結節性硬化症

BACKGROUND: The pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex) is approved by the the US Food and Drug Administration for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis in patients one year of age and older. Among the large volume of drug-resistant cases treated at pediatric Level 4 Epilepsy Centers, many patients fall outside of these categories but are still prescribed CBD for off label use. This study sought to characterize the real-world experience with CBD of a large single pediatric comprehensive epilepsy center and to compare response to CBD within and outside of its FDA-approved indications. METHODS: A retrospective chart review was performed of patients with a prescription for CBD at our institution between January 2020 and January 2022, excluding patients who were previously included in our center's 2019 analysis. Patients were not included in the analysis if initially prescribed CBD elsewhere, follow-up was outside our institution, medication was not started, patient expired during the study period, or diagnostic data was not available. Between-group differences were assessed via Wilcoxon rank-sum and Fisher exact tests, as appropriate. RESULTS: Of 223 patients with a CBD prescription during the study period, 144 patients had sufficient data available for review. Of these patients, 81 (56%) carried diagnoses of Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis, and 63 (44%) carried other diagnoses outside of FDA-labeled indications. Median (interquartile range) age at initiation was 10.0 years (5.0, 13.0), and median (interquartile range) number of concurrent anti-seizure medications was 3.0 (2.0, 3.0). There was no significant difference in the proportion of patients treated concurrently with vagus nerve stimulation or ketogenic diet between the two groups. The FDA-labeled (63%) group had a significantly higher proportion of patients with tonic seizures compared to the non-FDA labeled (29%) group (P < 0.001), otherwise there were no significant differences in baseline seizure types. Overall, 53 patients (65%) in the FDA-labeled group and 40 (63%) of the non-FDA labeled group had a documented responder rate at least 50% on CBD (P = 0.9). The most common side effects reported were nausea/diarrhea/gastrointestinal upset (19%), agitation (7.6%), insomnia (4.9%), weight loss (6.3%), and secretions/drooling (2.8%, seen only in patients on concurrent clobazam). CONCLUSIONS: Among our cohort of treatment-resistant pediatric epilepsy, purified CBD was efficacious in a broad range of pediatric epilepsies and was well tolerated as an adjunctive anti-seizure medication. This medication may be considered in pharmacoresistant pediatric epilepsies in conditions beyond its FDA-labeled indications.

Antipsychotic-associated hypothermia is a rare but potentially life-threatening adverse effect that remains underrecognized in clinical practice. This case adds evidence of recurrent hypothermia associated with two different atypical antipsychotics in a medically complex patient with multiple predisposing factors for thermoregulatory dysfunction. It also raises the possibility of a bidirectional interaction between hypothermia and acute kidney injury (AKI). We report the case of a 55-year-old woman with tuberous sclerosis, epilepsy, intellectual disability, and chronic kidney disease who developed recurrent episodes of hypothermia in temporal association with risperidone and subsequently olanzapine, with several episodes also accompanied by bradycardia, hypotension, and AKI. Extensive evaluation excluded common causes of hypothermia, including infection, endocrine dysfunction, hypoglycemia, and structural hypothalamic lesions. Recurrent episodes with a consistent clinical pattern resolved following substitution of atypical antipsychotics with haloperidol, supporting a probable drug-induced etiology. No further episodes of hypothermia, bradycardia, hypotension, or AKI occurred during two years of follow-up. Antipsychotic-associated hypothermia requires a high index of clinical suspicion, as diagnosis can be challenging in medically complex patients. This report highlights the importance of recognizing this rare adverse effect and ensuring careful monitoring and timely adjustment of psychotropic treatment. The temporal association with AKI also raises the possibility of a bidirectional interaction, although the underlying mechanisms remain incompletely understood.

OBJECTIVE: To explore the molecular mechanism of tuberous sclerosis type 2 caused by TSC2 synonymous mutations affecting normal splicing of precursor mRNA. METHODS: Review and analyses clinical diagnosis and treatment process of a patient with tuberous sclerosis complex type 2, summarize the relationship between genotype and clinical phenotype. Use bioinformatics methods to analyses the effect of TSC2 gene synonymous mutations on precursor mRNA splicing and use in vivo splicing experiments and in vitro minigene experiments to verify the possible pathogenic mechanism of TSC2 gene synonymous mutations. RESULTS: The proband exhibited tuberous sclerosis phenotype including epilepsy and depigmentation. A synonymous mutation in the TSC2 gene (c.1443G > A, p.Glu481=) associated with the phenotype was identified. Bioinformatics analysis suggested that this synonymous mutation may disrupt normal pre-mRNA splicing. Both in vivo splicing assays and minigene experiments confirmed that the synonymous mutation indeed affects proper pre-mRNA splicing. CONCLUSION: TSC2 c.1443G > A (p.Glu481=) synonymous mutation may be associated with tuberous sclerosis type 2 by disrupting normal pre-mRNA splicing.

OBJECTIVE: To describe the spectrum of MRI features, histopathological findings, and clinical outcomes of musculoskeletal PEComas at a single tertiary sarcoma center. MATERIALS AND METHODS: Following institutional ethics approval, orthopedic oncology and pathology databases were searched for histopathologically confirmed musculoskeletal soft tissue PEComas managed between 2000 and 2025. Inclusion required pretreatment MRI. Pulmonary, intra-abdominal/pelvic, and cutaneous lesions were excluded. Demographic and clinical features were reviewed for all cases. MRI examinations were reviewed in consensus by two fellowship-trained musculoskeletal radiologists and archival histopathology by a dedicated musculoskeletal pathologist. RESULTS: Twelve patients met inclusion criteria (7/12 male), mean age 64.3 years (range 16-89 years). One tuberous sclerosis complex (TSC)-associated fibroma-like PEComa appeared as a well-defined periarticular mass with homogeneously low T1 and T2 signal and no significant enhancement. The remaining 11 non-TSC tumors had a mean diameter of 13.0 cm; 10 of 11 were deep to deep fascia, and 6 of 11 showed trans-compartmental extension. Intratumoral nonenhancement consistent with necrosis was present in all 10 contrast-enhanced cases. Neurovascular encasement was identified in 4 of 11 (36%) and osseous invasion in 2 of 11 (18%). All nine histologically evaluable non-TSC cases showed malignant morphology. The overall metastatic rate was 91%, with disease-specific mortality of 64% at a median follow-up of 19 months. CONCLUSION: Musculoskeletal PEComas demonstrate large size, deep location, macroscopic intratumoral necrosis, as well as frequent trans-compartmental extension on MRI. Clinical outcomes reflect aggressive biologic behavior, with high metastatic rates and disease-specific mortality in non-TSC-related PEComas of the musculoskeletal system.

Kidney cystic epithelium primarily comprises proliferating A-intercalated (A-IC) cells in humans and mouse models of TSC. These studies explored the expression of transcription factors (TF) that drive the development of A-IC cells and the downregulation of B-intercalated (B-IC) cells, as well as the status and localization of Tsc1 and Tsc2 in epithelial cells lining the cysts. Transcriptome studies indicated enhanced expression of the following TFs: DMRT2, FOXI1, and FOXP1 in young TSC mice, and DMRT2 and FOXI1 in aged mice. The expression of Hmx2 decreased in TSC mice of all ages. Our studies further demonstrated: (1) distinct and predominant DMRT2 and FOXP1 localization in the cystic epithelium of in TSC mouse models; and (2) expression of Foxi1, Tsc1, and Tsc2 in epithelial cells lining the kidney cysts. Expression of DMRT2, FOXI1, and FOXP1 is enhanced in the A-IC cells lining the kidney cysts of TSC mouse models. In the same models, the expression of Hmx2 mRNA is decreased and is accompanied by the loss of B-IC cells in cyst epithelia. Both DMRT2 and FOXP1 localized to the nucleus of A-IC cells of the renal cysts, suggesting that TSC kidney cystogenesis is driven by factors that exclusively promote A-IC expansion.