Genetic and imaging features of cerebellar abnormalities in tuberous sclerosis complex: more insights into their pathogenesis

Manara, Renzo; Bugin, Samuela; Pelizza, Maria Federica; Sartori, Stefano; Nosadini, Margherita; Labriola, Flavio; Canevini, P; Toldo, Irene

doi:10.1111/dmcn.13769

Cited by 9 publications

(16 citation statements)

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“…Clinical, genetic and neuroimaging data of our cohort were similar to those of other series . Interestingly, we found cerebellar lesions in six (19%) patients; in the literature this finding varies from 8% to 44% . In our series, cerebellar lesions were clearly associated with TSC2 mutations (83%), whereas TSC1 mutations were not found in these patients.…”

Section: Discussionsupporting

confidence: 88%

“…1,16,17 Interestingly, we found cerebellar lesions in six (19%) patients; in the literature this finding varies from 8% to 44%. [18][19][20][21][22] In our series, cerebellar lesions were clearly associated with TSC2 mutations (83%), whereas TSC1 mutations were not found in these patients. The strong association between TSC2 mutation and cerebellar involvement has been recently highlighted.…”

Section: Discussioncontrasting

confidence: 40%

“…The strong association between TSC2 mutation and cerebellar involvement has been recently highlighted. [18][19][20][21][22] In our study, 25 patients had more than 4 TAND behavioural difficulties, whereas in the pilot validation study, 13 based on a lower number of cases (n=20) with a wider age range (3-48y), this corresponded to 93% of cases.…”

Section: Discussionmentioning

confidence: 50%

“…In our series, cerebellar lesions were clearly associated with TSC2 mutations (83%), whereas TSC1 mutations were not found in these patients. The strong association between TSC2 mutation and cerebellar involvement has been recently highlighted …”

Section: Discussionmentioning

confidence: 96%

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Tuberous sclerosis‐associated neuropsychiatric disorders: a paediatric cohort study

Toldo

Brasson

Miscioscia

et al. 2018

Develop Med Child Neuro

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Aim We aimed to study tuberous sclerosis‐associated neuropsychiatric disorders (TAND) in children and adolescents with tuberous sclerosis complex (TSC). Method Retrospective and prospective cohort study conducted at a Paediatric Neurology Unit of an Italian Tertiary Care Hospital. Clinical and neuroimaging data were reviewed. Scores for neurological and epilepsy outcomes (Extended Glasgow Outcome Scale, Paediatric Version and Early Childhood Epilepsy Severity Scale modified), semi‐structured interviews (authorized Italian version of the TAND checklist and Vineland Adaptive Behavior Scales) and questionnaires (Child Behavior Checklist [CBCL]) were applied at last follow‐up. Results Thirty‐two patients with TSC (age range 1–19y) were enrolled. Eighty‐eight per cent had at least one TAND and 47% had intellectual disability. The TAND checklist showed internalizing problems in 25.8% of cases (vs 41.9% by CBCL), and externalizing problems in 41.9% (vs 9.7% by CBCL). TAND prevailed in patients with de novo mutation of TSC2, high tuber load, and severe neurological and epilepsy outcomes. Interpretation In our cohort, 78% of patients had more than four TAND behavioural problems; nevertheless, they did not show a constant and specific neuropsychiatric profile. Clinical, neurophysiological, and neuroradiological features were associated with several TAND. The TAND checklist appeared more effective than the CBCL, particularly in detecting externalizing problems. What this paper adds The Tuberous sclerosis‐associated neuropsychiatric disorders (TAND) checklist is an effective tool for TAND screening. The TAND checklist helps define psychopathological and neuropsychiatric aspects in paediatric patients with Tuberous sclerosis complex (TSC). TAND were found in 88% of patients with TSC, whilst 78% had more than four TAND. TAND distribution depends on different clinical and neuroradiological features.

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Section: Discussionsupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 40%

Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 96%

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Tuberous sclerosis‐associated neuropsychiatric disorders: a paediatric cohort study

Toldo

Brasson

Miscioscia

et al. 2018

Develop Med Child Neuro

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“…In tuberous sclerosis complex (TSC), a multisystem autosomal dominant genetic disorder with neurological involvement in about 90% of cases, structural alterations of the brain (mainly cortical tubers, radial migration lines, and subependymal nodules [SENs]) typically involve the supratentorial regions . However, cerebellar involvement has been documented in patients with TSC, with a prevalence varying from 8% to 46% . Cerebellar lesions are thought to be predominantly tubers, although they are sometimes associated with dystrophy‐like focal cerebellar atrophy; partial or total cerebellar hypoplasia has also been reported .…”

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confidence: 99%

Cerebellar lesions as potential predictors of neurobehavioural phenotype in tuberous sclerosis complex

Toldo

Bugin

Perissinotto

et al. 2019

Develop Med Child Neuro

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ASDAutism spectrum disorder SEN Subependymal nodule TAND Tuberous sclerosis complexassociated neuropsychiatric disorders TSC Tuberous sclerosis complex AIM To improve the genetic, clinical, and neuroradiological characterization of cerebellar involvement in tuberous sclerosis complex (TSC) and determine whether cerebellar lesions could be a reliable biomarker of neurological impairment.METHOD This retrospective cohort study, held at two tertiary paediatric university centres, was conducted on patients with a confirmed diagnosis of TSC who underwent brain magnetic resonance imaging between October 2009 and May 2016. The study population consisted of 112 patients with TSC (median age 10y; range 5mo-38y; 61 females, 51 males). RESULTSThe results from multivariable statistical analysis indicated that cerebellar involvement (34 out of 112 patients, none carrying a TSC1 mutation) was the most powerful predictor of supratentorial cortical tuber load; however, cerebellar involvement was not the best predictor of clinical phenotype when supratentorial tuber load and TSC2 mutations were taken into consideration. The association between cerebellar lesions and a more severe clinical and neuroradiological phenotype was statistically significant and may be due to its strong association with TSC2 mutations and higher cortical tuber load.INTERPRETATION Cerebellar involvement is not the best predictor of neurobehavioural outcome, including TSC-related autism, after adjusting for TSC2 and the number of cortical tubers. Its role in the TSC clinical phenotype needs to be investigated further.In tuberous sclerosis complex (TSC), a multisystem autosomal dominant genetic disorder with neurological involvement in about 90% of cases, structural alterations of the brain (mainly cortical tubers, radial migration lines, and subependymal nodules [SENs]) typically involve the supratentorial regions. 1,2 However, cerebellar involvement has been documented in patients with TSC, with a prevalence varying from 8% to 46%. 3-25 Cerebellar lesions are thought to be predominantly tubers, 5,6,8,20,26 although they are sometimes associated with dystrophy-like focal cerebellar atrophy; 3,4,7,8,20 partial or total cerebellar hypoplasia has also been reported. 9 With regard to contrast enhancement, calcifications, or lesion size, 10,11,27 recent studies have recorded changes in cerebellar lesions in 20% to 46% of patients with TSC. 6,7,14 These changes manifest themselves during the first 8 years of life; 6 however, the underlying biological mechanism remains unclear. Cerebellar lesions have been associated with older age, 4,12 autism spectrum disorder (ASD), 13 and TSC2 mutations; 12,14,17,18 TSC2 is highly expressed in the cerebellum. 14 Patients with TSC with cerebellar lesions generally have more cortical tubers than patients with only supratentorial lesions 4,6,8,12,25 and a greater association with subependymal giant cell astrocytoma. 7,25 Conditional knockout mouse models of TSC1 and TSC2 support the link between cerebellar circuitry and the develo...

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Malformations of Cortical Development

Geraldo

Rossi

Severino³

2021

Pediatric Neuroradiology

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Genetic and imaging features of cerebellar abnormalities in tuberous sclerosis complex: more insights into their pathogenesis

Cited by 9 publications

References 5 publications

Tuberous sclerosis‐associated neuropsychiatric disorders: a paediatric cohort study

Tuberous sclerosis‐associated neuropsychiatric disorders: a paediatric cohort study

Cerebellar lesions as potential predictors of neurobehavioural phenotype in tuberous sclerosis complex

Malformations of Cortical Development

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