Determinants of age at onset in a Portuguese cohort of autosomal dominant spastic paraplegia

Rodrigues, Rita; Silva, Renata; Branco, Mariana; Brandão, Eva; Alonso, Isabel; Ruano, Luís; Loureiro, José

doi:10.1016/j.jns.2019.116646

Cited by 7 publications

(12 citation statements)

References 32 publications

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“…We found that 54.5% of probands with childhood-onset SPG4 carried missense pathogenic variants in SPAST , a greater proportion than the 33% (87/266) of missense variants reported by the French study for the overall SPG4 probands 29 . It was also a greater proportion than what was reported in recent Portuguese and Russian studies, which reported missense variants being responsible for 11/27 (40%) and 10/31 (32.2%) of SPG4 probands regardless of the age at onset, respectively 28 , 30 . Our results favor the concept that missense variants are associated to earlier ages at onset of SPG4, since our sample was exclusively of childhood-onset HSP subjects.…”

Section: Discussionmentioning

confidence: 54%

“…One of the core explanations for families with childhood-onset SPG4 is genotype–phenotype correlation, implicating missense variants to earlier onset 27 , 28 . A very large sample study that evaluated 842 SPG4 individuals most from France reported that missense variants were related to 10 years earlier ages at onset when compared to truncating variants in SPAST, and that most subjects with pathogenic missense variants in SPAST had disease onsets before the second decade of life 29 .…”

Section: Discussionmentioning

confidence: 99%

“…All childhood-onset subjects with SPG3A in our study carried missense variants, supporting this concept. However, considering that SPG3A is caused mainly by missense variants 28 , 30 and that it usually starts during childhood it is harder to establish this genotype–phenotype correlation. A toxic gain of function related to atlastin-1 modification by missense variants would be a plausible explanation for this disease being rarely caused by truncated variants; however, data from Genome Aggregation Database (gnomAD) indicate that this gene does not tolerate loss-of function with a pLI score of 0.98 23 .…”

Section: Discussionmentioning

confidence: 99%

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Clinical and molecular characterization of a large cohort of childhood onset hereditary spastic paraplegias

Giordani

Diniz

Fussiger

et al. 2021

Sci Rep

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The present study aimed to characterize clinical and molecular data of a large cohort of subjects with childhood-onset hereditary spastic paraplegias (HSPs). A multicenter historical cohort was performed at five centers in Brazil, in which probands and affected relatives' data from consecutive families with childhood-onset HSP (onset < 12 years-old) were reviewed from 2011 to 2020. One hundred and six individuals (83 families) with suspicion of childhood-onset HSP were evaluated, being 68 (50 families) with solved genetic diagnosis, 6 (5 families) with candidate variants in HSP-related genes and 32 (28 families) with unsolved genetic diagnosis. The most common childhood-onset subtype was SPG4, 11/50 (22%) families with solved genetic diagnosis; followed by SPG3A, 8/50 (16%). Missense pathogenic variants in SPAST were found in 54.5% of probands, favoring the association of this type of variant to childhood-onset SPG4. Survival curves to major handicap and cross-sectional Spastic Paraplegia Rating Scale progressions confirmed the slow neurological deterioration in SPG4 and SPG3A. Most common complicating features and twenty variants not previously described in HSP-related genes were reported. These results are fundamental to understand the molecular and clinical epidemiology of childhood-onset HSP, which might help on differential diagnosis, patient care and guiding future collaborative trials for these rare diseases.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Clinical and molecular characterization of a large cohort of childhood onset hereditary spastic paraplegias

Giordani

Diniz

Fussiger

et al. 2021

Sci Rep

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“…In line with previous study, the SPG4 family in present study showed genetic anticipation, with a decreased age at onset and increased severity in successive generations. In addition to SPG4, genetic anticipation has also been reported in other types of HPS, such as SPG3 and SPG31 (Kamada et al, 2018;Ming, 2007;Rodrigues et al, 2020). There may be other environmental and genetic modifiers influencing phenotype variability.…”

Section: Discussionmentioning

confidence: 93%

“…SPG4-associated HSP may exhibit high interfamilial and intrafamilial phenotypic variability including age at onset and disease severity (Tesson et al, 2015). Genetic anticipation has been reported in many SPG4-associated HSP families (Kawarai et al, 2017;Lan et al, 2012;Reddy et al, 2007;Rodrigues et al, 2020). None of pathogenic trinucleotiderepeats expansion, often responsible for genetic anticipation of repeat expansion diseases, was described in SPG4 or other types HSPs.…”

Section: Discussionmentioning

confidence: 99%

The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central‐Southern China

Wang

Zhang

et al. 2021

Molec Gen & Gen Med

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Clinical and Genetic Spectrum in a Large Cohort of Hereditary Spastic Paraplegia

Cao,

Zheng,

Zhu

et al. 2024

Movement Disorders

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BackgroundNext‐generation sequencing‐based molecular assessment has benefited the diagnosis of hereditary spastic paraplegia (HSP) subtypes. However, the clinical and genetic spectrum of HSP due to large fragment deletions/duplications has yet to be fully defined.ObjectiveWe aim to better characterize the clinical phenotypes and genetic features of HSP and to provide new thoughts on diagnosis.MethodsWhole‐exome sequencing (WES) was performed in patients with clinically suspected HSP, followed by multiple ligation‐dependent probe amplification (MLPA) sequentially carried out for those with negative findings in known causative genes. Genotype–phenotype correlation analyses were conducted under specific genotypes.ResultsWe made a genetic diagnosis in 60% (162/270) of patients, of whom 48.9% (132/270) had 24 various subtypes due to point mutations (SPG4/SPG11/SPG35/SPG7/SPG10/SPG5/SPG3A/SPG2/SPG76/SPG30/SPG6/SPG9A/SPG12/SPG15/SPG17/SPG18/SPG26/SPG49/SPG55/SPG56/SPG57/SPG62/SPG78/SPG80). Thirty patients were found to have causative rearrangements by MLPA (11.1%), among which SPG4 was the most prevalent (73.3%), followed by SPG3A (16.7%), SPG6 (3.3%), SPG7 (3.3%), and SPG11 (3.3%). Clinical analysis showed that some symptoms were often related to specific subtypes, and rearrangement‐related SPG3A patients seemingly had later onset. We observed a presumptive anticipation among SPG4 and SPG3A families due to rearrangement.ConclusionsBased on the largest known Asian HSP cohort, including the largest subgroup of rearrangement‐related pedigrees, we gain a comprehensive understanding of the clinical and genetic spectrum of HSP. We propose a diagnostic flowchart to sequentially detect the causative genes in practice. Large fragment mutations account for a considerable proportion of HSP, and thus, MLPA screening acts as a beneficial supplement to routine WES. © 2024 International Parkinson and Movement Disorder Society.

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Determinants of age at onset in a Portuguese cohort of autosomal dominant spastic paraplegia

Cited by 7 publications

References 32 publications

Clinical and molecular characterization of a large cohort of childhood onset hereditary spastic paraplegias

Clinical and molecular characterization of a large cohort of childhood onset hereditary spastic paraplegias

The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central‐Southern China

Clinical and Genetic Spectrum in a Large Cohort of Hereditary Spastic Paraplegia

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