Caenorhabditis elegans Models of Hereditary Spastic Paraplegia

Hedera, Peter

doi:10.1016/b978-0-12-405195-9.00074-3

Cited by 15 publications

(29 citation statements)

References 80 publications

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“…The presentation (Table 3) matched the classical clinical pattern and the early age of onset associated with SPG3A. 33 In family FM5, four patients from two branches presented with infantile onset progressive pyramidal syndrome with pseudobulbar palsy. This is in conformity with what was reported in Infantile Onset Ascending Spastic Paralysis associated with Alsin variants (OMIM #607225) ( Table 3).…”

Section: Phenotype-genotype Correlationsmentioning

confidence: 58%

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

et al. 2016

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Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSPrelated genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C4T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C4T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.

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Section: Phenotype-genotype Correlationsmentioning

confidence: 58%

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

et al. 2016

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“…However, recent observations from five independent studies in human patients have linked mutations in all four AP-4 subunits (µ1; AP4M1(SPG50), β1; AP4B1(SPG47), ε1; AP4E1(SPG51), and σ1; AP4S1(SPG52)) to progressive Spastic Paraplegia, a disease characterized by a complex phenotype that manifests in infancy or early childhood [22,62,68,69]. Core clinical features include hypotonia, cognitive and motor delays, seizures, facial dimorphism, stereotypic laughter with tongue protrusion, and thinning of the corpus callosum [68,70]. In fact, the phenotype is robust enough to be considered a clinically recognizable "AP-4 deficiency syndrome."…”

Section: Ap-4 Complexmentioning

confidence: 99%

Lysosome Function and Dysfunction in Hereditary Spastic Paraplegias

2021

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Hereditary Spastic Paraplegias (HSPs) are a genetically diverse group of inherited neurological diseases with over 80 associated gene loci. Over the last decade, research into mechanisms underlying HSPs has led to an emerging interest in lysosome dysfunction. In this review, we highlight the different classes of HSPs that have been linked to lysosome defects: (1) a subset of complex HSPs where mutations in lysosomal genes are causally linked to the diseases, (2) other complex HSPs where mutation in genes encoding membrane trafficking adaptors lead to lysosomal defects, and (3) a subset of HSPs where mutations affect genes encoding proteins whose function is primarily linked to a different cellular component or organelle such as microtubule severing and Endoplasmic Reticulum-shaping, while also altering to lysosomes. Interestingly, aberrant axonal lysosomes, associated with the latter two subsets of HSPs, are a key feature observed in other neurodegenerative diseases such as Alzheimer’s disease. We discuss how altered lysosome function and trafficking may be a critical contributor to HSP pathology and highlight the need for examining these features in the cortico-spinal motor neurons of HSP mutant models.

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“…Copyright © 2023 American Academy of Neurology. Unauthorized reproduction of this article is prohibited deafness, peripheral neuropathy, and extrapyramidal signs 7,8 . Our patient did not have any of these other characteristics making this diagnosis unlikely.…”

Section: Sensory Tricks Can Ameliorate Dystoniamentioning

confidence: 99%

Child Neurology: KMT2B -Related Dystonia in a Young Child With Worsening Gait Abnormality

et al. 2023

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KMT2B gene related dystonia (DYT-KMT2B) is a primarily childhood onset movement disorder that usually starts with lower limb dystonia progressing into generalized dystonia. Our patient described here experienced difficulty gaining weight, laryngomalacia and feeding difficulties during infancy and later developed gait difficulties, frequent falls and toe walking. Gait assessment revealed prominent bilateral intoeing and intermittent ankle inversion posturing, as well as extension of left leg. At times, the gait appeared to be spastic. Whole exome sequencing revealed a novel de novo heterozygous likely pathogenic variant, c.7913 T>A (p.V2638E), in the KMT2B gene located in chromosome 19. This variant, which has not been previously published as pathogenic or benign in the literature, can be added to the repertoire of KMT2B mutations causing inherited dystonias.

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Caenorhabditis elegans Models of Hereditary Spastic Paraplegia

Cited by 15 publications

References 80 publications

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

Lysosome Function and Dysfunction in Hereditary Spastic Paraplegias

Child Neurology: KMT2B -Related Dystonia in a Young Child With Worsening Gait Abnormality

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