Form Of Hereditary Spastic Paraplegia Research Articles

Selenoprotein I (selenoi) as a critical enzyme in the central nervous system

Selenoprotein I (selenoi) is a unique selenocysteine (Sec)-containing protein widely expressed throughout the body. Selenoi belongs to two different protein families: the selenoproteins that are characterized by a redox reactive Sec residue and the lipid phosphotransferases that contain the highly conserved cytidine diphosphate (CDP)-alcohol phosphotransferase motif. Selenoi catalyzes the third reaction of the CDP-ethanolamine branch of the Kennedy pathway within the endoplasmic reticulum membrane. This is not a redox reaction and does not directly involve the Sec residue, making selenoi quite distinct among selenoproteins. Selenoi is also unique among lipid phosphotransferases as the only family member containing a Sec residue near its C-terminus that serves an unknown function. The reaction catalyzed by selenoi involves the transfer of the ethanolamine phosphate group from CDP-ethanolamine to one of two lipid donors, 1,2-diacylglycerol (DAG) or 1-alkyl-2-acylglycerol (AAG), to produce PE or plasmanyl PE, respectively. Plasmanyl PE is subsequently converted to plasmenyl PE by plasmanylethanolamine desaturase. Both PE and plasmenyl PE are critical phospholipids in the central nervous system (CNS), as demonstrated through clinical studies involving SELENOI mutations as well as studies in cell lines and mice. Deletion of SELENOI in mice is embryonic lethal, while loss-of-function mutations in the human SELENOI gene have been found in rare cases leading to a form of hereditary spastic paraplegia (HSP). HSP is an upper motor disease characterized by spasticity of the lower limbs, which is often manifested with other symptoms such as impaired vision/hearing, ataxia, cognitive/intellectual impairment, and seizures. This article will summarize the current understanding of selenoi as a metabolic enzyme and discuss its role in the CNS physiology and pathophysiology.

The adaptor protein chaperone AAGAB stabilizes AP-4 complex subunits.

Adaptor protein 4 (AP-4) is a heterotetrameric complex composed of ε, β4, μ4, and σ4 subunits that mediates export of a subset of transmembrane cargos, including autophagy protein 9A (ATG9A), from the trans-Golgi network (TGN). AP-4 has received particular attention in recent years because mutations in any of its subunits cause a complicated form of hereditary spastic paraplegia referred to as "AP-4-deficiency syndrome." The identification of proteins that interact with AP-4 has shed light on the mechanisms of AP-4-dependent cargo sorting and distribution within the cell. However, the mechanisms by which the AP-4 complex itself is assembled have remained unknown. Here, we report that the alpha- and gamma-adaptin-binding protein (AAGAB, also known as p34) binds to and stabilizes the AP-4 ε and σ4 subunits, thus promoting complex assembly. The physiological importance of these interactions is underscored by the observation that AAGAB-knockout cells exhibit reduced levels of AP-4 subunits and accumulation of ATG9A at the TGN like those in cells with mutations in AP-4-subunit genes. These findings demonstrate that AP-4 assembly is not spontaneous but AAGAB-assisted, further contributing to the understanding of an adaptor protein complex that is critically involved in development of the central nervous system.

Reduced penetrance of an eastern French mutation in ATL1 autosomal-dominant inheritance (SPG3A): extended phenotypic spectrum coupled with brain 18F-FDG PET.

ATL1-related spastic paraplegia SPG3A is a pure form of hereditary spastic paraplegia. Rare complex phenotypes have been described, but few data concerning cognitive evaluation or molecular imaging of these patients are available. We relate a retrospective collection of patients with SPG3A from the Neurology Department of Nancy University Hospital, France. For each patient were carried out a 18F-FDG PET (positron emission tomography), a electromyography (EMG), a sudoscan®, a cerebral and spinal cord MRI (magnetic resonance imaging) with measurement of cervical and thoracic surfaces, a neuropsychological assessment. The present report outlines standardised clinical and paraclinical data of five patients from two east-France families carrying the same missense pathogenic variation, NM_015915.4(ATL1): c.1483C > T p.(Arg495Trp) in ATL1. Mean age at onset was 14 ± 15.01years. Semi-quantitatively and in comparison to healthy age-matched subjects, PET scans showed a significant cerebellar and upper or mild temporal hypometabolism in all four adult patients and hypometabolism of the prefrontal cortex or precuneus in three of them. Sudoscan® showed signs of small fibre neuropathy in three patients. Cervical and thoracic patients' spinal cords were significantly thinner than matched-control, respectively 71 ± 6.59mm2 (p = 0.01) and 35.64 ± 4.35mm2 (p = 0.015). Two patients presented with a dysexecutive syndrome. While adding new clinical and paraclinical signs associated with ATL1 pathogenic variations, we insist here on the variable penetrance and expressivity. We report small fibre neuropathy, cerebellar hypometabolism and dysexecutive syndromes associated with SPG3A. These cognitive impairments and PET findings may be related to a cortico-cerebellar bundle axonopathy described in the cerebellar cognitive affective syndrome (CCAS).

Combined neurodegenerative disease associated with mutations in SLC5A7 and TGM6 genes

Introduction. Hereditary neurodegenerative diseases are a large genetic deterministic group of nosologies, which is based on the clinic of steadily progressing processes of destruction of neuronal systems. Damage to the nervous system can have various combinations, but the most common are atrophy of the cerebellum, brain stem, spinal cord columns, and also possible damage to the peripheral nervous system. Despite the classical descriptions of the clinical picture of various forms of neurodegenerative pathology and the corresponding genetic markers of the disease, in the practice of a neurologist, there are cases that are difficult to determine the nosological form of the disease.Materials and methods. The article describes a case of combined hereditary pathology associated with laboratory-confirmed mutations in the SLC5A7 genes (associated with the development of type 7A hereditary motor sensory neuropathy) and TGM6 (affecting the development of type 35 spinocerebellar ataxia) and the clinical picture of lower spastic paraplegia.Results. The clinical case presents a combined form of hereditary spastic paraplegia with pseudobulbar syndrome, mild motor-sensory neuropathy of the lower extremities, signs of cerebellar hypotrophy on MRI and moderate impairment of walking and speech function against the background of two mutations previously identified in type 35 spinocerebellar ataxia and hereditary motor-sensory ataxia of type 35 type 7A neuropathy.Discussion. Diagnosis of nosological forms of hereditary pathology, manifested by a combination of lesions of the peripheral and central nervous systems, requires a detailed analysis of the hereditary history, neurological status and genetic examination results from a neurologist.Conclusion. The clinical case demonstrates polymorphism of clinical manifestations of hereditary forms of neurodegenerative pathology and a possible combination of various phenotypic and genotypic variants.

Generation of two SPAST knockout human induced pluripotent stem cell lines to create a model for Hereditary Spastic Paraplegia type 4

Spastin is a an ATPase that severs microtubules therby regulating amount and mobility of these structures. Mutations in the SPAST gene (SPG4) are the most common form of Hereditary Spastic Paraplegia (HSP). Here, we report the generation of a homozygous and a heterozygous SPAST knockout induced pluripotent stem cell (iPSC) line from a healthy control iPSC line using CRISPR/Cas9 technology.

Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4.

ObjectiveWhile the anticipated rise of disease‐modifying therapies calls for reliable trial outcome parameters, fluid biomarkers are lacking in spastic paraplegia type 4 (SPG4), the most prevalent form of hereditary spastic paraplegia. We therefore investigated serum neurofilament light chain (sNfL) as a potential therapy response, diagnostic, monitoring, and prognostic biomarker in SPG4.Methods: We assessed sNfL levels in 93 patients with SPG4 and 60 healthy controls. The longitudinal study of sNfL levels in SPG4 patients covered a baseline, 1‐year follow‐up and 2‐year follow‐up visit.ResultsLevels of sNfL were significantly increased in patients with genetically confirmed SPG4 compared to healthy controls matched in age and sex (p = 0.013, r = 0.2). Our cross‐sectional analysis revealed a greater difference in sNfL levels between patients and controls in younger ages with decreasing fold change of patient sNfL elevation at older ages. Over our observational period of 2 years, sNfL levels remained stable in SPG4 patients. Disease severity and progression did not correlate with sNfL levels.Interpretation: Our longitudinal data indicate a stable turnover of sNfL in manifest SPG4; therefore, sNfL levels are not suitable to monitor disease progression in SPG4. However, sNfL may be valuable as a therapy response biomarker, since its turnover could be modified by interventions. As the course of sNfL levels appears to be most dynamic around the onset of SPG4, the ability to detect a therapy response appears to be especially promising in younger patients, matching the need to initiate treatment in early disease stages.

Corticospinal tract and motor cortex degeneration in pure hereditary spastic paraparesis type 4 (SPG4)

Objective: SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder characterized by progressive retrograde degeneration, or “dying-back” phenomenon, of the corticospinal tract’s longest axons. Neuroimaging studies mainly focus on white matter changes and, although previous studies reported cortical thinning in complicated HSP forms, cortical changes remain unclear in SPG4 patients. This work aimed to compare changes in white matter microstructure and cortical thickness between 12 SPG4 patients and 22 healthy age-matched controls. We also explore whether white matter alterations are related to cortical thickness and their correlation with clinical symptoms. Methods: we used fixel-based analysis, an advanced diffusion-weighted imaging technique, and probabilistic tractography of the corticospinal tracts. We also analyzed cortical morphometry using whole-brain surface-based and atlas-based methods in sensorimotor areas. Results: SPG4 patients showed bilateral involvement in the corticospinal tracts; this was more intense in the distal portion than in the upper segments and was associated with the degree of clinical impairment. We found a significant correlation between disease severity and fiber density and cross-section of the corticospinal tracts. Furthermore, corticospinal tract changes were significantly correlated with bilateral cortical thinning in the precentral gyrus in SPG4 patients. Conclusions: Our data point to axonal damage of the corticospinal motor neurons in SPG4 patients might be related to cortical thinning in motor regions.

Necrotizing enterocolitis totalis complicates an infantile presentation of ARL6IP1-related spastic paraplegia 61

Spastic paraplegia 61 is a rare, complicated form of hereditary spastic paraplegia characterized by diffuse sensory and motor polyneuropathy. Knowledge about the clinical manifestations of disease in patients with this genetic condition is limited. We describe a case of a 4-month-old infant with spastic paraplegia 61 (SPG61) who developed severe bowel inflammation consistent with necrotizing enterocolitis totalis. To our knowledge, this is the first reported case of necrotizing enterocolitis in a patient with this genetic condition.

ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies

ABHD16A (abhydrolase domain-containing protein 16A, phospholipase) encodes the major phosphatidylserine (PS) lipase in the brain. PS lipase synthesizes lysophosphatidylserine, an important signaling lipid that functions in the mammalian central nervous system. ABHD16A has not yet been associated with a human disease. In this report, we present a cohort of 11 affected individuals from six unrelated families with a complicated form of hereditary spastic paraplegia (HSP) who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls. Our findings add ABHD16A to the growing list of lipid genes in which dysregulation can cause complicated forms of HSP and begin to describe the molecular etiology of this condition.

Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4M1-associated hereditary spastic paraplegia (SPG50)

Biallelic loss-of-function variants in the subunits of the adaptor protein complex 4 lead to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1), and SPG52 (AP4S1). Here, we describe the generation of induced pluripotent stem cells (iPSCs) from three AP-4-HSP patients with biallelic, loss-of-function variants in AP4M1 and their sex-matched parents (asymptomatic, heterozygous carriers). Following reprogramming using non-integrating Sendai virus, iPSCs were characterized following standard protocols including karyotyping, embryoid body formation, pluripotency marker expression and STR profiling. These first iPSC lines for SPG50 provide a valuable resource for studying this rare disease and related forms of hereditary spastic paraplegia.

Expanding the Spectrum of AP5Z1‐Related Hereditary Spastic Paraplegia (HSP‐SPG48): A Multicenter Study on a Rare Disease

Expanding the Spectrum of <scp><i>AP5Z1‐</i></scp>Related Hereditary Spastic Paraplegia (<scp>HSP‐SPG48</scp>): A Multicenter Study on a Rare Disease

Thalamic atrophy in patients with pure hereditary spastic paraplegia type 4.

SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder characterized by progressive spasticity and weakness of the lower limbs caused by degeneration of the corticospinal tract. In other neurodegenerative motor disorders, the thalamus and basal ganglia are affected, with a considerable impact on disease progression. However, only a few works have studied these brain structures in HSP, mainly in complex forms of this disease. Our research aims to detect potential alterations in the volume and shape of the thalamus and various basal ganglia structures by comparing 12 patients with pure HSP and 18 healthy controls. We used two neuroimaging procedures: automated segmentation of the subcortical structures (thalamus, hippocampus, caudate nucleus, globus pallidus, and putamen) in native space and shape analysis of the structures. We found a significant reduction in thalamic volume bilaterally, as well as an inward deformation, mainly in the sensory-motor thalamic regions in patients with pure HSP and a mutation in SPG4. We also observed a significant negative correlation between the shape of the thalamus and clinical scores (the Spastic Paraplegia Rating Scale score and disease duration). Moreover, we found a 'Group × Age' interaction that was closely related to the severity of the disease. No differences in volume or in shape were found in the remaining subcortical structures studied. Our results suggest that changes in structure of the thalamus could be an imaging biomarker of disease progression in pHSP.

In silico computation of functional SNPs of CYP2U1 protein leading to hereditary spastic paraplegia

Hereditary spastic paraplegia is a genetically heterogeneous neurological disease mainly characterized by growing spasticity in a lower limb area. Spastic paraplegia 56 (SPG56) causes the autosomal recessive form of hereditary spastic paraplegia. Over time, many attempts have been made to find heterogeneity in the genome to identify the major carriers of genetic disorders. In this work, computational tools were employed to identify the pathogenic missense variants of SPG56 (Spastic paraplegia 56) that can essentially cause HSP. Various in silico tools were utilized to perform variation analysis. A variant list containing 428 variants was retrieved from gnomAD, which was later passed through several phases of stringent analysis. Furthermore, the data was cross-checked to eventually determine the highly pathogenic missense variants of SPG56. Consequently, 12 missense variants were obtained which are predicted to induce highly damaging effects on the structural and functional characteristics of CYP2U1.

RNF170-Related Hereditary Spastic Paraplegia: Confirmation by a Novel Mutation.

Spastic paraparesis and biallelic variants functionally characterized as deleterious in the RNF170 gene have recently been reported by Wagner et al. 2019, strongly supporting the involvement of this gene in hereditary spastic paraplegia. Exome sequencing was performed on 6 hereditary spastic paraplegia families previously tested on an hereditary spastic paraplegia-specific panel. We describe here a novel hereditary spastic paraplegia family with 4 affected members carrying a homozygous p.(Tyr114*) stop gain variant in RNF170. We confirm the involvement of biallelic truncating variants in RNF170 in a novel form of hereditary spastic paraplegia. © 2020 International Parkinson and Movement Disorder Society.

Identification of a novel mutation in ATP13A2 associated with a complicated form of hereditary spastic paraplegia.

ObjectiveTo establish molecular diagnosis for a family with a complicated form of autosomal recessive hereditary spastic paraplegia with intellectual disability, cognitive decline, psychosis, peripheral neuropathy, upward gaze palsy, and thin corpus callosum (TCC).MethodsPhysical examinations, laboratory tests, structural neuroimaging studies, and exome sequence analysis were carried out.ResultsThe 3 patients exhibited intellectual disability and progressive intellectual decline accompanied by psychiatric symptoms. Gait difficulty with spasticity and pyramidal weakness appeared at the ages of 20s–30s. Brain MRI revealed TCC with atrophic changes in the frontotemporal lobes, caudate nuclei, and cerebellum. Exome sequence analysis revealed a novel homozygous c.2654C>A (p. Ala885Asp) variant in the ATP13A2, a gene responsible for a complicated form of hereditary spastic paraplegia (SPG78), Kufor-Rakeb syndrome, and neuronal ceroid lipofuscinosis. The predominant clinical presentations of the patients include progressive intellectual disability and gait difficulty with spasticity and pyramidal weakness, consistent with the diagnosis of SPG78. Of note, prominent psychiatric symptoms and extrapyramidal signs including rigidity, dystonia, and involuntary movements preceded the spastic paraparesis.ConclusionsOur study further broadens the clinical spectrum associated with ATP13A2 mutations.

CAPN1 and hereditary spastic paraplegia: a novel variant in an Iranian family and overview of the genotype-phenotype correlation

Purpose SPG76 is one of the rare forms of hereditary spastic paraplegia (HSP) which causes by mutations in the CAPN1 gene. The mode of inheritance of SPG76 is autosomal recessive (AR) and so far, only 24 families and 25 mutations in this gene have been reported worldwide. These mutations have been associated with a spectrum of disorders from pure HSP to spastic ataxia. HSP genetically is one of the most heterogeneous neurological disorders and to date, 79 types of HSP (SPG1-SPG79) have been identified, however, it has been suggested that many HSP-genes, particularly in AR-HSPs, remained unknown. AR-HSPs clinically overlap with other neurodegenerative disorders, making an accurate diagnosis of the disease difficult. Therefore, in addition to clinical examination, a high throughout genetic method like whole exome sequencing (WES) may be necessary for the diagnosis of this type of neurodegenerative disorders. Methods and Results Herein, we present the clinical features and results of WES in the first Iranian family with a novel CAPN1 variant, c.C853T:p.R285* and pure HSP. Conclusion Some of the previous studies have mentioned that the “spasticity-ataxia phenotype might be conducted to the diagnosis of SPG76” but recently the number of pure HSP patients with CAPN1 mutation is increasing. The present study also expands the mutation spectrum of pure CAPN1-related SPG76; emphasizing that CAPN1 screening is required in both pure HSP and spasticity-ataxia phenotypes. As noted in some other literature, we suggest the clinical spectrum of this disorder to be considered as “CAPN1-associated neurodegeneration”.

Novel MAG Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype.

Homozygous variants in MAG, encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in MAG (c.124T>C; p.Cys42Arg) in a Portuguese family with early-onset autosomal recessive cerebellar ataxia with neuropathy and oculomotor apraxia. We used homozygosity mapping and exome sequencing to identify the MAG variant, and cellular studies to confirm its detrimental effect. Our results showed that this variant reduces protein stability and impairs the post-translational processing (N-linked glycosylation) and subcellular localization of MAG, thereby associating a loss of protein function with the phenotype. Therefore, MAG variants should be considered in the diagnosis of hereditary cerebellar ataxia with oculomotor apraxia, in addition to spastic paraplegia.

SPG8 mutations in Italian families: clinical data and literature review.

Spastic paraplegia type 8 (SPG8) is an autosomal-dominant form of hereditary spastic paraplegia (AD-HSP) caused by a mutation in the KIAA0196 gene. SPG8 accounts for 1% of less of all AD-HSP and the genotype-phenotype correlation remains poorly understood. We report the first clinical and genetic description of SPG8 disease in Italian patients. We identified four new mutations in KIAA0196 gene. These variants were identified using a multigene targeted resequencing HSP panel. We took this opportunity to review the pertinent literature. Age at disease onset was in the third or fourth decade of life. Stiffness of the lower limb with spastic gait, walking impairment, and decreased vibration sense were common early symptoms. Subjects of two families had bladder control abnormalities. Unlike previous reported cases, Italian SPG8 subjects have pure form of spastic paraparesis without cranial nerve involvement, and onset is in adult life. By a clinical point of view, it is hard to differentiate SPG8 from the SPG4, in which bladder and vibration sense dysfunctions are frequent signs. The differential diagnosis with other forms of AD-HSPs seems relatively easier if one considers the early-onset manifestations in SPG3A and the peripheral nervous system and cerebellar involvement seen in SPG31.

Ascending Axonal Degeneration of the Corticospinal Tract in Pure Hereditary Spastic Paraplegia: A Cross-Sectional DTI Study.

Objective: To identify structural white matter alterations in patients with pure hereditary spastic paraplegia (HSP) using high angular resolution diffusion tensor imaging (DTI). Methods: We examined 37 individuals with high resolution DTI, 20 patients with pure forms of hereditary spastic paraplegia and 17 age and gender matched healthy controls. DTI was performed using a 3 T clinical scanner with whole brain tract-based spatial statistical (TBSS) analysis of the obtained fractional anisotropy (FA) data as well as a region-of-interest (ROI)-based analysis of affected tracts including the cervical spinal cord. We further conducted correlation analyses between DTI data and clinical characteristics. Results: TBSS analysis in HSP patients showed significantly decreased fractional anisotropy of the corpus callosum and the corticospinal tract compared to healthy controls. ROI-based analysis confirmed significantly lower FA in HSP compared to controls in the internal capsule (0.77 vs. 0.80, p = 0.048), the corpus callosum (0.84 vs. 0.87, p = 0.048) and the cervical spinal cord (0.72 vs. 0.79, p = 0.003). FA values of the cervical spinal cord significantly correlated with disease duration. Conclusion: DTI metrics of the corticospinal tract from the internal capsule to the cervical spine suggest microstructural damage and axonal degeneration of motor neurons. The CST at the level of the cervical spinal cord is thereby more severely affected than the intracranial part of the CST, suggesting an ascending axonal degeneration of the CST. Since there is a significant correlation with disease duration, FA may serve as a future progression marker for assessment of the disease course in HSP.

Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4B1-associated hereditary spastic paraplegia (SPG47)

Bi-allelic variants in the subunits of the adaptor protein complex 4 lead to childhood-onset, complex hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1), and SPG52 (AP4S1). Here, we describe the generation of induced pluripotent stem cells (iPSCs) from three AP-4-HSP patients with compound-heterozygous, loss-of-function variants in AP4B1 and sex-matched parents. Fibroblasts were reprogrammed using non-integrating Sendai virus. iPSCs were characterized according to standard protocols including karyotyping, embryoid body formation, pluripotency marker expression and STR profiling. These first iPSC lines for SPG47 provide a valuable resource for studying this rare disease and related forms of hereditary spastic paraplegia.