• Users Online: 288
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Contacts Login 


 
 Table of Contents  
REVIEW
Year : 2018  |  Volume : 3  |  Issue : 3  |  Page : 95-100

What the future holds for the challenging hereditary spastic paraplegia?


1 Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2 American University of the Caribbean School of Medicine, Cupecoy, St. Maarten
3 Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Date of Submission16-Apr-2018
Date of Decision05-Sep-2018
Date of Acceptance25-Sep-2018
Date of Web Publication23-Oct-2018

Correspondence Address:
Konstantinos Margetis
Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3975.242956

Rights and Permissions
  Abstract 

Since it was initially described by and named after Strumpell and Lorrain in the late 1800s, hereditary spastic paraplegia (HSP) or familial spastic paraplegia, has remained a source of interest and study for the medical community. This rare disease, or rather spectrum of neurological diseases, is undergoing a fresh wave of unveiling as molecular and genetic techniques have bolstered our understanding of HSP. HSP is a neurodegenerative disease with a wide range of effects on patients. The mainstays of lower extremity spasticity, urinary urgency and impairment of lower extremity vibratory sensation can present alone or accompanied by a list of additional symptoms such as: epilepsy, dementia and peripheral neuropathy. In this review, some of the more recent studies are discussed, in which pathophysiology, imaging, and genetics are investigated. The review of these studies may not only help to advance our knowledge and management of HSP, but may serve as a future paradigm for similar groups of diseases that experience a wide spectrum of clinical symptoms.

Keywords: spastic paraplegia, hereditary; hereditary sensory and motor neuropathy; spastic paraplegia genes; motor neuron disease; corticospinal tract; spasticity; review


How to cite this article:
Bisharat-Kernizan J, Watson C, Margetis K. What the future holds for the challenging hereditary spastic paraplegia?. Clin Trials Degener Dis 2018;3:95-100

How to cite this URL:
Bisharat-Kernizan J, Watson C, Margetis K. What the future holds for the challenging hereditary spastic paraplegia?. Clin Trials Degener Dis [serial online] 2018 [cited 2018 Dec 12];3:95-100. Available from: http://www.clinicaltdd.com/text.asp?2018/3/3/95/242956


  Introduction Top


The aim of this review is to provide a concise snapshot of the current status of hereditary spastic paraplegia (HSP), and to bring awareness to the fact that much of the disease is still in need of elucidation. Even topics such as prevalence and global distribution of disease are in great need of study. The fascinating HSP research that has already been conducted is a mere taste of what is hopefully to come. HSP is unique in that it encompasses an enormous spectrum of pathophysiological concepts; allowing itself to be examined by curious minds of many areas of expertise. An electronic search of the Medline database for literature in English language pertinent to HSP from 1946 to 2018 was performed using the following keywords: spastic paraplegia, hereditary; hereditary sensory and motor neuropathy; spastic paraplegia genes; motor neuron disease; corticospinal tract; spasticity.


  Prevalence Top


The scarcity of epidemiological studies of HSP around the globe leave much to the imagination in regards to its exact prevalence worldwide. Researchers have made strides in the direction of estimating disease prevalence and global HSP distribution, but still vast areas of the world including North America, South America, and the bulk of the African continent have limited data in regards to prevalence and remain largely unstudied.[1] In a recent study that looked at the prevalence of hereditary cerebellar ataxias (HCA) and hereditary spastic paraplegia based on 22 studies (12 of which included HSP data, 9 were HCA-only studies), there was an estimated prevalence within the range of 0.5–5.5/105 with an average of 1.8/105 (95% confidence interval (CI): 1.0–2.7) for autosomal dominant HSP (AD-HSP), and the range of 0.0–5.3/105 with an average of 1.8/105 (95% CI: 1.0–2.6) for autosomal recessive HSP (AR-HSP).[1] Several other studies, mostly limited to specific populations from regions in Europe, have total prevalences summarized in [Table 1]; there are apparent wide ranges in prevalence values.
Table 1: Prevalence rates in hereditary spastic paraplegia studies

Click here to view


However, there are postulated sources of this discrepancy in prevalence rates.[1] The ideas on what could explain the variation included a multifactorial list starting first with a point that has been made by several authors.[1],[3],[7] The authors state that there is a lack of studies done in populations with no identified probands, which is quite relevant given that up to 15% of patients were identified on the basis of genetic testing alone in the study conducted by Erichsen et al.[4] Additionally, unstable genetic elements (i.e., migratory and founder effect, the varied rates of consanguinity in studied areas), inclusion criteria (i.e., some studies only included only late-onset subtype patients) and under-recognition of the disease-given its wide range clinically benign and subclinical cases - all contribute to the blurring of a thorough analysis of the global prevalence of HSP.[1] Another challenging aspect of the epidemiology of HSP is the actual diagnosis itself, which requires exhaustive exclusion of differential diagnoses via laboratory analysis, electromyography, nerve conduction studies, neuroimaging as well as genetic studies, which may not be as readily available in all regions globally.[8]

However, despite the lack of large volumes of data in this area, some trends and conclusions are evident. The AD-HSP variant, spastic paraplegia gene (SPG4), was most prevalent in all cases reviewed by Ruano et al.[1] X-linked and mitochondrial modes of inheritance, which have been described in several studies[9],[10],[11] and summarized by Fink,[8] do not have as much established data on gene frequencies across populations. On the other hand, another interesting conclusion is the lack of genetic diagnosis after testing, which was reported by Coutinho et al.,[3] in which up to 82% of cases had unidentifiable genetic culprits. In summary, although falling under the generally accepted definition of a rare genetic disease in all studies thus far, there is much regarding the prevalence and incidence of HSP that is yet to be elucidated, and the need for an organized framework for future studies is greatly needed.[7]


  Pathophysiology Top


An ever evolving discussion in HSP is the identification and elucidation of pathophysiologic mechanisms underlying this disease. With each gene identified, a protein product can be investigated in the hopes that a functional correlation will follow. To date, there have been numerous such studies.[12],[13],[14] The basic mechanistic principal is that SPG, via a number of pathways, leads to a degeneration of neuronal axons with their terminal region being most severely affected.[8],[13],[15] The long descending motor tracts and ascending tracts of the posterior column are most affected; however, cerebellar and cortical neurons have been implicated as well.[15],[16],[17] Observations of terminal axonal swellings and decreased volume of spinal cord tracts in animal models and post mortem specimens have been described as evidence for this length dependent degeneration.[8],[18] From this, it has been postulated that the HSP mutations as a group result in cellular damage that manifest most severely in the neuronal tracts with the longest axons.[8],[13],[15]

Degeneration of a portion of a cell can be accomplished in many ways and thus far, SPG have been implicated in a gambit of molecular tasks that result in this phenomenon.[8],[13],[16] Microtubule formation, vesicle trafficking, endosome formation, fatty acid metabolism, phospholipid metabolism, myelin dysformation, DNA repair and neurodevelopment are all established roles of SPG to date.[8],[13],[18] In some cases, the damaging effect may be on a supporting cell rather than the neuron itself.[8] These diverse cellular processes and their resultant shared clinical presentation of lower extremity spasticity are analogous to a model such as that of pneumonitis. It can be caused by a host of microbes, viruses, fungi, radiation and more; each with complex and distinct cellular targets and molecular processes, but the finding of consolidation on chest radiography and alveolar wall inflammation on microscopic examination are largely shared; of course, each with its unique standouts in addition.

The pathophysiology of SPG4 is one of the more well studied. This gene, also called SPAST, is translated into a protein product called spastin.[10],[13],[15] Spastin is characterized as having a specialized ATPase that is associated with various cellular activities, microtubule binding regions, and several splice sites resulting in different isoforms.[13],[15] The function of this protein is to regulate the dynamics of microtubule plus ends. Without it, uncleaved and ultra-stable microtubules can be found.[13],[15]

There still remain many unanswered molecular questions; what mediates the fact that some HSP patients present in infancy and others as late as the 7th decade? Why do different family members with the same mutation show such variety in clinical symptomatology? What environmental factors could also be working to drive HSP phenotypes? How much is neurodevelopment involved versus purely degenerative processes? The fascinating emerging science behind the gut microbiome and its involvement in neurological diseases such as Alzheimer’s disease, multiple sclerosis (MS) and Huntington’s disease may also play a role but has yet to be studied in the HSP population.[19] The continued efforts at studying these mechanisms are critical, because with a better understanding of each SPG pathophysiology, we can look forward to focusing research on directed treatments and cures.


  Clinical Features and Natural History Top


There are several key features present in HSP. These features were initially used to categorize the disease into two groups, pure and complex.[17],[20] The three symptoms, which originally made up the pure form included symmetric bilateral lower limb spasticity, urinary urgency, and decreased lower extremity vibratory sensation.[20],[21] The complex form, on the other hand, included these three symptoms of pure HSP plus any combination of a myriad of other neurological signs and symptoms: peripheral neuropathy, epilepsy, and dementia to name a few.[20],[21],[22] Historically, sparing of both the bulbar and upper extremity tracts were a necessity to meet criteria for a diagnosis of HSP.[20] Interestingly, upper extremity and sensory involvement were described as occurring frequently in a study of pure and complex Italian HSP patients.[23] In addition to the neurological findings, HSP can present with a host of psychiatric comorbidities.[24] A study reported cases in which there was a correlation between loss of function mutation in the SPAST gene and mental health disorders that include but are not limited to severe depression, personality disorders, mania, and autism spectrum disorders.[24] These findings demonstrate the variety and complexity of symptomatic presentations across HSP patient populations.

More recently, with the ongoing discoveries of spastic paraplegia genes (SPG) the true complexity of the genotype-phenotype relationship of HSP has been revealed and the traditional grouping into pure and complex forms is not as applicable.[10],[25] Genes that were thought to cause pure HSP have been shown to cause complex forms as well, and vice versa.[10],[17] Patterns of inheritance also do not follow a linear relationship with phenotype as autosomal dominant, autosomal recessive, and X-linked patterns have been shown to be implicated in either pure or complex forms of varying severity.[10] However, there are features that present more commonly with some mutations, for example, it has been reported that there is an association between SPG11 and a thin corpus callosum. Some SPG have even named syndromes such as SPG20, or Troyer syndrome, because the consistency in the phenotype-genotype relationship is well established.[17],[22] To summarize these important relationships, several papers exist in which tables are presented in elegant detail about each SPG identified and the phenotypic features that are commonly observed with each one.[10],[17],[18],[20],[26],[27]

HSP is categorized according to disease progression as well.[17] Clinically, HSP can have a benign, relentless, or severe course with a subsequent plateau progression pattern.[8],[17] The average age of onset in the one study[28] was 30.8 years with a standard deviation of 18 and an age range of 0–73 years, while in another study[23] the average age of onset was 25.97 years with no reported standard deviation and with an age range of 0–64 years. It has also been described that early onset childhood cases tend to endure a less severe progression with an eventual plateau of disease progression, while late-onset cases tend to follow a more relenting course.[8],[29] Essentially, the pure form of HSP does not affect lifespan, but can range from mild spasticity in the lower extremities to having disabling effects on mobility, quality of life and functional capacity.[18],[20] The complex HSPs have such variability in onset time, associated neurologic symptoms and disease severity that it is difficult to comment on the natural course of these patients as a group.[17],[29] Documented common first clinical presentations for both types are urinary urgency, or toe walking in childhood.[8]

In order to specifically quantify disease-related impairment, the Spastic Paraplegia Rating Scale (SPRS) was developed.[28] The scale is intended to monitor the progression of the disease and is especially useful for evaluating the response to treatments aimed at reducing the spasticity of the lower extremities.[28] The rating system is based on the accumulation of points and is easily administered as it does not require specialized equipment. Prior to this, most studies relied on the Ashworth scale for quantitative analyses of spasticity.[30],[31],[32]


  Genetics Top


A full understanding of the genetic and molecular basis of a disease is a vital component in the context of providing medical care. In the case of HSP, there is a complex and multifactorial genetic story that has only been partially detangled. In the past 10 years alone, the number of HSP genes and loci have been summarized as being 41 loci, 17 genes by Salinas et al.,[15] 52 loci by Finsterer et al.,[10] greater than 80 genes and loci by Schüle et al.,[25] 84 loci and 67 genes by Tesson et al.,[18] over 40 genes by Kara et al.,[21] and Lo Giudice et al.[16] reports 72 loci and 55 SPG. The true number of SPG is yet unknown, and with each study of the HSP population’s genetics, there are several novel genes described as well as those that remain undiscovered.[21],[25] In the study of 619 HSP patients done by Schüle et al.,[25] 5 new mutations were discovered, and of the 47% of cases that were apparently sporadic, 72% did not have identifiable genetic mutations.

Thus far, HSP has been well established as having autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance patterns.[8],[10],[21],[31] There is also speculation that non-mendelian patterns of inheritance including digenic and polygenic mechanisms may also be at work.[21],[25] Complicating things further, is the discordance in reproducibility between genetic and clinical features making it challenging to test, diagnose, categorize and anticipate the clinical course of HSP patients based on genetic analyses alone.[10],[18],[33] Even in cases where extensive molecular and genetic testing is available, the predictive value for a clinical course has a highly unreliable correlation to known mutations.[21]

HSP can be described as having not only genetic heterogeneity, but allelic heterogeneity, and genetic pleomorphism as well. Families with the same SPG mutation experience a wide spectrum of onset times, symptoms, and clinical course.[10] Meanwhile, similar phenotypic assessments have been made for a set of distinctively different gene mutations across many of the chromosomes.[10] Also, there are cases in which a single allele can undergo many different mutations to produce an HSP phenotype.[18] In SPG4 alone, there are missense, and nonsense mutations, deletions and insertions along various portions of the length of the SPAST gene.[13]

Some studies have described overlap between SPG and other diseases such as Chediak Higashi, amyotrophic lateral sclerosis (ALS), Charcot Marie Tooth, and Plezaues-Merbacher in a “same gene, different mutation, different disease” fashion.[15],[34] Montecchiani et al.[34] reported an association between SPG11 and autosomal recessive axonal Charcot-Marie-Tooth disease. Furthermore, Orlacchio et al.[35] described the lack of a thin corpus callosum and the presence of amyotrophy placing emphasis on the association between SPG11 and ALS. It has been suggested that HSP lies in more of a spectrum of neurological disease rather than existing as a separate entity. This spectrum includes pathologies such as primary lateral sclerosis and spinal muscular atrophy.[18],[21] Despite the distinct modes of HSP inheritance, Novarino et al.[36] suggested an HSP interactome, where the HSP genes are highly connected and link HSP to cellular transport, nucleotide metabolism and synapse/axon development.


  Imaging Findings Top


HSP, in line with its other elusive and highly variable characteristics, has historically been indistinguishable on imaging studies.[29],[37] The use of brain magnetic resonance imaging (MRI) is still recommended during initial work up to rule out differential diagnoses, but has also been useful for following, or staging the disease.[23],[29],[38] In many cases, standard T2 weighted MRI in patients with pure HSP has been shown to be unremarkable, while complex HSP patients have been diagnosed with brain atrophy and/or white matter changes.[37],[38],[39] There have been reports of spinal cord atrophy, some with a selectivity for the cervical region, and some with the diminishment of the cord in its entirety.[33],[40],[41] Interestingly, it was reported that there was insignificant correlation between degree of spinal cord atrophy and clinical symptoms in a study.[40]

There are some key stand outs that must be discussed in regards to HSP imaging. SPG11, the most pervasive AR-HSP documented and accounting for an estimated 15–21% of cases of AR-HSP is well established to have bilateral thinning of the corpus callosum as a consistent finding.[1],[39],[42],[43] This finding of genu fiber hyperintensity on T2 weighted MRI, has been referred to as the “ears of the lynx” sign and was thought to be present with SPG11 alone, although recently, the ears of the lynx sign has been described in patients with mutations besides SPG11.[43] Ears of the lynx was characterized as having excellent specificity and sensitivity when comparing HSP against MS and normal control.[43] However, this has inherent limited utility given that most HSP patients do not carry the SPG11 mutation and in the same way, not all SPG11 mutation carriers will present with this characteristic imaging finding. A study looked at the utility of clinical presentation and neuroimaging and developed an algorithmic approach not only to determine a pure or complex HSP etiology, but to narrow down a particular gene inheritance primarily off of known genotypic-phenotypic associations.[27]

Some of the more promising HSP imaging data suggest that there may actually be a way to identify HSP patients of all mutant varieties, regardless of clinical expressivity. Diffusion Tensor Imaging (DTI), based on the diffusion of water through substrates is used to evaluate white matter microstructure.[23],[37],[40] Fractional anisotropy and median diffusivity are two analyses that can be evaluated through the use of DTI.[23],[37],[40] In a study of SPG4 only patients using DTI, there was significant white matter disturbance found in several parts of the brain compared to control subjects.[38] Also, SPG4 subjects were demonstrated to have white matter changes that preceded clinical symptoms and study authors concluded that DTI is a useful way to screen for HSP.[38] In a study of pure HSP patients carrying several different SPG mutations, findings of widespread white matter changes were again documented on DTI with variations in fractional anisotropy and median diffusivity compared to normal subjects and interestingly, no difference was shown between pure and complex disease forms.[40] While some studies reported that white matter changes are present in subclinical cases, others report that white matter changes are tightly correlated to severity of spasticity as graded by the SPRS.[38],[40]


  Treatments Top


Synofzick and Schüle[44] suggested a theoretical framework for the classification of the HSP treatment strategies, dividing them into causal (targeting genetic/epigenetic factors, affected cellular pathways and neuronal systems) and symptomatic treatments (targeting symptoms). With no curative medications or procedures known to date, current HSP treatments are aimed at symptomatic relief.[8],[17],[20],[31] With the breadth of symptoms experienced, lower extremity spasticity is the most common and thus often the first target for ameliorating efforts.[26] In general, these treatments are a combination of pharmacologic, physiotherapeutic, and device-based (orthotics); with an emphasis on maintaining cardiovascular fitness and functional capabilities.[20],[45]

The lower extremity spasticity that HSP patients experience may have largely unknown and multifactorial pathophysiology, but the pharmacologic targets are shared with spasmolytic treatments used, for example, in spinal cord injury and MS.[46] Baclofen, which is a spasmolytic drug commonly used in HSP, is a centrally acting GABA-B agonist, works to heighten the descending inhibitory interneuron signal by way of Ca2+ channel modulation.[31],[46],[47] Baclofen is administered either orally or via an intrathecal route, and the latter has been demonstrated in several studies to provide patient satisfaction and improvement of spasticity.[31],[46],[47],[48],[49],[50],[51] The blood-brain barrier creates a limitation to oral administration, while the intrathecal route is complicated by pump malfunctions, infections, and seromas, etc. Both routes of administration carry the risk of withdrawal, and side effects including: drowsiness (more so when given orally) and the potential of serious toxicity when overdosed.[31],[46] A special attention must be paid to the gradual dosing of intrathecal baclofen, because the spasmolytic effect may be so great it can diminish the ability of the patient to maintain upright posture by swinging the balance from spastic muscles to overt weakness.[31],[52] Typically, a trial intrathecal dose in initiated with gradual titration upwards until a good balance is achieved.[31],[52] Tizanidine, an alpha-2-agonist, and Botulinum toxin intramuscular injections have also been used to treat spastic lower extremities in HSP.[46],[53] There were no specific studies of Diazepam, Dantrolene, Clonazepam, or Gabapentin in HSP in the literature, but these are commonly used in other disorders with spasticity symptoms.[46]

Other studies in HSP treatments while promising, are not as applicable to the HSP population as a whole, given their specific targets. SPG5, a variant of HSP is known to have defects in the cholesterol and phospholipid metabolism pathway therefore; cholesterol-lowering drugs such as ezetimibe, simvastatin, and chenodeoxycholic acid have been used as treatment.[54],[55] Dalfampridine, a K+ channel modulator that improves action potential conduction that is used in demyelinating conditions to help with spasticity has been tried in patients with several different SPGs.[55],[56] Tubulin-binding drugs including Taxol and Vinblastine were given to SPG4 patients whose mutation is related to deficient microtubule stability and slowed peroxisome transport.[57] In a cell model, microtubule-targeted therapy has shown a reduction in axonal swelling, and may ultimately improve locomotor activity.[55] On a less molecular note, trials of robot-assisted therapy and hydrotherapy have also been described in HSP patients; all with mixed results.[58],[59] With spasticity often being the only shared symptom between different SPG carriers, it is likely that future treatments will include physical therapy and spasmolytic medications.


  Conclusion Top


There are few things we know about HSP, many things we know that we do not know and given the heterogeneity of the disease there are likely many things we do not know that we do not know. This modified quote by Donald Rumsfeld represents the current state of HSP. Much has been discovered [Figure 1], and yet there is much to be learned in this multifaceted disease. To date, research is ongoing in regards to the prevalence of disease across the world; however, an organized framework for future studies would be useful in extracting such data with the hope for a greater understanding of the many aspects of HSP. Thus, the aim of this review is to build awareness of HSP and encourage future studies in hopes that efforts be put towards clinical application with the goal of improving the quality of life for those affected.
Figure 1: A schematic providing a simplified overview of the clinico-genetic aspects of hereditary spastic paraplegia.

Click here to view


 
  References Top

1.
Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014;42:174-183.  Back to cited text no. 1
    
2.
Racis L, Tessa A, Di Fabio R, et al. The high prevalence of hereditary spastic paraplegia in Sardinia, insular Italy. J Neurol. 2014;261:52-59.  Back to cited text no. 2
    
3.
Coutinho P, Ruano L, Loureiro JL, et al. Hereditary ataxia and spastic paraplegia in Portugal: a population-based prevalence study. JAMA Neurol. 2013;70:746-755.  Back to cited text no. 3
    
4.
Erichsen AK, Koht J, Stray-Pedersen A, Abdelnoor M, Tallaksen CM. Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain. 2009;132:1577-1588.  Back to cited text no. 4
    
5.
Braschinsky M, Luus SM, Gross-Paju K, Haldre S. The prevalence of hereditary spastic paraplegia and the occurrence of SPG4 mutations in Estonia. Neuroepidemiology. 2009;32:89-93.  Back to cited text no. 5
    
6.
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;72:43-46.  Back to cited text no. 6
    
7.
Braschinsky M. The global epidemiology of hereditary ataxia and spastic paraplegia: what are the messages? Neuroepidemiology. 2014;42:184-185.  Back to cited text no. 7
    
8.
Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013;126:307-328.  Back to cited text no. 8
    
9.
Kobayashi H, Garcia CA, Alfonso G, Marks HG, Hoffman EP. Molecular genetics of familial spastic paraplegia: a multitude of responsible genes. J Neurol Sci. 1996;137:131-138.  Back to cited text no. 9
    
10.
Finsterer J, Löscher W, Quasthoff S, Wanschitz J, Auer-Grumbach M, Stevanin G. Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J Neurol Sci. 2012;318:1-18.  Back to cited text no. 10
    
11.
Jouet M, Rosenthal A, Armstrong G, et al. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet. 1994;7:402-407.  Back to cited text no. 11
    
12.
Tesson C, Nawara M, Salih MA, et al. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet. 2012;91:1051-1064.  Back to cited text no. 12
    
13.
Solowska JM, Baas PW. Hereditary spastic paraplegia SPG4: what is known and not known about the disease. Brain. 2015;138:2471-2484.  Back to cited text no. 13
    
14.
Montenegro G, Rebelo AP, Connell J, et al. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J Clin Invest. 2012;122:538-544.  Back to cited text no. 14
    
15.
Salinas S, Proukakis C, Crosby A, Warner TT. Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol. 2008;7:1127-1138.  Back to cited text no. 15
    
16.
Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A. Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms. Exp Neurol. 2014;261:518-539.  Back to cited text no. 16
    
17.
18.
Tesson C, Koht J, Stevanin G. Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology. Hum Genet. 2015;134:511-538.  Back to cited text no. 18
    
19.
Tremlett H, Bauer KC, Appel-Cresswell S, Finlay BB, Waubant E. The gut microbiome in human neurological disease: A review. Ann Neurol. 2017;81:369-382.  Back to cited text no. 19
    
20.
Fink JK. Hereditary spastic paraplegia: clinical principles and genetic advances. Semin Neurol. 2014;34:293-305.  Back to cited text no. 20
    
21.
Kara E, Tucci A, Manzoni C, et al. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain. 2016;139:1904-1918.  Back to cited text no. 21
    
22.
Manzini MC, Rajab A, Maynard TM, et al. Developmental and degenerative features in a complicated spastic paraplegia. Ann Neurol. 2010;67:516-525.  Back to cited text no. 22
    
23.
Martinuzzi A, Montanaro D, Vavla M, et al. Clinical and paraclinical indicators of motor system impairment in hereditary spastic paraplegia: a pilot study. PLoS One. 2016;11:e0153283.  Back to cited text no. 23
    
24.
Chelban V, Tucci A, Lynch DS, et al. Truncating mutations in SPAST patients are associated with a high rate of psychiatric comorbidities in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry. 2017;88:681-687.  Back to cited text no. 24
    
25.
Schüle R, Wiethoff S, Martus P, et al. Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Ann Neurol. 2016;79:646-658.  Back to cited text no. 25
    
26.
Hensiek A, Kirker S, Reid E. Diagnosis, investigation and management of hereditary spastic paraplegias in the era of next-generation sequencing. J Neurol. 2015;262:1601-1612.  Back to cited text no. 26
    
27.
de Souza PVS, de Rezende Pinto WBV, de Rezende Batistella GN, Bortholin T, Oliveira ASB. Hereditary spastic paraplegia: clinical and genetic hallmarks. Cerebellum. 2017;16:525-551.  Back to cited text no. 27
    
28.
Schüle R, Holland-Letz T, Klimpe S, et al. The Spastic Paraplegia Rating Scale (SPRS): a reliable and valid measure of disease severity. Neurology. 2006;67:430-434.  Back to cited text no. 28
    
29.
Fink JK. Hereditary Spastic Paraplegia Overview. In: Adam MP, Ardinger HH, Pagon RA, et al. eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993.  Back to cited text no. 29
    
30.
Wajima D, Hirabayashi H, Nishimura F, Motoyama Y, Nakase H. Adequate dose of intrathecal baclofen therapy for spasticity. No Shinkei Geka. 2011;39:345-350.  Back to cited text no. 30
    
31.
Margetis K, Korfias S, Boutos N, et al. Intrathecal baclofen therapy for the symptomatic treatment of hereditary spastic paraplegia. Clin Neurol Neurosurg. 2014;123:142-145.  Back to cited text no. 31
    
32.
Hecht MJ, Stolze H, Auf dem Brinke M, et al. Botulinum neurotoxin type A injections reduce spasticity in mild to moderate hereditary spastic paraplegia--report of 19 cases. Mov Disord. 2008;23:228-233.  Back to cited text no. 32
    
33.
Monrad P, Renaud DL. Severe spinal cord atrophy associated with spastic paraparesis. Pediatr Neurol. 2011;44:75-77.  Back to cited text no. 33
    
34.
Montecchiani C, Pedace L, Lo Giudice T, et al. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain. 2016;139:73-85.  Back to cited text no. 34
    
35.
Orlacchio A, Babalini C, Borreca A, et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010;133:591-598.  Back to cited text no. 35
    
36.
Novarino G, Fenstermaker AG, Zaki MS, et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014;343:506-511.  Back to cited text no. 36
    
37.
Aghakhanyan G, Martinuzzi A, Frijia F, et al. Brain white matter involvement in hereditary spastic paraplegias: analysis with multiple diffusion tensor indices. AJNR Am J Neuroradiol. 2014;35:1533-1538.  Back to cited text no. 37
    
38.
Duning T, Warnecke T, Schirmacher A, et al. Specific pattern of early white-matter changes in pure hereditary spastic paraplegia. Mov Disord. 2010;25:1986-1992.  Back to cited text no. 38
    
39.
Stromillo ML, Malandrini A, Dotti MT, et al. Structural and metabolic damage in brains of patients with SPG11-related spastic paraplegia as detected by quantitative MRI. J Neurol. 2011;258:2240-2247.  Back to cited text no. 39
    
40.
Agosta F, Scarlato M, Spinelli EG, et al. Hereditary spastic paraplegia: beyond clinical phenotypes toward a unified pattern of central nervous system damage. Radiology. 2015;276:207-218.  Back to cited text no. 40
    
41.
Poon M, Nguyen TP. Clinical reasoning: childhood-onset atrophy and spasticity. Neurology. 2016;86:e140-143.  Back to cited text no. 41
    
42.
Riverol M, Samaranch L, Pascual B, et al. Forceps minor region signal abnormality “ears of the lynx”: an early MRI finding in spastic paraparesis with thin corpus callosum and mutations in the spatacsin gene (SPG11) on chromosome 15. J Neuroimaging. 2009;19:52-60.  Back to cited text no. 42
    
43.
Masdeu J, Pascual B, Franca J, Marcondes, et al. Sensitivity and specificity of the “ears of the lynx” MRI sign in spastic paraparesis with SPG mutations (P2.038). Neurology. 2015;84.  Back to cited text no. 43
    
44.
Synofzik M, Schüle R. Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways. Mov Disord. 2017;32:332-345.  Back to cited text no. 44
    
45.
Richardson D, Thompson AJ. Management of spasticity in hereditary spastic paraplegia. Physiother Res Int. 1999;4:68-76.  Back to cited text no. 45
    
46.
Burchiel KJ, Hsu FP. Pain and spasticity after spinal cord injury: mechanisms and treatment. Spine (Phila Pa 1976). 2001;26:S146-160.  Back to cited text no. 46
    
47.
Ochs G, Struppler A, Meyerson BA, et al. Intrathecal baclofen for long-term treatment of spasticity: a multi-centre study. J Neurol Neurosurg Psychiatry. 1989;52:933-939.  Back to cited text no. 47
    
48.
Meythaler JM, Steers WD, Tuel SM, Cross LL, Sesco DC, Haworth CS. Intrathecal baclofen in hereditary spastic paraparesis. Arch Phys Med Rehabil. 1992;73:794-797.  Back to cited text no. 48
    
49.
Klebe S, Stolze H, Kopper F, et al. Objective assessment of gait after intrathecal baclofen in hereditary spastic paraplegia. J Neurol. 2005;252:991-993.  Back to cited text no. 49
    
50.
Molteni F, Carda S, Cazzaniga M, Magoni L, Rossini M, Caimmi M. Instrumental evaluation of gait modifications before and during intrathecal baclofen therapy: a 2-year follow-up case study. Am J Phys Med Rehabil. 2005;84:303-306.  Back to cited text no. 50
    
51.
Lambrecq V, Muller F, Joseph PA, Cuny E, Mazaux JM, Barat M. Intrathecal baclofen in hereditary spastic paraparesis: benefits and limitations. Ann Readapt Med Phys. 2007;50:577-581.  Back to cited text no. 51
    
52.
Heetla HW, Halbertsma JP, Dekker R, Staal MJ, van Laar T. Improved gait performance in a patient with hereditary spastic paraplegia after a continuous intrathecal baclofen test infusion and subsequent pump implantation: a case report. Arch Phys Med Rehabil. 2015;96:1166-1169.  Back to cited text no. 52
    
53.
de Niet M, de Bot ST, van de Warrenburg BP, Weerdesteyn V, Geurts AC. Functional effects of botulinum toxin type-A treatment and subsequent stretching of spastic calf muscles: a study in patients with hereditary spastic paraplegia. J Rehabil Med. 2015;47:147-153.  Back to cited text no. 53
    
54.
Mignarri A, Malandrini A, Del Puppo M, et al. Treatment of SPG5 with cholesterol-lowering drugs. J Neurol. 2015;262:2783-2785.  Back to cited text no. 54
    
55.
Di Fabio R, Storti E, Tessa A, Pierelli F, Morani F, Santorelli FM. Hereditary spastic paraplegia: pathology, genetics and therapeutic prospects. Expert Opin Orphan Drugs. 2016;4:429-442.  Back to cited text no. 55
    
56.
Bereau M, Anheim M, Chanson JB, et al. Dalfampridine in hereditary spastic paraplegia: a prospective, open study. J Neurol. 2015;262:1285-1288.  Back to cited text no. 56
    
57.
Fan Y, Wali G, Sutharsan R, et al. Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia. Biol Open. 2014;3:494-502.  Back to cited text no. 57
    
58.
Seo HG, Oh BM, Kim K. Robot-assisted gait training in a patient with hereditary spastic paraplegia. PM R. 2015;7:210-213.  Back to cited text no. 58
    
59.
Zhang Y, Roxburgh R, Huang L, Parsons J, Davies TC. The effect of hydrotherapy treatment on gait characteristics of hereditary spastic paraparesis patients. Gait Posture. 2014;39:1074-1079.  Back to cited text no. 59
    

Author contributions
Manuscript writing: JBK; manuscript editing: CW; project supervisation: KM.
Conflicts of interest
None declared.
Financial support
None.
Copyright license agreement
The Copyright License Agreement has been signed by all authors before publication.
Plagiarism check
Checked twice by iThenticate.
Peer review
Externally peer reviewed.


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Prevalence
Pathophysiology
Clinical Feature...
Genetics
Imaging Findings
Treatments
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed345    
    Printed43    
    Emailed0    
    PDF Downloaded66    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]