Clinical 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 pathogenic variant 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 pathogenic variant(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.

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, chromosome locus, and/or causative allelic variant. 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:

• Structural abnormalities involving the brain or spinal cord (e.g., tethered cord syndrome and spinal cord compression)
• Other motor neuron disorders such as slowly progressive amyotrophic lateral sclerosis (ALS) or primary lateral sclerosis (PLS)
• Leukodystrophies such as steadily progressive multiple sclerosis, B₁₂ deficiency, Krabbe disease, metachromatic leukodystrophy, and adrenomyeloneuropathy
• Spinocerebellar ataxias (SCAs) (e.g., Machado-Joseph disease [SCA 3], Friedreich ataxia, spastic ataxia of Charlevoix-Saguenay or other spastic ataxias). See Hereditary Ataxias.
• Infection (e.g., human immunodeficiency virus [HIV AIDs], tropical spastic paraplegia (also known as human T-cell leukemia virus 1 [HTLV1] -associated myelopathy), and neurosyphilis
• Metabolic disorders (reviewed in Sedel et al [2007]) including homocysteine re-methylation defects (due to methylene tetrahydrofolate reductase (MTHFR) deficiency) and cobalamin C disease, urea cycle defects, biotinidase deficiency, phenylketonuria, glycine encephalopathy, cerebral folate deficiency, homocarnosinosis, cerebrotendinous xanthomatosis, Sjögren-Larsson syndrome, adult polyglucosan body disease, and nucleoside phosphorylase deficiency
• Early-onset dementias including frontotemporal dementia-ALS (see Amyotrophic Lateral Sclerosis Overview) and familial Alzheimer disease caused by mutation of PSEN1 (encoding presenilin-1), PSEN2 (encoding presenilin-2), or APP (encoding amyloid precursor protein) (see Alzheimer Disease Overview)
• Dopa-responsive dystonia. It is important to consider dopa-responsive dystonia in all individuals-- particularly children-- with progressive gait disturbance. See GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia, Tyrosine Hydroxylase Deficiency.

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.

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 multigene 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 multigene panels vary by laboratory and over time.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Mode of Inheritance

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

Risk to Family Members – Autosomal Dominant HSP

Parents of a proband

• Most individuals diagnosed as having an autosomal dominant HSP have an affected parent, although occasionally a proband with HSP may have the disorder as the result of a de novo pathogenic variant.
• The frequency of de novo variants causing autosomal dominant HSP is unknown.

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 mutated allele, the risk to the sibs of inheriting the mutated 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 pathogenic variant, 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 pathogenic variant.

Risk to Family Members – Autosomal Recessive HSP

Parents of a proband

• The parents of an affected individual are obligate heterozygotes, and therefore carry one mutated 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 mutated allele causing HSP.

Risk to Family Members – X-Linked HSP

Parents of a proband

• Women who have an affected son and another affected male relative are obligate heterozygotes.
• If pedigree analysis reveals that an affected male represents a simplex case (an affected male with no known family history of spastic paraplegia), several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo pathogenic variant and his mother is not a carrier.
  • His mother has a de novo pathogenic variant, either as "germline mutation" (i.e., occurring at the time of her conception and thus present in every cell of her body), or as "germline mosaicism" (i.e., in her germ cells only).
  • His maternal grandmother has a de novo pathogenic variant.

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 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Sons who inherit the variant will be affected; daughters who inherit the variant 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 pathogenic variant, 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 HSP, autosomal dominant HSP with reduced penetrance, a de novo pathogenic variant, 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, 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.

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 in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Literature Cited

• Abou Jamra R, Philippe O, Raas-Rothschild A, Eck SH, Graf E, Buchert R, Borck G, Ekici A, Brockschmidt FF, Nöthen MM, Munnich A, Strom TM, Reis A, Colleaux L. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet. 2011;88:788–95. [PMC free article: PMC3113253] [PubMed: 21620353]
• Alazami AM, Adly N, Al Dhalaan H, Alkuraya FS. A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18). Neurogenetics. 2011;12:333–6. [PMC free article: PMC3215864] [PubMed: 21796390]
• Allan W, Herndon CN, Dudley FC. Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly. Am J Ment Defic. 1944;48:325–34.
• Al-Saif A, Bohlega S, Al-Mohanna F. Loss of ERLIN2 function leads to juvenile primary lateral sclerosis. Ann Neurol. 2012;72:510–6. [PubMed: 23109145]
• Al-Yahyaee S, Al-Gazali LI, De Jonghe P, Al-Barwany H, Al-Kindi M, De Vriendt E, Chand P, Koul R, Jacob PC, Gururaj A, Sztriha L, Parrado A, Van Broeckhoven C, Bayoumi RA. A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy. Neurology. 2006;66:1230–4. [PubMed: 16636240]
• Antonicka H, Ostergaard E, Sasarman F, Weraarpachai W, Wibrand F, Pedersen AM, Rodenburg RJ, van der Knaap MS, Smeitink JA, Chrzanowska-Lightowlers ZM, Shoubridge EA. Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect. Am J Hum Genet. 2010;87:115–22. [PMC free article: PMC2896764] [PubMed: 20598281]
• Auer-Grumbach M, Schlotter-Weigel B, Lochmüller H, Strobl-Wildemann G, Auer-Grumbach P, Fischer R, Offenbacher H, Zwick EB, Robl T, Hartl G, Hartung HP, Wagner K, Windpassinger C, et al. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol. 2005;57:415–24. [PubMed: 15732094]
• Beetz C, Schüle R, Deconinck T, Tran-Viet KN, Zhu H, Kremer BP, Frints SG, van Zelst-Stams WA, Byrne P, Otto S, Nygren AO, Baets J, Smets K, Ceulemans B, Dan B, Nagan N, Kassubek J, Klimpe S, Klopstock T, Stolze H, Smeets HJ, Schrander-Stumpel CT, Hutchinson M, van de Warrenburg BP, Braastad C, Deufel T, Pericak-Vance M, Schöls L, de Jonghe P, Züchner S. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain. 2008;131:1078–86. [PMC free article: PMC2841798] [PubMed: 18321925]
• Behan WM, Maia M. Strumpell's familial spastic paraplegia: genetics and neuropathology. J Neurol Neurosurg Psychiatry. 1974;37:8–20. [PMC free article: PMC494557] [PubMed: 4813430]
• Bialer MG, Lawrence L, Stevenson RE, Silverberg G, Williams MK, Arena JF, Lubs HA, Schwartz CE. Allan-Herndon-Dudley syndrome: clinical and linkage studies on a second family. Am J Med Genet. 1992;43:491–7. [PubMed: 1605231]
• Bian X, Klemm RW, Liu TY, Zhang M, Sun S, Sui X, Liu X, Rapoport TA, Hu J. Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes. Proc Natl Acad Sci U S A. 2011;108:3976–81. [PMC free article: PMC3054032] [PubMed: 21368113]
• Biancheri R, Ciccolella M, Rossi A, Tessa A, Cassandrini D, Minetti C, Santorelli FM. White matter lesions in spastic paraplegia with mutations in SPG5/CYP7B1. Neuromuscul Disord. 2009;19:62–5. [PubMed: 19187859]
• Blumen SC, Bevan S, Abu-Mouch S, Negus D, Kahana M, Inzelberg R, Mazarib A, Mahamid A, Carasso RL, Slor H, Withers D, Nisipeanu P, Navon R, Reid E. A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32. Ann Neurol. 2003;54:796–803. [PubMed: 14681889]
• Blumkin L, Lerman-Sagie T, Lev D, Yosovich K, Leshinsky-Silver E. A new locus (SPG47) maps to 1p13.2-1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum. J Neurol Sci. 2011;305:67–70. [PubMed: 21440262]
• Bouhouche A, Benomar A, Bouslam N, Chkili T, Yahyaoui M. Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia. J Med Genet. 2006b;43:441–3. [PMC free article: PMC2564519] [PubMed: 16399879]
• Bouhouche A, Benomar A, Bouslam N, Ouazzani R, Chkili T, Yahyaoui M. Autosomal recessive mutilating sensory neuropathy with spastic paraplegia maps to chromosome 5p15.31-14.1. Eur J Hum Genet. 2006a;14:249–52. [PubMed: 16333315]
• Boukhris A, Feki I, Elleuch N, Miladi MI, Boland-Augé A, Truchetto J, Mundwiller E, Jezequel N, Zelenika D, Mhiri C, Brice A, Stevanin G. A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum. Neurogenetics. 2010;11:441–8. [PubMed: 20593214]
• Bouslam N, Benomar A, Azzedine H, Bouhouche A, Namekawa M, Klebe S, Charon C, Durr A, Ruberg M, Brice A, Yahyaoui M, Stevanin G. Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Ann Neurol. 2005;57:567–71. [PubMed: 15786464]
• Bross P, Naundrup S, Hansen J, Nielsen MN, Christensen JH, Kruhøffer M, Palmfeldt J, Corydon TJ, Gregersen N, Ang D, Georgopoulos C, Nielsen KL. The Hsp60-(p.V98I) mutation associated with hereditary spastic paraplegia SPG13 compromises chaperonin function both in vitro and in vivo. J Biol Chem. 2008;283:15694–700. [PMC free article: PMC3259655] [PubMed: 18400758]
• Cambi F, Tang XM, Cordray P, Fain PR, Keppen LD, Barker DF. Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia. Neurology. 1996;46:1112–7. [PubMed: 8780101]
• Charvin D, Cifuentes-Diaz C, Fonknechten N, Joshi V, Hazan J, Melki J, Betuing S. Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus. Hum Mol Genet. 2003;12:71–8. [PubMed: 12490534]
• Chen S, Song C, Guo H, Xu P, Huang W, Zhou Y, Sun J, Li CX, Du Y, Li X, Liu Z, Geng D, Maxwell PH, Zhang C, Wang Y. Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families. Hum Mutat. 2005;25:135–41. [PubMed: 15643603]
• Criscuolo C, Filla A, Coppola G, Rinaldi C, Carbone R, Pinto S, Wang Q, de Leva MF, Salvatore E, Banfi S, Brunetti A, Quarantelli M, Geschwind DH, Pappatà S, De Michele G. Two novel CYP7B1 mutations in Italian families with SPG5: a clinical and genetic study. J Neurol. 2009;256:1252–7. [PubMed: 19363635]
• Crosby AH, Patel H, Patton MA, Proukakis C, Cross H. Spartin, the Troyer syndrome gene, suggests defective endosomal trafficking underlies some forms of hereditary spastic paraplegia. Am J Hum Genet. 2002;71:516.
• Cross HE, McKusick VA. The Troyer syndrome. A recessive form of spastic paraplegia with distal muscle wasting. Arch Neurol. 1967;16:473–85. [PubMed: 6022528]
• De Michele G, De Fusco M, Cavalcanti F, Filla A, Marconi R, Volpe G, Monticelli A, Ballabio A, Casari G, Cocozza S. A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3. Am J Hum Genet. 1998;63:135–9. [PMC free article: PMC1377251] [PubMed: 9634528]
• Dell'Angelica EC, Mullins C, Bonifacino JS. AP-4, a novel protein complex related to clathrin adaptors. J Biol Chem. 1999;274:7278–85. [PubMed: 10066790]
• Dick KJ, Al-Mjeni R, Baskir W, Koul R, Simpson MA, Patton MA, Raeburn S, Crosby AH. A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23. Neurology. 2008;71:248–52. [PubMed: 18463364]
• Dick KJ, Eckhardt M, Paisán-Ruiz C, Alshehhi AA, Proukakis C, Sibtain NA, Maier H, Sharifi R, Patton MA, Bashir W, Koul R, Raeburn S, Gieselmann V, Houlden H, Crosby AH. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum Mutat. 2010;31:E1251–60. [PubMed: 20104589]
• Du J, Hu YC, Tang BS, Chen C, Luo YY, Zhan ZX, Zhao GH, Jiang H, Xia K, Shen L. Expansion of the phenotypic spectrum of SPG6 caused by mutation in NIPA1. Clin Neurol Neurosurg. 2011;113:480–2. [PubMed: 21419568]
• Dursun U, Koroglu C, Kocasoy Orhan E, Ugur SA, Tolun A. Autosomal recessive spastic paraplegia (SPG45) with mental retardation maps to 10q24.3-q25.1. Neurogenetics. 2009;10:325–31. [PubMed: 19415352]
• Evans KJ, Gomes ER, Reisenweber SM, Gundersen GG, Lauring BP. Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing. J Cell Biol. 2005;168:599–606. [PMC free article: PMC2171748] [PubMed: 15716377]
• Fichera M, Lo Giudice M, Falco M, Sturnio M, Amata S, Calabrese O, Bigoni S, Calzolari E, Neri M. Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. Neurology. 2004;63:1108–10. [PubMed: 15452312]
• Fink JK, Sharp GB, Lange BM, Wu CB, Haley T, Otterud B, Peacock M, Leppert M. Autosomal dominant, familial spastic paraplegia, type I: clinical and genetic analysis of a large North American family. Neurology. 1995a;45:325–31. [PubMed: 7854534]
• Fink JK, Wu CT, Jones SM, Sharp GB, Lange BM, Lesicki A, Reinglass T, Varvil T, Otterud B, Leppert M. Autosomal dominant familial spastic paraplegia: tight linkage to chromosome 15q. Am J Hum Genet. 1995b;56:188–92. [PMC free article: PMC1801321] [PubMed: 7825577]
• Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013;126:307–28. [PMC free article: PMC4045499] [PubMed: 23897027]
• Fontaine B, Davoine CS, Dürr A, Paternotte C, Feki I, Weissenbach J, Hazan J, Brice A. A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34. Am J Hum Genet. 2000;66:702–7. [PMC free article: PMC1288122] [PubMed: 10677329]
• Garner CC, Garner A, Huber G, Kozak C, Matus A. Molecular cloning of microtubule-associated protein 1 (MAP1A) and microtubule-associated protein 5 (MAP1B): identification of distinct genes and their differential expression in developing brain. J Neurochem. 1990;55:146–54. [PubMed: 2355215]
• Hanein S, Dürr A, Ribai P, Forlani S, Leutenegger AL, Nelson I, Babron MC, Elleuch N, Depienne C, Charon C, Brice A, Stevanin G. A novel locus for autosomal dominant "uncomplicated" hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3. Hum Genet. 2007;122:261–73. [PubMed: 17605047]
• Hanein S, Martin E, Boukhris A, Byrne P, Goizet C, Hamri A, Benomar A, Lossos A, Denora P, Fernandez J, Elleuch N, Forlani S, Durr A, Feki I, Hutchinson M, Santorelli FM, Mhiri C, Brice A, Stevanin G. Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am J Hum Genet. 2008;82:992–1002. [PMC free article: PMC2427184] [PubMed: 18394578]
• Hansen JJ, Dürr A, Cournu-Rebeix I, Georgopoulos C, Ang D, Nielsen MN, Davoine CS, Brice A, Fontaine B, Gregersen N, Bross P. Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am J Hum Genet. 2002;70:1328–32. [PMC free article: PMC447607] [PubMed: 11898127]
• Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet. 1983;1:1151–5. [PubMed: 6133167]
• Hazan J, Fontaine B, Bruyn RP, Lamy C, van Deutekom JC, Rime CS, Dürr A, Melki J, Lyon-Caen O, Agid Y, Munnich A, Padberg GW, de Recondo J, Frants RR, Brice A, Welssenbach J. Linkage of a new locus for autosomal dominant familial spastic paraplegia to chromosome 2p. Hum Mol Genet. 1994;3:1569–73. [PubMed: 7833913]
• Hazan J, Lamy C, Melki J, Munnich A, de Recondo J, Weissenbach J. Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q. Nat Genet. 1993;5:163–7. [PubMed: 8252041]
• Hedera P, DiMauro S, Bonilla E, Wald J, Eldevik OP, Fink JK. Phenotypic analysis of autosomal dominant hereditary spastic paraplegia linked to chromosome 8q. Neurology. 1999a;53:44–50. [PubMed: 10408535]
• Hedera P, Rainier S, Alvarado D, Zhao X, Williamson J, Otterud B, Leppert M, Fink JK. Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q. Am J Hum Genet. 1999b;64:563–9. [PMC free article: PMC1377766] [PubMed: 9973294]
• Hentati A, Pericak-Vance MA, Hung WY, Belal S, Laing N, Boustany RM, Hentati F, Ben Hamida M, Siddique T. Linkage of 'pure' autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Hum Mol Genet. 1994a;3:1263–7. [PubMed: 7987300]
• Hentati A, Pericak-Vance MA, Lennon F, Wasserman B, Hentati F, Juneja T, Angrist MH, Hung WY, Boustany RM, Bohlega S. Iqbal1 Z, Huether CH, Hamida MB, Siddique T. Linkage of a locus for autosomal dominant familial spastic paraplegia to chromosome 2p markers. Hum Mol Genet. 1994b;3:1867–71. [PubMed: 7849714]
• Hirst J, Bright NA, Rous B, Robinson MS. Characterization of a fourth adaptor-related protein complex. Mol Biol Cell. 1999;10:2787–802. [PMC free article: PMC25515] [PubMed: 10436028]
• Hodgkinson CA, Bohlega S, Abu-Amero SN, Cupler E, Kambouris M, Meyer BF, Bharucha VA. A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14. Neurology. 2002;59:1905–9. [PubMed: 12499481]
• Hudson LD. Pelizaeus-Merzbacher disease and spastic paraplegia type 2: two faces of myelin loss from mutations in the same gene. J Child Neurol. 2003;18:616–24. [PubMed: 14572140]
• Hughes CA, Byrne PC, Webb S, McMonagle P, Patterson V, Hutchinson M, Parfrey NA. SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q. Neurology. 2001;56:1230–3. [PubMed: 11342696]
• Jouet M, Rosenthal A, Armstrong G, MacFarlane J, Stevenson R, Paterson J, Metzenberg A, Ionasescu V, Temple K, Kenwrick S. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet. 1994;7:402–7. [PubMed: 7920659]
• Klebe S, Azzedine H, Durr A, Bastien P, Bouslam N, Elleuch N, Forlani S, Charon C, Koenig M, Melki J, Brice A, Stevanin G. Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3. Brain. 2006;129:1456–62. [PubMed: 16434418]
• Kobayashi H, Hoffman EP, Marks HG. The rumpshaker mutation in spastic paraplegia. Nat Genet. 1994;7:351–2. [PubMed: 7522741]
• Kruer MC, Paisán-Ruiz C, Boddaert N, Yoon MY, Hama H, Gregory A, Malandrini A, Woltjer RL, Munnich A, Gobin S, Polster BJ, Palmeri S, Edvardson S, Hardy J, Houlden H, Hayflick SJ. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol. 2010;68:611–8. [PMC free article: PMC6059612] [PubMed: 20853438]
• Lin P, Li J, Liu Q, Mao F, Li J, Qiu R, Hu H, Song Y, Yang Y, Gao G, Yan C, Yang W, Shao C, Gong Y. A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42). Am J Hum Genet. 2008;83:752–9. [PMC free article: PMC2668077] [PubMed: 19061983]
• Lin P, Mao F, Liu Q, Shao C, Yan C, Gong Y. Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia (SPG42) caused by SLC33A1 mutation in a Chinese kindred. Prenat Diagn. 2010;30:485–6. [PubMed: 20306460]
• Lu J, Rashid F, Byrne PC. The hereditary spastic paraplegia protein spartin localises to mitochondria. J Neurochem. 2006;98:1908–19. [PubMed: 16945107]
• Lynex CN, Carr IM, Leek JP, Achuthan R, Mitchell S, Maher ER, Woods CG, Bonthon DT, Markham AF. Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders. BMC Neurol. 2004;4:20. [PMC free article: PMC544830] [PubMed: 15571623]
• Macedo-Souza LI, Kok F, Santos S, Amorim SC, Starling A, Nishimura A, Lezirovitz K, Lino AM, Zatz M. Spastic paraplegia, optic atrophy, and neuropathy is linked to chromosome 11q13. Ann Neurol. 2005;57:730–7. [PubMed: 15852396]
• Macedo-Souza LI, Kok F, Santos S, Licinio L, Lezirovitz K, Nascimento RM, Bueno C, Martyn M, Leão EK, Zatz M. Reevaluation of a large family defines a new locus for X-linked recessive pure spastic paraplegia (SPG34) on chromosome Xq25. Neurogenetics. 2008;9:225–6. [PubMed: 18463901]
• Mannan AU, Krawen P, Sauter SM, Boehm J, Chronowska A, Paulus W, Neesen J, Engel W. ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia. Am J Hum Genet. 2006;79:351–7. [PMC free article: PMC1559503] [PubMed: 16826525]
• Martínez Murillo F, Kobayashi H, Pegoraro E, Galluzzi G, Creel G, Mariani C, Farina E, Ricci E, Alfonso G, Pauli RM, Hoffman EP. Genetic localization of a new locus for recessive familial spastic paraparesis to 15q13-15. Neurology. 1999;53:50–6. [PubMed: 10408536]
• Martinez-Lage M, Molina-Porcel L, Falcone D, McCluskey L, Lee VM, Van Deerlin VM, Trojanowski JQ. TDP-43 pathology in a case of hereditary spastic paraplegia with a NIPA1/SPG6 mutation. Acta Neuropathol. 2012;124:285–91. [PMC free article: PMC3361549] [PubMed: 22302102]
• Marx J. Alzheimer's research moves to mice. Science. 1991;253:266–7. [PubMed: 1907022]
• McHale DP, Mitchell S, Bundey S, Moynihan L, Campbell DA, Woods CG, Lench NJ, Mueller RF, Markham AF. A gene for autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25. Am J Hum Genet. 1999;64:526–32. [PMC free article: PMC1377761] [PubMed: 9973289]
• McMonagle P, Webb S, Hutchinson M. The prevalence of "pure" autosomal dominant hereditary spastic paraparesis in the island of Ireland. J Neurol Neurosurg Psychiatry. 2002;72:43–6. [PMC free article: PMC1737699] [PubMed: 11784824]
• Meijer IA, Cossette P, Roussel J, Benard M, Toupin S, Rouleau GA. A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.1-10q24.1. Ann Neurol. 2004;56:579–82. [PubMed: 15455396]
• Meilleur KG, Traoré M, Sangaré M, Britton A, Landouré G, Coulibaly S, Niaré B, Mochel F, La Pean A, Rafferty I, Watts C, Shriner D, Littleton-Kearney MT, Blackstone C, Singleton A, Fischbeck KH. Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19. Neurogenetics. 2010;11:313–8. [PMC free article: PMC2891134] [PubMed: 20039086]
• Mitchell S, Bundey S. Symmetry of neurological signs in Pakistani patients with probable inherited spastic cerebral palsy. Clin Genet. 1997;51:7–14. [PubMed: 9084927]
• Montenegro G, Rebelo AP, Connell J, Allison R, Babalini C, D'Aloia M, Montieri P, Schüle R, Ishiura H, Price J, Strickland A, Gonzalez MA, Baumbach-Reardon L, Deconinck T, Huang J, Bernardi G, Vance JM, Rogers MT, Tsuji S, De Jonghe P, Pericak-Vance MA, Schöls L, Orlacchio A, Reid E, Züchner S. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J Clin Invest. 2012;122:538–44. [PMC free article: PMC3266795] [PubMed: 22232211]
• Moreno-De-Luca A, Helmers SL, Mao H, Burns TG, Melton AM, Schmidt KR, Fernhoff PM, Ledbetter DH, Martin CL. Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability. J Med Genet. 2011;48:141–4. [PMC free article: PMC3150730] [PubMed: 20972249]
• Muglia M, Criscuolo C, Magariello A, De Michele G, Scarano V, D'Adamo P, Ambrosio G, Gabriele AL, Patitucci A, Mazzei R, Conforti FL, Sprovieri T, Morgante L, Epifanio A, La Spina P, Valentino P, Gasparini P, Filla A, Quattrone A. Narrowing of the critical region in autosomal recessive spastic paraplegia linked to the SPG5 locus. Neurogenetics. 2004;5:49–54. [PubMed: 14658060]
• Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS, Chen W, Hosseini M, Behjati F, Haas S, Jamali P, Zecha A, Mohseni M, Püttmann L, Vahid LN, Jensen C, Moheb LA, Bienek M, Larti F, Mueller I, Weissmann R, Darvish H, Wrogemann K, Hadavi V, Lipkowitz B, Esmaeeli-Nieh S, Wieczorek D, Kariminejad R, Firouzabadi SG, Cohen M, Fattahi Z, Rost I, Mojahedi F, Hertzberg C, Dehghan A, Rajab A, Banavandi MJ, Hoffer J, Falah M, Musante L, Kalscheuer V, Ullmann R, Kuss AW, Tzschach A, Kahrizi K, Ropers HH. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011;478:57–63. [PubMed: 21937992]
• Orlacchio A, Kawarai T, Gaudiello F, St George-Hyslop PH, Floris R, Bernardi G. New locus for hereditary spastic paraplegia maps to chromosome 1p31.1-1p21.1. Ann Neurol. 2005;58:423–9. [PubMed: 16130112]
• Orlacchio A, Patrono C, Gaudiello F, Rocchi C, Moschella V, Floris R, Bernardi G, Kawarai T. Silver syndrome variant of hereditary spastic paraplegia: A locus to 4p and allelism with SPG4. Neurology. 2008;70:1959–66. [PubMed: 18401025]
• Orthmann-Murphy JL, Salsano E, Abrams CK, Bizzi A, Uziel G, Freidin MM, Lamantea E, Zeviani M, Scherer SS, Pareyson D. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain. 2009;132:426–38. [PMC free article: PMC2640216] [PubMed: 19056803]
• Oz-Levi D, Ben-Zeev B, Ruzzo EK, Hitomi Y, Gelman A, Pelak K, Anikster Y, Reznik-Wolf H, Bar-Joseph I, Olender T, Alkelai A, Weiss M, Ben-Asher E, Ge D, Shianna KV, Elazar Z, Goldstein DB, Pras E, Lancet D. Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am J Hum Genet. 2012;91:1065–72. [PMC free article: PMC3516605] [PubMed: 23176824]
• Patel H, Cross H, Proukakis C, Hershberger R, Bork P, Ciccarelli FD, Patton MA, McKusick VA, Crosby AH. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet. 2002;31:347–8. [PubMed: 12134148]
• Patel H, Hart PE, Warner TT, Houlston RS, Patton MA, Jeffery S, Crosby AH. The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12-q14, with evidence for genetic heterogeneity within this subtype. Am J Hum Genet. 2001;69:209–15. [PMC free article: PMC1226036] [PubMed: 11389484]
• Paternotte C, Rudnicki D, Fizames C, Davoine CS, Mavel D, Dürr A, Samson D, Marquette C, Muselet D, Vega-Czarny N, Drouot N, Voit T, Fontaine B, Gyapay G, Auburger G, Weissenbach J, Hazan J. Quality assessment of whole genome mapping data in the refined familial spastic paraplegia interval on chromosome 14q. Genome Res. 1998;8:1216–27. [PMC free article: PMC310792] [PubMed: 9847083]
• Proukakis C, Cross H, Patel H, Patton MA, Valentine A, Crosby AH. Troyer syndrome revisited. A clinical and radiological study of a complicated hereditary spastic paraplegia. J Neurol. 2004;251:1105–10. [PubMed: 15372254]
• Rainier S, Bui M, Mark E, Thomas D, Tokarz D, Ming L, Delaney C, Richardson RJ, Albers JW, Matsunami N, Stevens J, Coon H, Leppert M, Fink JK. Neuropathy target esterase gene mutations cause motor neuron disease. Am J Hum Genet. 2008;82:780–5. [PMC free article: PMC2427280] [PubMed: 18313024]
• Rainier S, Chai JH, Tokarz D, Nicholls RD, Fink JK. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet. 2003;73:967–71. [PMC free article: PMC1180617] [PubMed: 14508710]
• Reid E, Dearlove AM, Osborn O, Rogers MT, Rubinsztein DC. A locus for autosomal dominant "pure" hereditary spastic paraplegia maps to chromosome 19q13. Am J Hum Genet. 2000;66:728–32. [PMC free article: PMC1288126] [PubMed: 10677333]
• Reid E, Dearlove AM, Rhodes M, Rubinsztein DC. A new locus for autosomal dominant "pure" hereditary spastic paraplegia mapping to chromosome 12q13, and evidence for further genetic heterogeneity. Am J Hum Genet. 1999;65:757–63. [PMC free article: PMC1377983] [PubMed: 10441583]
• Ribai P, Stevanin G, Bouslam N, Pontier B, Nelson I, Fontaine B, Dussert C, Charon C, Durr A, Brice A. A new phenotype linked to SPG27 and refinement of the critical region on chromosome. J Neurol. 2006;253:714–9. [PubMed: 16511635]
• Roll-Mecak A, Vale RD. The Drosophila homologue of the hereditary spastic paraplegia protein, spastin, severs and disassembles microtubules. Curr Biol. 2005;15:650–5. [PubMed: 15823537]
• Saugier-Veber P, Munnich A, Bonneau D, Rozet JM, Le Merrer M, Gil R, Boespflug-Tanguy O. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet. 1994;6:257–62. [PubMed: 8012387]
• Schlipf NA, Beetz C, Schüle R, Stevanin G, Erichsen AK, Forlani S, Zaros C, Karle K, Klebe S, Klimpe S, Durr A, Otto S, Tallaksen CM, Riess O, Brice A, Bauer P, Schöls L. A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42). Eur J Hum Genet. 2010;18:1065–7. [PMC free article: PMC2987419] [PubMed: 20461110]
• Schüle R, Bonin M, Dürr A, Forlani S, Sperfeld AD, Klimpe S, Mueller JC, Seibel A, van de Warrenburg BP, Bauer P, Schöls L. Autosomal dominant spastic paraplegia with peripheral neuropathy maps to chr12q23-24. Neurology. 2009;72:1893–8. [PubMed: 19357379]
• Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ, Ben-Salem S, de Bot ST, Nijhof B, van de Vondervoort II, van der Graaf M, Nobau AC, Otte-Höller I, Vermeer S, Smith AC, Humphreys P, Schwartzentruber J, Ali BR, Al-Yahyaee SA, Tariq S, Pramathan T, Bayoumi R, Kremer HP, van de Warrenburg BP, van den Akker WM, Gilissen C, Veltman JA, Janssen IM, Vulto-van Silfhout AT, van der Velde-Visser S, Lefeber DJ, Diekstra A, Erasmus CE, Willemsen MA, Vissers LE, Lammens M, van Bokhoven H, Brunner HG, Wevers RA, Schenck A, Al-Gazali L, de Vries BB, de Brouwer AP, et al. Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet. 2012;91:1073–81. [PMC free article: PMC3516595] [PubMed: 23176823]
• Schwarz GA, Liu CN. Hereditary (familial) spastic paraplegia; further clinical and pathologic observations. AMA Arch Neurol Psychiatry. 1956;75:144–62. [PubMed: 13282534]
• Sedel F, Fontaine B, Saudubray JM, Lyon-Caen O. Hereditary spastic paraparesis in adults associated with inborn errors of metabolism: a diagnostic approach. J Inherit Metab Dis. 2007;30:855–64. [PubMed: 17957490]
• Seri M, Cusano R, Forabosco P, Cinti R, Caroli F, Picco P, Bini R, Morra VB, De Michele G, Lerone M, Silengo M, Pela I, Borrone C, Romeo G, Devoto M. Genetic mapping to 10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy. Am J Hum Genet. 1999;64:586–93. [PMC free article: PMC1377769] [PubMed: 9973297]
• Shimazaki H, Takiyama Y, Ishiura H, Sakai C, Matsushima Y, Hatakeyama H, Honda J, Sakoe K, Naoi T, Namekawa M, Fukuda Y, Takahashi Y, Goto J, Tsuji S, Goto Y, Nakano I, et al. A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). J Med Genet. 2012;49:777–84. [PubMed: 23188110]
• Simpson MA, Cross H, Proukakis C, Pryde A, Hershberger R, Chatonnet A, Patton MA, Crosby AH. Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am J Hum Genet. 2003;73:1147–56. [PMC free article: PMC1180493] [PubMed: 14564668]
• Słabicki M, Theis M, Krastev DB, Samsonov S, Mundwiller E, Junqueira M, Paszkowski-Rogacz M, Teyra J, Heninger AK, Poser I, Prieur F, Truchetto J, Confavreux C, Marelli C, Durr A, Camdessanche JP, Brice A, Shevchenko A, Pisabarro MT, Stevanin G, Buchholz F. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol. 2010;8:e1000408. [PMC free article: PMC2893954] [PubMed: 20613862]
• Steinmüller R, Lantigua-Cruz A, Garcia-Garcia R, Kostrzewa M, Steinberger D, Müller U. Evidence of a third locus in X-linked recessive spastic paraplegia. Hum Genet. 1997;100:287–9. [PubMed: 9254866]
• Subramony SH, Nguyen TV, Langford L, Lin X, Parent AD, Zhang J. Identification of a new form of autosomal dominant spastic paraplegia. Clin Genet. 2009;76:113–6. [PubMed: 19519683]
• Svenstrup K, Møller RS, Christensen J, Budtz-Jørgensen E, Gilling M, Nielsen JE. NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy. Eur J Neurol. 2011;18:1197–9. [PubMed: 21599812]
• Tamagaki A, Shima M, Tomita R, Okumura M, Shibata M, Morichika S, Kurahashi H, Giddings JC, Yoshioka A, Yokobayashi Y. Segregation of a pure form of spastic paraplegia and NOR insertion into Xq11.2. Am J Med Genet. 2000;94:5–8. [PubMed: 10982474]
• Tang BS, Chen X, Zhao GH, Shen L, Yan XX, Jiang H, Luo W. Clinical features of hereditary spastic paraplegia with thin corpus callosum: report of 5 Chinese cases. Chin Med J (Engl). 2004;117:1002–5. [PubMed: 15265372]
• Tesson C, Nawara M, Salih MA, Rossignol R, Zaki MS, Al Balwi M, Schule R, Mignot C, Obre E, Bouhouche A, Santorelli FM, Durand CM, Oteyza AC, El-Hachimi KH, Al Drees A, Bouslam N, Lamari F, Elmalik SA, Kabiraj MM, Seidahmed MZ, Esteves T, Gaussen M, Monin ML, Gyapay G, Lechner D, Gonzalez M, Depienne C, Mochel F, Lavie J, Schols L, Lacombe D, Yahyaoui M, Al Abdulkareem I, Züchner S, Yamashita A, Benomar A, Goizet C, Durr A, Gleeson JG, Darios F, Brice A, Stevanin G. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet. 2012;91:1051–64. [PMC free article: PMC3516610] [PubMed: 23176821]
• Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA, Laing NG, Wilkinson PA, Madrid RE, Patel H, Hentati F, Patton MA, Hentati A, Lamont PJ, Siddique T, Crosby AH. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am J Hum Genet. 2008;82:510–5. [PMC free article: PMC2426914] [PubMed: 18252231]
• Valdmanis PN, Meijer IA, Reynolds A, Lei A, MacLeod P, Schlesinger D, Zatz M, Reid E, Dion PA, Drapeau P, Rouleau GA. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am J Hum Genet. 2007;80:152–61. [PMC free article: PMC1785307] [PubMed: 17160902]
• Valente EM, Brancati F, Caputo V, Bertini E, Patrono C, Costanti D, Dallapiccola B. Novel locus for autosomal dominant pure hereditary spastic paraplegia (SPG19) maps to chromosome 9q33-q34. Ann Neurol. 2002;51:681–5. [PubMed: 12112072]
• Vazza G, Zortea M, Boaretto F, Micaglio GF, Sartori V, Mostacciuolo ML. A new locus for autosomal recessive spastic paraplegia associated with mental retardation and distal motor neuropathy, SPG14, maps to chromosome 3q27-q28. Am J Hum Genet. 2000;67:504–9. [PMC free article: PMC1287196] [PubMed: 10877981]
• Verkerk AJ, Schot R, Dumee B, Schellekens K, Swagemakers S, Bertoli-Avella AM, Lequin MH, Dudink J, Govaert P, van Zwol AL, Hirst J, Wessels MW, Catsman-Berrevoets C, Verheijen FW, de Graaff E, de Coo IF, Kros JM, Willemsen R, Willems PJ, van der Spek PJ, Mancini GM. Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am J Hum Genet. 2009;85:40–52. [PMC free article: PMC2706965] [PubMed: 19559397]
• Verny C, Guegen N, Desquiret V, Chevrollier A, Prundean A, Dubas F, Cassereau J, Ferre M, Amati-Bonneau P, Bonneau D, Reynier P, Procaccio V. Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation. Mitochondrion. 2011;11:70–5. [PubMed: 20656066]
• Wilkinson PA, Crosby AH, Turner C, Patel H, Wood NW, Schapira AH, Warner TT. A clinical and genetic study of SPG5A linked autosomal recessive hereditary spastic paraplegia. Neurology. 2003;61:235–8. [PubMed: 12874406]
• Wilkinson PA, Simpson MA, Bastaki L, Patel H, Reed JA, Kalidas K, Samilchuk E, Khan R, Warner TT, Crosby AH. A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1-12q14. J Med Genet. 2005;42:80–2. [PMC free article: PMC1735920] [PubMed: 15635080]
• Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Hörl G, Malli R, Reed JA, Dierick I, Verpoorten N, Warner TT, Proukakis C, Van den Bergh P, Verellen C, Van Maldergem L, Merlini L, De Jonghe P, Timmerman V, Crosby AH, Wagner K. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004;36:271–6. [PubMed: 14981520]
• Winner B, Uyanik G, Gross C, Lange M, Schulte-Mattler W, Schuierer G, Marienhagen J, Hehr U, Winkler J. Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (SPG11). Arch Neurol. 2004;61:117–21. [PubMed: 14732628]
• Zhao GH, Hu ZM, Shen L, Jiang H, Ren ZJ, Liu XM, Xia K, Guo P, Pan Q, Tang BS. A novel candidate locus on chromosome 11p14.1-p11.2 for autosomal dominant hereditary spastic paraplegia. Chin Med J (Engl). 2008;121:430–4. [PubMed: 18364116]
• Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber CH, Tukel T, Apak M, Heiman-Patterson T, Ming L, Bui M, Fink JK. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet. 2001;29:326–31. [PubMed: 11685207]
• Zivony-Elboum Y, Westbroek W, Kfir N, Savitzki D, Shoval Y, Bloom A, Rod R, Khayat M, Gross B, Samri W, Cohen H, Sonkin V, Freidman T, Geiger D, Fattal-Valevski A, Anikster Y, Waters AM, Kleta R, Falik-Zaccai TC. A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis. J Med Genet. 2012;49:462–72. [PubMed: 22717650]
• Zortea M, Vettori A, Trevisan CP, Bellini S, Vazza G, Armani M, Simonati A, Mostacciuolo ML. Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3-q24.1. J Med Genet. 2002;39:387–90. [PMC free article: PMC1735154] [PubMed: 12070243]
• Züchner S, Kail ME, Nance MA, Gaskell PC, Svenson IK, Marchuk DA, Pericak-Vance MA, Ashley-Koch AE. A new locus for dominant hereditary spastic paraplegia maps to chromosome 2p12. Neurogenetics. 2006a;7:127–9. [PubMed: 16565863]
• Züchner S, Wang G, Tran-Viet KN, Nance MA, Gaskell PC, Vance JM, Ashley-Koch AE, Pericak-Vance MA. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet. 2006b;79:365–9. [PMC free article: PMC1559498] [PubMed: 16826527]

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 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