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Hereditary Spastic Paraplegia Overview

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

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

Summary

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

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

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

Diagnosis/testing. HSP is diagnosed by:

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

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

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

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

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

Definition

Clinical Manifestations of HSP

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

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

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

Establishing the Diagnosis of HSP

HSP is diagnosed on the basis of the following:

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

Neurologic examination. Individuals with uncomplicated HSP demonstrate the following:

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

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

Differential Diagnosis of HSP

The differential diagnosis includes:

Prevalence of HSP

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

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

Table 1. Summary of Hereditary Spastic Paraplegia – Autosomal Dominant Inheritance

Gene / Locus Name
(Chromosome Locus 1)
Protein Clinical SyndromeReferences
ATL1 / SPG3A Atlastin-1Uncomplicated HSP
  • Typical onset: childhood (may be non-progressive); or adolescence to adulthood (w/insidious progression)
  • Genetic non-penetrance reported
  • De novo mutation reported presenting as spastic diplegic cerebral palsy
Hazan et al [1993], Paternotte et al [1998], Zhao et al [2001]
SPAST / SPG4 SpastinUncomplicated HSP; most common cause of AD HSP (~40%)
  • Onset: infancy to senescence
  • Variably present: late-onset cognitive impairment
Hazan et al [1994], Hentati et al [1994b], Charvin et al [2003], Evans et al [2005], Roll-Mecak & Vale [2005]
NIPA1 / SPG6 Non-imprinted in Prader-Willi / Angelman syndrome region protein 1 (magnesium transporter NIPA1)Uncomplicated HSP
  • Prototypic late-adolescent, early-adult onset, slowly progressive
  • Rarely, complicated by epilepsy or variable peripheral neuropathy; in 1 case, ALS
Fink et al [1995a], Fink et al [1995b], Rainier et al [2003], Chen et al [2005], Du et al [2011], Svenstrup et al [2011], Martinez-Lage et al [2012]
KIAA0196 / SPG8 KIAA0196 (WASH complex subunit strumpellin)Uncomplicated HSPHedera et al [1999a], Hedera et al [1999b], Reid et al [2000], Valdmanis et al [2007], Bian et al [2011]
SPG9
(10q23.3-q24.1)
UnknownComplicated HSP
  • Cataracts, gastroesophageal reflux, motor neuronopathy
Seri et al [1999], Meijer et al [2004]
KIF5A / SPG10Kinesin heavy chain isoform 5A Uncomplicated HSP or complicated by distal muscle atrophyReid et al [1999], Fichera et al [2004]
RTN2 / SPG12 Reticulon-2 Uncomplicated HSPReid et al [2000], Montenegro et al [2012]
HSPD1 / SPG13 Chaperonin 60 (heat shock protein 60, HSP60)Uncomplicated HSP
  • Onset: adolescent - adult
Fontaine et al [2000], Hansen et al [2002], Bross et al [2008]
BSCL2 / SPG17 BSCL2 (seipin)Complicated HSP:
  • Amyotrophy of hand muscles (Silver syndrome)
Patel et al [2001], Windpassinger et al [2004], Auer-Grumbach et al [2005]
SPG19
(9q)
UnknownUncomplicated HSPValente et al [2002]
SPG29
(1p31.1-21.1)
UnknownComplicated HSP
  • Hearing impairment; persistent vomiting due to hiatal hernia (inherited)
Orlacchio et al 2005
REEP1 / SPG31 Receptor expression- enhancing protein 1 Uncomplicated HSP or occasionally associated with peripheral neuropathyZuchner et al [2006a], Zuchner et al [2006b], Beetz et al [2008]
ZFYVE27 / SPG33 ProtrudinUncomplicated HSPMannan et al [2006]
SPG36
(12q23-q24)
Unknown
  • Onset: age 14-28 years
  • Motor sensory neuropathy
Schule et al [2009]
SPG37
(8p21.1-q13.3)
UnknownUncomplicated HSPHanein et al [2007]
SPG38
(4p16-p15)
UnknownIn 5 members of a single family
  • Onset age 16-21 years
  • Atrophy of intrinsic hand muscles (severe in 1 subject age 58)
Orlacchio et al [2008]
SPG40 (locus unknown)UnknownUncomplicated HSP
  • Onset age >35
  • Known AD HSP loci excluded
Subramony et al [2009]
SPG41
(11p14.1-p11.2)
UnknownIn a single Chinese family
  • Onset: adolescence
  • Mild weakness of intrinsic hand muscles
Zhao et al [2008]
SLC33A1 / SPG42 Acetyl -coenzyme A transporter Uncomplicated HSP in a single kindred
  • Onset: age 4-40 years
  • 1 possible instance of incomplete penetrance
Lin et al [2008], Lin et al [2010], Schlipf et al [2010]

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt.

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

1. Chromosome locus included only when the gene is not known

Table 2. Summary of Hereditary Spastic Paraplegia – Autosomal Recessive Inheritance

Gene / Locus Name
(Chromosome Locus 1)
ProteinClinical SyndromeReferences
CYP7B1 / SPG5A CYP7B1 proteinUncomplicated; or complicated by:
  • Axonal neuropathy
  • Distal or generalized muscle atrophy
  • White matter abnormalities on MRI
Hentati et al [1994a], Wilkinson et al [2003], Muglia et al [2004], Tang et al [2004], Tsaousidou et al [2008], Biancheri et al [2009], Criscuolo et al [2009]
SPG7 / SPG7 ParapleginUncomplicated; or variably complicated by:
  • Mitochondrial abnormalities on skeletal muscle biopsy
  • Dysarthria, dysphagia, optic disc pallor, axonal neuropathy, and evidence of vascular lesions,’ cerebellar atrophy, or cerebral atrophy on cranial MRI
Garner et al [1990], DeMichele et al [1998]
SPG11 / SPG11 SpatacsinReported to account for 50% of AR HSP
Uncomplicated; or variably complicated by:
  • Thin corpus callosum, intellectual disability, upper extremity weakness, dysarthria, and nystagmus
  • ‘Kjellin syndrome’ (childhood-onset, progressive spastic paraplegia with pigmentary retinopathy, intellectual disability, dysarthria, dementia, and distal muscle atrophy)
  • Juvenile, slowly progressive ALS
Martinez Murillo et al [1999], Winner et al [2004]
SPG14
(3q27-q28)
UnknownComplicated HSP in 3 members of a consanguineous Italian family
  • Onset: age ~30 years
  • Intellectual disability and distal motor neuropathy (sural nerve biopsy was normal)
Vazza et al [2000]
ZFYVE26 / SPG15 Zinc finger FYVE domain-containing protein 26Complicated HSP
  • Variably present: pigmented maculopathy, distal amyotrophy, dysarthria, intellectual disability, and further intellectual deterioration (Kjellin syndrome)
Hughes et al [2001], Hanein et al [2008]
ERLIN2 / SPG18 Erlin-2Complicated HSP in 2 families
  • Intellectual disability and thin corpus callosum
  • ERLIN2 mutations also identified in subjects with juvenile primary lateral sclerosis
Al-Yahyaee et al [2006], Alazami et al [2011], Al-Saif et al [2012]
SPG20 / SPG20 SpartinComplicated HSP
  • Distal muscle wasting (Troyer syndrome)
Cross & McKusick [1967], Crosby et al [2002], Patel et al [2002], Proukakis et al [2004], Lu et al [2006]
SPG21 / SPG21 MaspardinComplicated HSP
  • Dementia, cerebellar and extrapyramidal signs, thin corpus callosum, and white matter abnormalities (Mast syndrome)
Simpson et al [2003]
SPG23
(1q24-q32)
UnknownComplicated HSP
  • Onset: childhood
  • Skin pigment abnormality (vitiligo), premature graying, characteristic facies; Lison syndrome
Blumen et al [2003]
SPG24
(13q14)
UnknownComplicated HSP
  • Onset: childhood
  • Variably present: spastic dysarthria and pseudobulbar signs
Hodgkinson et al [2002]
SPG25
(6q23-q24.1)
UnknownIn 4 members of a consanguineous Italian family
  • Onset: adult (age 30-46 years)
  • Back and neck pain related to disk herniation and spastic paraplegia (Note: Surgical correction of disk herniation ameliorated pain and reduced spastic paraplegia.)
  • Other: peripheral neuropathy
Zortea et al [2002]
SPG26
(12p11.1–q14)
UnknownComplicated HSP in 5 members of a consanguineous Bedouin family
  • Onset: childhood (age 7-8 years)
  • Progressive spastic paraparesis with dysarthria and distal amyotrophy in both upper and lower limbs
  • Nerve conduction studies normal
  • Mild intellectual impairment, normal brain MRI
Wilkinson et al [2005]
SPG27
(10q22.1-q24.1)
UnknownUncomplicated HSP in 7 members of 1 family
  • Onset: adult (age 25-45 years)
  • Complicated HSP in 3 members of a 2nd family
  • Onset: childhood
  • Ataxia, dysarthria; intellectual disability, sensorimotor polyneuropathy, facial dysmorphism, and short stature
Meijer et al [2004], Ribai et al [2006]
DDHD1 / SPG28
(14q21.3-q22.3)
DDHD1Complicated or uncomplicated HSP
  • Onset: infancy, childhood, or adolescence
  • Variably present: axonal neuropathy, distal sensory loss, and cerebellar eye movement disturbance
Bouslam et al [2005], Tesson et al [2012]
KIF1A / SPG30KIF1AComplicated HSP
  • Distal wasting, saccadic ocular pursuit, peripheral neuropathy, mild cerebellar signs
Klebe et al [2006]
SPG32
(14q12-q21)
UnknownMild intellectual disability, brain stem dysraphia, clinically asymptomatic cerebellar atrophy
FA2H / SPG35Fatty acid 2-hydroxylase Complicated HSP in an Omani and a Pakistani kindred
  • Onset: childhood (age 6-11 years)
  • Extrapyramidal features, progressive dysarthria, dementia, seizures
  • Brain white matter abnormalities and brain iron accumulation
Dick et al [2008], Dick et al [2010], Kruer et al [2010]
PNPLA6 / SPG39 Neuropathy target esterase (NTE)Complicated HSP
  • Wasting of distal upper- and lower-extremity muscles
Rainier et al [2008]
C19orf12 / SPG43C19orf12In 2 sisters from Mali
  • Onset: ages 7 and 12 years
  • Progressive spastic paraplegia with atrophy of intrinsic hand muscles; dysarthria (in 1 sister)
Meilleur et al [2010]
GJC2 / SPG44 Gap junction protein GJA12/GJC2, also known as connexin 47 (Cx47)Complicated HSP
  • Onset: 1st-2nd decade
  • Mild phenotype with cognitive impairment, slowly progressive spastic paraplegia, dysarthria, and upper extremity involvement
  • MRI and MR spectroscopy imaging consistent with a hypomyelinating leukoencephalopathy
  • Allelic with Pelizeaus-Merzbacher-like disease (PMLD, early-onset dysmyelinating disorder with nystagmus, psychomotor delay, progressive spasticity, ataxia)
  • Caused by GJA/GJC2 mutation Ile33Met
Orthmann-Murphy et al [2009]
SPG45
(10q24.3-q25.1)
UnknownComplicated HSP in 5 members of a consanguineous kindred from Turkey
  • Onset: age <1 year
  • Intellectual disability, lower extremity spasticity and contractures
  • Optic atrophy in 1 individual
  • Pendular nystagmus in 2 individuals
  • Normal MRI in 1 individual
Dursun et al [2009]
GBA2 / SPG46 Non-lysosomal glucosylceramidaseDementia, congenital cataract, ataxia, thin corpus callosum Boukhris et al [2010]
AP4B1 / SPG47 AP-4 complex subunit beta-1Complicated HSP in 2 sibs from a consanguineous Arab family
  • Onset: early childhood
  • Slowly progressive spastic paraparesis, intellectual disability, and seizures
  • Ventriculomegaly in 1 sib; thin corpus callosum and periventricular white matter abnormalities in the other
Blumkin et al [2011]
AP5Z1 / SPG48 AP-5 complex subunit zeta-1Uncomplicated HSP in 2 sibs with homozygous mutations
  • Onset: 6th decade
‘Apparently sporadic’ spastic paraplegia in 1 individual with heterozygous mutation

Based on analysis of KIAA0415 in 166 unrelated individuals with spastic paraplegia (38 recessive, 64 dominant, 64 apparently sporadic) and controls
Slabicki et al [2010]
TECPR2 / SPG49 Tectonin beta-propeller repeat-containing protein 2 Complicated HSP in 5 individuals from 3 apparently unrelated families of Jewish Bukharian ancestry
  • Onset: infantile
  • Hypotonia, developmental delay with severe cognitive impairment, and dysmorphic features (short stature, brady-microcephaly, oral, facial, dental, nuchal abnormalities)
  • Spastic, ataxic, and rigid gait developed in childhood
  • Other: gastroesophageal reflux, recurrent apneic episodes, mild dysmorphic features
  • Epilepsy in 2 individuals
  • Thin corpus callosum and cerebellar atrophy on MRI in 2 individuals
Oz-Levi et al [2012]
AP4M1 / SPG50 AP-4 complex subunit mu-1In 5 members of a consanguineous Moroccan family
  • Onset: infantile
  • Non-progressive spastic quadriplegia with severe cognitive impairment
  • Variably present: adducted thumbs
  • Ventriculomegaly, white-matter abnormalities and variable cerebellar atrophy on neuroimaging
  • Neuroaxonal abnormalities, gliosis, and reduced myelin on post mortem examination
Verkerk et al [2009], Najmabadi et al [2011]
AP4E1 / SPG51 AP-4 complex subunit epsilon-1Complicated HSP in 2 sibs from a consanguineous Palestinian Jordanian family and 2 sibs from a consanguineous Syrian family
  • Microcephaly, hypotonia, psychomotor delay, spastic tetraplegia, marked cognitive impairment with severe language impairment, facial dysmorphic features; atrophy and diffuse white matter loss on brain MRI
  • Variably present: seizures
Abou-Jamra et al [2011], Moreno-De-Luca et al [2011], Najmabadi et al [2011]
AP4S1 / SPG52 AP-4 complex subunit sigma-1In 5 members of a consanguineous Syrian family
  • Neonatal hypotonia and severe cognitive impairment
  • Progressive early childhood-onset spastic paraplegia, microcephaly, short stature, facial dysmorphism
Dell'Angelica et al [1999], Hirst et al [1999], Abou-Jamra et al [2011]
VPS37A / SPG53 Vacuolar protein sorting-associated protein 37A Complicated HSP in 9 persons from 2 Arab Moslem families
  • Developmental delay, progressive lower-extremity spasticity, and subsequently progressive upper extremity involvement; skeletal dysmorphism (kyphosis and pectus carinatum); mild to moderate cognitive impairment; and variable hypertrichosis and impaired vibration sensation
Zivony-Elboum et al [2012]
DDHD2 / SPG54 DDHD2Complicated HSP in affected persons from 4 unrelated families
  • Onset: age <2 years
  • Psychomotor delay, cognitive impairment, progressive spasticity (leading to foot contractures), thin corpus callosum, periventricular white matter abnormalities
  • Variably present: dysarthria, dysphagia, strabismus, optic hypoplasia
Al-Yahyaee et al [2006], Schuurs-Hoeijmakers et al [2012]
C12orf65 / SPG55C12orf65, mitochondrialComplicated HSP in 2 Japanese brothers from consanguineous parents
  • Onset: childhood
  • Variably present: reduced visual acuity (with central scotoma and optic atrophy), reduced upper-extremity strength and dexterity, lower-extremity muscle atrophy, and motor sensory neuropathy
Antonicka et al [2010], Shimazaki et al [2012]
CYP2U1 / SPG56 Cytochrome P450 2U1Complicated HSP in 5 unrelated families
  • Onset: early childhood
  • Variably present: upper-extremity involvement, upper-extremity dystonia, cognitive impairment, thin corpus callosum, brain white-matter disturbance, axonal neuropathy, basal ganglia calcifications
Tesson et al [2012]
GAD1 / (no SPG designation)Glutamate decarboxylase 1In 4 sibs from a consanguineous Pakistani family
  • Spastic cerebral palsy and moderate to severe intellectual disability
Mitchell & Bundey [1997], McHale et al [1999], Lynex et al [2004]
SPOAN syndrome
(11q13)
UnknownComplicated HSP:
  • Spastic paraplegia associated with optic atrophy, neuropathy (SPOAN)
Macedo-Souza et al [2005]
5p15.31-14.1 (no SPG designation)Epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5)Complicated HSP associated with mutilating sensory neuropathyBouhouche et al [2006a], Bouhouche et al [2006b]

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt.

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

1. Chromosome locus included when the gene is not known

Table 3. Summary of Hereditary Spastic Paraplegia – X-Linked Inheritance

Gene / Locus Name
(Chromosome Locus 1)
ProteinClinical SyndromeReferences
L1CAM / SPG1Neural cell adhesion molecule L1Complicated HSP
  • Intellectual disability
  • Variably present: hydrocephalus, aphasia, and adducted thumbs
Jouet et al [1994]
PLP1 / SPG2Myelin proteolipid proteinComplicated HSP
  • Variably present: CNS white matter abnormality on MRI; peripheral neuropathy
Kobayashi et al [1994], Saugier-Veber et al [1994], Cambi et al [1996], Hudson [2003]
SPG16
(Xq11.2)
UnknownUncomplicated or complicated by:
  • Motor aphasia, reduced vision, nystagmus, mild intellectual disability, and dysfunction of the bowel and bladder
Steinmuller et al [1997], Tamagaki et al [2000]
SLC16A2 / SPG22 Monocarboxylate transport 8 Complicated HSP (Allan-Herndon-Dudley syndrome)
  • Onset: congenital
  • Neck muscle hypotonia in infancy, intellectual disability, dysarthria, ataxia, spastic paraplegia, abnormal facies
Allan et al [1944], Marx [1991], Bialer et al [1992]
SPG34
(Xq24-q25)
UnknownUncomplicated
  • Onset: age 12-25 years
Macedo-Souza et al [2008]

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt.

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

1. Chromosome locus included only when the gene is not known

Table 4. Summary of Hereditary Spastic Paraplegia – Maternal (Mitochondrial) Inheritance

Gene/Locus Name (Chromosome Locus 1)ProteinClinical SyndromeReferences
No SPG designationMitochondrial ATP6 geneProgressive spastic paraplegia
  • Onset: adult
  • Mild to severe symptoms
  • Variably present: axonal neuropathy, late-onset dementia, and cardiomyopathy
Verny et al [2011]

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt.

Evaluation Strategy

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

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

Genetic Counseling

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

Mode of Inheritance

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

Risk to Family Members — Autosomal Dominant HSP

Parents of a proband

Sibs of a proband

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

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

Risk to Family Members — Autosomal Recessive HSP

Parents of a proband

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

Sibs of a proband

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

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

Risk to Family Members — X-Linked HSP

Parents of a proband

Sibs of a proband

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

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

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

Related Genetic Counseling Issues

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

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

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

Prenatal Testing

If the disease-causing mutation(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutation(s) have been identified.

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.

  • 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.
    PO Box 1208
    Fortson GA 31808-1208
    Phone: 877-773-4483 (toll-free)
    Email: information@sp-foundation.org
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org

Management

Treatment of Manifestations

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

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

Prevention of Secondary Complications

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

Surveillance

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

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

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

Pregnancy Management

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

References

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Revision History

  • 6 February 2014 (me) Comprehensive update posted live
  • 3 February 2009 (cd) Revision: sequence analysis for SPG5A available clinically
  • 21 May 2008 (cd) Revision: mutations in ZFYVE26 identified as causative of SPG15
  • 4 March 2008 (cd) Revision: sequence analysis of entire coding region available for SPG8 and SPG33
  • 4 October 2007 (cd) Revision: sequence analysis for SPG10 available on a clinical basis
  • 11 July 2007 (me) Comprehensive update posted to live Web site
  • 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 to live Web site
  • 15 August 2000 (me) Overview posted to live Web site
  • 21 March 2000 (jf) Original submission
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