Novel TBK1 LoF variant in a family with upper motor neuron predominant motor neuron disease

Costa, Mariana Reis; Gromicho, Marta; Pronto-Laborinho, Ana Catarina; Miltenyi, Gabriel Miltenberger; Carvalho, Mamede de

doi:10.1016/j.jns.2019.06.029

Cited by 6 publications

(6 citation statements)

References 12 publications

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“…TBK1 (c.2044del, p. Thr682Hisfs*2) [10] and SQSMT1 (p.Glu-280del) mutations were identified in two PLS patients, and a TREM2 mutation (p.Glu151Lys) was identified in one ALS patient and not in his relative with PLS; this last variant was labeled a variant of uncertain significance according to the American College of Medical Genetics and Genomics criteria (Table 1) [15].…”

Section: Re Sultsmentioning

confidence: 99%

“…Until recently, the absence of familial history was mandatory for the diagnosis of PLS, in particular for excluding hereditary spastic paraplegia [5]. Over the past 2 decades, a number of reports have described the association of patients with PLS and other MND in the same family, in particular ALS [6][7][8][9][10], primary progressive aphasia [11,12], and spinal muscular atrophy [13]. These observations are in agreement with the concept that PLS is a different expression of TDP-43 proteinopathy [14].…”

Section: Introductionmentioning

confidence: 99%

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Familial clustering of primary lateral sclerosis and amyotrophic lateral sclerosis: Supplementary evidence for a continuum

Corcia

Lunetta

Couratier

et al. 2021

Euro J of Neurology

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Background and purpose: Primary lateral sclerosis (PLS) is a motor neuron disorder characterized by a pure upper motor neuron degeneration in the bulbar and spinal regions.The key difference with amyotrophic lateral sclerosis (ALS) is the lower motor neuron system integrity. Despite important literature on this disease, the pathophysiology of PLS remains unknown, and the link with ALS still balances between a continuum and a separate entity from ALS.Methods: We report nine families in which both PLS and ALS cases occurred, in general among first-degree relatives. Results:The patients with PLS and ALS had a typical disease presentation. Genetic studies revealed mutations in SQSMT1, TBK1, and TREM2 genes in two PLS patients and one ALS patient. Conclusions:These results strongly support a phenotypic continuum between PLS and ALS.

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Section: Re Sultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Familial clustering of primary lateral sclerosis and amyotrophic lateral sclerosis: Supplementary evidence for a continuum

Corcia

Lunetta

Couratier

et al. 2021

Euro J of Neurology

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“…On genetic testing, one patient had a heterozygous pathogenic variant in the TBK1 gene (NM_013254.3; c.682C > T, p. [Arg228Cys]). 11 A total of 20 HSP patients were included; 8 (40.0%) were women, all with pure forms of the disease. Spastic paraplegia (SPG) type 4 was the most common genetic form (14; 70.0%).…”

Section: Resultsmentioning

confidence: 99%

Upper motor neuron signs in primary lateral sclerosis and hereditary spastic paraplegia

Santos Silva,

Correia Rodrigues,

Fortuna Baptista

et al. 2024

Muscle and Nerve

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Introduction/AimsThe frequency and distribution of upper motor neuron (UMN) signs in primary lateral sclerosis (PLS) are unknown. We aimed to study the spectrum of UMN signs in PLS and compare it with hereditary spastic paraplegia (HSP).MethodsWe retrospectively analyzed the frequency of different UMN signs, including hyperreflexia (limbs and jaw), limb and tongue spasticity, Babinski, and Hoffman signs, in PLS patients at first observation and compared this respect to onset region and symptom duration. We also compared PLS versus HSP patients.ResultsWe included 34 PLS and 20 HSP patients, with a median symptom duration at first visit of 3.0 (interquartile range, IQR = 4.0) and 19.0 (IQR = 22.0) years, respectively. In PLS patients, hyperreflexia of upper (UL) (88.2%) and lower (LL) (91.2%) limbs, and LL spasticity (79.4%) were the most common findings. Spasticity of LL was significantly (p = .012) more frequent in LL‐spinal onset subgroup, tongue spasticity in bulbar‐onset subgroup (p = .021), and Hoffman sign in UL‐spinal onset subgroup (p = .024). The PLS subgroup with shorter disease duration had a higher frequency of abnormal jaw jerk reflex (p = .037). Compared with HSP, PLS patients had a higher frequency of UL hyperreflexia (88.2% vs. 42.1%, p < .001) and UL spasticity (44.1% vs. 0.0%, p < .001). Asymmetric distribution of UMN signs was present in PLS and not in HSP.DiscussionIn PLS, UL UMN signs are nearly always present and UMN sign distribution appears to be associated with onset region. At first observation, bulbar involvement, asymmetrical distribution of UMN signs and UL spasticity may indicate PLS versus HSP.

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“…Forty‐two related papers [6, 7, 22–61] were summarized and it was found that 178 of 9814 patients with ALS/FTD carried TBK1 variants, including 95 patients carrying LoF variants and 83 patients carrying missense variants (Table S4). Therefore, a meta‐analysis was performed of the frequency of TBK1 variants reported in ALS/FTD patients (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

TBK1 variants in Chinese patients with amyotrophic lateral sclerosis: Genetic analysis and clinical features

Zhao

Jiang

Lin

et al. 2023

Euro J of Neurology

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Background and purposeHaploinsufficiency of TANK‐binding kinase 1 (TBK1) loss‐of‐function (LoF) variants has been shown to be pathogenic in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the genetic spectrum of TBK1 and clinical features of ALS patients with TBK1 variants remain largely unknown in Asians.MethodsGenetic analysis was performed on 2011 Chinese ALS patients. Software was used to predict the deleteriousness of missense variants in TBK1. In addition, PubMed, Embase and Web of Science were searched for related literature.ResultsTwenty‐six TBK1 variants were identified in 33 of 2011 ALS patients, including six novel LoF variants (0.3%) and 20 rare missense variants, 12 of which were predicted to be deleterious (0.6%). In addition to TBK1 variants, 11 patients had other ALS‐related gene variants. Forty‐two previous studies found that the frequency of TBK1 variants was 1.81% in ALS/FTD patients. The frequency of TBK1 LoF variants in ALS was 0.5% (Asians 0.4%; Caucasian 0.6%) and that of missense variants was 0.8% (Asians 1.0%; Caucasian 0.8%). ALS patients with TBK1 LoF variants affecting the kinase domain had a significantly younger age of onset than patients carrying LoF variants affecting the coiled coil domains CCD1 and CCD2. FTD has a frequency of 10% in Caucasian ALS patients with TBK1 LoF variants, which was not found in our cohort.ConclusionOur study expanded the genotypic spectrum of ALS patients with TBK1 variants and found that the clinical manifestations of TBK1 carriers are diverse.

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Novel TBK1 LoF variant in a family with upper motor neuron predominant motor neuron disease

Cited by 6 publications

References 12 publications

Familial clustering of primary lateral sclerosis and amyotrophic lateral sclerosis: Supplementary evidence for a continuum

Familial clustering of primary lateral sclerosis and amyotrophic lateral sclerosis: Supplementary evidence for a continuum

Upper motor neuron signs in primary lateral sclerosis and hereditary spastic paraplegia

TBK1 variants in Chinese patients with amyotrophic lateral sclerosis: Genetic analysis and clinical features

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