BACKGROUND: Glucose Transporter Type 1 Syndrome (GLUT1DS) is a rare neurometabolic disease caused by mutations in the SLC2A1 gene, that limits the transport of glucose across the blood-brain barrier. Epilepsy, intellectu...BACKGROUND: Glucose Transporter Type 1 Syndrome (GLUT1DS) is a rare neurometabolic disease caused by mutations in the SLC2A1 gene, that limits the transport of glucose across the blood-brain barrier. Epilepsy, intellectual disability, movement disorders and coordination disorder are common characteristics found in the syndrome. OBJECTIVES: This study aims to describe the motor profile in a cohort of patients with GLUT1DS throughout the administration of Movement Assessment Battery for Children version 2 (MABC-2). METHODS: The MABC-2 test was assessed in 31 patients with GLUT1DS. RESULTS: Our sample performed in the clinical range across all the subscales and summary scores of the MABC-2 Test demonstrated an impaired motor performance. CONCLUSIONS: Despite the use of use of MABC-2 scores in adults despite age-related norms, and the potential influence of cognitive impairments on task comprehension and performance, which may affect the interpretation of motor outcomes we observed that patients with more complex and severe clinical pictures are those with major motor impairment. The high percentage of impaired performances in motor functioning observed in our population may have significant implications in terms of their long-term health and well being. Early identification of patient with GLUT1DS at risk of motor impairment is crucial to activate interventions to support cognitive, social and emotional development of the patient.
INTRODUCTION: The evolving spectrum of acute leukoencephalopathy with restricted diffusion (ALERD) in Indian children is distinct from that of their Japanese counterparts. METHODS: This study enrolled children presenting...INTRODUCTION: The evolving spectrum of acute leukoencephalopathy with restricted diffusion (ALERD) in Indian children is distinct from that of their Japanese counterparts. METHODS: This study enrolled children presenting with febrile infection-related epilepsy syndrome (FIRES) and radiological features of ALERD between May 2022 and April 2024. Intergroup comparisons were performed between the 'diffuse' versus 'multifocal' and the 'symmetrical' versus 'asymmetrical' diffusion restriction groups. Seizures recurring three months after discharge were designated as post-encephalopathic epilepsy (PEE). The outcome measures included the paediatric modified Rankin score (mRS) and development/intelligence quotients at the 12-month follow-up. RESULTS: This study enrolled 38 children, whose mean (standard deviation) age was 6.77 (3.22) years. Diffuse and multifocal ALERD occurred in 29 % and 71 % of children, respectively; the lesions were symmetrical and asymmetrical among 37 % and 63 % of children, respectively. The mRS score was <2 in 18 % of children, whereas intellectual disabilities and PEE were noted among 50 % and 42 % of children, respectively. Age under six years was a significant predictor of diffuse and symmetrical ALERD. Pearson analysis revealed significant positive correlations of the diffusion-weighted imaging scores, prolonged persistence of diffusion restriction, and seizure duration exceeding 2 h with the mRS scores. CONCLUSION: The children had a monophasic course and a higher frequency of multifocal and asymmetric ALERD. The nature of ALERD lesions did not influence the occurrence of PEE, although unilateral lesions had better outcomes. Children with a radiographic signature of ALERD constitute a unique subset of FIRES, with distinct therapeutic responses and long-term outcomes.
BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMS) is a rare pediatric immune-mediated disorder characterized by motor and behavioral disturbances, often with regression of previously acquired skills. While aggressiv...BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMS) is a rare pediatric immune-mediated disorder characterized by motor and behavioral disturbances, often with regression of previously acquired skills. While aggressive immunotherapy has improved motor outcomes, long-term cognitive and affective sequelae remain present. OBJECTIVE: To evaluate long-term motor, cognitive, affective, and communication outcomes in patients with sustained OMS remission treated with a unified immunotherapy protocol, with a specific focus on the presence and trajectory of Cerebellar Cognitive Affective Syndrome (CCAS). METHODS: Sixteen patients with OMS and ≥4 years of sustained remission were evaluated using standardized neurological, cognitive, and behavioral assessments. CCAS severity was assessed retrospectively at onset and categorized at outcome based on neuropsychological and behavioral data. Correlational analyses explored associations between clinical variables and functional outcomes. RESULTS: All patients demonstrated OMS remission; however, 50 % exhibited residual, mild motor symptoms. Cognitive impairments were present in 37.5 % of patients, with 25 % showing moderate to severe intellectual disability. Communication difficulties were reported in 37 %, and 50 % screened positive for anxiety. CCAS features were identified in all patients at onset and persisted in 50 % at outcome. Worse cognitive and motor outcomes were significantly associated with delayed treatment initiation, higher relapse frequency, and greater CCAS severity at onset. CONCLUSIONS: Despite remission of core motor symptoms, many OMS patients experience persistent CCAS-related cognitive, affective, and communication deficits. Our findings support the use of early CCAS assessment as a prognostic indicator, the development of an age-appropriate CCAS assessment tool for young children, and the inclusion of CCAS features in OMS diagnostic criteria.
BACKGROUND: Tuberous Sclerosis Complex (TSC) is a rare, multisystem genetic disorder with highly variable clinical manifestations. While international registries such as TOSCA have provided large-scale data, national-lev...BACKGROUND: Tuberous Sclerosis Complex (TSC) is a rare, multisystem genetic disorder with highly variable clinical manifestations. While international registries such as TOSCA have provided large-scale data, national-level studies remain limited. This study represents the first national cohort analysis of TSC patients in Greece, providing comprehensive insights into clinical characteristics, genotype-phenotype correlations, and previously underreported rare manifestations. METHODS: A descriptive analysis was conducted on 115 TSC patients diagnosed based on the latest criteria. Clinical, genetic, and treatment-related data were analysed, with a particular focus on neurological, renal, cardiac, dermatological, and pulmonary manifestations, as well as rare or atypical disease presentations. RESULTS: The median age at diagnosis was 1.2 years (range: 0-43 years). Epilepsy was the most frequent initial symptom (70.4 %), with drug-resistant epilepsy (DRE) affecting 39.5 % of cases. Intellectual disability, autism spectrum disorder, and behavioral issues correlated significantly with early seizure onset and TSC2 variants. Common manifestations include cortical tubers (93.9 %), subependymal nodules (92.2 %), angiomyolipomas (48.7 %), and cardiac rhabdomyoma (33 %). Notably, we report several rare manifestations, including high-grade glioma in a pediatric patient, diffuse lipomatosis, pancreatic neuroendocrine tumours, rectal polyps, and erythema nodosum presented in a patient on everolimus therapy, further highlighting the systemic complexity and malignancy risks in TSC. CONCLUSIONS: Our study provides novel epidemiological and clinical data on TSC in Greece, reinforcing genotype-phenotype correlations and expanding the spectrum of rare manifestations. These findings emphasise the need for lifelong surveillance, multidisciplinary management, and early detection strategies to mitigate long-term complications. This study also contributes to the broader understanding of TSC by documenting atypical presentations that may inform future clinical guidelines and patient care strategies.
OBJECTIVES: This study assessed impacts of non-seizure outcomes and caregiver priorities for improvement in individuals with severe neurodevelopmental encephalopathy with or without epilepsy (SNDE ). METHODS: In an onlin...OBJECTIVES: This study assessed impacts of non-seizure outcomes and caregiver priorities for improvement in individuals with severe neurodevelopmental encephalopathy with or without epilepsy (SNDE ). METHODS: In an online survey of parents recruited from several patient advocacy groups, parents rated the impacts of 17 non-seizure outcome domains on their children and identified their top three priority domains for improvement. Bivariate and stratified analyses compared impacts and priorities by burden of severe functional impairments, age, and diagnoses. RESULTS: Of 267 participants, 149 (56 %) were female (median [interquartile range] age: 8.7y [4.2y - 14.7y) and 169 (63 %) had epilepsy diagnoses. Profound impairments were reported for mobility (N = 142, 53 %), communication (N = 208, 78 %), eating (N = 100, 37 %), and hand use (N = 93, 35 %). Expressive communication had overwhelming or significantly negative impacts in 217 (83 %) followed by receptive communication (N = 185, 70 %). Parents identified expressive communication as a top (N = 211, 79 %) priority for improvement. The impact and prioritization of expressive communication were independent of other functional impairments, age, and other diagnoses. For those with epilepsy, relative to non-seizure outcomes, seizures were rated as more important by 35 % and of similar or less importance by 65 %; this strongly depended on recency of the last seizure (p < 0.0001). CONCLUSIONS: Improvement in expressive communication is a top priority in the SNDEs and could be a valuable non-seizure outcome in future therapeutic trials for these rare diseases.
BACKGROUND: Data regarding treatment in pediatric relapsing MOGAD are limited. OBJECTIVE: To evaluate response of intravenous immunoglobulin (IVIG) compared to other therapies in relapsing pediatric MOGAD. METHODS: In th...BACKGROUND: Data regarding treatment in pediatric relapsing MOGAD are limited. OBJECTIVE: To evaluate response of intravenous immunoglobulin (IVIG) compared to other therapies in relapsing pediatric MOGAD. METHODS: In this retrospective multicenter study, children with MOGAD were recruited from different medical centers. Inclusion criteria encompassed: age <18 years, MOGAD diagnosis, relapsing disease course, >6 months of maintenance treatment and >12 months follow-up. RESULTS: Seventy children with relapsing MOGAD were stratified into two groups. The first group received IVIG alone (n = 23), IVIG preceded by (n = 16) or in combination with other immunomodulating therapies (IMT) (n = 7). The second group received mycophenolate mofetil, azathioprine, rituximab, or other IMTs (n = 24). 13 % (6/46) of patients with IVIG relapsed in the first year, compared to 33 % (8/24) in the IMT group (relative risk 0.70, 95 % CI 0.53 to 0.99, p = 0.061). Annual relapse rate (ARR) was decreased under therapy compared to pre-treatment in both groups (IVIG: p < 0.001; other IMTs: p = 0.006). ARR was lower in the IVIG group (p = 0.040) in addition to a reduced risk of an early relapse compared to the other IMT group (hazard ratio 0.36, 95 % CI 0.15 to 0.87, p = 0.023). CONCLUSION: Our study supports monthly IVIG as maintenance therapy in children after the second MOGAD episode.
Wendel EM, Baumann M, Barisic N
… +22 more, Blaschek A, de Oliveira Koch EC, Della Marina A, Diepold K, Hackenberg A, Hahn A, von Kalle T, Karenfort M, Kornek B, Lechner C, Leiz S, Merkenschlager A, Nosadini M, Schanda K, Schimmel M, Seemann L, Tüngler V, Waltz S, Wegener-Panzer A, Wiegand G, Reindl M, Rostásy K
BACKGROUND: The search for convenient and effective biomarkers is a critical and pressing need for spinal muscular atrophy (SMA) in the era of disease-modifying treatment. METHODS: Data from 65 SMA children treated with...BACKGROUND: The search for convenient and effective biomarkers is a critical and pressing need for spinal muscular atrophy (SMA) in the era of disease-modifying treatment. METHODS: Data from 65 SMA children treated with nusinersen and followed up for 18 months were retrospectively collected. Motor function was assessed at baseline, 6, 10, 14 and 18 months using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), the Hammersmith Functional Motor Scale Expanded (HFMSE), and the Revised Upper Limb Module (RULM). Serum creatine kinase (CK) and creatinine (Crn) levels were measured, and the correlations were further analyzed. RESULTS: Significant differences in CK and Crn levels were found among different types before treatment. Baseline CK levels in children with SMA type 3 were higher than those with types 1 and 2 (P = 0.008 and 0.042, respectively), while baseline Crn levels were higher in type 3 than in type 2 (P < 0.001). During the follow-up, baseline Crn levels in types 2 and 3 patients with clinically meaningful improvements in HFMSE scores were higher than those without such improvements (P = 0.013). Additionally, a correlation was observed between HFMSE scores and CK and Crn levels in types 2 and 3 patients (CK: P < 0.001, ρ = 0.473; Crn: P < 0.001, ρ = 0.642). RULM scores were correlated with Crn levels (P < 0.001, ρ = 0.642). CONCLUSIONS: Serum CK and Crn levels appear to correlate with clinical severity in later-onset SMA. Moreover, baseline serum Crn may serve as a potential biomarker for predicting the degree of motor function improvement under nusinersen treatment in children with later-onset SMA.
OBJECTIVE: This research sought to understand the experiences of healthcare providers working at the coalface of paediatric sleep medicine in a large tertiary children's hospital with a focus on the current service needs...OBJECTIVE: This research sought to understand the experiences of healthcare providers working at the coalface of paediatric sleep medicine in a large tertiary children's hospital with a focus on the current service needs, challenges, and strategies. METHOD: This qualitative study utilised semi-structured focus groups undertaken in an Australian tertiary paediatric sleep medicine department. There were 17 participants, encompassing paediatric sleep medicine specialists, clinical nurses, sleep scientists and administrative staff. Focus group interviews were transcribed verbatim, and member checked. Thematic analysis was undertaken. RESULTS: Three themes were identified: 1) Patient care optimisation, 2) Families' unrealistic expectations for their child's diagnostic testing and treatment adherence, 3) Families' difficult experiences with diagnostic and specific sleep therapies. CONCLUSION: This study provides unique insights and perspectives of healthcare providers regarding the current challenges faced within the growing demand and complexity of patients accessing paediatric sleep medicine service. Despite clinicians optimising sleep medicine services, wait lists continue to grow, which in turn impact staff workload and patient care. Innovation in areas of sleep diagnostics, monitoring and therapy continue to be explored by tertiary services. Education and training for both primary healthcare providers and the public are still urgently required to optimise sleep and sleep disorders.
Nedelcu M, Craiu D, Neagu E
… +14 more, Burloiu CM, Iliescu CM, Budisteanu M, Minciu I, Barca DG, Sandu C, Tarta-Arsene O, Pomeran C, Motoescu C, Dica A, Anghelescu C, Surlica D, Iancu D, Butoianu N
Duchenne muscular dystrophy (DMD) is a rare fatal genetic disorder with a tight correlation between the genotype and the phenotype of the patients. However, the relationship between genotype and phenotype is yet incomple...Duchenne muscular dystrophy (DMD) is a rare fatal genetic disorder with a tight correlation between the genotype and the phenotype of the patients. However, the relationship between genotype and phenotype is yet incompletely understood, with some cases manifesting a different phenotype than predicted from their genotype. Since the genetic diagnosis is often targeted to specific gene sections, and the genotype-phenotype correlations guide early treatment decisions, accumulating clinical and epidemiological data for these rare disorders is required to refine local management strategies. This article describes the genotype and phenotype landscape of 239 patients treated in the Pediatric Neurology Clinic of the Clinic Psychiatry Hospital "Prof. Dr. Alexandru Obregia" in Bucharest, using randomly collected data from a ten-year interval (2012-2022). It revealed a significant improvement in the quality of care, highlighted by a notable reduction in the average age at diagnosis in recent years, although considerable variability remains across counties. The study identified three mutations that were not previously described in the Edystrophin or TREAT-NMD DMD Global Database. The accuracy of the Reading-Frame rule was 88.4 % for deletions. For exceptions from the rule, the involvement of different isoforms, binding domains, structural domains, and the disturbance of the three-dimensional structure of the rod domain were not reliable indicators of the phenotype. 12.9 % of all patients had nonsense mutations with a DMD phenotype that could benefit from Ataluren treatment within the National Treatment Program, and 15 % were eligible for exon-skipping therapies, with exon 51 having the broadest applicability (7.1 %).
Goj G, Helfferich J, El Naggar I
… +14 more, Noßwitz U, Bültmann E, Kumaran D, Chung J, Biebl A, Steigleder L, Holzwarth D, Wendel EM, Bevot A, Nobel HA, Hengstler JG, Cleaveland R, Panzer A, Rostasy K
BACKGROUND: Acute flaccid myelitis (AFM) is characterized by acute onset of flaccid limb weakness, MRI abnormalities in the spinal cord grey matter and CSF pleocytosis often associated with enterovirus infections. MOG-as...BACKGROUND: Acute flaccid myelitis (AFM) is characterized by acute onset of flaccid limb weakness, MRI abnormalities in the spinal cord grey matter and CSF pleocytosis often associated with enterovirus infections. MOG-associated diseases (MOGAD) can manifest with similar neuroradilogical features. OBJECTIVE: To analyze MRI findings in patients with AFM at baseline and follow-up in comparison to other forms of childhood transverse myelitis such as MOGAD. PATIENTS AND METHODS: Children from 11 European centers who fulfilled the clinical criteria of AFM were included. Brain and spinal MRI was performed at various stages of the disease course. MRI scans were evaluated using a previously established scoring table and compared with MRI scans of a recently published cohort of children with different forms of transverse myelitis including MOGAD. RESULTS: We included 15 patients (8 females, 7 males, age range: 9 months-9,11 years). In 10/15 patients enterovirus was detected in respiratory/rectal specimens. At first presentation 13/15 patients presented with a longitudinal extensive transverse myelitis like involvement. Cervical grey matter was involved in almost all children. Axial involvement either manifested as grey matter alone or a mixture of white matter and grey matter hyperintensity in T2. Nerve root enhancement was found in 2/15 and leptomeningeal enhancement in 1/15 patients. 5/15 children had brainstem lesions. Follow-up MRI revealed residual T2 hyperintensities in 7/11 patients. Compared to patients with MOGAD AFM patients showed equally good resolution of MRI lesions overtime. CONCLUSION: Longitudinal spinal cord lesions mainly affecting the grey matter are characteristic of AFM whereas supratentorial lesions are less common. There is no significant difference between AFM and MOGAD concerning the resolution of lesions overtime.
INTRODUCTION: Information on health-related quality of life (HRQoL) after traumatic brain injury (TBI) for paediatric patients is scarce. Therefore, the aim of this study was to determine HRQoL and its risk factors in ch...INTRODUCTION: Information on health-related quality of life (HRQoL) after traumatic brain injury (TBI) for paediatric patients is scarce. Therefore, the aim of this study was to determine HRQoL and its risk factors in children several years after TBI. METHODOLOGY: Data were obtained from a prospectively follow-up cohort study of paediatric TBI patients (aged 0-18 years) admitted to the emergency department of the UMCG between 2008 and 2016. Long-term HRQoL was measured by the PedsQL 4.0 questionnaire. Patient and trauma characteristics were collected from digital patient files and posttraumatic complaints were evaluated by a health questionnaire. RESULTS: 416 children completed the PedsQL and the health questionnaire (17 % minor TBI, 65 % mild TBI, 8 % moderate TBI, and 10 % severe TBI). 52 % Of the children experienced long-term concentration problems, 52 % headache problems and 39 % memory problems. Memory problems were more present in the moderate-severe TBI group (p < 0.01). The mean total PedsQL score for the total group of children was good: 84.8 ± 13.3 (SD) with a comparable score for parent-proxies (84.5 ± 14.0). Lower HRQoL was associated with lower GCS score at the ED (B 0.31 (95% CI 0.02 to 0.59)), posttraumatic memory problems (B -6.97 (95% CI -9.66 to -4.28)), concentration problems (B -6.76 (95% CI -9.36 to -4.15) and headache (B -4.06 (95% CI -6.33 to -1.78)). CONCLUSIONS: Most paediatric TBI patients score their HRQoL as good several years after injury despite posttraumatic cognitive complaints and headache experienced by half of the patients. These complaints and lower GCS score have a negative influence on HRQoL.
INTRODUCTION: Anticholinergic medication is an important treatment option for paediatric drooling. We explored the practical application of glycopyrronium, an anticholinergic medicine registered for the paediatric popula...INTRODUCTION: Anticholinergic medication is an important treatment option for paediatric drooling. We explored the practical application of glycopyrronium, an anticholinergic medicine registered for the paediatric population, focusing on treatment patterns, effectiveness and impact, adverse drug reactions (ADRs), and caregiver satisfaction. METHODS: A longitudinal, observational study was performed, including 22 children (3-18 years) newly treated with glycopyrronium for anterior and/or posterior drooling in our tertiary children's hospital between November 2020 and February 2024. We assessed a verbal numerical rating scale for drooling severity, Drooling Severity and Frequency Scale (DSFS), Measure of Performance and Satisfaction for Saliva Control (MPS), prevalence of ADRs, and dosage adjustments. RESULTS: At baseline, drooling was typically profuse and occurred frequently to constantly. The majority of children (86 %) took glycopyrronium thrice daily, with dose titration tailored to each child and medication primarily administered with food (56 %). A clinically important reduction in DSFS was observed in 53 % at the first follow-up appointment. Correspondingly, median MPS scores increased from 0.0 at baseline to 5.6 at follow-up (p < .001) (0 = not dry; 10 = perfectly dry), indicating improved saliva control in situations impacted by drooling. ADRs were reported in 73 %, leading to treatment cessation in 36 %, primarily due to gastrointestinal issues and behavioural changes. CONCLUSIONS: Our findings confirm the applicability of glycopyrronium under real-world conditions, complementing results from studies with more rigid designs. Insights into inter-individual differences in dose titration, timing of medication administration, and changes in effect or ADRs over time highlight the relevance of a tailored treatment approach.
BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is a rare disease characterized by encephalopathy, polyfocal symptoms and demyelination. Although its prognosis is generally favorable, there is growing evidence th...BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is a rare disease characterized by encephalopathy, polyfocal symptoms and demyelination. Although its prognosis is generally favorable, there is growing evidence that subtle neuropsychological and motoric sequelae may persist years after the initial episode. AIM: To assess the relationship between clinical, laboratory and radiological characteristics of the acute monophasic ADEM episode in children, and its immediate outcome, and long(er) term disability/functional status. METHODS: Retrospective chart review embraced all children managed for monophasic ADEM over 18 years at a single tertiary center. They were invited for a follow-up medical, neurological assessment, and disability/functional outcomes assessment [modified Rankin scale (mRS), Extended Disability Status Scale and Functional Systems Scores (EDSS-FSS)]. RESULTS: Of the 65 children (age 10-250 months, median 90; 46.2 % boys), 40 (61.5 %) were judged as fully recovered, and 25 had sequelae, two of whom (aged 23 and 13 months) suffered severe ocular or cortical symptoms. Follow-up assessment 21-211 months (median 154) after hospital discharge embraced 41 children, 27 discharged as recovered, 14 with sequelae. Of the latter, the two children with severe sequelae were seriously disabled with decrease in mentation, while 11/14 had mRS 0, and EDSS-FSS 0. Of the former, 7 had mRS = 1 and one had mRS = 2, whereas 5 had EDSS-FSS = 2, and 2 had EDSS-FSS = 3, including 2 children with mood alterations and 2 with mild decrease in mentation. CONCLUSIONS: Unless truly severe, acute episode sequelae do not predict long-term disability/functional deficiency. Children recovered after the acute episode may have mild symptoms/deficiencies in long term.
BACKGROUND: Tuberous Sclerosis Complex (TSC) is a multisystemic neurocutaneous disorder caused by pathogenic loss of function variants in the tumour suppressor genes TSC1 and TSC2. The resultant hamartomas confer signifi...BACKGROUND: Tuberous Sclerosis Complex (TSC) is a multisystemic neurocutaneous disorder caused by pathogenic loss of function variants in the tumour suppressor genes TSC1 and TSC2. The resultant hamartomas confer significant medical risks by disruption of local tissues. Risk of mortality in TSC is known to be elevated, but only recently have multiple studies assessed specific causes of mortality in TSC. METHODS: A critical literature review of all available studies examining mortality in TSC was conducted using the terms "TSC", "Tuberous Sclerosis Complex", "mortality", "death", and "life expectancy", in PubMed and Google Scholar, until December 15, 2024. RESULTS: We identified 13 studies that reported a total of 411 deaths from 6735 TSC individuals. Data were typically incomplete and causes of death in many cases were obtained from death certificates. Crude mortality per 100 individuals ranged from 1.4 to 13.8 over average intervals of 11-45 years. Standardized Mortality Ratios or hazard ratios (versus control group) ranged from 3.0 to 4.9 (mean 4.3). Mean life expectancy was 66.2 years compared to an average of 81.8 in the general population. In the seven studies that reported specific causes of mortality in the general TSC population, 6/7 studies (85 %) had renal or central nervous system disease as the most common cause of mortality. Lymphangioleiomyomatosis was also found to confer significant risk of mortality in adult women and cardiac rhabdomyomas were the dominant cause of neonatal mortality. TSC-associated neuropsychiatric disorders-related mortality and morbidity may be underestimated. CONCLUSION: Mortality in TSC is elevated compared to the general population, with central nervous system and renal disease most frequently culpable. Further cohort studies will be required to establish and characterize the risk of mortality in TSC in the age of disease-modifying therapies.