Fenfluramine in Rett syndrome: A multidimensional clinical study

Abstract

Objective

Rett syndrome (RTT) is a severe neurodevelopmental disorder frequently associated with drug‐resistant epilepsy, autonomic dysfunction, respiratory abnormalities, sleep disturbances, and behavioral impairment. Fenfluramine has shown efficacy in developmental and epileptic encephalopathies and may provide broader therapeutic benefits through modulation of serotonergic and sigma‐1 receptor pathways.

Methods

We conducted a prospective, open‐label, single‐center study to evaluate the efficacy, safety, and tolerability of adjunctive fenfluramine in patients with classic RTT carrying pathogenic MECP2 variants. Clinical assessments were performed at baseline and after 3 and 6 months of treatment. Outcomes included seizure frequency; clinician‐reported measures of RTT severity, including the Clinical Global Impression–Improvement (CGI‐I) scale, Clinical Severity Scale (CSS), and Motor Behavior Assessment (MBA); caregiver‐reported measures, including the Rett Syndrome Behavior Questionnaire (RSBQ), Sleep Disturbance Scale for Children (SDSC), the EQ‐5D‐5L quality of life scale; and neurophysiological measures using auditory evoked potentials.

Results

Eight patients with classic RTT and drug‐resistant epilepsy were included. Median age was 12 years (range, 6–17 years), and the median number of previously failed antiseizure medications was 5 (range, 2–10). All patients achieved a >50% reduction in seizure frequency. Significant improvements were observed in clinician‐reported outcomes, including CGI‐I, CSS, and MBA scores, and in caregiver‐reported behavioral symptoms assessed with the RSBQ at 3 and 6 months (−7 and −9, respectively). Sleep disturbances improved markedly, with normalization of SDSC scores in all patients by month 6. Respiratory dysfunction, including hyperventilation‐related symptoms, improved during follow‐up. Neurophysiological assessments showed improved attentional and auditory discrimination processing in a subset of patients. Adverse events occurred in 71% of patients, most commonly somnolence; no patient discontinued treatment because of tolerability issues.

Significance

Fenfluramine was associated with clinically meaningful improvements across several symptom domains in patients with RTT, including seizures, respiratory dysfunction, behavior, sleep, and overall disease severity, with an acceptable safety profile. Further evaluation of fenfluramine as a potential multisymptomatic treatment strategy in RTT in prospective controlled studies is warranted.

Plain Language Summary

Rett syndrome is a rare genetic disorder with complex symptoms that affect many aspects of daily life. In this study, fenfluramine was associated with improvements in seizures and several other important symptoms, including behavior, sleep, breathing, and clinical severity. The treatment was generally well tolerated. These results support further studies to determine whether fenfluramine could become a treatment for multiple symptoms of Rett syndrome.

Key points.

• Fenfluramine showed potential as a multisymptomatic treatment for Rett syndrome, improving seizures and multiple core clinical manifestations.

• Clinical benefits included improvements in behavioral symptoms, sleep disturbances, daytime respiratory symptoms, and clinical severity.

• Fenfluramine was generally well tolerated, with no new safety concerns identified during follow‐up.

• These findings support prospective controlled trials of fenfluramine in Rett syndrome.

1. INTRODUCTION

Rett syndrome (RTT) is a genetic neurodevelopmental encephalopathy predominantly affecting girls and most often caused by mutations in the MECP2 gene located on the X chromosome. ¹ , ² , ³ However, the presence of MECP2 mutations is neither necessary nor sufficient for the diagnosis of RTT, which remains based primarily on clinical criteria. ⁴

The clinical phenotype is complex and progressive. It is typically characterized by an apparently normal early developmental period followed by regression, with loss of motor and communication skills and the emergence of characteristic stereotypic hand movements. In addition to these core features, patients frequently present multiple comorbidities, including epilepsy, intellectual disability, scoliosis, feeding difficulties, growth impairment, sleep disturbances, motor dysfunction, and behavioral abnormalities. ⁵ , ⁶

Epilepsy is among the most common and clinically relevant comorbidities in RTT, affecting 70%–90% of patients. Age at onset is variable, and patients have a high rate of pharmacoresistance. ⁷ , ⁸ , ⁹ Suboptimal seizure control contributes significantly to overall morbidity and represents an important unmet therapeutic need.

The pathophysiology of RTT involves disruption of neuronal network organization and function, including dysfunction of neurotransmitter systems that regulate cortical excitability, such as GABAergic, glutamatergic, and serotonergic pathways. ¹⁰ , ¹¹ These alterations, which are shared with other developmental and epileptic encephalopathies (DEEs), support the rationale for therapeutic strategies aimed at broader modulation of neuronal excitability. In particular, abnormalities in serotonergic and noradrenergic systems have been implicated in key comorbidities, including respiratory dysfunction and autonomic instability, suggesting that modulation of monoaminergic neurotransmission may represent a promising therapeutic approach. ¹²

Fenfluramine hydrochloride (FFA) is an antiseizure medication with a multimodal mechanism of action. Randomized controlled trials in patients aged ≥2 years have demonstrated its efficacy for seizures associated with Dravet syndrome and Lennox–Gastaut syndrome, ¹³ as well as benefits across clinical domains beyond seizure control. In addition, a reduced risk of sudden unexpected death in epilepsy (SUDEP) has been reported in patients with Dravet syndrome treated with FFA. ¹⁴

The pharmacological effects of FFA include serotonin release and activation of serotonergic receptors (5‐HT1D, 5‐HT2A, and 5‐HT2C), as well as positive modulation of the sigma‐1 receptor, which contributes to reduced neuronal hyperexcitability and restoration of inhibitory control. FFA also influences other neurotransmitter systems, including dopaminergic and noradrenergic pathways. ¹⁵ Notably, the sigma‐1 receptor has emerged as a promising therapeutic target in RTT. Other sigma‐1 modulators, such as ANAVEX2‐73 (blarcamesine), have shown encouraging clinical signals in this population, further supporting the rationale for exploring fenfluramine in RTT. ¹⁶

Given that alterations in serotonergic neurotransmission and excitatory–inhibitory balance play a central role in both epileptogenesis and other clinical manifestations of RTT, ¹⁰ FFA may offer pleiotropic therapeutic benefits beyond seizure control. Consistent with this hypothesis, fenfluramine has also shown efficacy in other developmental and epileptic encephalopathies (DEEs), such as CDKL5 deficiency disorder, in which certain phenotypic features overlap with RTT. ¹⁷

However, clinical evidence on the use of fenfluramine in patients with RTT secondary to MECP2 mutations remains very limited and is confined to isolated reports and specific clinical experiences, ¹⁸ including its use for hypoxic spells or paroxysmal autonomic episodes. ¹⁹

In the absence of controlled studies in this population, this prospective study evaluates the efficacy, safety, and tolerability of FFA in a cohort of patients with RTT. We use a multidimensional approach, including validated clinical and functional scales, to assess the drug's effects on core features, including behavioral disturbances and autonomic dysfunction, alongside its established role in seizure control.

2. MATERIALS AND METHODS

2.1. Participants

This was a prospective, open‐label, single‐arm study designed to evaluate the efficacy, safety, and tolerability of FFA as adjunctive therapy in pediatric patients with RTT secondary to MECP2 mutations. Patients were recruited between January 2024 and October 2025 from the Neurology Department of Niño Jesús University Children's Hospital (Madrid, Spain), a tertiary referral center with a multidisciplinary Rett syndrome clinic currently providing follow‐up for approximately 100 patients with RTT, nearly 70% of whom have epilepsy.

The study included eight patients with RTT secondary to MECP2 mutations. Seven patients were followed prospectively, and one was included retrospectively. All patients received FFA (Fintepla®, 2.2 mg/mL oral solution) as add‐on therapy. All patients received oral feeding, and none required gastrostomy throughout the study. Patients were eligible for treatment if they had no echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension before treatment initiation.

The study was conducted in accordance with the International Council for Harmonization Good Clinical Practice (ICH‐GCP) guidelines and local standard operating procedures.

2.2. Inclusion and exclusion criteria

Eligible participants were children aged 2–18 years with a diagnosis of typical or classic RTT according to the RettSearch Consortium 2010 revised criteria and a documented pathogenic mutation in the MECP2 gene. Patients were excluded if adequate clinical follow‐up at our center could not be ensured, as discontinuation of follow‐up precluded complete data collection.

2.3. Procedures, study design, and assessment of efficacy

Demographic and clinical data, including MECP2 variants, were collected for all participants. The study consisted of a baseline observation period followed by a titration phase conducted according to routine clinical practice and a subsequent maintenance phase. During this phase, patients received FFA (Fintepla® oral solution) as add‐on therapy, initially at a dose of 0.2 mg/kg/day and titrated up to 0.7 mg/kg/day. FFA was administered twice daily according to clinical response and tolerability, up to a maximum dose of 26 mg/day. In all prospectively enrolled patients, dose titration was completed before the first scheduled follow‐up visit. Clinical assessments were performed at baseline and at 3 and 6 months of treatment.

Efficacy outcomes were prospectively categorized into four domains reflecting clinically relevant aspects of RTT (Table 1). Seizure‐related outcomes during the baseline period and throughout follow‐up were assessed using caregiver‐completed daily seizure diaries. The diaries were used to document all countable seizure types according to the 2017 International League Against Epilepsy (ILAE) classification. ²⁰

TABLE 1.

Efficacy domains and assessment tools.

Efficacy domain	Assessment tools
Domain 1: Seizures	Caregiver‐reported seizure diaries (ILAE 2017 classification)
Domain 2: Clinician‐reported outcomes	Clinical Global Impression–Improvement (CGI‐I) Clinical Severity Scale (CSS) Motor Behavior Assessment (MBA) Clinical Global Impression of Change–Breathing disorders scale (CGIC‐Breathing Disorders)
Domain 3: Caregiver‐reported outcomes	Rett Syndrome Behavior Questionnaire (RSBQ) Sleep Disturbance Scale for Children (SDSC) Quality of life assessed using the EQ‐5D‐5L Caregiver Global Impression of Change–Breathing Disorders scale (CaCGIC‐Breathing Disorders)
Domain 4: Neurophysiological measures	Auditory evoked potentials (AEPs)
Time points: Baseline, 3 months, 6 months

Drug‐resistant epilepsy (DRE) was defined according to ILAE criteria as failure to achieve sustained seizure freedom after adequate trials of two appropriately selected and well tolerated antiseizure medication regimens, either as monotherapy or in combination. ²¹

Antiseizure efficacy was evaluated by per‐protocol analysis comparing frequency of seizures at baseline with seizure frequency at 3 and 6 months after treatment initiation. Treatment response was categorized as seizure freedom, ≥50% reduction in seizure frequency, <50% reduction, no change, or worsening. A ≥50% reduction was considered a clinically meaningful response.

Clinician‐reported syndrome‐specific outcomes included validated scales commonly used in RTT clinical trials, such as the Clinical Global Impression–Improvement (CGI‐I) scale. In this study, the CGI‐I was assessed using Rett syndrome–specific anchors, ²² consistent with its use in randomized clinical trials of trofinetide that demonstrated sensitivity to treatment effects. ²³ Additional clinician‐rated measures included the Rett Syndrome Motor Behavior Assessment (R‐MBA) ²⁴ and the Clinical Severity Scale (CSS). ²⁵ The Clinical Global Impression of Change (CGIC) was also used as a clinician‐rated global measure of improvement or worsening from baseline and, in this study, was specifically applied to assess changes in clinically relevant daytime respiratory disturbances, particularly hyperventilation and apneic episodes.

The primary efficacy endpoint was defined as the change from baseline to 3 and 6 months in these Rett syndrome–specific clinical scales.

Caregiver‐reported outcomes included the Rett Syndrome Behavior Questionnaire (RSBQ), a validated instrument that assesses behavioral and emotional features associated with RTT and widely used in clinical trials, including studies accepted by regulatory agencies as co‐primary outcome measures. ²³ Sleep disturbances were assessed using the Sleep Disturbance Scale for Children (SDSC), with scores below 39 considered within the normal range. ²⁶ Caregiver quality of life was evaluated using the EQ‐5D‐5L, a standardized and validated instrument. ²⁷ The Caregiver Global Impression of Change–Breathing Disorders scale (CaCGIC‐Breathing Disorders) was used to specifically assess improvement or worsening of respiratory disorders.

Changes from baseline to 3 and 6 months were analyzed, with particular emphasis on total RSBQ scores and individual RSBQ domains.

Neurophysiological measures included objective assessment of alertness using auditory evoked potentials (AEPs), specifically P100, mismatch negativity (MMN), and P300 components, which were analyzed to evaluate changes in attentional processing over time.

2.4. Statistical methods

A descriptive analysis of qualitative and quantitative variables was performed. Qualitative variables were reported as frequency and percentage values, and quantitative variables as median, range, and interquartile range. Comparisons between two time points were performed using the McNemar test for dichotomous variables and the Wilcoxon signed‐rank test for continuous variables. Associations between a continuous variable and an independent dichotomous variable were analyzed using the Mann–Whitney U test. Correlations were assessed using Spearman's rank correlation coefficient (rho).

Data were analyzed using IBM SPSS 30 (IBM Corporation, Armonk, NY, USA). The threshold for statistical significance was based on a 95% confidence interval.

3. RESULTS

3.1. Sample description

Eight patients fulfilling clinical criteria for classic RTT and carrying pathogenic variants in the MECP2 gene were included. The cohort harbored a heterogeneous spectrum of pathogenic MECP2 variants, including one missense mutation (R306C), two nonsense mutations (R294X and P389X), three frameshift variants (L386QfsX4, A263PfsX26, and P388RfsX8), and two large deletions involving the MECP2 locus (partial deletion of exons 3–4 and an Xq28 deletion). The median age was 12 years (range, 6–17 years).

All patients had epilepsy, and all met criteria for DRE. ²¹ The median number of previously failed ASMs was 5 (range, 2–10), and two patients had also received ketogenic diet therapy. At baseline, the median number of concomitant ASMs was 2 (range, 1–4). Topiramate, lacosamide, and valproic acid were the most commonly used concomitant ASMs. During follow‐up, concomitant ASM regimens remained generally stable, although dose reduction or discontinuation of one or more concomitant ASMs was possible in some patients.

The most common seizure type was focal seizures, observed in 62.5% of patients. According to the ILAE epilepsy syndrome classification, ²⁸ two patients met the diagnostic criteria for Lennox–Gastaut syndrome, two had unspecified DEE, two had generalized epilepsy, and two had focal epilepsy. Reflex seizures associated with respiratory dysrhythmia, predominantly following apneic episodes, were observed in four patients (50%).

Fenfluramine was initiated at a dose of 0.2 mg/kg/day. The median dose increased to 0.4 mg/kg/day at month 3 and 0.5 mg/kg/day at month 6.

Eight patients were included in the study. Seven were enrolled prospectively, whereas one was included retrospectively and contributed only 6‐month follow‐up data. Among the prospectively enrolled patients, one discontinued fenfluramine after 5 months because of lack of efficacy and therefore did not complete the scheduled 6‐month assessment. Consequently, efficacy analyses included seven patients at both the 3‐ and 6‐month follow‐up visits, although different patients contributed to each time point.

3.2. Efficacy

3.2.1. Seizures

All patients experienced a reduction in seizure frequency greater than 50%. At month 3, four patients (57%) achieved complete seizure freedom, and three patients (43%) remained seizure‐free at month 6 (Table 2).

TABLE 2.

Treatment response according to seizure frequency reduction.

Response to treatment	3 months (n = 7)	6 months (n = 7)
Seizure‐free	4 (57%)	3 (43%)
>90% reduction	1 (14%)	3 (43%)
>50% reduction	2 (29%)	1 (14%)
<50% reduction	0 (0%)	0 (0%)
No change	0 (0%)	0 (0%)

3.2.2. Clinician‐reported outcomes

The median baseline CGI‐I score was 5. Treatment with fenfluramine was associated with significant improvement at both month 3 and month 6, with median changes from baseline of −0.7 at month 3 (95% CI, −0.8 to −0.3; p = 0.028) and − 0.8 at month 6 (95% CI, −1.2 to −0.2; p = 0.018) (Figure 1).

FIGURE 1.

Longitudinal changes in clinician‐ and caregiver‐reported outcome measures during fenfluramine treatment at baseline, 3 months, and 6 months. (A) Clinical Global Impression–Improvement (CGI‐I); (B) Clinical Severity Scale (CSS); (C) Quality of life (EQ‐5D‐5L); (D) Motor Behavior Assessment (R‐MBA); (E): Rett Syndrome Behavior Questionnaire (RSBQ); (F) Sleep Disturbance Scale for Children (SDSC).

The median baseline MBA score was 22 (range, 11–25). Significant improvements were observed at month 3 and month 6, with median changes of −2 at month 3 (95% CI, −4 to −1; p = 0.041) and − 2 at month 6 (95% CI, −9 to 0; p = 0.027) (Figure 1).

The median baseline CSS score was 27 (range, 19–34). Fenfluramine treatment was associated with significant improvement at both follow‐up visits, with median changes of −2 at month 3 (95% CI, −6 to 0; p = 0.026) and −2 at month 6 (95% CI, −9 to 0; p = 0.017) (Figure 1C).

Sustained improvement in breathing disorders was observed in six of seven patients after fenfluramine initiation; in three of these patients, the disorders were rated as “much better” on the CGIC (Figure 2).

FIGURE 2.

Response of breathing disorders according to the CGIC (Clinical Global Impression Change) and CaCGIC (Caregiver Global Impression of Change) scales at 3 and 6 months after treatment with fenfluramine.

3.2.3. Caregiver‐reported outcomes

The median baseline RSBQ total score was 41 (range, 32–57). Significant improvements were observed following fenfluramine treatment, with a median change from baseline of −7 (95% CI, −22 to −2; p = 0.017) at month 3 and − 9 (95% CI, −22 to −4; p = 0.018) at month 6 (Figure 1). Changes across all RSBQ domain subscores consistently favored fenfluramine treatment at both Month 3 and Month 6, with improvements observed in general mood, breathing problems, hand behaviors, repetitive face movements, body rocking and facial expressions, nighttime behaviors, fear/anxiety, walking/standing, and uncategorized behaviors (Figure 3).

FIGURE 3.

RSBQ subscores. Treatment differences with 95% CIs for changes in RSBQ subscores from baseline to Month 3 and Month 6.

With respect to sleep outcomes assessed using the SDSC, six patients (75%) had pathological baseline scores (>39 points). At month 3, only one patient continued to have an abnormal score, whereas by month 6 all patients had normalized SDSC scores (<39 points). The median baseline SDSC score was 45 (range, 35–53), with significant reductions of −5 at month 3 (95% CI, −16 to 2; p = 0.041) and −3 at month 6 (95% CI, −8 to −2; p = 0.018) (Figure 1).

No statistically significant changes were observed in parental quality of life, as assessed using the EQ‐5D‐5L questionnaire. The median baseline score was 80 points (range, 55–97), with a median score of 90 at month 3 and no significant differences from baseline at either follow‐up assessment (Figure 1).

According to caregivers, treatment with fenfluramine was associated with improvement in apnea and hyperventilation in seven patients at 3 months and seven patients at 6 months, as measured using the CaCGIC (Figure 2).

No significant correlations were identified between fenfluramine dose and efficacy outcomes across the evaluated scales using Spearman rho correlations, except for the SDSC score at month 3 (p = 0.018), an association that was not maintained at month 6.

3.2.4. Neurophysiological measures

Evoked potentials were assessed at baseline, month 3, and month 6 in five patients. Improvement in the brain's automatic response to discriminable changes in auditory stimulation was observed in 3/5 (60%) patients.

One patient developed a newly detectable P300 (P3a potential), suggesting improved attentional orienting and auditory discrimination processing. Another patient showed evidence of improved cortical auditory function, with the emergence of the N100 component. A third patient demonstrated discrete improvements in both latency and amplitude of the P300 (P3a) component.

These findings suggest enhanced attentional and auditory discrimination processing, with effects persisting through month 6.

3.3. Adverse events

Adverse events (AEs) were reported in five patients (71%). The most common AEs at month 3 were drowsiness (60%, n = 3), diarrhea (40%, n = 2), and motor restlessness (20%, n = 1). The frequency of AEs decreased by month 6, with only one patient continuing to report drowsiness and one patient reporting persistent motor restlessness. No patients discontinued treatment because of AEs. No clinically relevant weight loss or appetite‐related adverse events were observed during follow‐up.

4. DISCUSSION

This study contributes promising initial evidence regarding the efficacy of fenfluramine across multiple clinical domains of Rett syndrome, assessed using validated clinical scales. Fenfluramine was evaluated on the basis of the hypothesis that its multimodal mechanism of action may provide therapeutic benefits in RTT. ¹⁵ Fenfluramine is a particularly attractive therapeutic strategy due to its effects on serotonergic neurotransmission, modulation of the excitation–inhibition balance, and influence on noradrenalinic pathways. From a pathophysiological perspective, these systems play a key role in several core manifestations of Rett syndrome, including apneas, autonomic dysfunction, and respiratory disturbances, particularly during wakefulness or under conditions of physiological stress. ¹⁰ , ¹² , ²⁹

The efficacy of fenfluramine for epileptic seizures observed in our cohort is consistent with previous reports demonstrating its efficacy in convulsive seizure types. ³⁰ , ³¹ In our study population, five of eight patients (62.5%) had focal seizures. Moreover, the efficacy of fenfluramine in LGS has been demonstrated in randomized clinical trials, which is particularly relevant given that two patients in our cohort fulfilled the diagnostic criteria for LGS. ³²

Respiratory dysfunction is highly prevalent in RTT, affecting up to 93% of patients, and includes manifestations such as hyperventilation, apneas, breath‐holding spells, and aerophagia. These abnormalities are thought to reflect dysfunction of brainstem regulatory circuits. ¹⁰ , ¹¹ Currently, therapeutic options specifically targeting respiratory dysfunction in RTT are very limited, with topiramate being one of the few antiseizure medications reported to have beneficial effects on hyperventilation. ³³ , ³⁴

In our cohort of 100 patients with RTT, approximately 30% of focal seizures in classic RTT corresponded to reflex seizures triggered by hyperventilation and apnea (unpublished data). In the present study, all four patients with this seizure subtype achieved complete freedom from these events following initiation of fenfluramine and remained seizure‐free throughout follow‐up. This finding suggests that seizure improvement may be partially mediated by the beneficial effects of fenfluramine on respiratory dysfunction, an observation further supported by improvements in breathing disorders as assessed using the CGIC and CaCGIC scales.

Improvement in respiratory abnormalities with fenfluramine has previously been reported. ¹⁹ , ³⁵ In a series of patients with autism spectrum disorder and associated respiratory disturbances treated with fenfluramine, four of five patients with frequent Valsalva maneuvers experienced suppression of stereotyped respiratory behaviors and syncopal episodes over periods ranging from 2 to 18 months. ¹⁹ These findings support the hypothesis that fenfluramine may have a direct effect on central mechanisms involved in respiratory regulation. These findings should be interpreted with caution, as respiratory outcomes were based on clinician‐ and caregiver‐reported clinical scales rather than objective measures of respiratory function.

Patients with Rett syndrome are also at increased risk of SUDEP, ³⁶ likely due to the interaction between DRE (particularly generalized tonic–clonic seizures) and severe baseline autonomic dysfunction. This autonomic impairment involves abnormal regulation of both cardiac and respiratory function, particularly under conditions of physiological stress such as epileptic seizures. ²⁹ Evidence from studies of Dravet syndrome suggests that fenfluramine may reduce the risk of SUDEP through a dual mechanism: first, by providing sustained control of severe convulsive seizures, and second, through direct modulation of central respiratory and neuronal excitability pathways mediated by serotonergic and sigma‐1 receptor systems. ¹⁴ These mechanisms may also be relevant in Rett syndrome, particularly given the pathophysiological overlap between the two disorders in autonomic and respiratory dysfunction. ²⁹ , ³⁶

Rett syndrome is a complex multisystem disorder characterized by a broad spectrum of neurological and systemic manifestations. Treatments capable of improving multiple clinical domains simultaneously are of particular therapeutic interest. The marked improvement observed across several Rett syndrome–specific scales in our cohort suggests that fenfluramine may exert a multisymptomatic effect beyond seizure control. Improvements were observed not only in behavioral and neuropsychiatric domains, as reflected by the RSBQ, which does not specifically evaluate epileptic seizures, but also in global measures of disease severity, including CGI, CSS, and MBA scores. Importantly, several items included in these scales correspond to relatively stable clinical characteristics that are generally not expected to change substantially over short follow‐up periods, further supporting the clinical relevance of the observed changes.

Sleep disturbances constitute another major source of morbidity in Rett syndrome, affecting up to 80% of patients and requiring pharmacological treatment in a substantial proportion of cases. ³⁷ Following 6 months of fenfluramine treatment, all patients in our cohort achieved normalization of sleep‐related scale scores, suggesting a potential beneficial effect on sleep regulation. Although the mechanisms underlying this improvement remain incompletely understood, they may be related to serotonergic modulation and the overall improvement in autonomic and respiratory dysfunction observed after treatment. ¹⁵

AEPs provide an unbiased, stable measure of cortical function that reflects the neural underpinnings of RTT. ³⁸ In our cohort, 3/5 patients showed more robust automatic responses, suggesting enhanced detection of environmental regularity. ³⁹ Since reduced AEP amplitudes correlate with greater clinical severity, ³⁸ the emergence of the N100 component indicates improved basic auditory decoding. ⁴⁰ Furthermore, newly detectable P3a responses and improved P300 metrics reflect optimized involuntary attention and processing efficiency, ³⁹ , ⁴¹ functions usually attenuated in RTT. The persistence of these findings through month 6 confirms intersession repeatability and a stable therapeutic impact. ³⁸ Given the exploratory nature of these assessments and the limited number of patients studied, these findings should be interpreted cautiously. Nevertheless, AEPs have emerged as promising objective biomarkers in Rett syndrome and may provide useful outcome measures for future therapeutic trials.

Currently, several therapeutic strategies are under development for the treatment of Rett syndrome. Among them, blarcamesine (ANAVEX2‐73), a sigma‐1 receptor agonist currently undergoing phase 2/3 clinical trials, has shown promising results through modulation of cellular homeostasis and neuroprotective mechanisms. ¹⁶ The potential overlap between the mechanisms of action of blarcamesine and fenfluramine, particularly at the sigma‐1 receptor level, further supports the biological rationale for exploring fenfluramine as a therapeutic option in RTT. In parallel, gene therapy approaches remain in preclinical stages of development. Trofinetide became the first and only FDA‐approved treatment for RTT in 2023, ⁴² highlighting the urgent need for additional therapies targeting the multiple clinical manifestations of this disorder.

Adverse events were frequent, occurring in 71% of patients, with somnolence being the most commonly reported event. However, adverse events persisted at 6 months in only two patients, and no patient discontinued treatment because of tolerability issues, suggesting an acceptable safety profile in this population.

Our study has several limitations, including its single‐center design and small sample size. In addition, although the cohort included a broad spectrum of pathogenic MECP2 variants, the limited sample size precluded genotype–phenotype or genotype‐treatment response analyses. Furthermore, only patients with DRE were included, limiting the generalizability of the findings to the broader Rett syndrome population. Furthermore, the absence of a control group and the observational nature of the study preclude definitive causal conclusions. Nevertheless, the findings support the development of prospective controlled clinical trials to evaluate the potential of fenfluramine as a symptomatic treatment for Rett syndrome beyond its antiseizure effects.

5. CONCLUSIONS

Fenfluramine was associated with promising and clinically meaningful improvements in seizures, behavioral symptoms, sleep disturbances, daytime respiratory symptoms, and overall disease severity in patients with Rett syndrome and DRE. Fenfluramine was generally well tolerated, supporting its potential role as a multisymptomatic treatment in Rett syndrome. Prospective controlled studies incorporating objective respiratory outcome measures will be required to confirm these findings.

AUTHOR CONTRIBUTIONS

Elena González‐Alguacil, as the lead investigator of the study, Elena González‐Alguacil contributed substantially to the conceptualization and design of the study, the analysis and interpretation of the results, and the overall supervision of the study. She was responsible for drafting and writing the manuscript and coordinated the integration of the clinical and research findings. Nuria Lamagrande Casanova, as a member of the clinical team involved in the management of patients with Rett syndrome, Nuria Lamagrande Casanova contributed substantially to the clinical follow‐up of patients and acquisition of clinical data. She also contributed to the analysis and interpretation of the results, and critically reviewed and revised the manuscript for important intellectual content. María Ballará Petitbó, as a clinician involved in the clinical care and follow‐up of patients with Rett syndrome included in the study, contributed to the acquisition of clinical data and critically reviewed and revised the manuscript for important intellectual content. Verónica Cantarín‐Extremera, as a clinician involved in the clinical care and follow‐up of patients with Rett syndrome included in the study, Verónica Cantarín‐Extremera contributed to the acquisition of clinical data and critically reviewed and revised the manuscript for important intellectual content. César Rodríguez Sánchez, as a clinician involved in the clinical care and follow‐up of patients with Rett syndrome included in the study, contributed to the acquisition of clinical data. Raquel Díaz Conejo, as a clinician involved in the clinical care and follow‐up of patients with Rett syndrome included in the study, Raquel Díaz Conejo contributed to the acquisition of clinical data. Rocío Trincado Lamuño, as a clinician involved in the clinical care and follow‐up of patients with Rett syndrome included in the study, contributed to the acquisition of clinical data. Víctor Soto Insuga, as a senior investigator involved in the study, Víctor Soto Insuga contributed substantially to the conceptualization and design of the study and to its overall supervision. He also provided intellectual input into the interpretation of the findings and critically reviewed and revised the manuscript for important intellectual content. Adrián García Ron, adrián García Ron contributed to the critical review and revision of the manuscript for important intellectual content. Manuel Luján Bonete, as a member of the neurophysiology team involved in the study, Manuel Luján Bonete contributed substantially to the neurophysiological assessment of the patients and critically reviewed and revised the manuscript for important intellectual content. David Mansilla Lozano, as a member of the neurophysiology team involved in the study, David Mansilla Lozano contributed substantially to the neurophysiological assessment of the patients and critically reviewed and revised the manuscript for important intellectual content. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

FUNDING INFORMATION

Financial support for medical editorial assistance was provided through a grant from UCB.

CONFLICT OF INTEREST STATEMENT

Dr. Gonzalez Alguacil received funding for research and educational activities from UCB, Eisai, Nutricia, Jazz Pharma, and Acadia Pharma. Dr. Soto Insuga, Dr. García Peñas, Dr. Lamagrande, and Dr. García Ron received funding for research and educational activities from UCB, Eisai, Nutricia, Biocodex, Jazz Pharma, and Takeda. Dr. Cantarín Extremera received funding for research and educational activities from UCB, Eisai, Nutricia, Takeda and Jazz Pharma. Dr. Ballará Petitbó received funding for research and educational activities from UCB and Jazz Pharma. Dr. Díaz Conejo and Dr. Rodríguez Sánchez have no conflicts of interest to declare.

ETHICAL APPROVAL

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

The study protocol was approved by the Research Ethics Committee of Hospital Infantil Universitario Niño Jesús, Madrid, Spain (approval number: R‐0105/25).

CONSENT

Written informed consent for participation in the study and for publication of anonymized data was obtained from the participants' parents or caregivers.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.