Novel genotype-phenotype and MRI correlations in a large cohort of patients with
            <i>SPG7</i>
            mutations

Hewamadduma, Channa; Hoggard, Nigel; O’Malley, Ronan; Robinson, Megan K.; Beauchamp, Nick; Segamogaite, Ruta; Martindale, Joanne; Rodgers, Tobias; Rao, Ganesh; Sarrigiannis, Ptolemaios G.; Shanmugarajah, Priya; Zis, Panagiotis; Sharrack, Basil; McDermott, Christopher J.; Shaw, Pamela J.; Hadjivassiliou, Marios

doi:10.1212/nxg.0000000000000279

Cited by 46 publications

(41 citation statements)

References 22 publications

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“…This finding is similar to that for the Canadian population, for which Ala510Val was the most frequent variant and cerebellar features, including ataxia, were more pronounced than spasticity. 27 In contrast with the recent report on the English cohort, 23 we did not found significant difference in age at onset of the disease between Ala510Val homozygous and Ala510Val compound heterozygous patients. Since Ala510Val variants represented 73% of the missense variant group, the cerebellar phenotype is biased towards one single variant.…”

Section: Discussioncontrasting

confidence: 99%

“…Clinical features matched previous work that defined SPG7 as a relevant cause of late onset spastic ataxia. 5,6,18,22,23 Lower limb spasticity or cerebellar ataxia, both affecting gait stability, were present at onset making difficult to consider SPG7 as primarily an HSP or an ataxia gene. 24 We were able to show that, among patients with a disease duration > 20 years, 88% had pyramidal syndrome and 72% cerebellar ataxia.…”

Section: Discussionmentioning

confidence: 99%

“…26 Furthermore, we confirm that the Ala510Val variant is the most common variant in patients (58.5%), showing a minor allele frequency of 0.5% in public databases, in agreement with other reports. 7,15,17,23,27 This variant was associated with a delayed onset of disease and a less complicated phenotype, i.e. fewer pyramidal signs.…”

Section: Discussionmentioning

confidence: 99%

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Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

Coarelli

Schüle

Warrenburg³

et al. 2019

Neurology

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word count: 239 Character count for the title: 88 Number of references: 32 Number of tables: 3 Number of figures: 4 Search terms: cerebellar ataxia, hereditary spastic paraplegia, SPG7, paraplegin, Ala510Val variant Study fundingThe study received funding from the "Agence Nationale de la Recherche" (SPATAX-QUEST, to GS), the "Connaitre les Syndromes Cérébelleux" association (to GS), Verum foundation (to AD and GS), and SPATAX Hospital Abstract Objective: We took advantage of a large multinational recruitment to delineate genotypephenotype correlations in a large, trans-European multicenter cohort of SPG7 patients. Methods:We analyzed clinical and genetic data from 241 SPG7 patients, integrating neurological follow-up data. One case was examined neuropathologically.Results: SPG7 patients had a mean age of 35.5±14.3 years (n=233) at onset and presented with either spasticity (n=89), ataxia (n=74), or both (n=45). At the first visit, patients with a longer disease duration (>20 years, n=62) showed more cerebellar dysarthria (p<0.05), deep sensory loss (p<0.01), muscle wasting (p<0.01), ophthalmoplegia (p<0.05), sphincter dysfunction (p<0.05) than those with a shorter duration (<10 years, n=93). Progression, measured by SARA evaluations, showed a mean annual increase of 1.0±1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n=65) presented significantly more often with pyramidal signs (p<0.05), diminished visual acuity due to optic atrophy (p<0.0001), and deep sensory loss (p<0.0001) than those with at least one missense variant (n=176). Patients with at least one Ala510Val variant (58%) were older (37.6±13.7 vs 32.8±14.6, p<0.05) and showed ataxia at onset (p<0.05). Neuropathological examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons.Conclusions: This is the largest SPG7 cohort study to date, and shows a spasticitypredominant phenotype of LOF variants and more frequent cerebellar ataxia and later onset in patients carrying at least one Ala510Val variant. Word 239/250 6 Abbreviations AD: autosomal dominant AR: autosomal recessive LOF: loss of function MBP-SF: myelin basic protein serum factor MLPA: multiplex ligation-dependent probe amplification PolyQ: polyglutamine SARA: Scale for the Assessment and Rating of AtaxiaSCA: spinocerebellar ataxia SPRS: Spastic Paraplegia Rating Scale XL: X-linked Cerebellar ataxia, % (n) 66% (87/132) 58% (56/97) 0.2 Cerebellar dysarthria, % (n) 36% (51/131) 36% (35/93) 0.7 Brisk reflexes, % (n) 76% (96/126) 92% (80/87) 0.003 Babinski sign, % (n) 71% (89/125) 77% (66/86) 0.4 Pyramidal syndrome, % (n) 86% (116/134) 97% (93/96) 0.01 Pes cavus, % (n) 17% (22/129) 30% (28/92) 0.02 Parkinsonism, % (n) 4% (5/131) 5% (5/94) 0.74

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

Coarelli

Schüle

Warrenburg³

et al. 2019

Neurology

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“…Beside cerebellar atrophy, re-evaluation of MRI images in our SCA48 patients confirms the frequent occurrence of T2-weighted signal hyperintensities in the dentate nuclei, a feature also described in SPG7 patients [28] that was recently emphasized as being also associated to SCA48 [16].…”

Section: Discussionsupporting

confidence: 81%

The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families

Lieto

Riso

Galatolo

et al. 2019

Euro J of Neurology

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Background and purpose Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive‐affective syndrome (CCAS), named SCA48. Methods Molecular screening was performed in a cohort of 235 unrelated patients with adult‐onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole‐exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico‐diagnostic findings were reviewed to define the phenotypic spectrum. Results Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. Conclusions Our results support SCA48 as a significant cause of adult‐onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1.

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“…Due to its high iron content, the dentate nuclei usually appears hypointense in T2; hyperintensity is described in a variety of acquired and genetic disorders, such as multiple sclerosis, Leigh syndrome or glutaric aciduria type 1 [33]. Over the past years, it has also been described in degenerative diseases, such as SCA48 and SPG7 [34,35].…”

Section: Discussionmentioning

confidence: 99%

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

Santos

Damásio

Kun‐Rodrigues

et al. 2020

JCM

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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.

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Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations

Cited by 46 publications

References 22 publications

Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families

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

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