Materiały źródłowe

• #1 Hereditary Spastic Paraplegia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/306713-overview

  Hereditary spastic paraplegia (HSP) is not a single disease entity; it is a group of clinically and genetically diverse disorders that share a primary feature, which is the causation of progressive and generally severe lower extremity weakness and spasticity. […] The most useful classifications now are based on the mode of inheritance and genetic linkage. HSP may also be classified as autosomal dominant, autosomal recessive, or X-linked, and each type has several subtypes, which are based on the location of the gene. […] To date, over 80 genes or genomic loci associated with HSP have been identified. […] HSP causes degeneration of the ends of the corticospinal tracts within the spinal cord. […] Impaired cellular membrane trafficking, more particularly, axonal transport of macromolecules and organelles, is the best-characterized genetic mechanism of HSP.

• #1 Hereditary spastic paraplegia | About the Disease | GARD

  https://rarediseases.info.nih.gov/diseases/6637/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia (HSP) is a group of hereditary, degenerative, neurological disorders that primarily affect the upper motor neurons. […] The different forms of HSP are caused by genetic changes in different genes. Inheritance varies. […] This disease is caused by a change in the genetic material (DNA). […] Hereditary spastic paraplegia is caused by genetic mutations, also known as pathogenic variants. Genetic mutations can be hereditary, when parents pass them down to their children, or they may occur randomly when cells are dividing. […] Yes. It is possible for a biological parent to pass down genetic mutations that cause or increase the chances of getting this disease to their child. […] There are multiple ways, or patterns, a disease can be inherited depending on the gene(s) involved. Based on GARD’s current data, this disease can be inherited in the following pattern(s): Autosomal Dominant, Autosomal Recessive, X-Linked.

• #1 Hereditary Spastic Paraplegia: What It Is, Symptoms & Types

  https://my.clevelandclinic.org/health/diseases/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia is a genetic condition that causes weakness and muscle tightness in your legs. There are over 80 different types. Its progressive and can affect your mobility. […] A genetic variant causes hereditary spastic paraplegia. The gene changes the instructions that proteins receive. As a result, the proteins arent able to do their job as expected, which affects how the nerves in your spinal cord function. Several different gene variants lead to this condition. […] Hereditary spastic paraplegia is inherited meaning, you receive at least one copy of the gene from your biological parents in one of the following ways: Autosomal dominant: You receive one copy of the gene from one of your parents. Autosomal recessive: You receive two copies of the gene, one from each of your parents. X-linked: A female parent passes one gene on a sex chromosome to their male child. Mitochondrial inheritance (maternal transmission): A female parent passes a mitochondrial gene to their child of any sex.

• #1 The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment

  https://www.mdpi.com/1422-0067/23/14/7665

  Inherited neurodegenerative pathology characterized by lower muscle tone and increasing spasticity in the lower limbs is termed hereditary spastic paraplegia (HSP). HSP is associated with changes in about 80 genes and their products involved in various biochemical pathways, such as lipid droplet formation, endoplasmic reticulum shaping, axon transport, endosome trafficking, and mitochondrial function. […] HSP pathologies are designated as spastic paraplegia genes (SPG); to date, 80 SPGs have been identified with a rare prevalence of 1–5 in 100,000 individuals varying around the globe. […] The presence of diverse genetic markers implies the existence of a wide range of clinical manifestations, from distinct pyramidal signs in the legs, primarily involving the upper motor neurons, to a group of other motor neurons to trigger other neurological manifestations, such as peripheral neuropathy, cognitive disability, and cerebellar ataxias.

• #1 Hereditary Spastic Paraplegia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/306713-overview

  Mitochondrial dysfunction is the second process that leads to HSPs. […] In most cases of HSP, the primary problem may be disturbance of the ends of the long axons, with little or no loss of myelin and no abnormal myelin. […] A rare type of X-linked HSP, however, has been associated with a myelin protein gene mutation. […] A study by Agosta et al suggested that the various neurologic disorders designated as HSP share a common neurodegenerative cascade. […] As previously stated, more than 80 genes or genomic loci associated with HSP have been identified. […] Most cases of pure HSP are autosomal dominant, whereas complicated forms tend to be autosomal recessive. […] At least 19 autosomal dominant spastic paraplegia (SPG) genes (ie, genes for autosomal dominant HSP) have been identified, with autosomal dominant HSP accounting for 75-80% of registered HSP cases.

• #1 What are the causes of Spastic Paraplegia? | Paris Brain Institute

  https://parisbraininstitute.org/disease-files/hereditary-spastic-paraplegia-hsp/what-are-causes-spastic-paraplegia

  With regard to the causes of spastic paraplegia, in 70% of cases the mode of transmission of the disease is autosomal dominant. 20% of the families have autosomal recessive transmission and transmissions of spastic paraplegia linked to the X chromosome are estimated at 2%. […] Today, more than 73 chromosomal regions are known to carry mutations responsible for spastic paraplegia, however, it is estimated that nearly 50% of the families in which the genetic mutation is not known, which justifies active genetic research on these pathologies. […] The study, Identification of a key mechanism in hereditary spastic paraplegia type 11, led by Frdric Darios and Giovanni Stevanin, demonstrated the role of lipid accumulation in hereditary spastic paraplegia type 11. […] The collaborative study, Hereditary spastic paraplegia type 58, a demyelinating disease, led by Khalid Hamid El Hachimi of the Institut du Cerveau and Amandine Duchesne of INRA, reports that mutations in the KIF1C gene, responsible for hereditary spastic paraplegia type 58 (SPG58/SPAX2), cause a loss of myelin.

• #1 Hereditary Spastic Paraplegia: What It Is, Symptoms & Types

  https://my.clevelandclinic.org/health/diseases/hereditary-spastic-paraplegia

  While less common, genetic changes happen randomly or sporadically and may show up for the first time in a persons biological family history. […] Hereditary spastic paraplegia can affect anyone. Youre more at risk of developing the condition if one or both of your biological parents carry the genetic variant that causes this condition.

• #1 Hereditary Spastic Paraplegia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/306713-overview

  The most common autosomal dominant genes are SPG4 (SPAST), ATL1 (for SPG3A), REEP1 (for SPG31), and KIF5A (for SPG10). […] Spastic paraplegia 4 (SPG4) is the single most common dominantly inherited HSP, representing approximately 40% of such cases. […] The autosomal dominant HSP SPG3A (gene ATL1) shows a linkage to band 14q11-q21 and accounts for approximately 10% of dominantly inherited cases. […] There are at least 52 autosomal recessive genes, linked to 57 loci. […] The most common autosomal recessive genes are SPG11 (KIAA1840), CYP7B1 (for SPG5A), SPG7, and SPG15 (ZFYVE26). […] X-linked HSP is complex but rare, and the border between pure and complicated HSP syndromes is blurred. […] Preliminary genotype-phenotype correlations […] Thus far, genetically diverse types of autosomal dominant HSP (those linked to 2p, 14q, and 15q) appear to be clinically and electrophysiologically similar.

• #1 Spastic paraplegia type 2: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/spastic-paraplegia-type-2/

  Spastic paraplegia type 2 is part of a group of genetic disorders known as hereditary spastic paraplegias. […] Mutations in the PLP1 gene cause spastic paraplegia 2. The PLP1 gene provides instructions for producing proteolipid protein 1 and a modified version (isoform) of proteolipid protein 1, called DM20. A lack of proteolipid protein 1 and DM20 can cause a reduction in the formation of myelin (dysmyelination) which can impair nervous system function, resulting in the signs and symptoms of spastic paraplegia type 2. […] This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes.

• #1 SciELO Brazil – Hereditary spastic paraplegia from 1880 to 2017: an historical review Hereditary spastic paraplegia from 1880 to 2017: an historical review

  https://www.scielo.br/j/anp/a/pZxkFzKktLqn5VSgjTwCWcL/?lang=en

  The presence of a family history or consanguinity strengthens the possibility of a hereditary condition; its absence, on the contrary, should not dissuade the clinician from the diagnosis. […] The now current clinical classification of HSP into pure and complicated forms was proposed. […] The complicated forms were recognized to be rarer and genetically heterogeneous. […] Numerous HSP genetic studies have been published since the 1980s. Several genetic subtypes of HSP have been described and numbered sequentially, based on the order of the gene discovery. […] This was the first gene discovered that caused HSP; L1CAM codes for an axonal glycoprotein involved in neuronal migration and differentiation. […] The next-generation sequencing techniques, encompassing gene panels, whole exome sequencing and whole genome sequencing have initiated a new era of knowledge in the field. […] Today, more than 80 different loci related to hereditary spastic paraplegias are recognized, with more than 50 genes already identified.

• #1

  https://link.springer.com/article/10.1007/s11910-021-01099-x

  Due to the rapid rate of progress of HSP research, new genes are being identified on a regular basis. Examples of recently identified HSP genes include UCHL1 (SPG79), UBAP1 (SPG80), SELENOI (SPG81), PCYT2 (SPG82), HPDL (SPG83), and those not yet assigned a locus (RNF170 and FAR1). Some genes are much rarer than others, and it cannot be excluded that certain mutations may be private to individual families. […] There is a large overlap between HSP and other disorders such as inherited forms of hereditary ataxia, peripheral neuropathy, amyotrophic lateral sclerosis (ALS) and Parkinsons disease. […] Many forms of HSP overlap with the inherited neuropathies. Notable examples include mutations in BSCL2, which cause Silver syndrome, a complicated form of HSP in which affected individuals present with early-onset hand muscle wasting and leg spasticity.

• #1 Hereditary spastic paraplegia: clinical changes and association with neuroimaging findings.

  https://oatext.com/hereditary-spastic-paraplegia-clinical-changes-and-association-with-neuroimaging-findings.php

  Hereditary spastic paraparesis is a group of diseases that have as their main clinical aspect weakness and spasticity in the lower limbs, associated with a large number of genes, but involving a more restricted number of cellular functions that cause dysfunction of the neurons that make up the corticospinal tract. […] Currently there are at least 60 types of genetic changes related to the disease. Large series of cases in developed countries record about 70% of cases with autosomal dominant pattern. This pattern usually presents in the pure form, that is to say, with predominant spastic paraparesis, being able to be associated with vesical alterations, slight cognitive decline, cavus feet and alterations of appendicular distal sensibility. The most common mutation in these cases is SPG4.

• #1 Hereditary spastic paraplegia: clinical changes and association with neuroimaging findings.

  https://oatext.com/hereditary-spastic-paraplegia-clinical-changes-and-association-with-neuroimaging-findings.php

  The other cases present an autosomal recessive or X-linked pattern, being associated with the so-called complicated form of the disease, which usually presents with several neurological manifestations resulting from the involvement of several, long or non-dependent treatments. The main neurological manifestations presented together are: amyotrophy, optic atrophy, pigmentary retinopathy, dementia, parkinsonism, deafness, peripheral neuropathy and epilepsy. The mutation most related to these cases is SPG11, which is also the most related to neuroimaging characteristic alterations, such as fine corpus callosum and signs of the lynx ears. […] The pathophysiology of the disease is still not well understood, but it is believed that the genetic alterations are related to dysfunction of the axoplasmic flow of the corticospinal tract through molecular changes in neuronal cytoskeletal structures responsible for membrane trafficking and axonal transport of vesicles and endosomes.

• #1 Hereditary spastic paraplegia (HSP) | MedLink Neurology

  https://www.medlink.com/articles/hereditary-spastic-paraplegia

  De novo mutations should be considered in patients with childhood-onset, nonprogressive, spastic diplegia with no previous family history of hereditary spastic paraplegia. […] Pertinent genotype-phenotype correlations of hereditary spastic paraplegia described in the literature are summarized below. […] The effects of unknown genetic factors or environment on the development or progression of the disease are still not known.

• #1 What Is Hereditary Spastic Paraplegia? An Overview

  https://drchandrilchugh.com/hereditary-spastic-paraplegia/what-is-hereditary-spastic-paraplegia-an-overview/

  Hereditary spastic paraplegia (HSP) is a rare problem passed down in families. It makes leg muscles weak and tight. Over time, these signs can get worse. […] The main cause of hereditary spastic paraplegia (HSP) is a genetic issue. Most often, people get a bad gene from one parent. If its a more severe type, they might get bad genes from both parents. These genes affect how the nerves in the spine work. Normally, these nerves help control muscle tone and movement in the legs. […] Scientists have found over 80 places in our genes that can cause HSP. The most seen types usually happen when one of the genes passed down is wrong. The main types are from a parent, like SPG4, SPG3A, and SPG6. Less common types come from both parents, found in SPG5, SPG7, and SPG11. Sometimes, extra genetic changes can show up, causing more symptoms.

• #1 Hereditary spastic paraplegia: clinical changes and association with neuroimaging findings.

  https://oatext.com/hereditary-spastic-paraplegia-clinical-changes-and-association-with-neuroimaging-findings.php

  In relation to case 2, it can be considered an etiological diagnosis of PEH associated with the SPG21 gene, or Mast’s syndrome, which relates the presentation to early adulthood, associated with the finding of a thin corpus callosum neuroimaging, cognitive decline, alterations extrapyramidal and cerebellar alterations. […] Another possibility would be PEH SPG11, which usually presents in childhood, with cognitive decline and peripheral neuropathy. We can consider this as the probable alteration of case 3, by the age of compatible presentation and the most specific finding to neuroimaging, called signal of the lynx ears. […] Definitive diagnosis requires genetic testing, which is generally inaccessible in most neurology services, even at referral centers. In these cases, the clinical diagnosis is imposed after the vascular, infectious, toxic, autoimmune, metabolic, inflammatory and neoplastic differential diagnoses are excluded. […] Brain MRI, however, may help in the etiological diagnosis, evidencing relatively specific alterations within the clinical and evolutionary context, related to some forms of PEH.

• #1 Hereditary spastic paraplegia – UpToDate

  https://www.uptodate.com/contents/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia (HSP) refers to a group of familial diseases that are characterized by progressive degeneration of the corticospinal tracts. Clinically, they present with lower limb spasticity and weakness. […] The genetic classification of HSP is based upon mode of inheritance, chromosomal locus, and causative mutation (if known). Hereditary spastic paraplegias include autosomal dominant, autosomal recessive, and X-linked forms. […] The correlation of clinical classification (pure or complicated) with genetic classification (SPG type) is imperfect, and some genetic types of HSP are associated with both pure and complicated phenotypes.

• #1

  https://link.springer.com/article/10.1007/s11910-021-01099-x

  There are many shared genes between HSP and ALS. For example, mutations in ERLIN1 have been implicated in SPG62, but may also be the cause of a slowly progressive early-onset ALS. […] HSP may be due to mutations in many other genes outside of the SPG loci, typically causing complicated phenotypes. […] The genetic diagnosis of HSP is complex and can represent a major challenge for clinicians. The complexity arises in part because of the high degree of genetic heterogeneity, with over 80 different genetic forms, and a growing number of genes being identified. Furthermore, there is a high level of phenotypic complexity, with HSP clinically and genetically overlapping with a variety of neurological phenotypes, including inherited forms of cerebellar ataxia, ALS, Parkinsons disease, and peripheral neuropathy.

• #1 Hereditary Spastic Paraplegia – Neurologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/neurologic-disorders/spinal-cord-disorders/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia is a group of rare hereditary disorders characterized by progressive, spinal, nonsegmental spastic leg paresis, sometimes with intellectual disability, seizures, and other extraspinal deficits. […] The genetic basis of hereditary spastic paraplegia varies and, for many forms, is unknown. There are over 80 known gene mutations for hereditary spastic paraplegia. […] In all forms, the descending corticospinal tracts and, to a lesser extent, the dorsal columns and spinocerebellar tracts degenerate, sometimes with loss of anterior horn cells. […] Diagnosis of hereditary spastic paraplegia is by exclusion of other causes and sometimes (eg, if the cause is unclear) by genetic testing. […] In all forms of hereditary spastic paraplegia, the descending corticospinal tracts and, to a lesser extent, the dorsal columns and spinocerebellar tracts degenerate.

• #1 MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia | American Journal of Neuroradiology

  http://www.ajnr.org/content/30/5/936

  Hereditary spastic paraplegia (HSP) is a disorder characterized by degeneration of the corticospinal tracts and posterior column of the spinal cord. […] Dominant, recessive, and X-linked patterns of inheritance have been described. Approximately 70% of cases follow a dominant pattern of inheritance, and 20% show a recessive pattern. […] Recent genetic studies have identified multiple loci on different chromosomes responsible for autosomal recessive, autosomal dominant, or X-linked forms of HSP and some of the proteins encoded by those genes. […] The radiologic findings of HSP are nonspecific, including mild-to-moderate brain atrophy, thinning of the corpus callosum, nonspecific white matter lesions in the cerebral hemispheres, abnormal T2 high signal intensity in the posterior limb of the internal capsules, and atrophy of the spinal cord.

• #1 MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia | American Journal of Neuroradiology

  http://www.ajnr.org/content/30/5/936

  In our study, the atrophy of the corpus callosum was present in 44% of patients. […] The new MR imaging techniques like proton MR spectroscopy, diffusion tensor imaging (DTI), single-photon emission CT (SPECT), and fluorodeoxyglucosepositron-emission tomography (FDG-PET) have rarely been reported in patients with HSP. […] Those metabolic changes are consistent with the progressive neuroaxonal loss and astrocytic proliferation known to occur in HSP. […] At the level of the spinal cord, studies by Sperfeld et al showed significant atrophy of the upper spinal cord in patients with HSP compared with the controls, both at the cervical and thoracic levels. […] The previous MR imaging studies could not analyze separately the size of the different anterior (descending) and posterior (ascending) spinal cord tracts responsible for the great part of the atrophy of the spinal cord.

• #1 Hereditary spastic paraplegia (HSP) | MedLink Neurology

  https://www.medlink.com/articles/hereditary-spastic-paraplegia

  Over 80 genetic types have been described with all patterns of inheritance seen. […] Significant overlap exists between hereditary spastic paraplegia and other neurodegenerative disorders both from a clinical and genetic perspective. […] The major pathological finding of hereditary spastic paraplegia is the degeneration of axons of the pyramidal tract and dorsal column pathways of the spinal cord. […] Knowledge about the molecular and genetic basis of pathogenic mechanisms of hereditary spastic paraplegia continues to increase. Current research underscores the crucial role of the presynaptic endoplasmic reticulum in regulating synaptic function via Ca2+ dynamics, suggesting a promising hypothesis for pathogenesis. […] Hereditary spastic paraplegias are genetically determined. Autosomal dominant, autosomal recessive, X-linked, and mitochondrial forms of inheritance have been described.

• #1 Hereditary spastic paraplegia (HSP) | Paris Brain Institute

  https://parisbraininstitute.org/disease-files/hereditary-spastic-paraplegia-hsp

  Hereditary spastic paraplegia (HSP), also known as Strmpell-Lorrain disease, is a highly heterogeneous group of diseases. […] These conditions are primarily hereditary, through several different modes of transmission (autosomal dominant, recessive or X-linked). […] Multiple chromosomal regions are now known to carry mutations responsible for these diseases, and more than 70 genes have been identified. […] The causes of spastic paraplegia are typically a degeneration of the corticospinal neurons that control voluntary motricity, i.e. the transmission of information from the brain to the muscles via the spinal cord, leading to the motor disorders observed in patients. […] Hereditary spastic paraplegias are a heterogeneous group of pathologies and share clinical similarities with other neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). […] A research team of the Institut du Cerveau – ICM institute took part to an international study identifying 18 new genes implicated in hereditary spastic paraplegias (HSP). […] Hereditary spastic paraplegias: mutations in three novel genes highlight lipid metabolism in motor neuron degeneration.

• #1 What are the causes of Spastic Paraplegia? | Paris Brain Institute

  https://parisbraininstitute.org/disease-files/hereditary-spastic-paraplegia-hsp/what-are-causes-spastic-paraplegia

  The study, Hereditary spastic paraplegia: identifying the impact of each mutation, by the research team led by Giovanni Stevanin (INSERM/EPHE) highlights the effect of certain mutations in hereditary spastic paraplegia. […] Numerous proteins, encoded by genes affected in hereditary spastic paraplegia, are also repeatedly involved in these mechanisms, the understanding of which opens the way to new therapeutic avenues.

• #1 Hereditary Spastic Paraplegia | PM&R KnowledgeNow

  https://now.aapmr.org/hereditary-spastic-paraplegia/

  The increasing number of genes being identified in association with HSP has led to the growing recognition about the heterogeneous nature of this disorder. With advances in gene sequencing technology, more genes for HSP and related disorders are likely to continue to be uncovered. Although there have been significant advances in genotype-targeted therapy in some other hereditary neurodegenerative diseases, there has not been much progress in HSP because of genetic heterogenicity, diverse underlying cellular mechanisms, and slow clinical disease progression.

• #1

  https://www.dzne.de/en/research/studies/clinical-studies/hsp-net/

  Hereditary spastic paraplegia (HSP) is a rare, slowly progressing disease that characteristically causes patients to have spastic gaits. […] Thanks to progress in genetic techniques, the causes of HSP are being gradually illuminated and are now able to serve as models for more-common degenerative diseases. […] The research is aimed especially at identifying new genetic causes of HSP. […] In cases in which no genetic causes have been identified, genetic testing for all known HSP genes will be carried out. […] In family groups in which the causes of the disease remain unclear, a search for new HSP genes will be conducted, entailing sequencing of all gene regions that encode information for human-protein formation.

• #1 Hereditary spastic paraplegia (HSP) | MedLink Neurology

  https://www.medlink.com/articles/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia occurs due to the dysfunction of the upper motor neurons of the corticospinal tracts. More than 80 causative genetic mutations have been identified. The genes encode proteins involved in normal neuronal function. Disease mechanisms implicated include those relating to vesicular trafficking and organelle shaping, axonal transport, axonal development and myelination, mitochondrial functions, and complex lipid metabolism. […] Genetic mutations affect many different biological functions, including axonal transport, mitochondrial functions, fatty acid, and cholesterol pathways and DNA repair defects, causing hereditary spastic paraplegia. […] Hereditary spastic paraplegias are a heterogeneous group of disorders that can be categorized into pure or complex forms based on the presence or absence of significant additional neurologic or extraneurologic abnormalities.

• #1 The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment

  https://www.mdpi.com/1422-0067/23/14/7665

  The cellular functions related to HSP pathophysiology are linked to defects in the metabolism of lipid molecules, organelles morphology, endo-lysosomal functioning, and axons transportation. […] The HSP pathology is identified using the designated SPG gene mutation analysis molecularly, with the exclusion of acquired spastic paraparesis caused by structural and inflammatory infections plus Vitamin B12 or copper deficiencies. […] The fundamental approach for treating and controlling HSP addresses symptoms such as stiffness, deformities, spasms, and cramps. […] The current necessity is to find a cure or effective management therapy for HSP.

• #2 Orphanet: Hereditary spastic paraplegia

  https://www.orpha.net/en/disease/detail/685

  A genetically and clinically heterogeneous group of slowly progressive neurological disorders which in the pure form is characterized by pyramidal signs (weakness, spasticity, brisk tendon reflexes, and extensor plantar responses) predominantly affecting the lower limbs and with possible association of sphincter disturbances and deep sensory loss; and in the complex form by the addition of variable neurological or non-neurological features. […] The disease is due to the dysfunction of the upper motor neurons of the corticospinal tract. To date, more than 80 genes have been linked. The encoded proteins are involved in many processes, including axonal transport, myelination, endo-membrane trafficking, mitochondria functions, complex lipid and nucleotide metabolism. The most common causative genes include SPAST(2p22.3), ATL1(14q22.1), REEP1(2p11.2) and KIF5A(12q.13.3) for autosomal dominant HSPs, and SPG7(16q24.3), SPG11 (15q21.1), and CYP7B1 (8q12.3) for autosomal recessive HSP. However, a significant number of patients are without a genetic diagnosis after systematic testing.

• #2 Hereditary Spastic Paraplegia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/306713-overview

  Hereditary spastic paraplegia (HSP) is not a single disease entity; it is a group of clinically and genetically diverse disorders that share a primary feature, which is the causation of progressive and generally severe lower extremity weakness and spasticity. […] The most useful classifications now are based on the mode of inheritance and genetic linkage. HSP may also be classified as autosomal dominant, autosomal recessive, or X-linked, and each type has several subtypes, which are based on the location of the gene. […] To date, over 80 genes or genomic loci associated with HSP have been identified. […] HSP causes degeneration of the ends of the corticospinal tracts within the spinal cord. […] Impaired cellular membrane trafficking, more particularly, axonal transport of macromolecules and organelles, is the best-characterized genetic mechanism of HSP.

• #2 Hereditary spastic paraplegia (HSP) | MedLink Neurology

  https://www.medlink.com/articles/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia occurs due to the dysfunction of the upper motor neurons of the corticospinal tracts. More than 80 causative genetic mutations have been identified. The genes encode proteins involved in normal neuronal function. Disease mechanisms implicated include those relating to vesicular trafficking and organelle shaping, axonal transport, axonal development and myelination, mitochondrial functions, and complex lipid metabolism. […] Genetic mutations affect many different biological functions, including axonal transport, mitochondrial functions, fatty acid, and cholesterol pathways and DNA repair defects, causing hereditary spastic paraplegia. […] Hereditary spastic paraplegias are a heterogeneous group of disorders that can be categorized into pure or complex forms based on the presence or absence of significant additional neurologic or extraneurologic abnormalities.

• #2 Hereditary Spastic Paraplegia: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/306713-overview

  Mitochondrial dysfunction is the second process that leads to HSPs. […] In most cases of HSP, the primary problem may be disturbance of the ends of the long axons, with little or no loss of myelin and no abnormal myelin. […] A rare type of X-linked HSP, however, has been associated with a myelin protein gene mutation. […] A study by Agosta et al suggested that the various neurologic disorders designated as HSP share a common neurodegenerative cascade. […] As previously stated, more than 80 genes or genomic loci associated with HSP have been identified. […] Most cases of pure HSP are autosomal dominant, whereas complicated forms tend to be autosomal recessive. […] At least 19 autosomal dominant spastic paraplegia (SPG) genes (ie, genes for autosomal dominant HSP) have been identified, with autosomal dominant HSP accounting for 75-80% of registered HSP cases.

• #2 SciELO Brazil – Clinical features and management of hereditary spastic paraplegia Clinical features and management of hereditary spastic paraplegia

  https://www.scielo.br/j/anp/a/T7KKdbXLLnppT3RqhgN4GKg/

  Mutations in the SPG7 gene, which encodes paraplegin, is the second most common cause of AR-HSP. […] HSPs are characterized by retrograde degeneration of the longest neurons of the spinal cord, the corticospinal tract and the posterior columns. […] Despite its genetic heterogeneity, disruptive processes involving membrane trafficking and organelle morphogenesis and distribution seem to play a central role in the pathophysiology of most HSPs. […] HSP-related proteins cluster into overlapping functional classes: membrane trafficking, organelle shaping, mitochondrial regulation, lipid metabolism and axon path finding. […] The three most common AD-HSPs (SPG4, SPG3A, SPG31) are due to altered function of proteins involved in shaping the endoplasmic reticulum.

• #2 The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment

  https://www.mdpi.com/1422-0067/23/14/7665

  The cellular functions related to HSP pathophysiology are linked to defects in the metabolism of lipid molecules, organelles morphology, endo-lysosomal functioning, and axons transportation. […] The HSP pathology is identified using the designated SPG gene mutation analysis molecularly, with the exclusion of acquired spastic paraparesis caused by structural and inflammatory infections plus Vitamin B12 or copper deficiencies. […] The fundamental approach for treating and controlling HSP addresses symptoms such as stiffness, deformities, spasms, and cramps. […] The current necessity is to find a cure or effective management therapy for HSP.

• #2 Hereditary Spastic Paraplegia – Neurologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/neurologic-disorders/spinal-cord-disorders/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia is a group of rare hereditary disorders characterized by progressive, spinal, nonsegmental spastic leg paresis, sometimes with intellectual disability, seizures, and other extraspinal deficits. […] The genetic basis of hereditary spastic paraplegia varies and, for many forms, is unknown. There are over 80 known gene mutations for hereditary spastic paraplegia. […] In all forms, the descending corticospinal tracts and, to a lesser extent, the dorsal columns and spinocerebellar tracts degenerate, sometimes with loss of anterior horn cells. […] Diagnosis of hereditary spastic paraplegia is by exclusion of other causes and sometimes (eg, if the cause is unclear) by genetic testing. […] In all forms of hereditary spastic paraplegia, the descending corticospinal tracts and, to a lesser extent, the dorsal columns and spinocerebellar tracts degenerate.

• #2 Hereditary spastic paraplegia | About the Disease | GARD

  https://rarediseases.info.nih.gov/diseases/6637/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia (HSP) is a group of hereditary, degenerative, neurological disorders that primarily affect the upper motor neurons. […] The different forms of HSP are caused by genetic changes in different genes. Inheritance varies. […] This disease is caused by a change in the genetic material (DNA). […] Hereditary spastic paraplegia is caused by genetic mutations, also known as pathogenic variants. Genetic mutations can be hereditary, when parents pass them down to their children, or they may occur randomly when cells are dividing. […] Yes. It is possible for a biological parent to pass down genetic mutations that cause or increase the chances of getting this disease to their child. […] There are multiple ways, or patterns, a disease can be inherited depending on the gene(s) involved. Based on GARD’s current data, this disease can be inherited in the following pattern(s): Autosomal Dominant, Autosomal Recessive, X-Linked.

• #2 What are the causes of Spastic Paraplegia? | Paris Brain Institute

  https://parisbraininstitute.org/disease-files/hereditary-spastic-paraplegia-hsp/what-are-causes-spastic-paraplegia

  With regard to the causes of spastic paraplegia, in 70% of cases the mode of transmission of the disease is autosomal dominant. 20% of the families have autosomal recessive transmission and transmissions of spastic paraplegia linked to the X chromosome are estimated at 2%. […] Today, more than 73 chromosomal regions are known to carry mutations responsible for spastic paraplegia, however, it is estimated that nearly 50% of the families in which the genetic mutation is not known, which justifies active genetic research on these pathologies. […] The study, Identification of a key mechanism in hereditary spastic paraplegia type 11, led by Frdric Darios and Giovanni Stevanin, demonstrated the role of lipid accumulation in hereditary spastic paraplegia type 11. […] The collaborative study, Hereditary spastic paraplegia type 58, a demyelinating disease, led by Khalid Hamid El Hachimi of the Institut du Cerveau and Amandine Duchesne of INRA, reports that mutations in the KIF1C gene, responsible for hereditary spastic paraplegia type 58 (SPG58/SPAX2), cause a loss of myelin.

• #2 Hereditary spastic paraplegia (HSP) | MedLink Neurology

  https://www.medlink.com/articles/hereditary-spastic-paraplegia

  Over 80 genetic types have been described with all patterns of inheritance seen. […] Significant overlap exists between hereditary spastic paraplegia and other neurodegenerative disorders both from a clinical and genetic perspective. […] The major pathological finding of hereditary spastic paraplegia is the degeneration of axons of the pyramidal tract and dorsal column pathways of the spinal cord. […] Knowledge about the molecular and genetic basis of pathogenic mechanisms of hereditary spastic paraplegia continues to increase. Current research underscores the crucial role of the presynaptic endoplasmic reticulum in regulating synaptic function via Ca2+ dynamics, suggesting a promising hypothesis for pathogenesis. […] Hereditary spastic paraplegias are genetically determined. Autosomal dominant, autosomal recessive, X-linked, and mitochondrial forms of inheritance have been described.

• #2 Paraparesis: Causes, Treatment, and More

  https://www.healthline.com/health/paraparesis

  HSP is a genetic disorder, meaning its passed from parents to children. There are more than 30 genetic types and subtypes of HSP. The genes can be passed on with dominant, recessive, or X-linked modes of inheritance. […] About 30 percent of people with HSP dont have any family history of the disease. In these cases, the disease starts randomly as a new genetic change that wasnt inherited from either parent.

• #2 Hereditary Spastic Paraplegia | PM&R KnowledgeNow

  https://now.aapmr.org/hereditary-spastic-paraplegia/

  The genetics of HSP are complex and heterogeneous. The genetic classification for HSP is based on sequential numbering of specific genes as they were identified using spastic paraplegia gene (SPG) designation. Over 80 SPG loci have been identified to date. The mode of inheritance for HSP can be autosomal dominant, recessive, or X-linked. Autosomal dominant HSP is the most prevalent form and accounts for approximately 70% of all cases. Most cases of uncomplicated (pure) HSP are inherited in the autosomal dominant fashion. The most common HSP subtypes are SPG4, which is associated with mutations in SPAST and accounts for up to a third of all HSP cases, and SPG3A. In contrast to uncomplicated HSP subtypes, the complex forms tend to demonstrate autosomal recessive inheritance. […] Less than 30% of patient with HSP demonstrate an autosomal-recessive inheritance pattern. These cases are seen in a higher proportion of consanguineous marriages. SPG11 is the most common autosomal-recessive subtype, comprising 8% of HSP cases. Autosomal-recessive subtypes often present with lower extremity spasticity in the second decade of life and are associated with learning disabilities, ataxia, dysarthria, axonal motor neuropathies, and visual deficits. X-linked recessive inheritance patterns comprise 1-2% of HSP cases.

• #2 Spastic paraplegia type 4: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/spastic-paraplegia-type-4/

  Spastic paraplegia type 4 (also known as SPG4) is the most common of a group of genetic disorders known as hereditary spastic paraplegias. […] Mutations in the SPAST gene cause spastic paraplegia type 4. The SPAST gene provides instructions for producing a protein called spastin. […] Spastin likely helps restrict microtubule length and disassemble microtubule structures when they are no longer needed. Mutations in spastin impair the microtubules’ ability to transport cell compartments (organelles), especially in nerve cells; researchers believe this contributes to the major signs and symptoms of spastic paraplegia type 4. […] This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

• #2 Homozygous mutation in Atlastin GTPase 1 causes recessive hereditary spastic paraplegia | Journal of Human Genetics

  https://www.nature.com/articles/jhg20166

  Hereditary spastic paraplegia (HSP) is an extremely heterogeneous disease caused by mutations of numerous genes leading to lower limb spasticity (pure forms) that can be accompanied by neurological symptoms (complex forms). […] We identified a consanguineous family with the early-onset HSP. Whole-exome sequencing revealed homozygosity for a novel Atlastin GTPase 1 gene stop mutation in three affected siblings. […] This was unexpected as mutations in the Atlastin 1 gene are known to cause autosomal dominant HSP. But our study showed that Atlastin 1 mutations may cause autosomal recessively inherited paraplegia with an underlying loss-of-function mechanism. Hence, patients with recessive forms of HSP should also be tested for the Atlastin 1 gene. […] HSPs are caused by mutations of genes encoding for proteins involved in the maintenance of corticospinal tract neurons.

• #2 Hereditary Spastic Paraplegia (HSP) Miller School of Medicine

  https://med.miami.edu/centers-and-institutes/hihg/research-programs/hereditary-spastic-paraplegia

  Hereditary Spastic Paraplegia (HSP) refers to a group of inherited spinal cord disorders that manifest themselves first as trouble in walking and maintaining balance. […] HSP is caused by a gradual degeneration of the nerve pathways that carry signals from the brain down the spinal cord. […] Investigators at the John P. Hussman Institute for Human Genomics (HIHG) have made major breakthroughs in the identification of one gene that causes HSP. […] More recently, the HIHGs Stephan Zchner, M.D., identified the REEP1 gene that is now established as the third most common HSP gene. […] The HIHG is also actively enrolling HSP patients and their families in special studies to identify the remaining genes, which may account for about 40 percent of the disease.

• #2 SciELO Brazil – Clinical features and management of hereditary spastic paraplegia Clinical features and management of hereditary spastic paraplegia

  https://www.scielo.br/j/anp/a/T7KKdbXLLnppT3RqhgN4GKg/

  Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. […] A significant proportion of patients with sporadic spastic paraplegia also have a genetic etiology. […] All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. […] Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. […] To date, there are up to 60 genetic subtypes described. […] Mutations in the gene SPG11, encoding spastacsin, are the most frequent cause of AR-HSP, corresponding to up to 20%. […] This proportion increases to 60-80% when considering patients with thinning of the corpus callosum and mental impairment.

• #2 KEGG DISEASE: Hereditary spastic paraplegia

  https://www.genome.jp/dbget-bin/www_bget?ds:H00266

  Hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive distal limb weakness and lower extremity spasticity. […] Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. […] Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. […] Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. […] NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). […] Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. […] Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12.

• #2 KEGG DISEASE: Hereditary spastic paraplegia

  https://www.genome.jp/dbget-bin/www_bget?ds:H00266

  Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. […] Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. […] Mutations in CAPN1 cause autosomal-recessive hereditary spastic paraplegia. […] A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia. […] Genetic and phenotypic characterization of complex hereditary spastic paraplegia. […] Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy. […] A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis.

• #2 Spastic paraplegia type 2: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/spastic-paraplegia-type-2/

  Spastic paraplegia type 2 is part of a group of genetic disorders known as hereditary spastic paraplegias. […] Mutations in the PLP1 gene cause spastic paraplegia 2. The PLP1 gene provides instructions for producing proteolipid protein 1 and a modified version (isoform) of proteolipid protein 1, called DM20. A lack of proteolipid protein 1 and DM20 can cause a reduction in the formation of myelin (dysmyelination) which can impair nervous system function, resulting in the signs and symptoms of spastic paraplegia type 2. […] This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes.

• #2 SciELO Brazil – Hereditary spastic paraplegia from 1880 to 2017: an historical review Hereditary spastic paraplegia from 1880 to 2017: an historical review

  https://www.scielo.br/j/anp/a/pZxkFzKktLqn5VSgjTwCWcL/?lang=en

  The presence of a family history or consanguinity strengthens the possibility of a hereditary condition; its absence, on the contrary, should not dissuade the clinician from the diagnosis. […] The now current clinical classification of HSP into pure and complicated forms was proposed. […] The complicated forms were recognized to be rarer and genetically heterogeneous. […] Numerous HSP genetic studies have been published since the 1980s. Several genetic subtypes of HSP have been described and numbered sequentially, based on the order of the gene discovery. […] This was the first gene discovered that caused HSP; L1CAM codes for an axonal glycoprotein involved in neuronal migration and differentiation. […] The next-generation sequencing techniques, encompassing gene panels, whole exome sequencing and whole genome sequencing have initiated a new era of knowledge in the field. […] Today, more than 80 different loci related to hereditary spastic paraplegias are recognized, with more than 50 genes already identified.

• #2 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-is-Hereditary-Spastic-Paraplegia.aspx

  Examples of SPG loci include SPG3A which codes Atlastin resulting in an early-onset but slowly progressing form of HSP. Mutations to ALDH18A1 (SPG9A) causes complicated HSP with cataracts, gastroesophageal reflux, ataxia and cognitive impairment. Some SPG loci e.g. SPG23 SPG24 contain unidentified genes, and give rise to complicated versions of HSP, usually starting in childhood and presenting with additional symptoms including vitiligo and premature graying. […] Rarer forms such as SPG1, which is due to X-linked mutations to L1CAM, produces an extremely complicated form of HSP with symptoms of mental retardation (severe disability), hydrocephalus (enlarged head with high pressure), aphasia (impairment of language) and adducted thumbs.

• #2 Hereditary spastic paraplegia – UpToDate

  https://www.uptodate.com/contents/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia (HSP) refers to a group of familial diseases that are characterized by progressive degeneration of the corticospinal tracts. Clinically, they present with lower limb spasticity and weakness. […] The genetic classification of HSP is based upon mode of inheritance, chromosomal locus, and causative mutation (if known). Hereditary spastic paraplegias include autosomal dominant, autosomal recessive, and X-linked forms. […] The correlation of clinical classification (pure or complicated) with genetic classification (SPG type) is imperfect, and some genetic types of HSP are associated with both pure and complicated phenotypes.

• #2 Hereditary Spastic Paraplegia | Conditions | Liverpool Neuro Physio

  https://www.liverpoolneurophysio.co.uk/conditions-we-treat/hereditary-spastic-paraplegia.php

  Hereditary spastic paraplegia (HSP) is a term used to describe a range of inherited genetic neurological disorders that cause extreme muscle stiffness and sometimes paralysis in the muscles of the lower limbs. […] Hereditary spastic paraplegia causes motor neurons in the brain and spinal cord to waste away or die, so they can no longer transmit impulses to the muscles. […] In uncomplicated hereditary spastic paraplegia the individual will experience progressive muscle spasticity, however there will be an absence of other neurological deficits. […] In complicated hereditary spastic paraplegia the individual will experience spasticity and progressive weakening of the muscles in the lower limb alongside additional neurological deficits such as dementia, deafness, and speech problems. […] Hereditary spastic paraplegia is characterised by progressive spasticity, which is felt as muscle stiffness.

• #2 Hereditary spastic paraplegia: clinical changes and association with neuroimaging findings.

  https://oatext.com/hereditary-spastic-paraplegia-clinical-changes-and-association-with-neuroimaging-findings.php

  In relation to case 2, it can be considered an etiological diagnosis of PEH associated with the SPG21 gene, or Mast’s syndrome, which relates the presentation to early adulthood, associated with the finding of a thin corpus callosum neuroimaging, cognitive decline, alterations extrapyramidal and cerebellar alterations. […] Another possibility would be PEH SPG11, which usually presents in childhood, with cognitive decline and peripheral neuropathy. We can consider this as the probable alteration of case 3, by the age of compatible presentation and the most specific finding to neuroimaging, called signal of the lynx ears. […] Definitive diagnosis requires genetic testing, which is generally inaccessible in most neurology services, even at referral centers. In these cases, the clinical diagnosis is imposed after the vascular, infectious, toxic, autoimmune, metabolic, inflammatory and neoplastic differential diagnoses are excluded. […] Brain MRI, however, may help in the etiological diagnosis, evidencing relatively specific alterations within the clinical and evolutionary context, related to some forms of PEH.

• #2 Hereditary Spastic Paraparesis/Paraplegia – Child Neurology Foundation

  https://www.childneurologyfoundation.org/disorder/hereditary-spastic-paraplegia/

  Hereditary Spastic Paraparesis/Paraplegia (HSP) causes difficulty walking. […] HSP is a genetic disorder. It can be caused by a mutation in any of a large number of genes. […] HSP occurs due to gene mutations. Two gene mutations are most often responsible when HSP begins in childhood. These are mutations in the SPG3A and SPG4 genes. However, over 80 genes are known to affect HSP.

• #2 Hereditary Spastic Paraplegia | American Journal of Neuroradiology

  https://www.ajnr.org/ajnr-case-collections-diagnosis/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia (HSP) is a heterogeneous group of familial neurodegenerative disorders characterized by degeneration of the corticospinal tracts and posterior column of the spinal cord with progressive lower limb spasticity. […] The ears of the lynx sign on FLAIR MR imaging is highly specific for the most common genetic subtypes of hereditary spastic paraplegia with a thin corpus callosum. When this sign is present, there is a high likelihood of a genetic mutation, particularly associated with SPG11 or SPG15, even in the absence of a family history. […] No specific treatment is known that would prevent, slow, or reverse HSP.

• #2

  https://link.springer.com/article/10.1007/s11910-021-01099-x

  There are many shared genes between HSP and ALS. For example, mutations in ERLIN1 have been implicated in SPG62, but may also be the cause of a slowly progressive early-onset ALS. […] HSP may be due to mutations in many other genes outside of the SPG loci, typically causing complicated phenotypes. […] The genetic diagnosis of HSP is complex and can represent a major challenge for clinicians. The complexity arises in part because of the high degree of genetic heterogeneity, with over 80 different genetic forms, and a growing number of genes being identified. Furthermore, there is a high level of phenotypic complexity, with HSP clinically and genetically overlapping with a variety of neurological phenotypes, including inherited forms of cerebellar ataxia, ALS, Parkinsons disease, and peripheral neuropathy.

• #2 Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations | BMC Neurology | Full Text

  https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-022-02708-z

  Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by lower-limb spastic paraplegia with highly genetic and clinical heterogeneity. […] HSP can be transmitted in autosomal dominant (AD), autosomal recessive (AR), X-linked or mitochondrial maternal modes, with 1340% of cases being sporadic. […] ADHSP is the most prevalent form of HSP and accounts for approximately 70% of cases. […] Mutations in the CYP7B1 (SPG5), SPG7 (SPG7), SPG11 (SPG11), and ZFYVE26 (SPG15) genes are described as the most frequent causes for ARHSP. […] HSP had widespread clinical and genetic heterogeneity, and leukodystrophy, hereditary ataxia, Charcot-Marie-Tooth atrophy and homocysteine remethylation disorders accounted for a significant proportion of the proposed HSP. […] The average duration from onset to diagnosis in the HSP group was remarkably longer than that in the Hcy remethylation disorders group and LD group, suggesting a slow progression.

• #2 Hereditary spastic paraplegia: clinical changes and association with neuroimaging findings.

  https://oatext.com/hereditary-spastic-paraplegia-clinical-changes-and-association-with-neuroimaging-findings.php

  The other cases present an autosomal recessive or X-linked pattern, being associated with the so-called complicated form of the disease, which usually presents with several neurological manifestations resulting from the involvement of several, long or non-dependent treatments. The main neurological manifestations presented together are: amyotrophy, optic atrophy, pigmentary retinopathy, dementia, parkinsonism, deafness, peripheral neuropathy and epilepsy. The mutation most related to these cases is SPG11, which is also the most related to neuroimaging characteristic alterations, such as fine corpus callosum and signs of the lynx ears. […] The pathophysiology of the disease is still not well understood, but it is believed that the genetic alterations are related to dysfunction of the axoplasmic flow of the corticospinal tract through molecular changes in neuronal cytoskeletal structures responsible for membrane trafficking and axonal transport of vesicles and endosomes.

• #2 Hereditary spastic paraplegia | nidirect

  https://www.nidirect.gov.uk/conditions/hereditary-spastic-paraplegia

  Most people with pure hereditary spastic paraplegia will have inherited a faulty gene from one of their parents. […] People with the complicated form of the condition will have usually inherited a faulty gene from both parents. […] The gene abnormality causes the long nerves in the spine to deteriorate. These nerves normally control muscle tone and movement in the lower body.

• #2 MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia | American Journal of Neuroradiology

  http://www.ajnr.org/content/30/5/936

  Hereditary spastic paraplegia (HSP) is a disorder characterized by degeneration of the corticospinal tracts and posterior column of the spinal cord. […] Dominant, recessive, and X-linked patterns of inheritance have been described. Approximately 70% of cases follow a dominant pattern of inheritance, and 20% show a recessive pattern. […] Recent genetic studies have identified multiple loci on different chromosomes responsible for autosomal recessive, autosomal dominant, or X-linked forms of HSP and some of the proteins encoded by those genes. […] The radiologic findings of HSP are nonspecific, including mild-to-moderate brain atrophy, thinning of the corpus callosum, nonspecific white matter lesions in the cerebral hemispheres, abnormal T2 high signal intensity in the posterior limb of the internal capsules, and atrophy of the spinal cord.

• #2 MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia | American Journal of Neuroradiology

  http://www.ajnr.org/content/30/5/936

  Pathologic studies have shown that the corticospinal tracts, which route through the posterior limb of the internal capsules on their way to the brain stem and spinal cord, are the main tracts involved in HSP. […] The MR imaging findings of HSP are nonspecific and variable; however, the most prominent features include atrophy of the corpus callosum, T2 signal intensity in the posterior limb of the internal capsule, and spinal cord atrophy. […] The etiology of a thin corpus callosum is still debated concerning whether it is secondary to congenital hypoplasia or progressive atrophy. […] However, Kuru et al and Casali et al reported cases with progressive thinning of the corpus callosum and suggested progressive atrophy of the corpus callosum, a neurodegenerative process secondary to severe gliosis in the cerebral white matter.

• #2 MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia | American Journal of Neuroradiology

  http://www.ajnr.org/content/30/5/936

  Mild atrophy of the cervical and thoracic spinal cord (not quantified) was also reported by Durr et al, Lesca et al, Nicolau et al, and Nielsen et al. […] In our study, patient 1 had mild atrophy of the cervical spinal cord and 2 patients of family II presented an unusual finding, namely the round T2 high signal intensity in the posterior aspect of the spinal cord representing either an enlarged and posteriorly displaced ependymal canal or a direct high signal intensity along the dorsal columns of the cord; in both cases, it reflects the neuropathologic finding of degeneration and atrophy of the dorsal columns of the spinal cord. […] HSP is a group of neurodegenerative disorders, genetically heterogeneous and progressive with time, characterized by multisystem degeneration.

• #2 What are the causes of Spastic Paraplegia? | Paris Brain Institute

  https://parisbraininstitute.org/disease-files/hereditary-spastic-paraplegia-hsp/what-are-causes-spastic-paraplegia

  The study, Hereditary spastic paraplegia: identifying the impact of each mutation, by the research team led by Giovanni Stevanin (INSERM/EPHE) highlights the effect of certain mutations in hereditary spastic paraplegia. […] Numerous proteins, encoded by genes affected in hereditary spastic paraplegia, are also repeatedly involved in these mechanisms, the understanding of which opens the way to new therapeutic avenues.

• #2 Hereditary Spastic Paraplegia | PM&R KnowledgeNow

  https://now.aapmr.org/hereditary-spastic-paraplegia/

  The increasing number of genes being identified in association with HSP has led to the growing recognition about the heterogeneous nature of this disorder. With advances in gene sequencing technology, more genes for HSP and related disorders are likely to continue to be uncovered. Although there have been significant advances in genotype-targeted therapy in some other hereditary neurodegenerative diseases, there has not been much progress in HSP because of genetic heterogenicity, diverse underlying cellular mechanisms, and slow clinical disease progression.

• #3 Hereditary spastic paraplegia (HSP) | MedLink Neurology

  https://www.medlink.com/articles/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia occurs due to the dysfunction of the upper motor neurons of the corticospinal tracts. More than 80 causative genetic mutations have been identified. The genes encode proteins involved in normal neuronal function. Disease mechanisms implicated include those relating to vesicular trafficking and organelle shaping, axonal transport, axonal development and myelination, mitochondrial functions, and complex lipid metabolism. […] Genetic mutations affect many different biological functions, including axonal transport, mitochondrial functions, fatty acid, and cholesterol pathways and DNA repair defects, causing hereditary spastic paraplegia. […] Hereditary spastic paraplegias are a heterogeneous group of disorders that can be categorized into pure or complex forms based on the presence or absence of significant additional neurologic or extraneurologic abnormalities.

• #3 What is HSP? – HSP Research Foundation

  https://hspersunite.org.au/about-hsp/what-is-hsp/

  Hereditary Spastic Paraplegia (HSP) is a genetic, inherited or hereditary disease that is, it is passed on from generation to generation. […] It is caused by abnormal variations (mutations) in the genes that may be passed on from an affected parent to the unborn child in their DNA (genetic material). […] As at 2016, more than 70 genes/loci have been separately implicated in causing HSP. […] The number of genes so identified has increased from 9 in 2004, and many more discoveries are to be expected. […] Multiple mutation locations and types have also been identified, with over 150 for the SPAST/SPG4 gene alone. […] Any of these identified mutations can cause HSP. […] Specifically, they cause the production of too much or too little of either the normal protein or another protein that causes nerve damage through degeneration of the corticospinal tracts.

• #3 Orphanet: Hereditary spastic paraplegia

  https://www.orpha.net/en/disease/detail/685

  A genetically and clinically heterogeneous group of slowly progressive neurological disorders which in the pure form is characterized by pyramidal signs (weakness, spasticity, brisk tendon reflexes, and extensor plantar responses) predominantly affecting the lower limbs and with possible association of sphincter disturbances and deep sensory loss; and in the complex form by the addition of variable neurological or non-neurological features. […] The disease is due to the dysfunction of the upper motor neurons of the corticospinal tract. To date, more than 80 genes have been linked. The encoded proteins are involved in many processes, including axonal transport, myelination, endo-membrane trafficking, mitochondria functions, complex lipid and nucleotide metabolism. The most common causative genes include SPAST(2p22.3), ATL1(14q22.1), REEP1(2p11.2) and KIF5A(12q.13.3) for autosomal dominant HSPs, and SPG7(16q24.3), SPG11 (15q21.1), and CYP7B1 (8q12.3) for autosomal recessive HSP. However, a significant number of patients are without a genetic diagnosis after systematic testing.

• #3 Hereditary spastic paraplegia (HSP) | MedLink Neurology

  https://www.medlink.com/articles/hereditary-spastic-paraplegia

  Over 80 genetic types have been described with all patterns of inheritance seen. […] Significant overlap exists between hereditary spastic paraplegia and other neurodegenerative disorders both from a clinical and genetic perspective. […] The major pathological finding of hereditary spastic paraplegia is the degeneration of axons of the pyramidal tract and dorsal column pathways of the spinal cord. […] Knowledge about the molecular and genetic basis of pathogenic mechanisms of hereditary spastic paraplegia continues to increase. Current research underscores the crucial role of the presynaptic endoplasmic reticulum in regulating synaptic function via Ca2+ dynamics, suggesting a promising hypothesis for pathogenesis. […] Hereditary spastic paraplegias are genetically determined. Autosomal dominant, autosomal recessive, X-linked, and mitochondrial forms of inheritance have been described.

• #3 Hereditary Spastic Paraplegia | PM&R KnowledgeNow

  https://now.aapmr.org/hereditary-spastic-paraplegia/

  The genetics of HSP are complex and heterogeneous. The genetic classification for HSP is based on sequential numbering of specific genes as they were identified using spastic paraplegia gene (SPG) designation. Over 80 SPG loci have been identified to date. The mode of inheritance for HSP can be autosomal dominant, recessive, or X-linked. Autosomal dominant HSP is the most prevalent form and accounts for approximately 70% of all cases. Most cases of uncomplicated (pure) HSP are inherited in the autosomal dominant fashion. The most common HSP subtypes are SPG4, which is associated with mutations in SPAST and accounts for up to a third of all HSP cases, and SPG3A. In contrast to uncomplicated HSP subtypes, the complex forms tend to demonstrate autosomal recessive inheritance. […] Less than 30% of patient with HSP demonstrate an autosomal-recessive inheritance pattern. These cases are seen in a higher proportion of consanguineous marriages. SPG11 is the most common autosomal-recessive subtype, comprising 8% of HSP cases. Autosomal-recessive subtypes often present with lower extremity spasticity in the second decade of life and are associated with learning disabilities, ataxia, dysarthria, axonal motor neuropathies, and visual deficits. X-linked recessive inheritance patterns comprise 1-2% of HSP cases.

• #3 MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia | American Journal of Neuroradiology

  http://www.ajnr.org/content/30/5/936

  Hereditary spastic paraplegia (HSP) is a disorder characterized by degeneration of the corticospinal tracts and posterior column of the spinal cord. […] Dominant, recessive, and X-linked patterns of inheritance have been described. Approximately 70% of cases follow a dominant pattern of inheritance, and 20% show a recessive pattern. […] Recent genetic studies have identified multiple loci on different chromosomes responsible for autosomal recessive, autosomal dominant, or X-linked forms of HSP and some of the proteins encoded by those genes. […] The radiologic findings of HSP are nonspecific, including mild-to-moderate brain atrophy, thinning of the corpus callosum, nonspecific white matter lesions in the cerebral hemispheres, abnormal T2 high signal intensity in the posterior limb of the internal capsules, and atrophy of the spinal cord.

• #3 Hereditary Spastic Paraplegia: An Update

  https://www.mdpi.com/1422-0067/23/3/1697

  Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disorder with the predominant clinical manifestation of spasticity in the lower extremities. HSP is categorised based on inheritance, the phenotypic characters, and the mode of molecular pathophysiology, with frequent degeneration in the axon of cervical and thoracic spinal cord’s lateral region, comprising the corticospinal routes. […] HSPs can be triggered at infancy, toddling, puberty, or adulthood, with about 40% sporadic form. […] Genetically, HSP categorization relies on the positions of causative genes with the designation “spastic paraplegia genes (SPGs)”, and personalized therapy is an unpopular solution, as treatment should target all the 80 genes. […] The current review focuses on the chromosomes and the genes’ specific loci registered to date for HSPs and suggests possibilities for drug discoveries.

• #3 What is HSP? – HSP Research Foundation

  https://hspersunite.org.au/about-hsp/what-is-hsp/

  The probability of hereditary transmission to the child if one parent has HSP is 50% for AD-HSP. […] So, a dominant or strong defective gene will need only one copy to cause disease, but a weak defective gene will need two copies, one from each parent, to cause disease (known as recessive). […] Of the AD-HSP cases, about 40% are caused by a mutation of the SPAST (SPG4) gene, which is known to code for the production of the protein spastin. […] Scientists believe more causal genes will continue to be identified.

• #3 Identification and analyses of exonic and copy number variants in spastic paraplegia | Scientific Reports

  https://www.nature.com/articles/s41598-024-64922-8

  Spastic paraplegia type 11 (SPG11) variants have been commonly described as cause of autosomal recessive hereditary spastic paraplegia (ARHSP) in some studies. […] A thin corpus callosum is observed in 4177% of reported cases due to SPG11 variants. […] The SPG11-encoded transmembrane protein spatacsin plays a role in intracellular trafficking. […] Another complex form of HSP known as SPG54 is caused by recessively inherited variants in DDHD2, which encodes the DDHD domain-containing protein. […] The involvement of all four subunits of the AP-4 complex in the etiology of neurological disorders is evidence for the essential role of this complex in the function of neurons and the brain. […] The aim of the present study was to molecularly characterize three families, each having two or more HSP patients from the Punjab province in Pakistan.

• #3 KEGG DISEASE: Hereditary spastic paraplegia

  https://www.genome.jp/dbget-bin/www_bget?ds:H00266

  Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia. […] Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. […] Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia. […] TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia. […] Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia. […] Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. […] SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia. […] BiP inactivation due to loss of the deAMPylation function of FICD causes a motor neuron disease.

• #3 Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations | BMC Neurology | Full Text

  https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-022-02708-z

  Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by lower-limb spastic paraplegia with highly genetic and clinical heterogeneity. […] HSP can be transmitted in autosomal dominant (AD), autosomal recessive (AR), X-linked or mitochondrial maternal modes, with 1340% of cases being sporadic. […] ADHSP is the most prevalent form of HSP and accounts for approximately 70% of cases. […] Mutations in the CYP7B1 (SPG5), SPG7 (SPG7), SPG11 (SPG11), and ZFYVE26 (SPG15) genes are described as the most frequent causes for ARHSP. […] HSP had widespread clinical and genetic heterogeneity, and leukodystrophy, hereditary ataxia, Charcot-Marie-Tooth atrophy and homocysteine remethylation disorders accounted for a significant proportion of the proposed HSP. […] The average duration from onset to diagnosis in the HSP group was remarkably longer than that in the Hcy remethylation disorders group and LD group, suggesting a slow progression.

• #3 HSP : HSP & PLS : Spastic Paraplegia Foundation

  https://sp-foundation.org/understanding-pls-hsp/hsp.html

  Hereditary Spastic Paraplegia (HSP) is a group of rare, inherited neurological disorders. Their primary symptoms are progressive spasticity and weakness of the leg and hip muscles. Researchers estimate that some 90 different types of HSP exist; the genetic causes are known for about fifty. […] HSP is caused by degeneration of the upper motor neurons in the brain and spinal cord. Upper motor neurons control voluntary movement. The cell bodies of these neurons are located in the motor cortex area of the brain. […] There are some seventy different forms of HSP, with three different modes of inheritance: autosomal dominant, autosomal recessive and X-linked. Each mode has a different risk factor, which ranges from almost none to 50%. […] HSP is hereditary, and examining family history is important in diagnosing HSP. However, many individuals with all the signs and symptoms of HSP do not have a family history.

• #3 MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia | American Journal of Neuroradiology

  http://www.ajnr.org/content/30/5/936

  In our study, the atrophy of the corpus callosum was present in 44% of patients. […] The new MR imaging techniques like proton MR spectroscopy, diffusion tensor imaging (DTI), single-photon emission CT (SPECT), and fluorodeoxyglucosepositron-emission tomography (FDG-PET) have rarely been reported in patients with HSP. […] Those metabolic changes are consistent with the progressive neuroaxonal loss and astrocytic proliferation known to occur in HSP. […] At the level of the spinal cord, studies by Sperfeld et al showed significant atrophy of the upper spinal cord in patients with HSP compared with the controls, both at the cervical and thoracic levels. […] The previous MR imaging studies could not analyze separately the size of the different anterior (descending) and posterior (ascending) spinal cord tracts responsible for the great part of the atrophy of the spinal cord.

• #3 Hereditary Spastic Paraplegia | American Journal of Neuroradiology

  https://www.ajnr.org/ajnr-case-collections-diagnosis/hereditary-spastic-paraplegia

  Hereditary spastic paraplegia (HSP) is a heterogeneous group of familial neurodegenerative disorders characterized by degeneration of the corticospinal tracts and posterior column of the spinal cord with progressive lower limb spasticity. […] The ears of the lynx sign on FLAIR MR imaging is highly specific for the most common genetic subtypes of hereditary spastic paraplegia with a thin corpus callosum. When this sign is present, there is a high likelihood of a genetic mutation, particularly associated with SPG11 or SPG15, even in the absence of a family history. […] No specific treatment is known that would prevent, slow, or reverse HSP.

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