Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Aberrant activation of the RAS-RAF-MEK-ERK signaling pathway contributes to numerous malignancies, congenital syndromes, and cardiovascular disorders, establishing MEK inhibitors (MEKi) as crucial therapeutic agents. MEKi demonstrate substantial clinical benefit as monotherapy (e.g., NF1-associated tumors) or combination therapy (e.g., melanoma, glioma, congenital RASopathies). Cardiovascular adverse events, primarily asymptomatic reductions in left ventricular ejection fraction (LVEF), have prompted intensive echocardiographic monitoring. RECENT FINDINGS/RESULTS:Emerging evidence indicates that isolated mild LVEF decreases rarely progress to symptomatic heart failure, raising concerns about unnecessary treatment interruptions driven by overly rigorous imaging protocols. Integrating cardiac biomarkers into monitoring strategies could offer a more pragmatic approach, guiding echocardiographic evaluations based on biomarker elevation or symptoms. Expert recommendations advocate personalized, risk-adapted surveillance frameworks. High-risk patients include those with baseline cardiovascular conditions, abnormal biomarker profiles, or significant clinical symptoms. Normal-risk patients can be safely monitored clinically, reserving imaging for biomarker changes or symptom onset. Prospective studies should seek to validate these recommendations.

BACKGROUND:The United States-based Early Access Program (US EAP) provided access to arimoclomol for individuals with Niemann-Pick disease Type C (NPC) ineligible or unable to enroll in clinical trials, generating 4 years of real-world safety and effectiveness data. METHODS:Participants were enrolled at 14 US sites. Investigators collected adverse events (AEs) and assessed disease severity using the 5-domain NPC Clinical Severity Scale (5DNPCCSS) at Baseline and follow-up visits as part of routine clinical care. RESULTS:Among 109 participants, 53 (48.6%) were adults (≥18 years) and 71 (65.1%) received miglustat alongside arimoclomol. Mean (SD) arimoclomol exposure was 820 (539) days. Of 248 reported AEs, 17 events in 13 participants (12.8%) were treatment related. 5DNPCCSS scores remained relatively stable throughout the program, with mean (SD) total scores of 11.0 (6.15) at Baseline (n = 100) and 12.0 (7.32) at Year 4 (n = 22). Among participants with Baseline and Year 1 assessments, mean (SD) scores were 11.2 (6.33) at Baseline and 11.1 (6.63) at Year 1 (n = 78). Similar patterns were observed for those with Baseline and Year 2, Year 3, or Year 4 assessments. Rescored 4-domain NPCCSS (R4DNPCCSS) scores (calculated based on 5DNPCCSS data) showed comparable longitudinal trends. CONCLUSION/CONCLUSIONS:The US EAP provides robust real-world evidence data up to 4 years, supporting the tolerability and effectiveness of arimoclomol in a broad NPC population, including adults and those not treated with miglustat. These findings complement and extend clinical trials results, reinforcing the role of arimoclomol, especially in combination with miglustat, as an important therapeutic option in routine clinical practice.

BACKGROUND:The GM2 gangliosidoses (GM2) are ultra-rare neurodegenerative disorders caused by deficient hexosaminidase A and/or B activity, leading to lysosomal GM2 ganglioside accumulation. Disease onset ranges from infancy to adulthood, with earlier onset associated with more rapid progression. Neurofilament light chain (NfL), a sensitive marker of axonal injury, has been extensively investigated as a biomarker for neurodegenerative disorders, including GM2. METHODS:To evaluate its clinical utility as a biomarker for GM2, NfL was measured in patients with GM2 enrolled in a Phase 2b, multinational, rater-blinded study of levacetylleucine [NCT03759665], and in its open-label Extension Phase (EP). RESULTS:Nineteen participants had viable samples for NfL analysis at baseline, after six weeks of treatment, and after a six-week washout; 10 had samples in the long-term EP. After the initial 6-week treatment phase, NfL concentration declined a mean - 8.9% (SD 13%; p < 0.008), followed by a rebound of + 9.2% (SD 16.1%; p = 0.022) during the post-treatment 6-week washout. Changes in NfL correlated with the statistically significant and clinically meaningful changes captured on the primary Clinical Impression of Change in Severity (CI-CS), and secondary Scale for the Assessment and Rating of Ataxia (SARA) and Modified Disability Rating Scale (mDRS). In the EP, patients showed a mean NfL reduction of - 16.9% after 1 year (SD 15.0; p = 0.010) and - 33.5% after 2 years (SD 12.8; p < 0.001) of levacetylleucine treatment. CONCLUSIONS:These findings support NfL as a promising surrogate outcome candidate for GM2 and link biochemical improvement with functional benefit, which is reasonably likely to predict both disease activity and treatment response/clinical benefit.

PURPOSE/OBJECTIVE:Pediatric low-grade gliomas (pLGGs) typically have excellent long-term outcomes; intratumoral hemorrhage is a rare, potentially dangerous complication. Hemorrhage risk in the context of molecular alterations and targeted therapies remains poorly characterized. We analyzed the incidence, timing, and independent risk factors for hemorrhage in a large contemporary pLGG cohort. METHODS:We conducted a retrospective cohort study of 236 children with pLGG treated at a single center (2011-2025). Clinical, radiographic, and molecular variables were abstracted. The primary endpoint was spontaneous tumoral hemorrhage. Time-to-event analyses utilized Kaplan-Meier methods and Cox proportional hazards modeling; penalized regression mitigated overfitting given the event rarity. RESULTS:Twelve patients (5.1%) experienced hemorrhage over 2,234 person-years (incidence: 0.54/100 person-years). Hemorrhage typically occurred years after initial tumor diagnosis (median 6.4 years). The presence of a KIAA1549::BRAF fusion in the tumor had the strongest association with hemorrhage, persisting across multivariable models (approximately sixfold increased risk), although estimates were limited by low event number. MAPK inhibitor exposure (specifically binimetinib and tovorafenib) was associated with hemorrhage in univariate analysis but partially confounded by fusion status. CSF diversion independently increased risk at brainstem, optic pathway, and hypothalamic locations. No hemorrhages occurred among patients with underlying genetic syndromes, including neurofibromatosis type 1 and tuberous sclerosis. CONCLUSION/CONCLUSIONS:Hemorrhage in pLGG is an infrequent late complication associated with tumor biology. KIAA1549::BRAF fusion may identify a higher-risk subgroup, with MAPK inhibitor exposure and CSF diversion further modifying risk. These findings support biology-informed surveillance and personalized management strategies for at-risk children.

PURPOSE/OBJECTIVE:SET is a member of the inhibitor of histone acetyltransferases (INHAT) complex, involved in transcriptional silencing and gene regulation. Pathogenic variants in SET are postulated to cause neurodevelopmental disorder (NDD) phenotypes, but as only few individuals are described, detailed clinical information is scarce. Hence, currently counseling on phenotype and prognosis of this condition remains challenging. METHODS:Here we describe the clinical phenotype and mutational spectrum of 23 unreported individuals harboring (likely) pathogenic variants in SET. RESULTS:Phenotypes include global developmental delay with often pronounced hypotonia, delayed motor development and speech and language delay, ultimately evolving into (mild) intellectual disability. Comorbidities include behavioral concerns, sleeping disturbance and variable unspecific ocular problems. Next generation computer-assisted phenotyping using GestaltMatcher showed limited overlapping facial features between affected individuals and differences compared to disorders caused by related chromatin modifying genes. In addition, we generated a DNA methylation signature, able to distinguish individuals carrying pathogenic variants in SET from individuals with other NDDs and healthy controls. We used this DNA methylation signature to assess pathogenicity of two variants of uncertain significance in SET found in two additional individuals. CONCLUSION/CONCLUSIONS:Together, this expands the knowledge on the SET-related disorder and provides novel approaches for its diagnosis.

BACKGROUND:Recently, the gene therapy eladocagene exuparvovec received accelerated approval from the US Food and Drug Administration (as eladocagene exuparvovec-tneq) for treatment of aromatic L-amino acid decarboxylase deficiency (AADCd), a rare, infantile-onset disorder characterized by developmental delays. OBJECTIVES/OBJECTIVE:To conduct a US, modified societal perspective cost-utility analysis comparing eladocagene exuparvovec versus best supportive care (BSC). METHODS:Multistate survival modeling was implemented tracking disease progression from a "no motor function" health state to achievement of motor-function improvements, measured by: (1) multiples of the meaningful score difference (MSD) of the Peabody Developmental Motor Scales-Second Edition (PDMS-2) total score and (2) motor milestones. Eladocagene exuparvovec trials informed clinical inputs. Health-state utilities were from a US time-trade-off study that valued AADCd quality-of-life impacts. Outcomes were discounted (3%); costs were reported in 2024 US dollars. Scenario analyses, characterizing alternative approaches of the multistate survival model analyses and probabilistic sensitivity analysis to assess the impact of parameter uncertainty, were conducted. RESULTS:Discounted incremental quality-adjusted life-years (QALYs) for eladocagene exuparvovec were 20.83 (multiples of the MSD of total PDMS-2) and 18.44 (motor milestones). Incremental cost per QALY ranged from $199,007-$224,104. The scenario and sensitivity analyses results supported the validity of the base case analysis. CONCLUSIONS:Eladocagene exuparvovec is associated with considerable QALY gains compared with BSC. Within the context of other ultra-rare and/or one-time treatments, eladocagene exuparvovec provides substantial clinical improvements at lower cost than many other rare-disease treatments. Findings from this study highlight that eladocagene exuparvovec is an important treatment option for patients with AADCd.

OBJECTIVE:NF2-related schwannomatosis (NF2-SWN) is an autosomal dominant genetic disorder characterized by the development of schwannomas, meningiomas, and spinal ependymomas. Treatment with bevacizumab, a monoclonal antibody against VEGF, has been shown to result in decreased vestibular schwannoma size and hearing improvement in ~50% of NF2-SWN patients. It is unknown whether the same degree of benefit is seen in younger patients compared with older patients. The objective of this study is to determine the association between age and bevacizumab treatment outcomes in NF2-SWN. STUDY DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Thirty-seven patients with NF2-SWN. INTERVENTIONS/METHODS:Bevacizumab. MAIN OUTCOME MEASURES/METHODS:Change in tumor size of 20% or more. RESULTS:This study includes 37 patients with NF2-SWN who were treated with bevacizumab at our institution between 2014 and 2024. They were divided into 2 groups: 22 adults over the age of 25 (26 to 71 y) and 15 adolescent and young adult (AYA) patients under the age of 25 (12 to 24 y). The median treatment duration was 2.1 years. A significantly higher proportion of AYA schwannomas (37.5%, n=9) exhibited radiographic tumor progression during the treatment period compared with those of the older patient group (11.9%, n=5) (P=0.026), despite similar pre-treatment growth rates. There was no significant difference in the proportion of older and younger patients with hearing decline, improvement, or stability (P>0.05). CONCLUSIONS:AYA patients were significantly more likely to exhibit progression of tumor growth during bevacizumab treatment compared with older patients, though no significant differences were detected in hearing outcomes.

BACKGROUND:Spinocerebellar ataxia type 27 B (SCA27B) caused by GAA trinucleotide repeats in the fibroblast growth factor 14 gene is emerging as a common cause of late-onset ataxia. Oscillopsia due to downbeat nystagmus (DBN) and diplopia are common symptoms, yet the causes of diplopia and strabismus patterns are poorly defined. METHODS:Retrospective chart review of 18 patients diagnosed with SCA27B over the past year. RESULTS:Ten of 18 patients had episodic or persistent oscillopsia or diplopia at disease onset, neurologically isolated in 4. Seventeen had detectable DBN, although it was often delayed in onset and was clinically obvious in only 5. Diplopia was present in 14 patients: vertical due to skew deviation (static and or alternating on lateral gaze) (n = 8) and/or horizontal due to vergence dysfunction (n = 11). Symptomatic vergence dysfunction included convergence insufficiency (CI) (n = 4) and divergence insufficiency (n = 5). Thirteen of 16 patients experienced improvement in oscillopsia or imbalance on 4-aminopyridine (4-AP). CONCLUSIONS:Strabismus patterns causing diplopia in patients with SCA27B are, not unexpectedly, largely attributable to cerebellar dysfunction and are not unique to SCA27B. The exceptions to cerebellar localization were CI, sixth nerve palsy, and slow saccades. Careful assessment for DBN in patients presenting with episodic or persistent diplopia from skew deviation or vergence disorders is important, as this may be key to confirming a cerebellar localization, subtle on examination, and guide toward genetic testing and 4-AP treatment.

IMPORTANCE/UNASSIGNED:Acute necrotizing encephalopathy (ANE) is a rare, but severe, neurologic condition for which epidemiologic and management data remain limited. During the 2024-2025 US influenza season, clinicians at large pediatric centers anecdotally reported an increased number of children with influenza-associated ANE, prompting this national investigation. OBJECTIVE/UNASSIGNED:To understand the clinical presentation, interventions, and outcomes among US children diagnosed with influenza-associated ANE. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This study was a multicenter case series of children diagnosed with ANE with longitudinal follow-up. A call for cases was issued via academic societies, public health agencies, and by directly contacting pediatric specialists at 76 US academic centers, requesting cases between October 1, 2023, and May 30, 2025. Inclusion criteria required acute encephalopathy with radiologic evidence of acute thalamic injury and laboratory confirmation of influenza infection in individuals aged 21 years or younger. EXPOSURE/UNASSIGNED:Influenza-associated ANE. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Presenting symptoms, vaccination history, laboratory and genetic findings, interventions, and clinical outcomes, including modified Rankin Scale score (0: no symptoms; 1-2: mild disability; 3-5: moderate to severe disability; 6: death), length of stay, and functional outcomes. RESULTS/UNASSIGNED:Of 58 submitted cases, 41 cases (23 females; median age, 5 years [IQR, 2-8]) from 23 US hospitals met inclusion criteria. Thirty-one cases (76%) had no significant medical history; 5 (12%) were medically complex. Clinical presentation included fever in 38 patients (93%), encephalopathy in 41 (100%), and seizures in 28 (68%). Thirty-nine patients (95%) had influenza A (14 with A/H1pdm/2009, 7 with A/H3N2, and 18 with no subtype) and 2 had influenza B. Laboratory deviations included elevated liver enzymes (78%), thrombocytopenia (63%), and elevated cerebrospinal fluid protein (63%). Among 32 patients (78%) with genetic testing, 15 (47%) had genetic risk alleles potentially related to risk of ANE including 11 (34%) with RANBP2 variants. Among 38 patients with available vaccination history, only 6 (16%) had received age-appropriate seasonal influenza vaccination. Most patients received multiple immunomodulatory treatments, including methylprednisolone (95%), intravenous immunoglobulin (66%), tocilizumab (51%), plasmapheresis (32%), anakinra (5%), and intrathecal methylprednisolone (5%). Median intensive care unit and hospital lengths of stay were 11 days (IQR, 4-19) and 22 days (IQR, 7-36), respectively. Eleven patients (27%) died a median of 3 days (IQR, 2-4) from symptom onset, primarily from cerebral herniation (91%). Among the 27 survivors with 90-day follow-up, 63% had at least moderate disability (modified Rankin Scale score ≥3). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this case series of children with influenza-associated ANE from the 2 most recent influenza seasons in the US, the condition was associated with high morbidity and mortality in this cohort of predominantly young and previously healthy children. The findings emphasize the need for prevention, early recognition, intensive treatment, and standardized management protocols.

BACKGROUND:Small tectal gliomas (TGs) may be unrecognized at initial diagnosis of noncommunicating hydrocephalus, with the etiology typically attributed to idiopathic congenital aqueductal stenosis (CAS). There are 2 published cases of TGs found on follow-up imaging after treatment with endoscopic third ventriculostomy (ETV). The authors investigated for this phenomenon in a large cohort of patients with TG or CAS treated with ETV or CSF shunting. OBSERVATIONS/METHODS:The authors reviewed records at their institution from 1999 to 2024, identifying 10 patients initially diagnosed with presumed idiopathic CAS and later found to have underlying TG. Of these, 7 were younger than 1 year of age at hydrocephalus presentation. The median time from CAS to glioma diagnosis was 13 months. Reasons for repeat imaging that identified glioma included postoperative surveillance and recurrent hydrocephalus. Five (50%) lesions grew over follow-up, and 2 required chemotherapy. LESSONS/CONCLUSIONS:The authors describe the eventual emergence of TG as a probable cause of hydrocephalus in a cohort of patients initially diagnosed with CAS. As most of these cases were identified incidentally on interval imaging to evaluate adequate function of CSF diversion procedures, follow-up imaging to evaluate for tectal expansion should be considered in children, particularly infants, with a new diagnosis of idiopathic CAS. https://thejns.org/doi/10.3171/CASE24695.