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Hereditary Spastic Paraplegia Overview

Synonyms: Hereditary Spastic Paraparesis, Strumpell-Lorrain Syndrome

, MD, PhD, FACMG.

Author Information

Initial Posting: ; Last Update: September 27, 2018.

Estimated reading time: 27 minutes

Summary

The purpose of this overview is to increase the awareness of clinicians regarding hereditary spastic paraplegia.

The following are the goals of this overview.

Goal 1.

Describe the clinical characteristics of hereditary spastic paraplegia and recommended treatment.

Goal 2.

Review the causes of hereditary spastic paraplegia.

Goal 3.

Consider the differential diagnosis of hereditary spastic paraplegia.

Goal 4.

Provide an evaluation strategy to identify the genetic cause of hereditary spastic paraplegia in a proband.

Goal 5.

Inform genetic counseling of family members of a proband with hereditary spastic paraplegia.

1. Clinical Characteristics and Recommended Treatment: Hereditary Spastic Paraplegia

The predominant signs and symptoms of hereditary spastic paraplegia (HSP) are lower-extremity weakness and spasticity.

Neurologic examination. Individuals with 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

Symptom onset

  • Early onset. When symptoms begin in very early childhood, they may be non-progressive and resemble spastic diplegic cerebral palsy.
  • Later onset. When symptoms begin in later childhood or after 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).

  • Uncomplicated (or "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]. Individuals with uncomplicated HSP experience the following:
    • Difficulty walking (may either be non-progressive or worsen insidiously)
    • Often, the need for canes, walkers, or wheelchairs
    • Possible urinary urgency and lower-extremity paresthesias
    • Typically, normal strength and dexterity of the upper extremities
    • No involvement of speech, chewing, or swallowing
    Though symptoms may be disabling, life span is not shortened.
  • Complicated HSP is characterized by the impairments present in uncomplicated HSP plus other system involvement or other neurologic findings including any of the following:*
    • Ataxia
    • Seizures
    • Intellectual disability
    • Dementia
    • Muscle atrophy
    • Extrapyramidal disturbance
    • Peripheral neuropathy
    *In the absence of other causes for these additional features

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. Individuals 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.

Current recommendations:

  • Daily regimen of physical therapy directed toward improving cardiovascular fitness, maintaining and improving muscle strength and gait, and reducing spasticity
  • Occupational therapy, assistive walking devices, and ankle-foot orthotics as needed
  • Drugs to reduce muscle spasticity (e.g., Lioresal® [oral or intrathecal], tizanidine, dantrolene, botulinum A and B toxin injections [Botox®, Dysport, Xeomin, or Myoblock]) and urinary urgency (e.g., oxybutynin, solifenacin, mirabegron, or intrabladder injections with Botox®)

2. Causes of Hereditary Spastic Paraplegia

Genetic types of hereditary spastic paraplegia (HSP). To date, more than 80 genetic types of HSP have been defined by genetic linkage analysis and identification of HSP-related gene variants. In the past, genetic loci for HSP were designated SPG (for "spastic paraplegia") and numbered in order of their discovery. With the identification of the causative genes at those loci, reference by clinicians and clinical labs to a specific genetic type of HSP has moved to the name of the gene rather than the locus designation. Autosomal dominant, autosomal recessive, X-linked, and maternally inherited (mitochondrial) forms of HSP have been identified.

Autosomal dominant HSP is the most common type of HSP, found in 75%-80% of affected individuals.

  • SPG4, caused by a pathogenic variant in SPAST, is the most common type, accounting for approximately 40% of all autosomal dominant HSP.
  • SPG3A, caused by a pathogenic variant in ATL1, is the second most common type of autosomal dominant HSP, accounting for approximately 10%-15% of all autosomal dominant HSP. SPG3A is the main cause of autosomal dominant HSP with early onset (occurs in >75% of individuals in this category).
  • SPG31, caused by a pathogenic variant in REEP1, is relatively common, accounting for about 5% of all autosomal dominant HSP.
  • Other types of autosomal dominant HSP with a predominantly adult onset are relatively rare and most of them account for 1% or less of all autosomal dominant HSP.

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. AR HSP is found in an estimated 25%-30% of all individuals with HSP.

Most common types of autosomal recessive HSP are encountered in the general population:

  • SPG5A, caused by pathogenic variants in CYP7B1, accounts for 7.3% of all autosomal recessive HSP and 3% of apparently sporadic pure spastic paraplegia.
  • SPG7, caused by pathogenic variants in SPG7, may account for approximately 5% of all autosomal recessive HSP.
  • SPG11, caused by pathogenic variants in SPG11, accounts for 3%-5% of all autosomal recessive HSP but is found in 75% of individuals with all types of HSP who have radiologic signs of thin or absent corpus callosum.

X-linked HSP and mitochondrial HSP are the rarest genetic forms of HSP, accounting for fewer than 1%-2% of all individuals affected with HSP.

Other. Several types of HSP (e.g., those associated with pathogenic variants in ATL1 [Khan et al 2014], SPG7 [McDermott et al 2001], and ALDH18A1 [Coutelier et al 2015]) may be inherited as either autosomal recessive or autosomal dominant disorders.

Table 1.

Hereditary Spastic Paraplegia: Genes and Distinguishing Clinical Features – Autosomal Dominant Inheritance

Gene 1HSP DesignationType of HSPOnsetDistinguishing Clinical FeaturesOtherReferences
GeneReview or OMIM EntryCitation
ADARNot assignedUncomplicatedEarly childhoodAbnormal pattern of interferon expression determined by reverse transcription PCR assayReported in a single Hispanic individualCrow et al [2014]
ALDH18A1SPG9AComplicatedAdolescence to adulthood (1 subject w/infantile onset)
  • Cataracts
  • Gastroesophageal reflux
  • Motor neuronopathy
Variably present:
  • Dysarthria
  • Ataxia
  • Cognitive impairment
  • Rare
  • Allelic w/AR HSP (SPG9B)
OMIM 601162Coutelier et al [2015]
ATAD3ANot assignedComplicatedEarly onset
  • Amyotrophy
  • Hyperkinetic movements
  • May be confused w/hyperkinetic cerebral palsy
RareCooper et al [2017]
ATL1SPG3AUncomplicatedInfantile to childhood (rarely adult onset)
  • Progression may be minimal w/static course.
  • May present as spastic diplegic cerebral palsy
  • Complicated phenotype w/peripheral neuropathy or autonomic failure reported
  • 80% of early-onset AD HSP
  • 10%-15% of all AD HSP
Spastic Paraplegia 3AZhao et al [2001], Namekawa et al [2006], Rainier et al [2006], Ivanova et al [2007]
BICD2Not assignedComplicatedChildhood or adult
  • Infantile onset associated w/SMA w/variable upper motor signs & contractures
  • Adult onset associated w/mild amyotrophy
RareOates et al [2013]
BSCL2 2SPG17ComplicatedAdulthood
  • Distal amyotrophy affecting hands & feet
  • Motor neuropathy
  • Can be indistinguishable from ALS
RareBSCL2-Related Neurologic Disorders/ SeipinopathyWindpassinger et al [2004], Musacchio et al [2017]
CPT1CSPG73UncomplicatedEarly adulthoodFoot deformity may be present.Single familyOMIM 616282Rinaldi et al [2015]
DNM2 3Not assignedComplicatedBefore age 20 years
  • Axonal polyneuropathy may be present.
  • Mild distal amyotrophy in feet
Single familySambuughin et al [2015]
ERLIN2SPG18 4UncomplicatedJuvenile to adulthoodNone
  • Single family
  • Most pathogenic variants associated w/AR HSP (see Table 2)
Rydning et al [2018]
HSPD1SPG13UncomplicatedAdulthoodMild distal amyotrophyRareOMIM 605280Hansen et al [2002]
KIF5A 4SPG10ComplicatedJuvenile or adulthood
  • Polyneuropathy
  • Pes cavus
  • 1%-2% of all AD HSP
  • 5%-8% of all complicated AD HSP
OMIM 604187Reid et al [2002], Blair et al [2006], Liu et al [2014]
NIPA1SPG6UncomplicatedAdulthood (infantile onset rare)
  • Severe weakness & spasticity
  • Rapidly progressive
  • Rarely, complicated by epilepsy or variable peripheral neuropathy
Rare (~1% of AD HSP)OMIM 600363Rainier et al [2003], Du et al [2011], Svenstrup et al [2011], Hedera [2013]
ATP2B4 (PMCA4)Not assignedUncomplicatedAdulthoodNoneSingle familyLi et al [2014]
REEP1SPG31UncomplicatedVariable from 2nd to 7th decadesMild amyotrophy variably present.Common, 4%-6% of all AD HSPOMIM 610250Züchner et al [2006], Hewamadduma et al [2009]
REEP2SPG72UncomplicatedVery early, average age 4 years
  • Musculoskeletal problems
  • Mild postural tremor
  • Rare
  • Inheritance can be dominant or recessive
OMIM 615625Esteves et al [2014]
RTN2SPG12UncomplicatedBefore age 20 yearsNone5% of early-onset AD HSP but overall rareOMIM 604805Montenegro et al [2012]
SLC33A1SPG42UncomplicatedEarly adulthood
  • Slowly progressive
  • Mild pes cavus
Single family knownOMIM 612539Lin et al [2008]
SPASTSPG4UncomplicatedVariable from infancy to 7th decade
  • Cognitive decline & dementia common
  • Distal amyotrophy variably present
  • Complicated phenotype w/ataxia variably present
40% of AD HSPSpastic Paraplegia 4Hazan et al [1999], Fonknechten et al [2000], Nielsen et al [2004], Murphy et al [2009]
SPG7SPG7Uncomplicated or complicatedJuvenile or adulthood
  • Dysarthria
  • Ataxia
  • Optic atrophy
  • Supranuclear palsy
  • Mitochondrial abnormalities on skeletal muscle biopsy
AD inheritance suggested for some pathogenic variants, but overall this is rareSpastic Paraplegia 7McDermott et al [2001]
WASHC5SPG8UncomplicatedAdulthood (rare infantile onset reported)Severe motor deficit in some individualsRare (~1% of AD HSP)Spastic Paraplegia 8Hedera et al [1999], Valdmanis et al [2007]
TUBB4A 5Not assignedComplicatedJuvenile
  • Cerebellar ataxia
  • MRI evidence of hypomyelination
RareKancheva et al [2015]
ZFYVE27SPG33UncomplicatedAdulthoodMild pes cavusSingle family knownOMIM 610244Mannan et al [2006]

AD = autosomal dominant; AR = autosomal recessive; ALS = amyotrophic lateral sclerosis; CMT = Charcot-Marie-Tooth neuropathy; DI-CMT = dominant intermediate Charcot-Marie-Tooth neuropathy; HMN = hereditary motor neuropathy; HSP = hereditary spastic paraplegia; SMA = spinal muscular atrophy

1.

Genes are listed alphabetically.

2.

Allelic w/distal hereditary motor neuropathy type V (dHMN-V) and variants of Charcot-Marie-Tooth disease type 2

3.

Allelic with CMT2M; DI-CMTB, centronuclear myopathy; & lethal congenital contractures syndrome type 5

4.

Allelic to Charcot-Marie-Tooth disease axonal CMT2A and ALS25 (susceptibility to ALS)

5.

Allelic with hypomyelinating leukodystrophy type 6 and autosomal dominant dystonia type 4

Table 2.

Hereditary Spastic Paraplegia: Genes and Distinguishing Clinical Features – Autosomal Recessive Inheritance

Gene 1HSP DesignationType of HSPOnsetDistinguishing Clinical FeaturesOtherReferences
GeneReview
or OMIM Entry
Citation
SPG21
(ACP33)
SPG21ComplicatedChildhood
  • Ataxia
  • Adult-onset dementia & parkinsonism
  • Polyneuropathy
  • Akinetic mutism seen in advanced cases
  • Rare, first described in Old Order Amish population (later identified in various ethnic groups)
  • Also known as Mast syndrome
OMIM 248900Cross & McKusick [1967a], Simpson et al [2003], Ishiura et al [2014]
ALDH18A1SPG9BComplicatedAdolescence to adulthood (one subject w/infantile onset)
  • Cataracts
  • Gastroesophageal reflux
  • Motor neuronopathy
Variably present:
  • Dysarthria
  • Ataxia
  • Cognitive impairment
  • Rare
  • Allelic w/AD HSP (SPG9A)
OMIM 616586Coutelier et al [2015]
ALDH3A2Not assignedComplicatedChildhood
  • Congenital ichthyosis
  • Macular dystrophy
  • Leukodystrophy
  • Seizures occur in ~40% of patients.
  • Rare
  • Most common in people of Swedish ancestry
  • Known as Sjögren-Larsson syndrome
Rizzo et al [1999], Gordon [2007]
AMPD2 2SPG63ComplicatedInfancy
  • Short stature
  • Thin corpus callosum
  • White matter changes
RareOMIM 615686Novarino et al [2014], Kortüm et al [2018]
AP4B1SPG47ComplicatedInfancy
  • Severe ID
  • Facial dysmorphism
  • Seizures
  • Stereotypic laughter w/tongue protrusion
RareOMIM 614066Abou Jamra et al [2011], Bauer et al [2012]
AP4E1SPG51ComplicatedInfancy
  • Severe ID
  • Facial dysmorphism
  • Seizures
  • Stereotypic laughter w/tongue protrusion
RareOMIM 613744Abou Jamra et al [2011], Moreno-De-Luca et al [2011]
AP4M1SPG50ComplicatedInfancy
  • Severe ID
  • Facial dysmorphism
  • Seizures
  • Stereotypic laughter w/tongue protrusion
RareOMIM 612936Verkerk et al [2009]
AP4S1SPG52ComplicatedInfancy
  • Severe ID
  • Facial dysmorphism
  • Seizures
  • Stereotypic laughter w/tongue protrusion
RareOMIM 614067Abou Jamra et al [2011], Hardies et al [2015]
AP5Z1SPG48UncomplicatedTypically adulthood; rarely infancy
  • Urinary incontinence
  • Parkinsonism
  • Dystonia
  • Thin corpus callosum
  • Leukodystrophy
  • Severe DD in infantile onset
Single familyOMIM 613647Słabicki et al [2010], Pensato et al [2014]
ATL1SPG3AUncomplicatedInfantile to childhood (rarely adult onset)
  • Progression may be minimal w/static course
  • May present as spastic diplegic cerebral palsy
  • Complicated phenotype w/peripheral neuropathy or autonomic failure reported
AR inheritance is very rare.Spastic Paraplegia 3AKhan et al [2014]
B4GALNT1SPG26ComplicatedJuvenile
  • Amyotrophy
  • Dysarthria
  • Ataxia
  • DD
  • Dystonia
RareOMIM 609195Boukhris et al [2013], Harlalka et al [2013]
BICD2Not assignedComplicatedChildhood
  • Amyotrophy
  • Contractures
RareOates et al [2013]
C12orf65SPG55ComplicatedChildhood
  • DD
  • Visual loss
  • Polyneuropathy
  • Arthrogryposis
  • Signs of mitochondrial encephalomyopathy, some classified as Leigh's syndrome
RareOMIM 615035Shimazaki et al [2012]
C19orf12SPG43ComplicatedChildhood
  • Amyotrophy
  • Dysarthria
  • Multiple contractures
  • Neurodegeneration w/brain iron accumulation in some
RareOMIM 615043Landouré et al [2013], Schubert et al [2016]
CYP2U1SPG56ComplicatedInfancy
  • Severe DD
  • Dystonia
  • Polyneuropathy
  • Calcification of basal ganglia
RareOMIM 615030Tesson et al [2012]
CYP7B1SPG5AUncomplicated or complicatedJuvenile to early adulthood
  • Ataxia
  • Polyneuropathy
  • Extrapyramidal signs
  • MRI signs of leukodystrophy
SPG5A was diagnosed in 9 of 172 families w/histories consistent w/AR inheritance of HSP. 3OMIM 270800Tsaousidou et al [2008], Goizet et al [2009]
DDHD1SPG28UncomplicatedChildhoodScoliosisRareOMIM 609340Tesson et al [2012]
DDHD2SPG54ComplicatedInfancy
  • Severe DD
  • Optic atrophy
  • Thin corpus callosum
  • Leukodystrophy
RareOMIM 615033Schuurs-Hoeijmakers et al [2012]
ENTPD1SPG64ComplicatedInfancy
  • Mild cognitive disability
  • Behavioral disturbances
  • White matter changes
RareOMIM 615683Novarino et al [2014]
ERLIN1SPG62ComplicatedChildhood
  • Amyotrophy
  • Ataxia
  • Phenotype consistent w/juvenile onset of ALS reported
RareOMIM 615681Novarino et al [2014], Tunca et al [2018]
ERLIN2SPG18Complicated (rarely pure AR HSP reported)Childhood
  • DD
  • Seizures
  • Contractures
  • Juvenile primary lateral sclerosis phenotype reported
  • Allelic w/AD pure HSP
RareOMIM 611225Alazami et al [2011], Yıldırım et al [2011], Al-Saif et al [2012]
FA2H 4SPG35ComplicatedChildhood
  • Seizures
  • Dystonia
  • Parkinsonism w/iron accumulation in basal ganglia
RareOMIM 612319Edvardson et al [2008], Dick et al [2010], Pensato et al [2014]
GAD1Not assignedComplicatedChildhood
  • Moderate to severe ID
  • Single reported family was described as having AR cerebral palsy
Rare (single family reported)Lynex et al [2004]
GBA2SPG46ComplicatedChildhood
  • DD
  • Ataxia
  • Hearing loss
  • Polyneuropathy
RareOMIM 614409Hammer et al [2013], Coarelli et al [2018]
GJC2 5SPG44ComplicatedChildhood
  • Febrile seizures
  • Deafness
  • Episodic spasms
  • Variable degree of leukodystrophy
RareOMIM 613206Uhlenberg et al [2004], Orthmann-Murphy et al [2009]
GRID2 6Not assignedComplicatedChildhood
  • Amyotrophy
  • Ataxia
RareUtine et al [2013], Maier et al [2014]
IBA57 7SPG74ComplicatedChildhood
  • Optic atrophy
  • Peripheral neuropathy
RareOMIM 616451Lossos et al [2015], Torraco et al [2017]
KIF1A 8SPG30ComplicatedChildhood
  • Spastic ataxia
  • Polyneuropathy
RareOMIM 610357Hamdan et al [2011], Rivière et al [2011], Klebe et al [2012]
KIF1CSPG58ComplicatedChildhood
  • Spastic ataxia
  • Dystonia
RareCaballero Oteyza et al [2014], Dor et al [2014]
KLC2Not assignedComplicatedChildhood
  • Optic atrophy
  • Neuropathy
  • Contractures in later stages
  • Cognition remains intact
  • Rare
  • Also known as spastic paraplegia optic atrophy, & neuropathy (SPOAN)
OMIM 609541Melo et al [2015]
KLC4Not assignedComplicatedChildhood
  • Ataxia
  • Multiple contractures
  • Variable degree of leukodystrophy
RareBayrakli et al [2015]
MARS 9SPG70ComplicatedInfancy
  • Nephrotic syndrome, polyneuropathy
  • Mild ID
  • Late onset of CMT2 (axonal) type also reported
RareGonzalez et al [2013], Novarino et al [2014]
NT5C2SPG45ComplicatedChildhood
  • Optic atrophy
  • Nystagmus
  • Strabismus
  • ID
  • Hypoplastic corpus callosum
RareOMIM 613162Novarino et al [2014], Elsaid et al [2017]
PGAP1 10SPG67ComplicatedInfancy
  • Severe DD
  • Tremor
  • Agenesis of corpus callosum
  • Hypomyelination
RareMurakami et al [2014], Novarino et al [2014]
PNPLA6 11SPG39ComplicatedChildhood
  • Amyotrophy
  • Endocrine abnormalities w/short stature or hypogonadotropic hypogonadism
  • Chorioretinal dystrophy
RarePNPLA6-Related DisordersRainier et al [2008], Synofzik et al [2014],
Hufnagel et al [2015]
REEP2SPG72UncomplicatedEarly childhood
  • Musculoskeletal problems
  • Mild postural tremor
  • Rare
  • Inheritance can be dominant or recessive.
OMIM 615625Esteves et al [2014]
SPARTSPG20ComplicatedJuvenile
  • Distal amyotrophy
  • Short stature
  • Kyphoscoliosis
  • Multiple limb contractures
  • Rare
  • Mostly seen among Old Order Amish
Troyer SyndromeCross & McKusick, [1967b], Patel et al [2002]
SPG7SPG7Uncomplicated or complicatedJuvenile or adulthood
  • Dysarthria
  • Ataxia
  • Optic atrophy
  • Supranuclear palsy
  • Mitochondrial abnormalities on skeletal muscle biopsy
  • 5%-12% of AR HSP
  • AD inheritance suggested for some pathogenic variants; this remains controversial
Spastic Paraplegia 7Casari et al [1998], McDermott et al [2001], Arnoldi et al [2008], Brugman et al [2008]
SPG11SPG11ComplicatedChildhood or early adulthood
  • DD
  • Optic atrophy
  • Ataxia
  • Pseudobulbar signs
  • Polyneuropathy
  • Levodopa-responsive parkinsonism
  • Hypoplastic or absent corpus callosum
  • 5% of AR HSP
  • 75% of HSP w/DD & hypoplasia of corpus callosum
Spastic Paraplegia 11Stevanin et al [2007], Paisan-Ruiz et al [2008], Riverol et al [2009], Guidubaldi et al [2011]
TECPR2SPG49ComplicatedChildhood
  • Central apnea
  • Severe DD
  • Microcephaly
  • Dysmorphic features
RareOMIM 615031Oz-Levi et al [2012]
TFGSPG57ComplicatedChildhood
  • Optic atrophy
  • Severe polyneuropathy
RareOMIM 615658Beetz et al [2013]
USP8SPG59UncomplicatedChildhoodNoneRareNovarino et al [2014]
WDR48SPG60ComplicatedInfancy
  • Polyneuropathy
  • DD
RareNovarino et al [2014]
ZFYVE26SPG15ComplicatedChildhood or early adulthood
  • DD
  • Optic atrophy
  • Ataxia
  • Central retinal degeneration
  • Polyneuropathy
1%-2% of AR HSPOMIM 270700Hanein et al [2008], Pensato et al [2014]

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.

Allelic with pontocerebellar hypoplasia type 9

3.
4.
5.

Allelic with Pelizaeus-Merzbacher-like disease 1 and hereditary lymphedema type IC

6.

Allelic with autosomal recessive spinocerebellar ataxia 18 (see Hereditary Ataxia Overview)

7.

Allelic with multiple mitochondrial dysfunctions syndrome 3

8.

Allelic with hereditary sensory and autonomic neuropathy type 2C and AD intellectual disability type 9

9.
10.

Allelic with autosomal recessive intellectual disability type 42

11.

Allelic with Boucher-Neuhauser syndrome, Gordon-Holmes syndrome, Oliver-McFarlane syndrome, and Laurence-Moon syndrome

Table 3.

Hereditary Spastic Paraplegia: Genes and Distinguishing Clinical Features – X-Linked Inheritance

Gene 1HSP DesignationType of HSPOnsetDistinguishing Clinical FeaturesOtherReferences
GeneReview
or OMIM Entry
Citation
L1CAM 2SPG1ComplicatedInfancy
  • ID
  • Adducted thumbs
  • Corpus callosum hypoplasia
  • Aphasia
  • Obstructive hydrocephalus
RareL1 SyndromeJouet et al [1994], Schrander-Stumpel et al [1995], Yamasaki et al [1995], Finckh et al [2000]
PLP1 3SPG2ComplicatedEarly childhood to juvenile onset
(in manifesting female heterozygotes: onset in 4th-7th decade)
  • Pure HSP phenotype present in early stages; later, other signs emerge
  • Nystagmus
  • Optic atrophy
  • Dysarthria
  • ID
  • Variable degree of leukodystrophy on MRI
PLP1-Related DisordersSaugier-Veber et al [1994], Cambi et al [1996], Hodes et al [1999], Sivakumar et al [1999]
SLC16A2SPG22ComplicatedEarly childhood
  • Severe ID
  • Infantile hypotonia
  • Progressive spasticity
  • Ataxia
  • Dystonia
  • ↑ T3 & normal to mildly ↑ TSH
  • ↓ T4 hypomyelination on neuroimaging
  • Rare
  • SPG22 is a proposed designation. 4
  • Also referred to as Allan-Herndon-Dudley syndrome 5
MCT8-Specific Thyroid Hormone Cell-Membrane Transporter DeficiencyDumitrescu et al [2004], Boccone et al [2010]

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

1.

Genes are listed alphabetically.

2.

Allelic with X-linked hydrocephalus with stenosis of the aqueduct of Sylvius; MASA syndrome (mental retardation, aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs); and X-linked complicated corpus callosum agenesis accounting for 5%-10% of all non-syndromic congenital obstructive hydrocephalus

3.

Allelic with Pelizaeus-Merzbacher disease

4.

OMIM 300523

5.

Because of the overlap between the clinical phenotype in individuals with SLC16A2 abnormalities and in those with a previously described syndrome, Allan-Herndon-Dudley syndrome (AHDS), Schwartz et al [2005] analyzed SLC16A2 in six families with AHDS. SLC16A2 pathogenic variants were identified in all six; therefore, AHDS is now synonymous with MCT8-specific thyroid hormone cell-membrane transporter deficiency due to pathogenic variants in SLC16A2 (see MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency).

Table 4.

Hereditary Spastic Paraplegia: Gene and Distinguishing Clinical Features – Maternal (Mitochondrial) Inheritance

GeneHSP DesignationType of HSPOnsetDistinguishing Clinical Features
MT-ATP6Not assignedComplicatedAdultCardiomyopathy, diabetes mellitus, sensory polyneuropathy

3. Differential Diagnosis of Hereditary Spastic Paraplegia

The differential diagnosis includes the following:

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

Establishing a specific genetic cause of 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.

Medical history and physical examination is directed at identifying neurologic features associated with HSP as well as any additional features that could indicate the presence of a complicated HSP (see Clinical Characteristics and Tables 1-4).

Family history includes 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. Autosomal dominant, autosomal recessive, and X-linked or maternal (mitochondrial) inheritance patterns have all been reported with HSP.

Exclusion of other disorders. See Differential Diagnosis.

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

  • Concurrent or serial single-gene testing can be considered if clinical findings and/or family history indicate that involvement of a particular gene or small subset of genes is most likely (see Tables 1-4).
  • A multigene panel that includes some or all of the genes listed in Table 1 is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants 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. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

5. 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) can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner or by maternal (mitochondrial) inheritance, depending on the genetic subtype in a family.

Several types of HSP (e.g., those associated with pathogenic variants in ATL1, SPG7, ALDH18A1, and possibly SPG11) may be inherited either as autosomal recessive or autosomal dominant disorders (see Causes of Hereditary Spastic Paraplegia).

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 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant 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.
  • If the HSP-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant 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 is affected, his or her family members may be at risk.

Risk to Family Members – Autosomal Recessive HSP

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one HSP-related pathogenic variant).
  • Heterozygotes (carriers) are typically asymptomatic. The only known exception to this rule is SPG7, where an apparently dominant inheritance was suggested for otherwise autosomal recessive HSP [McDermott et al 2001].

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.
  • Heterozygotes are typically asymptomatic if the pattern of inheritance is consistent with autosomal recessive mode and affected individuals harbor biallelic pathogenic variants.

Offspring of a proband. The offspring of an individual with autosomal recessive 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.

Risk to Family Members – X-Linked HSP

Parents of a male proband

Parents of a female proband

  • A female proband may have inherited the HSP-related pathogenic variant from either her mother or her father, or the pathogenic variant may be de novo.
  • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can determine if the pathogenic variant was inherited.

Sibs of a male proband

  • The risk to sibs depends on the genetic status of the mother.
    • If the mother of the proband with X-linked HSP has an HSP-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes and may have a range of clinical manifestations (see Table 3).
    • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the HSP-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal germline mosaicism.
  • 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.

Sibs of a female proband

  • The risk to sibs depends on the genetic status of the parents.
    • If the mother of the proband has an HSP-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes and may have a range of clinical manifestations (see Table 3).
    • If the father of the proband has an HSP-related pathogenic variant, he will transmit it to all of his daughters and none of his sons.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the HSP-related pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.
  • 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 male proband. Affected males transmit the HSP-related pathogenic variant to:

  • All of their daughters, who will be heterozygotes and may have a range of clinical manifestations (see Table 3);
  • None of their sons.

Offspring of a female proband. Women with an HSP-related pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child:

  • Males who inherit the pathogenic variant will be affected.
  • Females who inherit the variant will be heterozygotes and may have a range of clinical manifestations (see Table 3). This is best documented for SPG2, where female heterozygotes may show a mild paraparesis with late onset of the disease [Sivakumar et al 1999].

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, his or her family members may be at risk.

Heterozygote (carrier) detection. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Note:

(1) Females who are heterozygous for X-linked HSP may have a range of clinical manifestations (see Table 3).

(2) Identification of female heterozygotes requires either (a) prior identification of the HSP-related pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Risk to Family Members – Maternal (Mitochondrial) Inheritance

Parents of a proband

Sibs of a proband

  • The risk to the sibs depends on the genetic status of the mother.
  • If the mother has the MT-ATP6 pathogenic variant, all sibs of a proband will inherit the MT-ATP6 pathogenic variant and may or may not have symptoms.

Offspring of a proband

  • All offspring of females with a mtDNA pathogenic variant will inherit the pathogenic variant.
  • Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's mother. If the mother has an MT-ATP6 pathogenic variant, her sibs and mother are also at risk.

Related Genetic Counseling Issues

Caution must be exercised when counseling an individual who has all the signs and symptoms of HSP but no 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, a mtDNA pathogenic variant, mistaken paternity, or an environmentally acquired disorder.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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, carriers, or at risk of being affected or a carrier; however, it is not possible to make specific predictions about the potential severity of disease in offspring.

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.

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.

  • EURO HSP
    Plateforme Maladies Rares
    99 Rue Didot
    Paris 75014
    France
    Phone: 33 1 56 53 52 61
    Email: president@eurohsp.eu
  • 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)
    Email: information@sp-foundation.org
  • Tom Wahlig-Foundation
    Tom Wahlig Stiftung
    Büro Veghestrasse 22
    Germany
    Phone: 49 (0) 251 - 20 07 91 20
    Email: nfo@hsp-info.de
  • A.I. Vi.P.S.
    Associazione Italiana Vivere la Paraparesi Spastica Onlus
    Via Tevere, 7
    20020 Lainate (MI)
    Italy
    Phone: 39 392 9825622
    Email: nfo@vipsonlus.it

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Chapter Notes

Author History

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

Revision History

  • 27 September 2018 (ha) Comprehensive update posted live
  • 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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