Tuberous Sclerosis Complex Genotypes and Developmental Phenotype

Farach, Laura S.; Woodhouse, John P.; Schraw, Jeremy M.; Bebin, E. Martina; Lupo, Philip J.; Au, Kit Sing; Şahin, Mustafa; Krueger, Darcy A.; Bebin, Martina; Wu, Joyce; Warfield, Simon K.; Peters, Jurriaan M.; Scherrer, Benoît; Goyal, Monisha; Filip-Dhima, Rajna; Dies, Kira; Bruns, Stephanie; Hanson, Ellen; Bing, Nicole M.; Kent, Bridget; O’Kelley, Sarah; Williams, Marian E.; Pearson, Deborah A.; Cutter, Gary; Roberds, Steven L.; Murray, Donna S.

doi:10.1016/j.pediatrneurol.2019.03.003

Cited by 27 publications

(22 citation statements)

References 38 publications

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“…It was first found that the TSC1/TSC2 group reported significantly worse QOL. Similar to previous studies, TSC1/TSC2 pathogenic variants could generally cause a more severe clinical phenotype 4,24‐28 …”

Section: Discussionsupporting

confidence: 88%

Quality of life in children with tuberous sclerosis complex: A pediatric cohort study

et al. 2020

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Aims To evaluate the quality‐of‐life (QOL) impairment and identify the possible risk factors in patients with tuberous sclerosis complex (TSC) in China. Methods The parent proxy‐report PedsQL 4.0 Generic Core Scales were administered to 124 caregivers of children with TSC (aged 2‐18 years). For comparison, the survey was also conducted in a demographically group‐matched sample of healthy controls (HCs) (aged 2‐18 years). Results A total of 124 children with TSC and 206 HCs were recruited. The mean parent proxy‐report total scale score, physical health summary score, and psychosocial health summary score for children with TSC were 65.0 (SD 19.7), 77.6 (SD 22.9), and 58.0 (SD 21.3), respectively, compared with the HC values of 83.6 (SD 14.3), 87.2 (SD 16.9), and 82.8 (SD 15.9). There were statistically significant differences between the two groups (P < .0001). TSC2 mutation (P = .033), epilepsy (P = .011), seizure before 2 years old (P = .001), course of epilepsy (more than 2 years) (P = .001), high reported seizure frequency (more than once a month) (HRSF) (P = .007), multiple antiepileptic drugs (≥2) (P = .002), intellectual disability (ID) (mild and moderate ID, P < .0001, and severe and profound ID, P < .0001), and TANDs (P < .0001) (ADHD, P = .004; agoraphobia, P = .007; and social anxiety disorder, P < .0001) were closely related to lower QOL scores. Conclusion This study is the first large cohort study on QOL in children with TSC in China. The results of the PedsQL 4.0 indicated that the QOL of children with TSC is significantly lower than that of HCs. TSC2 mutation, epilepsy, early onset, long disease course and HRSF, ID, and TANDs are risk factors for poor QOL.

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Section: Discussionsupporting

confidence: 88%

Quality of life in children with tuberous sclerosis complex: A pediatric cohort study

et al. 2020

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“…5,10,28 In a recent prospective study, Farach et al observed that infants with a TSC2 pathogenic variant had significantly lower developmental scores at age 24 months, independent of seizures. 29 In this study, early Vigabatrin treatment initiated before seizure onset did not significantly decrease the risk of ASD at 24 months, when compared to conventional treatment.…”

Section: Discussionmentioning

confidence: 53%

Is autism driven by epilepsy in infants with Tuberous Sclerosis Complex?

Moavero

Kotulska

Lagae

et al. 2020

Ann Clin Transl Neurol

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Objective To evaluate the relationship between age at seizure onset and neurodevelopmental outcome at age 24 months in infants with TSC, as well as the effect on neurodevelopmental outcome of early versus conventional treatment of epileptic seizures with vigabatrin (80–150 mg/kg/day). Methods Infants with TSC, aged ≤4 months and without previous seizures were enrolled in a prospective study and closely followed with monthly video EEG and serial standardized neurodevelopmental testing (Bayley Scales of Infant Development and Autism Diagnostic Observation Schedule). Results Eighty infants were enrolled. At the age of 24 months testing identified risk of Autism Spectrum Disorder (ASD) in 24/80 children (30.0%), and developmental delay (DD) in 26/80 (32.5%). Children with epilepsy (51/80; 63.8%) had a higher risk of ASD (P = 0.02) and DD (P = 0.001). Overall, no child presented with moderate or severe DD at 24 months (developmental quotient < 55). In 20% of children abnormal developmental trajectories were detected before the onset of seizures. Furthermore, 21% of all children with risk of ASD at 24 months had not developed seizures at that timepoint. There was no significant difference between early and conventional treatment with respect to rate of risk of ASD (P = 0.8) or DD (P = 0.9) at 24 months. Interpretation This study confirms a relationship between epilepsy and risk of ASD/DD. However, in this combined randomized/open label study, early treatment with vigabatrin did not alter the risk of ASD or DD at age 2 years.

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“…We are aware of only one other recent report of genetic analysis in a cohort of TSC infants. 24 There were several important observations in the present genetic analysis of the EPISTOP cohort.…”

Section: Discussionmentioning

confidence: 86%

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study

Ogórek¹,

Hamieh²,

Hulshof

et al. 2020

Genetics in Medicine

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Purpose: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. Methods: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. Results: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizurefree survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. Conclusion: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

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Tuberous Sclerosis Complex Genotypes and Developmental Phenotype

Cited by 27 publications

References 38 publications

Quality of life in children with tuberous sclerosis complex: A pediatric cohort study

Quality of life in children with tuberous sclerosis complex: A pediatric cohort study

Is autism driven by epilepsy in infants with Tuberous Sclerosis Complex?

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study

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