Spastic paraplegia, optic atrophy, and neuropathy is linked to chromosome 11q13

Macedo‐Souza, Lúcia Inês; Kok, Fernando; Santos, Silvana; Amorim, Simone; Starling, Alessandra; Nishimura, Agnes L.; Lezirovitz, Karina; Lino, Angelina Maria Martins; Zatz, Mayana

doi:10.1002/ana.20478

Cited by 60 publications

(46 citation statements)

References 34 publications

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“…Our findings may be relevant as well to other complex neurodegenerative processes in which lipofuscin accumulates (36). A number of unexplained adult onset peripheral neuropathies are linked to the region from 11q12 to 11q14 region containing the cat F gene (18,42). However, some of these have recently been shown to be caused by mutations in BSCL2 and are inherited in an autosomal dominant manner (12).…”

Section: Discussionmentioning

confidence: 65%

Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

Tang

Lee

Galvez

et al. 2006

Molecular and Cellular Biology

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Cathepsin F (cat F) is a widely expressed lysosomal cysteine protease whose in vivo role is unknown. To address this issue, mice deficient in cat F were generated via homologous recombination. Although cat F−/− mice appeared healthy and reproduced normally, they developed progressive hind leg weakness and decline in motor coordination at 12 to 16 months of age, followed by significant weight loss and death within 6 months. cat F was found to be expressed throughout the central nervous system (CNS). cat F−/− neurons accumulated eosinophilic granules that had features typical of lysosomal lipofuscin by electron microscopy. Large amounts of autofluorescent lipofuscin, characteristic of the neurodegenerative disease neuronal ceroid lipofuscinosis (NCL), accumulated throughout the CNS but not in visceral organs, beginning as early as 6 weeks of age. Pronounced gliosis, an indicator of neuronal stress and neurodegeneration, was also apparent in older cat F−/− mice. cat F is the only cysteine cathepsin whose inactivation alone causes a lysosomal storage defect and progressive neurological features in mice. The late onset suggests that this gene may be a candidate for adult-onset NCL.

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Section: Discussionmentioning

confidence: 65%

Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

Tang

Lee

Galvez

et al. 2006

Molecular and Cellular Biology

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“…The very unusual combination of symptoms including the corresponding ages of onset is highly reminiscent of spastic paraplegia, optic atrophy, neuropathy (SPOAN), a recessive form of HSP, which has so far only been described in a large, inbred Brazilian family (25). We therefore performed genome-wide SNP genotyping and analyzed in detail the SPOAN critical region on chromosome 11q13.…”

Section: Resultsmentioning

confidence: 99%

“…The phenotypes exhibited by patients with the p.R106C mutation in TFG are more severe than those associated with pure forms of the disease that can result from mutations in SPAST, ATL1, or REEP1. By comparison, the patients we studied were substantially more similar to those with a complicated form of HSP known as SPOAN (25). Analysis of the genes within this region revealed the presence of at least three that are known to function in ER morphogenesis: RAB1B (a Rab-type GTPase required for vesicle secretion from the ER), YIF1A (a transmembrane protein also implicated in the early secretory pathway), and RTN3 (a member of the reticulon family of ER shaping proteins) (49)(50)(51).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure

Beetz

Johnson

Schuh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.membrane trafficking | COPII-mediated secretion | ER exit site H ereditary spastic paraplegias (HSPs) are a diverse group of disorders characterized by spastic weakness in the lower extremities, which results from degeneration of upper motoneuron axons in the corticospinal tract (1, 2). Based on the presence or absence of other neurological abnormalities, HSPs are classified as complicated or pure, respectively. In addition to lower-limb spasticity, complicated forms of HSP may be associated with ataxia, mental retardation, dementia, extrapyramidal signs, visual dysfunction, and/or epilepsy. HSPs are typically progressive, but age of onset is highly variable. The heterogeneity in clinical presentation is accompanied by genetic heterogeneity. To date, more than 40 different genetic loci, which include nearly all modes of inheritance, have been linked to HSPs (1-5). However, in nearly half of these cases, the identities of the causative genes remain unknown. The identification of additional HSP genes and, more importantly, the functional characterization of their encoded products, will both contribute to our understanding of the pathomechanisms underlying HSPs and reveal the general requirements for lifelong axonal maintenance.More than half the HSP cases in North America and Northern Europe can be attributed to defects in organelle dynamics (6). In particular, mutations that impact the architecture of the endoplasmic reticulum (ER) are common in patients with HSP. The ER is comprised of a network of membrane tubules and sheetlike cisternae that extend throughout the cytoplasm and encase the nucleus (7-9). Several factors contribute to this architecture, including (i) membrane-bending proteins of the REEP and reticulon families; (ii) regulators of the microtubule cytoskeleton, which governs the spatial patterning of the ER network; and (iii) components of the ear...

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“…Age at ascertainment ranged from 5 to 72 years [mean age of 34 (±13) years]. Clinical data of those patients have already been presented elsewhere 1,2 . Information used in this study was collected through direct observation and with patients interview, usually conducted close to their hometown.…”

mentioning

confidence: 99%

Motor and functional evaluation of patients with spastic paraplegia, optic atrophy, and neuropathy (SPOAN)

Graciani

Santos

Macedo‐Souza

et al. 2010

Arq. Neuro-Psiquiatr.

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Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive complicated form of hereditary spastic paraplegia, which is clinically defined by congenital optic atrophy, infancy-onset progressive spastic paraplegia and peripheral neuropathy. In this study, which included 61 individuals (age 5-72 years, 42 females) affected by SPOAN, a comprehensive motor and functional evaluation was performed, using modified Barthel index, modified Ashworth scale, hand grip strength measured with a hydraulic dynamometer and two hereditary spastic paraplegia scales. Modified Barthel index, which evaluate several functional aspects, was more sensitive to disclose disease progression than the spastic paraplegia scales. Spasticity showed a bimodal distribution, with both grades 1 (minimum) and 4 (maximum). Hand grip strength showed a moderate inverse correlation with age. Combination of early onset spastic paraplegia and progressive polyneuropathy make SPOAN disability overwhelming. Key words: hereditary spastic paraplegia, peripheral nervous system disorder, optic atrophy, scales, psychomotor performance.Avaliação motora e funcional de pacientes com paraplegia espástica, atrofia óptica e neuropatia (spoAn) resumo A paraplegia espástica, atrofia óptica e neuropatia (SPOAN) é uma forma complicada de paraplegia espástica de herança autossômica recessiva, caracterizada por atrofia óptica congênita, paraplegia espástica progressiva de início na infância e neuropatia periférica. Este estudo avaliou o desempenho motor e funcional de 61 indivíduos com SPOAN (5 a 72 anos), por meio do índice de Barthel modificado, a escala modificada de Ashworth, da avaliação da força de preensão das mãos com dinamômetro hidráulico de Jamar e escalas de paraplegia espástica hereditária. O índice de Barthel modificado, que investiga aspectos funcionais, mostrou-se mais sensível para avaliar a progressão da doença do que as escalas de paraplegia espástica. A espasticidade apresentou distribuição bimodal, com o grau 1 (mínimo) e 4 (máximo). A força de preensão mostrou correlação inversa moderada com a idade. A combinação de paraplegia espástica de início precoce com polineuropatia progressiva faz da SPOAN uma condição incapacitante. Palavras-chave: paraplegia espástica hereditária, doença do sistema nervoso periférico, atrofia óptica, escalas, performance psicomotora.

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Spastic paraplegia, optic atrophy, and neuropathy is linked to chromosome 11q13

Cited by 60 publications

References 34 publications

Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure

Motor and functional evaluation of patients with spastic paraplegia, optic atrophy, and neuropathy (SPOAN)

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