Hereditary spastic paraplegia

INTRODUCTION — Hereditary spastic paraplegia (HSP) refers to a group of familial diseases that are characterized by progressive degeneration of the corticospinal tracts. Clinically, they present with lower limb spasticity and weakness.

CLASSIFICATION — HSP, also called familial spastic paraplegia, was initially referred to as Strumpell-Lorrain disease, a name given for the two physicians who in the late 19th century independently described key features of spastic paraplegia. It has become evident that HSP is not one disease but a mixed group of genetically heterogeneous conditions that result in broadly overlapping clinical features.

HSPs are clinically differentiated into "pure" forms if spastic paraplegia with bladder involvement is the only clinical finding, and "complicated" (or complex) forms if there are additional neurologic or systemic abnormalities. In the pre-genetic era, attempts were made to further classify HSP based upon age of onset, degree of spasticity, and rate of progression [1]. Today, however, the classification of HSP is increasingly based upon genetics, especially given the phenotypic heterogeneity of HSP within the same family harboring the same genetic defect.

The genetic classification of HSP is based upon mode of inheritance, chromosomal locus, and causative mutation (if known). Hereditary spastic paraplegias include autosomal dominant, autosomal recessive, and X-linked forms. The genetic loci are designated as SPG (for SPastic parapleGia) and are numbered sequentially as SPG1, SPG2, SPG3, and so on (table 1). The numbering of the SPGs is based upon the order of locus discovery and not on the mechanism of genetic transmission. The number of loci continues to expand and is available from the Online Mendelian Inheritance in Man at Phenotypic Series - PS303350.

The correlation of clinical classification (pure or complicated) with genetic classification (SPG type) is imperfect, and some genetic types of HSP are associated with both pure and complicated phenotypes [2].

PATHOPHYSIOLOGY — While the HSPs are genetically diverse, a shared pathway for these disorders is length-dependent degeneration of the corticospinal tract axons, which is maximal in the thoracic spinal cord, and dorsal column axons in the fasciculus gracilis, which is maximal in the cervical cord [2,3]. Thus, the longest motor and sensory axons in the central nervous system appear to be particularly vulnerable to the degenerative process. Although primarily considered as a disorder of long-tract spinal cord axons, the neuropathology of many types of HSP involves additional components of the central and peripheral nervous system, including abnormalities of shorter axons in the cerebellum and corpus callosum, lower motor neurons, peripheral nerves, and myelin. Laboratory and genetic studies suggest a variety of molecular causes for HSP, including disruption in intracellular trafficking, nucleotide metabolism, synapse formation and axon development, axonal transport, mitochondrial function, and myelin maintenance and assembly [2-5].

EPIDEMIOLOGY — HSP is rare, with an overall prevalence of approximately 1 to 10 per 100,000 [2,3,6]. The disorder affects diverse ethnic groups. The age of onset is variable and ranges from neonates to older adults.

CLINICAL MANIFESTATIONS — In most cases, HSP presents with gait impairment caused by leg weakness and spasticity along with other corticospinal signs, such as brisk tendon reflexes and extensor plantar (ie, Babinski) responses. The spasticity is more or less symmetric. Based upon the severity and progression, gait disability may range from mild to severe. In addition, there can be subtle dorsal column impairment in the legs with diminished vibratory sensation distally, though sensory complaints are usually minimal [7]. Bladder dysfunction is relatively common in HSP, and urinary urgency may be an early or presenting sign. Pes cavus and hammer toes may be seen in HSP.

With the pure types of HSP, the symptoms are restricted to involvement of the longest tracts of the spinal cord. Speech is not affected, nor is there weakness in the bulbar muscles or arms.

With the complicated types of HSP, paraplegia coexists with additional neurologic or systemic derangements. Examples of complicated HSP types include spastic paraplegia in combination with the following manifestations [2,8]:

●Peripheral neuropathy in SPG2, 3A, 5, 6, 7, 10, 25, 27, 30, 31, 55, 56, 74, 75, 76, and 79

●Distal amyotrophy in SPG3A (rarely), 4 (rarely), 5, 10 11, 14, 15, 17, 20, 26, 30, 38, 39, 41, 43, and 55

●Intellectual disability in SPG1, 11, 14, 16,18, 20, 22, 26, 27, 32, 44, 45, 47, 49, 50, 51, 52, 53, 54, 56, 75, 78, 81, and 82

●Dementia in SPG4, 15, 21, 35, 46, and 78

●MRI brain abnormalities in SPG1, 2, 5, 7 (variably), 11, 15, 18, 21, 32, 35, 44, 46, 47, 49, 50, 54, 56, 75, 78, 81, and 82

●Ataxia in SPG7, 21, 22, 27, 30, 32, 46, 49, 62, 76, and 78

●Extrapyramidal symptoms in SPG21, 35, and 56

●Visual loss in SPG15, 16, 45, 46, 54, 55, 74, 75, 79, and 81

●Hearing loss in SPG29

●Skeletal abnormalities or dysmorphic features in SPG25, 49, 50, 51, 52, and 53

●Epilepsy in SPG6, 35, 47, 51, and 81

●Dysarthria in SPG7, 15, 22, 24, 27, 35, 43, 44, and 54

In addition to age of onset, the rate of progression and severity of different types of HSP are highly variable among and even within specific genetic types. Several patterns of progression have been described, including a relatively nonprogressive course, inexorable decline, and progressive worsening that stabilizes over time, reaching a functional plateau with little further increase in disability. (See 'Prognosis' below.)

Autosomal dominant HSP — The most common autosomal dominant HSPs (table 1) are SPG4 and SPG3A [9]. SPG4 accounts for 33 to 40 percent of autosomal dominant HSPs [9,10], while SPG3 accounts for 6 to 10 percent of cases [7,9]. SPG31 accounts for 4 to 6 percent of autosomal dominant HSPs [11].

Autosomal dominant HSPs usually cause a pure HSP phenotype, with the exceptions of SPG9, 17, 29, 36, and 38.

Below we describe the features of some of the more common autosomal dominant HSPs.

●SPG3A is characterized in most cases by a pure spastic paraplegia with onset in childhood [2]. Symptoms usually start before the age of 10 years and the course may be nonprogressive. Because of this early onset, sporadic cases have been misdiagnosed as cerebral palsy. Less often, SPG3A is associated with complicated HSP features, including motor-sensory axonal neuropathy, distal muscle wasting, a thin corpus callosum, and cognitive impairment [12-15]. SPG3A is caused by mutations in the ATL1 gene [16].

●SPG4 is the most common form of autosomal dominant HSP [2,3]. It is typically characterized by a pure HSP phenotype. The mean age of onset is 34 years [10], but varies considerably with a range that extends from birth to the eighth decade due to incomplete penetrance [7]. As with many other pure forms of HSP, a minority of SPG4 cases are associated with complicated features, such as cognitive impairment, psychiatric disorders, ataxia, thin corpus callosum, or muscle wasting [17-22]. There can be significant variability even in the same family, suggesting a role for modifiers [23]. SPG4 is caused by mutations in the SPAST gene [24,25].

●SPG6 typically exhibits a pure HSP phenotype. It caused by mutations in the NIPA1 gene [3,26]. Onset is usually in late adolescence or early adulthood, but ranges from 8 to 40 years [3]. Rare cases are "complicated" with variable peripheral neuropathy or epilepsy [2,27,28].

●SPG8 is a relatively frequent autosomal dominant, pure form of HSP caused by mutations in the KIAA1096 gene [29]; onset ranges from 18 to 60 years [3].

●SPG10 is characterized by a pure, early-onset spastic paraplegia caused by mutations in the KIF5A gene [30]. The age of onset ranges from 2 to 51 years [3].

●SPG17 is characterized by a complicated HSP phenotype with spastic paraparesis in the legs and marked weakness and atrophy of hand muscles (a pattern also known as Silver syndrome) [2]. The age of onset is variable [3]. The cause is mutations in the BSCL2 gene that encodes seipin, a protein that is mainly localized to the endoplasmic reticulum membrane [31]. Mutations in this gene cause two other allelic disorders, which are congenital lipodystrophy type 2 and autosomal dominant distal hereditary motor neuropathy type VA [32].

●SPG31 is a relatively frequent autosomal dominant HSP that typically exhibits a pure HSP phenotype, although occasionally complicated by peripheral neuropathy [2,33]. Limited data suggest a bimodal age of onset: either before the age of 20 years or after the age of 30 years [33]. SPG31 is caused by mutation in receptor expression-enhancing protein 1 gene (REEP1), a mitochondrial transmembrane protein of unknown function [34].

Autosomal recessive HSP — Autosomal recessive HSP (table 1) is rare in the outbred White population. Unlike autosomal dominant types of HSP, autosomal recessive HSPs are usually associated with a complicated phenotype, with the exceptions of SPG5, 24, 28, and 30 [3]. In addition, the phenotypes of the more common autosomal recessive subtypes, SPG11 and SPG15, are broadly overlapping, with both subtypes typically presenting with early cognitive impairment in childhood followed by gait impairment and spasticity in the second and third decades of life [35].

●SPG5 is a predominantly pure form that accounts for approximately 10 percent of autosomal recessive HSP, making it the second most frequent of the autosomal recessive forms [3]. Occasional cases are complicated by axonal neuropathy, distal or generalized muscle atrophy, and white matter lesions detected by brain MRI [2,36-38]. It is caused by mutations in the CYP7B1 gene, which encodes a hydrolase involved in cholesterol metabolism and modification of neurosteroids in the brain [39]. Thus, this disease links cholesterol metabolism to neurodegeneration.

●SPG7 is characterized by either a pure or a complicated phenotype [2]. Onset is mostly in adulthood, although symptoms may start as early as age 11 years [3]. Complicated forms are variably associated with dysarthria, dysphagia, optic disc pallor, axonal neuropathy, and MRI brain abnormalities including vascular-type lesions, cerebellar ataxia, cerebellar atrophy, or cerebral atrophy [2,40-42]. SPG7 is caused by mutation in the paraplegin (SPG7) gene and accounts for 1 to 4 percent of autosomal recessive HSPs [3,43]. There are also reports of SPG7 occurring as an autosomal dominant disorder with heterozygous SPG7 mutations [44].

●SPG11 is the most frequent form of autosomal recessive HSP, accounting for 20 to 50 percent of cases [2,3]. SPG11 is caused by mutations in the SPG11 gene that encodes spatacsin, a potential transmembrane protein [45,46]. Onset is typically early and ranges from age 1 to 27 years. Many SPG11 cases are complicated, involving spastic paraparesis variably associated with cognitive impairment, thin corpus callosum or white matter abnormalities on MRI, dysarthria, nystagmus, or arm weakness [2,45,47,48]. SPG11, along with SPG15 discussed below, are two known genetic causes of the Kjellin syndrome, characterized by childhood-onset, progressive spastic paraplegia variably associated with pigmentary retinopathy, intellectual disability, dysarthria, dementia, and distal muscle atrophy.

The most common form of autosomal recessive familial amyotrophic lateral sclerosis, ALS5, has been linked to mutations of the SPG11 gene. The onset is in the second decade. The clinical features of patients with ALS5 differ from those associated with HSP/SPG11 due to the presence of bulbar symptoms, upper motor neuron involvement, and pathologic manifestations of ALS. In addition, the patients with familial ALS5 have not developed the corpus callosum thinning, ocular abnormalities, cognitive deficits, or psychiatric problems that are observed in SPG11-related HSP. (See "Familial amyotrophic lateral sclerosis", section on 'ALS5 (SPG11 gene)'.)

●SPG15 accounts for 2 to 4 percent of autosomal recessive HSP [2,3]. The complicated phenotype has been associated with the Kjellin syndrome, characterized by early-onset spastic paraplegia variably associated with intellectual disability and/or dementia, dysarthria, distal muscle atrophy, and retinal degeneration. A thin corpus callosum and white matter hyperintensities are usually found on brain MRI [49]. SPG15 is caused by mutation in ZFYVE26 gene [50].

●SPG20, also known as Troyer syndrome, was initially described in Amish kindred from Ohio [51,52]. The syndrome is characterized by onset in early childhood of spastic paraplegia with distal muscle wasting, dysarthria, and difficulty in learning to walk. It is caused by a mutation in spartin (SPG20) gene [53].

●SPG21, or Mast syndrome, is a complicated form of HSP with dementia, cerebellar and extrapyramidal signs that is present at a relatively high frequency among the Old Order Amish [54]. The age of onset ranges from 20 to 40 years [3]. Thin corpus callosum and white matter abnormalities can be seen on MRI. It is caused by a mutation in ACP33 encoding the protein maspardin [55].

●SPG44 has been described in three patients from one large Italian family with a late-onset, slowly progressive, complicated spastic paraplegia, with normal or near-normal psychomotor development, preserved walking capability through adulthood, and no nystagmus [56]. MRI and MR spectroscopy imaging were consistent with a hypomyelinating leukoencephalopathy. These three patients had mutation in the GJA12/GJC2, the gene that encodes the gap junction protein connexin 47 (Cx47). Mutations in this gene are also known to cause one form of Pelizaeus-Merzbacher-like disease, a genetically heterogeneous, early-onset dysmyelinating disorder of the central nervous system, characterized by nystagmus, psychomotor delay, progressive spasticity, and cerebellar signs. (See "Pelizaeus-Merzbacher disease", section on 'Pelizaeus-Merzbacher-like disease'.)

X-linked HSP — X-linked HSP (table 1) is associated with four genes (SPG1, 2, 16, and 32). All of these typically cause complicated forms of HSP.

●SPG1, the most common X-linked HSP, is characterized by onset in infancy of spastic paraparesis complicated by intellectual disability and variable presence of aphasia, hydrocephalus, and adducted thumbs [2,3,57]. This constellation is also known as the MASA syndrome (for Mental retardation, Aphasia, Shuffling gait, and Adducted thumbs). SPG1 is caused by mutations in the L1 cell adhesion molecule (L1CAM) gene [58]. X-linked hydrocephalus is an allelic syndrome. (See "Hydrocephalus in children: Physiology, pathogenesis, and etiology", section on 'X-linked hydrocephalus'.)

●SPG2 is caused by a mutation in the PLP1 gene. This gene encodes the proteolipid protein (lipophilin), the primary constituent of myelin in the central nervous system [59]. The phenotype is that of spastic paraparesis complicated by variable presence of peripheral neuropathy and white matter lesions on MRI [2]. The age of onset ranges from infancy to the early teenage years. In most cases, there is normal motor development in the first year of life, followed by progressive weakness and spasticity of the legs [60]. Some patients later develop nystagmus, dysarthria, sensory disturbance, optic atrophy, or intellectual disability. SPG2 is allelic to Pelizaeus-Merzbacher disease. (See "Pelizaeus-Merzbacher disease".)

DIAGNOSIS — The diagnosis of HSP is based upon the presence of characteristic clinical manifestations (gait impairment with leg spasticity and weakness, often associated with urinary urgency), a family history of a similar disorder (though not universally present), and the exclusion of acquired cause of progressive spastic paraparesis [8]. Identification of a pathogenic variant in an SPG gene by molecular genetic testing confirms the diagnosis [8]. The diagnosis is most easily made when there is a family history of spastic paraplegia and the classic symptoms and signs of pyramidal dysfunction with a chronic course.

Diagnostic evaluation — The evaluation of a patient with suspected HSP should include the following:

●Neurologic examination, which typically demonstrates bilateral leg weakness and spasticity (one or the other may predominate, or both may be approximately equal in severity), hyperreflexia, extensor plantar (Babinski) responses, and variably impaired vibration sensation in the distal legs

●A three-generation family history to screen for relatives with possible HSP and determine mode of inheritance (eg, autosomal dominant, autosomal recessive, or X-linked)

●Exclusion of other disorders (see 'Differential diagnosis' below) with investigations that include the following:

•MRI of the brain and spine with and without contrast to identify structural, demyelinating, and degenerative central nervous system lesions, including cerebellar degeneration in spinocerebellar ataxias that have significant spasticity. In HSP, there may be reduced cross-sectional area of the spinal cord, particularly in the cervical and thoracic regions. In addition, some complicated HSPs can have associated brain abnormalities such as a thin corpus callosum (particularly SPG11, SPG15, SPG32, and SPG21) or hydrocephalus (SPG1).

•MR angiography of the spinal cord to look for spinal dural arteriovenous fistula.

•Cerebrospinal fluid studies to rule out chronic infections (such as neurosyphilis and neuroborreliosis) and demyelinating conditions (eg, primary progressive multiple sclerosis or an atypical presentation of neuromyelitis optica).

•Electrodiagnostic testing with nerve conduction studies and electromyography are useful to exclude motor neuron disease and can be abnormal in complicated HSP with anterior horn cell involvement or peripheral neuropathy.

•Anti-aquaporin-4 antibodies to exclude atypical presentations of neuromyelitis optica.

•C22-26 long chain fatty acid levels to exclude adrenoleukodystrophy.

•Antibodies to human T-lymphotropic virus 1 (HTLV-1).

•HIV testing.

•Serum B12 and copper levels (to exclude B12 or copper deficiency).

•Ophthalmologic studies to look for pigmentary retinopathy in select patients with complicated HSP.

Genetic testing — Molecular genetic testing is available for many of the HSPs, and therefore may be useful to confirm the diagnosis or identify potential mimics including spinocerebellar ataxia or Friedreich ataxia. Testing with a multigene panel targeting known HSP-related genes is often used as the first approach to determine a genetic diagnosis; whole-exome sequencing or whole-genome sequencing may identify the causative gene variant when the multigene panel is nondiagnostic [61-63].

Genetic testing can be informative even in the absence of family history. As an example, in a study that screened for SPG4 mutations among 146 patients with progressive spastic paraplegia and no known family history after exclusion of neurologic causes, the overall rate of SPG4 mutations was 12 percent [64].

Of note, the absence of a mutation in a causative gene for HSP does not exclude the diagnosis, since genetic testing does not include all genes that cause HSP.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of HSP is broad and includes the following disease categories [8,65]:

●Motor neuron disease, particularly slowly progressive amyotrophic lateral sclerosis or primary lateral sclerosis. Amyotrophic lateral sclerosis can mimic HSP when it affects the legs without significant amyotrophy or fasciculations. However, progression in amyotrophic lateral sclerosis is usually more rapid than HSP. Because of a lack of lower motor neuron findings, primary lateral sclerosis is more likely to mimic HSP than amyotrophic lateral sclerosis. Unlike HSP, however, primary lateral sclerosis typically affects the bulbar muscles and arms as well. Moreover, vibration sense is spared in both amyotrophic lateral sclerosis and primary lateral sclerosis, while it is often affected in HSP. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

●Structural compromise of the spinal cord, such as tethered spinal cord syndrome and spinal cord compression. (See "Closed spinal dysraphism: Clinical manifestations, diagnosis, and management", section on 'Tethered cord syndrome'.)

●Leukodystrophies and demyelinating disorders, such as:

•Progressive multiple sclerosis (see "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis", section on 'Course' and "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Disease onset and pattern')

•Neuromyelitis optica (see "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis")

•Adrenomyeloneuropathy (see "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Myeloneuropathy')

•Krabbe disease [66] (see "Krabbe disease")

•Pelizaeus-Merzbacher disease (see "Pelizaeus-Merzbacher disease")

•Metachromatic leukodystrophy (see "Metachromatic leukodystrophy")

●Neurologic impairments due to vitamin B12 deficiency (see "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Neuropsychiatric changes') and copper deficiency (see "Copper deficiency myeloneuropathy").

●Vascular malformations, most notably spinal dural arteriovenous fistulas, which typically present after the fifth decade of life with progressive or, less often, fluctuating symptoms including weakness, sensory disturbances, gait abnormalities, sphincter dysfunction, and pain, sometimes exacerbated by exercise. (See "Disorders affecting the spinal cord", section on 'Vascular malformations'.)

●Dopa-responsive dystonia, which typically begins in early childhood and is treatable with levodopa in relatively low doses. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Dopa-responsive dystonia'.)

●Metabolic disorders, such as:

•Methylene tetrahydrofolate reductase deficiency and cobalamin C deficiency (see "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency")

•Arginase deficiency and urea cycle defects (see "Urea cycle disorders: Clinical features and diagnosis")

•Biotinidase deficiency

•Phenylketonuria (see "Overview of phenylketonuria")

•Glycine encephalopathy (nonketotic hyperglycinemia)

•Cerebral folate deficiency

•Cerebrotendinous xanthomatosis (see "Cerebrotendinous xanthomatosis")

•Sjögren-Larsson syndrome (see "Sjögren-Larsson syndrome")

•Adult polyglucosan body disease (see "Glycogen branching enzyme deficiency (glycogen storage disease IV, Andersen disease)", section on 'Clinical features')

•Nucleoside phosphorylase deficiency (see "Purine nucleoside phosphorylase deficiency")

•Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (see "Hyperkinetic movement disorders in children", section on 'Lesch-Nyhan syndrome')

●Infectious diseases, particularly:

•Tropical spastic paraparesis caused by human T-lymphotropic virus 1 (see "Disorders affecting the spinal cord", section on 'HTLV-I myelopathy')

•Human immunodeficiency virus (see "Disorders affecting the spinal cord", section on 'AIDS myelopathy')

•Neurosyphilis (see "Neurosyphilis")

•Neuroborreliosis (see "Nervous system Lyme disease", section on 'Lyme encephalomyelitis')

●Hereditary ataxias with significant spasticity [67]; these can present with an HSP-like onset if the ataxia is confined to the spastic lower extremities. Examples include:

•Certain spinocerebellar ataxias (see "Autosomal dominant spinocerebellar ataxias")

•Friedreich ataxia (see "Friedreich ataxia")

•Autosomal recessive spastic ataxia of Charlevoix-Saguenay (see "Overview of cerebellar ataxia in adults", section on 'Autosomal recessive ataxias')

●Early-onset dementias, including:

•Amyotrophic lateral sclerosis with frontotemporal dementia (see "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Cognitive symptoms' and "Familial amyotrophic lateral sclerosis", section on 'C9ORF72 gene')

•Familial Alzheimer disease (see "Genetics of Alzheimer disease", section on 'Early-onset Alzheimer disease')

The diagnostic work-up should address this broad differential diagnosis. (See 'Diagnostic evaluation' above.)

MANAGEMENT — Like most neurodegenerative diseases, there is no disease-modifying treatment for HSP. However, much can be done to help the symptoms. The goal of symptomatic treatment is to improve mobility, increase range of motion, and relieve the discomfort associated with spasticity. Supportive treatment can be subdivided into pharmacologic treatment of spasticity and physical therapy and rehabilitation.

●Pharmacologic therapy of spasticity – There are several pharmacological approaches to improve spasticity. These include oral baclofen, oral tizanidine (starting at the lowest dose and titrating slowly as tolerated), and botulinum toxin injections into spastic muscles. Benzodiazepines also help in reducing spasticity but their use is now limited because of side effects. To improve their tolerance, antispasticity drugs are started at a low dose and titrated up slowly. The most common side effect of these agents is sedation. Intrathecal baclofen can be used in the more severe cases. Spastic bladder and its associated urge symptoms can be treated with anticholinergic agents such as oxybutynin.

●Physical medicine and rehabilitation – Under the guidance of physical and occupational therapists and rehabilitation physicians, patients with HSP should be encouraged to exercise and engage in therapy that focuses on stretching, reducing spasticity, and improving balance and strength. Some patients can benefit from assistive devices such as ankle-foot orthoses, walkers, or wheelchairs.

As with any genetic disease, genetic counseling can help patients learn about the disease transmission and the risk of passing on genetic mutations to their children, particularly for those planning on starting families (see "Genetic testing"). However, genetic counseling can be difficult when the mode of transmission is not evident or when there is variable penetrance. In particular, the frequency of de novo mutations causing autosomal dominant HSP is uncertain, and the full phenotypic spectrum and genetic penetrance of many types of HSP are unknown [2]. Counseling with respect to SPG7 should account for the observation that SPG7 is associated with both autosomal dominant and autosomal recessive inheritance patterns (see 'Autosomal recessive HSP' above). Prenatal genetic testing is possible for certain forms of HSP if the disease-causing mutation has been identified in an affected family member [65].

PROGNOSIS — Pure HSPs do not typically affect lifespan, although they can have a significant deleterious impact on the quality of life.

The rate of progression and severity of different types of HSP is highly variable among and even within specific genetic types. Several patterns of progression have been described:

●A relatively nonprogressive course

●Progressive worsening that stabilizes over time

●Inexorable decline

With early childhood onset, the symptoms of HSP tend to be relatively non-progressive over many years and can mimic the spastic diplegia form of cerebral palsy [2]. A subset of children experience a decline in gait for 5 to 10 years, followed by a "functional plateau" with relatively little or no further decline. With onset later in childhood or adulthood, the most typical pattern is slow but relentless progression over many years, though some individuals experience variable phases of faster or slower progression.

In a cohort of 608 cases of HSP, progression to loss of independent ambulation occurred at a median disease duration of 22 years, and wheelchair dependency at a median disease duration of 37 years [68]. Factors associated with more severe disease included longer disease duration, later age of onset, and the SPG11 genotype.

SUMMARY AND RECOMMENDATIONS

●Hereditary spastic paraplegia (HSP) refers to a group of familial diseases that are characterized primarily by progressive degeneration of the corticospinal tracts. Clinically, they present with lower limb spasticity and weakness. HSPs are clinically differentiated into "pure" forms if spastic paraplegia with bladder involvement is the only clinical finding, and "complicated" (or complex) forms if there are additional neurologic or systemic abnormalities. The genetic classification of HSP is based upon mode of inheritance, chromosomal locus, and causative mutation. The genetic loci are designated as SPG and are numbered sequentially as SPG1, SPG2, SPG3, and so on (table 1). (See 'Classification' above.)

●While the HSPs are genetically diverse, a shared pathway for these disorders is length-dependent degeneration of the corticospinal tract axons. Laboratory and genetic studies suggest a variety of molecular causes for HSP. (See 'Pathophysiology' above.)

●In most cases, HSP presents with gait impairment caused by leg weakness and spasticity. Bladder dysfunction is relatively common. With the pure types of HSP, the symptoms are restricted to involvement of the longest tracts of the spinal cord. Speech is not affected, nor is there weakness in the bulbar muscles or arms. With the complicated types of HSP, paraplegia coexists with additional neurologic or systemic derangements, such as peripheral neuropathy, MRI brain abnormalities, cognitive impairment, ataxia, distal muscle atrophy, visual loss, or epilepsy. (See 'Clinical manifestations' above.)

●Autosomal dominant HSPs usually cause a pure HSP phenotype. SPG4 and SPG3A are the most common autosomal dominant HSPs. By contrast, autosomal recessive HSPs are usually associated with a complicated phenotype. SPG5 and SPG11 are the most common autosomal recessive types. X-linked HSPs typically cause complicated forms of HSP. (See 'Autosomal dominant HSP' above and 'Autosomal recessive HSP' above and 'X-linked HSP' above.)

●The diagnosis of HSP is based upon the presence of characteristic clinical manifestations (gait impairment with leg spasticity and weakness, often associated with urinary urgency), a family history of a similar disorder (though not universally present), the exclusion of other disorders, and, increasingly, on molecular genetic testing.

●The differential diagnosis of HSP is broad and includes the following disease categories (see 'Differential diagnosis' above):

•Motor neuron disease

•Structural compromise of the spinal cord, such as tethered cord syndrome

•Vascular malformations of the spinal cord, particularly spinal dural arteriovenous fistula

•Leukodystrophies such as adult-onset adrenoleukodystrophy and adult-onset metachromatic leukodystrophy

•Demyelinating disorders, including progressive multiple sclerosis

•Dopa-responsive dystonia

•Metabolic disorders, such as methylene tetrahydrofolate reductase deficiency and cobalamin C deficiency

•Infectious diseases, particularly tropical spastic paraparesis and human immunodeficiency virus

•Hereditary ataxias associated with significant spasticity

●There is no disease-modifying treatment for HSP. The goal of symptomatic treatment is to improve mobility, increase range of motion, and relieve the discomfort associated with spasticity. (See 'Management' above.)

●The rate of progression and severity of different types of HSP is highly variable. (See 'Prognosis' above.)