Prevalence of oropharyngeal dysphagia in hereditary spastic paraplegias

Jacinto-Scudeiro, Laís Alves; Machado, Gustavo Dariva; Ayres, A. Jean; Burguêz, Daniela; Polese-Bonatto, Márcia; González-Salazar, Carelis; Siebert, Marina; França, Marcondes Cavalcante; Olchik, Maira Rozenfeld; Saute, Jonas Alex Morales

doi:10.1590/0004-282x20190180

Cited by 4 publications

(4 citation statements)

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“…A few studies previously reported some of these symptoms in patients with SPG7 mutations. 6,[62][63][64][65] Optic atrophy and dopa-responsive parkinsonism were also reported in a patient with concurrent AFG3L2 and SPG7 heterozygous variants. 42 Similar to other genes involved in HSP, SPG7 may be involved in a continuum of spastic neurogenetic disorders, and SPG7 variants should not be ruled out only because of the presence of rare clinical manifestations.…”

Section: Discussionmentioning

confidence: 77%

“…We also report several rare clinical features of SPG7, including dopa‐responsive parkinsonism, dysphagia, dysmetria, jaw jerk, ptosis, ophthalmoplegia, optic atrophy, and hands dystonia in biallelic SPG7 patients. A few studies previously reported some of these symptoms in patients with SPG7 mutations 6,62‐65 . Optic atrophy and dopa‐responsive parkinsonism were also reported in a patient with concurrent AFG3L2 and SPG7 heterozygous variants 42 .…”

Section: Discussionmentioning

confidence: 82%

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Evidence for Non‐Mendelian Inheritance in Spastic Paraplegia 7

Estiar

Salem

et al. 2021

Movement Disorders

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A BS TRACT: Background: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP). Objectives: We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP. Methods: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole-exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls. Results: The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24-6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49-13.07, P = 0.005). Similar results were obtained after including only genetically-undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05-365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. Conclusions: Our results provide evidence for complex inheritance in SPG7-associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 82%

Evidence for Non‐Mendelian Inheritance in Spastic Paraplegia 7

Estiar

Salem

et al. 2021

Movement Disorders

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“…In this study we also report several rare clinical features of SPG7, including dopa-responsive parkinsonism, dysphagia, dysmetria, jaw jerk, ptosis, ophthalmoplegia, optic atrophy and hands dystonia in bi-allelic SPG7 patients. A few studies previously reported some of these symptoms in patients with SPG7 mutations (Van Gassen et al , 2012; Pfeffer et al , 2014; Pedroso et al , 2018; De la Casa-Fages et al , 2019; Jacinto-Scudeiro et al , 2019). Optic atrophy and dopa-responsive parkinsonism were also reported in a patient with concurrent AFG3L2 and SPG7 heterozygous variants (Magri et al , 2018).…”

Section: Discussionmentioning

confidence: 99%

Evidence for non-Mendelian inheritance in spastic paraplegia 7

Estiar

Salem

et al. 2020

Preprint

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Hereditary spastic paraplegia is a group of rare motor neuron diseases considered to be inherited in a classical monogenic Mendelian manner. Although the typical inheritance of spastic paraplegia type 7 is autosomal recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant HSP. We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of hereditary spastic paraplegia patients and controls to examine the association of SPG7 and hereditary spastic paraplegia. In total, 585 hereditary spastic paraplegia patients from 372 families and 1,175 controls, including 580 unrelated individuals, were analyzed for the presence of SPG7 variants. Whole exome sequencing was performed on 400 hereditary spastic paraplegia patients (291 index cases) and all 1,175 controls. After excluding 38 biallelic hereditary spastic paraplegia type 7 patients, the frequency of heterozygous pathogenic/likely pathogenic SPG7 variant carriers (4.8%) among hereditary spastic paraplegia unrelated index cases who underwent WES, was significantly higher than among unrelated controls (1.7%; OR=2.88, 95%CI=1.24-6.66, p=0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index cases vs. 0.85% in unrelated controls (OR=4.42, 95%CI=1.49-13.07, p=0.005). We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in genes known to cause hereditary spastic paraplegia, compared to zero in controls (OR=19.58, 95%CI=1.05-365.13, p=0.0031; Fisher Exact test with Haldane-Anscombe correction), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2 and MORC2). Out of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. Our results provide evidence for complex inheritance in SPG7-associated hereditary spastic paraplegia, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance.

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“…In this issue of Arquivos de Neuropsiquiatria, Jacinto-Scudeiro et al 4 analyzed affected individuals with pure and complicated forms of HSP and they detected that clinically significant oropharyngeal dysphagia was only present in complicated forms of the disease. Specifically, SPG11 and CTX presented highest risks for dysphagia, indicating that surveillance of swallowing function should be part of the management of patients with these disorders.…”

mentioning

confidence: 99%

Evaluation of swallowing in patients with hereditary spastic paraplegias

Orlacchio

2019

Arq. Neuro-Psiquiatr.

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Prevalence of oropharyngeal dysphagia in hereditary spastic paraplegias

Cited by 4 publications

References 18 publications

Evidence for Non‐Mendelian Inheritance in Spastic Paraplegia 7

Evidence for Non‐Mendelian Inheritance in Spastic Paraplegia 7

Evidence for non-Mendelian inheritance in spastic paraplegia 7

Evaluation of swallowing in patients with hereditary spastic paraplegias

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