration of disease in patients with HSP
  • based on retrospective cohort study
  • 608 patients (mean age 31 years, 55% men) with HSP were assessed for clinical progression of disease
  • median disease duration until loss of independent walking about 22 years
  • proportion of patients relying on walking aid by disease duration
    • 25% at 10 years
    • 48% by 20 years
    • 64% by 30 years
    • 72% by 40 years
  • proportion of patients relying on wheelchair by disease duration
    • 5% by 10 years
    • 12% by 20 years
    • 18% by 30 years
    • 29% by 40 years
  • Reference – Ann Neurol 2016 Apr;79(4):646

Prevention and Screening

Prevention

• not applicable

Genetic Screening

• genetic screening and counseling in families of affected patients can be helpful in determining risk of disease transmission⁽¹⁾
• caution is necessary when counseling on SPG7; in a minority of cases it can be inherited in an autosomal dominant pattern rather than its more common autosomal recessive transmission^(1,2)
• screening family members of a proband with⁽³⁾
  • autosomal dominant HSP
    • most individuals with autosomal dominant HSP have an affected parent, but occasionally autosomal dominant HSP arises from a de novo pathogenic variant
    • in individuals presumed to have a de novo pathogenic variant, screen both parents for pathogenic variant identified in affected offspring using molecular genetic testing
    • if one parent is found to have pathogenic variant, risk to siblings of proband is 50%
    • if pathogenic variant is not detected in either parent, risk to siblings of proband is slightly greater than general population but < 1%
    • risk of disease in offspring of proband with autosomal dominant HSP is 50%
  • autosomal recessive HSP
    • parents are obligate heterozygotes and are typically asymptomatic
    • siblings of proband have 25% risk of disease and 50% risk of being asymptomatic carrier
    • offspring of proband are obligate heterozygotes or carriers for pathogenic variant
    • siblings of proband’s parents have 50% risk of being a carrier
  • sex-linked (X-linked) HSP
    • male proband
      • father does not require screening
      • if > 1 family member is affected, mother is an obligate carrier
      • if proband is only affected family member, mother may be heterozygous or male proband may have de novo HSP-related pathogenic variant
      • risk of passing pathogenic variant to siblings is 50% if mother is carrier
      • all female offspring of proband will be heterozygous; male offspring will be unaffected
    • female proband
      • screen both parents and obtain detailed family history to determine if pathogenic variant was inherited or occurred de novo
      • risk of passing pathogenic variant to siblings is 50% if mother is carrier
      • if father has pathogenic variant, all female siblings of proband will be affected and no male siblings will be affected
      • female proband has 50% chance of passing variant to offspring
    • other family members of a proband with X-linked HSP may be at risk if parent of proband is a carrier
  • maternal or mitochondrial inheritance for MT-ATP6 pathogenic variant
    • father is not at risk
    • mother usually carries MT-ATP6 pathogenic variant, but may be asymptomatic
    • all siblings of proband whose mother is carrier will inherit MT-ATP6 pathogenic variant
    • all offspring of female proband will inherit variant
    • offspring of male proband not at risk of inheriting variant
    • siblings of proband’s mother may be at risk if mother is a carrier

Guidelines and Resources

Guidelines

European Guidelines

• European Federation of Neurological Science (EFNS) guideline on molecular diagnosis of ataxias and spastic paraplegias can be found in Eur J Neurol 2010 Feb;17(2):179

Review Articles

• review can be found in Neurol Sci 2021 Mar;42(3):883
• review can be found in GeneReviews 2021 Feb 11full-text
• review can be found in Lancet Neurol 2019 Dec;18(12):1136
• review of treatments can be found in Front Neurol 2019;10:3full-text
• review of current and experimental medical treatments can be found in Fac Rev 2021;10:27full-text

MEDLINE Search

• to search MEDLINE for (Hereditary spastic paraplegia) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

• handout from National Organization for Rare Disorders
• handout and audio from NIH Genetic and Rare Disease Information Center or in Spanish

References

1. Murala S, Nagarajan E, Bollu PC. Hereditary spastic paraplegia. Neurol Sci. 2021 Mar;42(3):883-894.
2. Shribman S, Reid E, Crosby AH, Houlden H, Warner TT. Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches. Lancet Neurol. 2019 Dec;18(12):1136-1146.
3. Hedera P. Hereditary Spastic Paraplegia Overview. GeneReviews 2021 Feb 11.