Clinical features and management of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. 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. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

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A Japanese hereditary spastic paraplegia family with a rare nonsynonymous variant in the SPAST gene

Human Genome Variation ◽

10.1038/s41439-021-00153-x ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Takuya Morikawa ◽

Shiroh Miura ◽

Takahisa Tateishi ◽

Kazuhito Noda ◽

Hiroki Shibata

Keyword(s):

Molecular Diagnosis ◽

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Family Members ◽

Pathogenic Variant ◽

Lower Limbs ◽

Spastic Paraplegia ◽

Nonsynonymous Variant ◽

Japanese Family ◽

Functional Variants

AbstractSpastic paraplegia (SPG) type 4 is an autosomal dominant SPG caused by functional variants in the SPAST gene. We examined a Japanese family with three autosomal dominant SPG patients. These patients presented with typical symptoms of SPG, such as spasticity of the lower limbs. We identified a rare nonsynonymous variant, NM_014946.4:c.1252G>A [p.Glu418Lys], in all three family members. This variant has previously been reported in a Russian SPG family as a “likely pathogenic” variant.5 Ascertainment of additional patients carrying this variant in an unrelated Japanese SPG family further supports its pathogenicity. Molecular diagnosis of SPG4 in this family with hereditary spastic paraplegia is confirmed.

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Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia

Nature Communications ◽

10.1038/s41467-019-12620-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Matias Wagner ◽

Daniel P. S. Osborn ◽

Ina Gehweiler ◽

Maike Nagel ◽

Ulrike Ulmer ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Hereditary Spastic Paraplegia ◽

Degradation Pathway ◽

Therapeutic Interventions ◽

Spastic Paraplegia ◽

Ubiquitin E3 Ligase ◽

Wide Range ◽

Inositol 1,4,5 Trisphosphate ◽

Cerebellar Ataxias ◽

Trisphosphate Receptor

Abstract Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.

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Hereditary spastic paraplegia: An “ears of the lynx” magnetic resonance imaging sign in a patient with recessive genetic type 11

The Neuroradiology Journal ◽

10.1177/1971400920953820 ◽

2020 ◽

pp. 197140092095382

Author(s):

Emiliano Ruiz Romagnoli ◽

Manuel Perez Akly ◽

Luis A Miquelini ◽

Jorge A Funes ◽

Cristina H Besada

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Corpus Callosum ◽

Hereditary Spastic Paraplegia ◽

Brain Magnetic Resonance Imaging ◽

Lower Limbs ◽

Spastic Paraplegia ◽

Resonance Imaging ◽

Hereditary Spastic Paraplegias ◽

Monogenic Diseases

Hereditary spastic paraplegias are an uncommon group of monogenic diseases that include 79 types of genetic disorders. The most frequent cause of recessive hereditary spastic paraplegia is a mutation in the spastic paraplegia gene type 11 followed by type 15. This group is usually associated with non-specific clinical features like cognitive decline and may precede the progressive weakness and spasticity of lower limbs. The magnetic resonance imaging hallmark of hereditary spastic paraplegia is thinning of the spinal cord. However, brain magnetic resonance imaging may provide relevant clues for specific hereditary spastic paraplegia subtypes, and thinning of the corpus callosum has been described as the most frequent abnormality in almost one-third of recessive hereditary spastic paraplegias. Moreover, a characteristic abnormality affecting the forceps minor of the corpus callosum has been recently reported as the “ears of the lynx” sign and is highly suggestive of type 11 and 15 hereditary spastic paraplegias. We report a patient who was diagnosed with hereditary spastic paraplegia type 11 by exome genetic testing, presenting the ears of the lynx sign in the first magnetic resonance imaging assessment.

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Distant homologies and domain conservation of the Hereditary Spastic Paraplegia protein SPG11/ALS5/spatacsin

10.1101/2020.03.08.982389 ◽

2020 ◽

Cited By ~ 1

Author(s):

Alexander L Patto ◽

Cahir J O’Kane

Keyword(s):

Hereditary Spastic Paraplegia ◽

Mass Spectrometry Analysis ◽

Main Function ◽

Spastic Paraplegia ◽

Sm Proteins ◽

Trna Synthetases ◽

Aminoacyl Trna Synthetases ◽

Wide Range ◽

Independent Functions

AbstractLoss-of-function mutations in SPG11 protein (spatacsin) are a common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. To identify regions of the protein that may have functions that are disrupted in disease, we carried out bioinformatic analyses of its conserved regions. An N-terminal region of around 650 amino-acid residues, present in SPG11 across a wide range of metazoan animals, was missing from many insect lineages. Evolutionary loss of this domain correlated with loss of its binding partner, the AP-5 adaptor complex, suggesting that its main function is interaction with AP-5 in intracellular trafficking, and that the remainder of SPG11 carries out AP-5-independent functions. At the C-terminus of SPG11, a spatacsin_C domain showed sequence similarity and predicted structural homology to the Vps16_C domain of the HOPS complex protein Vps16. It localized to acidic compartments, consistent with a role in endolysosomal or autolysosomal transport, like Vps16. Mass spectrometry analysis of binding partners of this domain identified membrane trafficking proteins, some SM proteins, and several aminoacyl-tRNA synthetases. Since mutations affecting SPG11 or aminoacyl-tRNA synthetases can both cause Charcot-Marie-Tooth neuropathy (CMT) type 2, we suggest autolysosomal trafficking as a target process in CMT type 2.

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Recent advances in hereditary spastic paraplegia

Current Opinion in Neurology ◽

10.1097/00019052-200108000-00005 ◽

2001 ◽

Vol 14 (4) ◽

pp. 457-463 ◽

Cited By ~ 48

Author(s):

Chantal M.E. Tallaksen ◽

Alexandra Dürr ◽

Alexis Brice

Keyword(s):

Hereditary Spastic Paraplegia ◽

Spastic Paraplegia ◽

Recent Advances

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Hereditary spastic paraplegia

NATIONAL JOURNAL OF NEUROLOGY ◽

10.28942/nnj.v1i3.175 ◽

2019 ◽

pp. 1-6

Author(s):

Akgun Olmez ◽

Haluk Topaloglu

Keyword(s):

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Case Reports ◽

Original Description ◽

Lower Limbs ◽

Clinical Feature ◽

Spastic Paraplegia ◽

Pyramidal Tracts ◽

Spastic Gait ◽

Mode Of Inheritance

Historical note and nomenclature. Hereditary spastic paraplegia is the name given to a group of diseases that are heterogenous and inherited, in which the main clinical feature is progressive spasticity of the lower limbs. The original description of hereditary spastic paraplegia was made by Strümpell in 1880. He described “a pure spastic movement disorder of the legs” in 2 brothers who developed a spastic gait at the ages of 37 and 56 years. Their father was said to be “a little lame,” suggesting that the mode of inheritance might be autosomal dominant (Strumpell 1880). He later defined additional cases and described the pathological changes of the spinal cord, especially the degeneration of the pyramidal tracts. At the end of 19th century, Lorrain published 3 cases with similar clinical features (Lorrain 1898). The disease was also called Strümpell-Lorrain syndrome. Many cases with additional neurologic features were added to the literature, and many case reports seem to have given different names to possibly the same disease.

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Structural consequences of hereditary spastic paraplegia disease-related mutations in kinesin

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1810622115 ◽

2018 ◽

Vol 115 (46) ◽

pp. E10822-E10829 ◽

Cited By ~ 9

Author(s):

Mandira Dutta ◽

Michael R. Diehl ◽

José N. Onuchic ◽

Biman Jana

Keyword(s):

Solvent Effects ◽

Hereditary Spastic Paraplegia ◽

Bioinformatics Analysis ◽

Catalytic Domain ◽

Coiled Coil ◽

Coarse Grained ◽

Spastic Paraplegia ◽

Bioinformatics Analyses ◽

Wide Range ◽

Subsequent Integration

A wide range of mutations in the kinesin motor Kif5A have been linked to a neuronal disorder called hereditary spastic paraplegia (HSP). The position of these mutations can vary, and a range of different motile behaviors have been observed, indicating that the HSP mutants can alter distinct aspects of kinesin mechanochemistry. While focusing on four key HSP-associated mutants, this study examined the structural and dynamic perturbations that arise from these mutations using a series of different computational methods, ranging from bioinformatics analyses to all-atom simulations, that account for solvent effects explicitly. We show that two catalytic domain mutations (R280S and K253N) reduce the microtubule (MT) binding affinity of the kinesin head domains appreciably, while N256S has a much smaller impact. Bioinformatics analysis suggests that the stalk mutation A361V perturbs motor dimerization. Subsequent integration of these effects into a coarse-grained structure-based model of dimeric kinesin revealed that the order–disorder transition of the neck linker is substantially affected, indicating a hampered directionality and processivity of kinesin. The present analyses therefore suggest that, in addition to kinesin-MT binding and coiled-coil dimerization, HSP mutations affecting motor stepping transitions and processivity can lead to disease.

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A complete overview of REEP1: old and new insights on its role in hereditary spastic paraplegia and neurodegeneration

Reviews in the Neurosciences ◽

10.1515/revneuro-2019-0083 ◽

2020 ◽

Vol 31 (4) ◽

pp. 351-362 ◽

Cited By ~ 1

Author(s):

Alessio Guglielmi

Keyword(s):

Neurodegenerative Diseases ◽

Sigmund Freud ◽

Neurological Disorders ◽

Hereditary Spastic Paraplegia ◽

Dna Analysis ◽

Therapeutic Strategies ◽

Lower Limbs ◽

Spastic Paraplegia ◽

Adolf Von Strümpell

AbstractAt the end of 19th century, Adolf von Strümpell and Sigmund Freud independently described the symptoms of a new pathology now known as hereditary spastic paraplegia (HSP). HSP is part of the group of genetic neurodegenerative diseases usually associated with slow progressive pyramidal syndrome, spasticity, weakness of the lower limbs, and distal-end degeneration of motor neuron long axons. Patients are typically characterized by gait symptoms (with or without other neurological disorders), which can appear both in young and adult ages depending on the different HSP forms. The disease prevalence is at 1.3–9.6 in 100 000 individuals in different areas of the world, making HSP part of the group of rare neurodegenerative diseases. Thus far, there are no specific clinical and paraclinical tests, and DNA analysis is still the only strategy to obtain a certain diagnosis. For these reasons, it is mandatory to extend the knowledge on genetic causes, pathology mechanism, and disease progression to give clinicians more tools to obtain early diagnosis, better therapeutic strategies, and examination tests. This review gives an overview of HSP pathologies and general insights to a specific HSP subtype called spastic paraplegia 31 (SPG31), which rises after mutation of REEP1 gene. In fact, recent findings discovered an interesting endoplasmic reticulum antistress function of REEP1 and a role of this protein in preventing τ accumulation in animal models. For this reason, this work tries to elucidate the main aspects of REEP1, which are described in the literature, to better understand its role in SPG31 HSP and other pathologies.

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Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking

Human Molecular Genetics ◽

10.1093/hmg/ddz310 ◽

2020 ◽

Vol 29 (2) ◽

pp. 320-334 ◽

Cited By ~ 7

Author(s):

Robert Behne ◽

Julian Teinert ◽

Miriam Wimmer ◽

Angelica D’Amore ◽

Alexandra K Davies ◽

...

Keyword(s):

Protein Complex ◽

Protein Trafficking ◽

Hereditary Spastic Paraplegia ◽

Adaptor Protein ◽

Spastic Paraplegia ◽

Childhood Onset ◽

Trans Golgi Network ◽

Wide Range ◽

Golgi Network ◽

The Impact

Abstract Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3–5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

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In Silico Analysis of Variants of Uncertain Significance in AP4S1 Gene

BioScientific Review ◽

10.32350/bsr.0201.01 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Sobia Nazir Chaudry ◽

Ammara Akhtar ◽

Ayman Naeem ◽

Dr. Mureed Husaain

Keyword(s):

Splice Site ◽

Protein Function ◽

Hereditary Spastic Paraplegia ◽

In Silico ◽

Low Frequency ◽

In Silico Analysis ◽

Neurological Complications ◽

Lower Limbs ◽

Spastic Paraplegia ◽

Silico Analysis

Hereditary spastic paraplegia is a group of heterogeneous neurological disorders with genetic etiologies. It is characterized by spasticity in lower limbs along with neurological complications. Sequencing technologies have identified numerous disease causing variants in AP4S1 gene. However, many very low frequency variations in AP4S1 have the potential to cause hereditary spastic paraplegia in a recessive inheritance manner. This study was designed to identify these potential disease causing variants in AP4S1 gene using in silico tools. These tools predict the effects of deleterious variants on protein function and pre-mRNA splicing. To predict the pathogenicity of missense variants PhD-SNPg, PROVEAN, SNPs&GO, and CADD were used. Splice site variants were analyzed using Spliceman, SPiCE, and Human Splice Finder (HSF). In silico analysis identified six missense and five splice site variants with the potential to cause hereditary spastic paraplegia.

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