Rett syndrome (RTT) is a severe neurodevelopmental disorder (1) affecting approximately 1 in every 10,000–15,000 live female births, caused by variant in the MECP2 gene on chromosome Xq28, which encodes a protein essential for transcriptional regulation and the development and plasticity of the central nervous system (2). Genotype–phenotype correlation studies have shown that while large deletions in MECP2 are linked to the most severe forms of RTT, specific missense variant (e.g., R133C, T158M, and R306C) account for roughly 25% of cases and are generally associated with milder clinical presentations (3).Clinically, RTT is classified into typical (classic) and atypical (variant) forms (4). Among the atypical subtypes, the Zappella variant—also known as the Preserved Speech Variant (PSV) (Z-RTT)—is most frequently associated with the R133C variant. This variant is marked by a delayed regression phase and milder deficits in hand function and intellectual abilities. R133C variant is associated with a milder clinical presentation, characterized by improved ambulation, better hand function, and a higher likelihood of speech acquisition (5) (See Supplementary Table S1). To our knowledge, the most recent studies detailing the clinical profiles of Z-RTT/PSV date back to 2016 (6).

We present the case of a 13.9-year-old female patient with the p.R133C variant of RTT, who has been followed for over 10 years at the Child and Adolescent Psychiatry Unit of Bambino Gesù Children's Hospital, IRCCS. This case report aims to describe her developmental trajectory, clinical features, and the therapeutic approaches implemented over the years.

F. is the firstborn of non-consanguineous parents, he pregnancy was uneventful except for a threatened miscarriage during the first trimester, managed with maternal rest. She was born at 41 weeks by dystocic delivery with vacuum extraction; growth parameters at birth were normal (3,170 g; head circumference 35 cm). Her parents reported that early motor milestones were achieved on time (head control by 3 months, trunk control by 6 months, and independent walking at 14 months). Clinical symptoms began at 24 months, when F. exhibited social withdrawal, reduced eye contact, difficulties in relationships, and limited verbal communication. Hand stereotypies (e.g., midline pinching and hand clapping) were evident from the initial evaluation. Consequently, she underwent an outpatient assessment at our center, and at 3 years of age (in 2014) she received a diagnosis of autism spectrum disorder. At age 5, exome analysis identified a variant in the MECP2 gene, confirming a diagnosis of Z-RTT/PSV. Around the age of 9, the patient began showing vocal and complex motor tics, mainly affecting the upper limbs and trunk. These movements appeared distinct from her pre-existing autistic stereotypies and led to a clinical diagnosis of TS. TS is a neurodevelopmental disorder characterized by sudden, repetitive, non-rhythmic motor and vocal tics (1), typically emerging in school-age children and affecting approximately 0.5% of those aged 4–18 (7). Diagnosis requires the presence of multiple motor tics and at least one vocal tic, persisting for more than one year (8). About a year after the onset of tics, she developed anxiety symptoms. By the age of 13.5, self-injurious behaviors such as skin picking had appeared. Currently, she presents with toe walking, broad-based gait, and progressive hypertonia with rigidity of the limbs. She has moderate intellectual disability, limited verbal output, and worsening hand stereotypies that have impaired her fine motor abilities and made the use of augmentative and alternative communication (AAC) has become increasingly challenging.

Figure 1 illustrates the timeline of F.'s clinical history.

This study examines the developmental trajectory, clinical and genetic features, and therapeutic approaches in a young female patient with Z-RTT/PSV, contextualizing these aspects within the existing literature.

The preserved speech variant (Z-RTT/PSV) (6, 20), is generally associated with a milder clinical presentation compared to classic RTT (20). The recurrent p.R133C variant in MECP2, found in our patient, has been previously described in individuals with preserved speech and in families with mildly affected members (two mildly affected sisters and an asymptomatic mother) (21).

Zappella et al. analyzed a cohort of females with preserved language, including two with the R133C variant, and proposed that R133C may serve as a predictive marker of a less severe phenotype (20). In this context, our patient exhibits some similarities with the typical presentation of Z-RTT/PSV, specifically in the phenotypic profile most commonly observed in patients with the R133C variant, such as the achievement of motor developmental milestones within expected timelines, early language development leading to verbal communication characterized by combinations of two to three words (6), and the classic hand stereotypies (5, 6). However, our patient also presents certain characteristics that deviate from those described in the “Zappella criteria” and support the phenotypic traits observed in a small percentage of females with of Z-RTT/PSV in the most recent cohort study available in the literature (22). These include the loss of previously acquired language skills, including comprehension (20), more severe intellectual disability with a progressive decline in cognitive abilities over the years (6), autistic traits that appear to be more pronounced and have worsened during adolescence (6), a decrease in head circumference despite normal stature (22), a progressive decline in fine motor skills and the gradual onset of rigidity and hypertonia (22). While these features have been observed in some cases of R133C phenotypes (5) the developmental trajectories of such abilities, particularly their potential regression, have not been described in detail in the literature. These aspects, observed in our patient, are crucial for prognosis and treatment planning. Given these atypical clinical features, not commonly reported in Z-RTT/PSV alone, we further explored the possibility of a modifying genetic mechanism. Although Rett-like phenotypes are primarily driven by MECP2 loss-of-function, it is well established that MECP2 deficiency disrupts GABAergic signaling to such an extent that GABAergic modulators have been proposed as potential therapeutic targets in RTT. Importantly, reduced GABAergic inhibition has been demonstrated in Tourette syndrome (23), supporting the hypothesis that GABAergic dysfunction plays a central role in Tourette pathophysiology. The coexistence of the GABBR1 p.F692S variant of uncertain significance raises the hypothesis that this allele could further impair GABA_B receptor–mediated neurotransmission, thereby exacerbating specific features in our proband—namely late-onset regression, complex motor and vocal tics, skin-picking, and severe behavioral dysregulation—that are not typically seen in Z-RTT/PSV. This model reconciles the dual-genotype concept with our segregation data: the GABBR1 variant may potentially act additively or as a modifier of the MECP2 phenotype, intensifying the GABAergic dysfunction already present in the proband. Functional studies are required to validate this interaction.Medical co-occurrence: F. did not present any respiratory or cardiac abnormalities, consistent with what is described in the literature regarding the Z-RTT/PSV (6). However, she has experienced gastroesophageal reflux with cyclic vomiting for approximately two years (in the absence of any organic alterations (EGDS and negative biopsy). This autonomic alteration has been found in less than half of females with Z-RTT/PSV, specifically in those carrying the R133C variant (5), and according to the literature, it presents in a milder form compared to classic forms (22). From a growth perspective, our patient, in accordance with “Zappella criteria”, did not exhibit growth abnormalities during childhood and currently shows height and weight within the appropriate percentiles for her age (6). Head circumference exhibited consistent growth during the first year of life, like all cases of Rett syndrome (22). In the following years, she currently falls below the 3rd percentile, as reported in a small percentage of patients with the R133C variant described in the literature (5). In terms of motor skills, our patient achieved motor development milestones within the typical timeframe, as outlined in the Zappella criteria (6), although she has consistently demonstrated gross motor difficulties (e.g., she is unable to ride a bicycle). Over the past two years, she has exhibited progressive postural rigidity, with the onset of muscle hypertonia. At age 13.9, cogwheel rigidity was noted during the neurological examination. Such features have been observed in females with Z-RTT/PSV carrying the R133C variant, albeit generally to a lesser extent than in classic RTT, with only a very small percentage of patients losing the ability to walk independently (5, 22). In the case of F., the hypertonia and rigidity observed have proven to be highly disabling and noteworthy. Furthermore, consistent with the literature, we did not observe significant scoliosis or kyphosis (6).

Neuropsychological and psychopathological features: Our patient has demonstrated a progressive and homogeneous decline in cognitive abilities (See Table 1). In just under 10 years, F. has lost 46 points in her cognitive level, resulting in a NVIQ of 45, indicating moderate intellectual disability. This characteristic deviates from what females with the clinical variant known as Z-RTT/PSV usually exhibit—a milder cognitive impairment compared to those with typical RTT (22). To the best of our knowledge, no quantitative data on intellectual development have been documented in the literature for individuals with the R133C variant.

Regarding adaptive functioning, to our knowledge, there are no descriptions in the literature in both typical RTT and Z-RTT/PSV. Our patient consistently exhibited levels lower than those corresponding to her cognitive development (See Table 1). Future research is necessary to evaluate other cases of deterioration in acquired skills. From a linguistic perspective, our patient initially exhibited normal language development (4), followed by the characteristic regression observed in Rett syndrome, although this occurred at a later age (after 5 years), consistent with the criteria for the clinical variant of Z-RTT (6). However, our patient experienced a gradual recovery of language abilities starting at age seven, in line with what Zappella described in his criteria for the preserved speech variant (6) and in some clinical cases reported in the literature (24). Based on the available data on the R133C variant, it emerges that most patients retain at least a minimal level of language, although verbal abilities show significant variability (5). However, to our knowledge, the literature does not provide a detailed description of the developmental trajectory and potential regression of these abilities. Unlike most females with the Z-RTT/PSV, our patient began to experience a gradual decline in her language functions from the age of eleven, reaching a point at 13.9 years where she only occasionally used single words, primarily for requests. This significant regression in language has been described in a minority of cases in the literature (25), highlighting that while some patients may show language skill regression, their language comprehension typically remains relatively intact, a characteristic not observed in our patient (25). Concerning the autistic symptomatology F. appears to align with the criteria described by Zappella, which mention autism characterized by an improvement during the latter part of the first decade of life, followed by a significant deterioration (22).

Hands stereotypies a defining feature of RTT (26) worsened since the age of 10, significantly impacting her previously acquired autonomies, such as eating and drinking independently, as well as her usage of AAC strategies. In addition to finger-twisting movements, our patient began exhibiting challenging behaviours, such as self-directed and other-directed skin-picking at the age of 11. Specific cases of skin-picking have not been documented in relation to the clinical variant of Z-RTT/PSV in the literature. Finally, internalizing and externalizing symptoms have significantly impacted her overall functioning since the age of 13. The presence of anxiety and depression has been documented in patients with classic RTT, while externalizing symptoms appear more prevalent in those with greater preserved motor function (27). Literature on the atypical Z-RTT form is limited, although it seems that the intensity of general anxiety is inversely proportional to the clinical severity presented by the patient (22). The emergence of coprolalia and complex motor tics in our patient at age 9.4 (2020) is likely more associated with a family history of TS than with Z-RTT. Genetic testing is underway to confirm this hypothesis.

Psychosocial and pharmacological interventions In line with the literature (28), integrated psychosocial interventions (ABA, DIR) and the use of AAC tools were applied. During the last Day Hospital observation in September 2024, our patient showed increased environmental participation and fewer crying episodes while listening to music. Regarding pharmacological treatment, no recognized effective medications for RTT exist, except for Trofinetide (an analog of the C-terminal domain of insulin-like growth factor 1), which was recently FDA-approved for RTT and is available only in the United States (29).

Several pharmacological attempts were made in our patient, including antipsychotics for emotional and behavioral dysregulation and sleep disturbances (30). Selective serotonin reuptake inhibitors (SSRIs) were also tried, but these resulted in a paradoxical effect (28). Additionally, Xenatina was used for managing coprolalia and tic-like movements, showing benefits in reducing motor and vocal tics as well as repetitive finger-twisting and skin-picking behaviors, although this medication has not been documented for Z-RTT.

In this clinical case, we analyzed the developmental trajectory of a female patient diagnosed with the Zappella variant of Rett syndrome in 2016, highlighting deviations from the expected course. Advances in genetic research suggest moving beyond broad phenotypic classifications, such as the “Zappella variant,” toward a more precise analysis of individual genetic variants. Even the same variant, such as R133C, can present with different phenotypes, underscoring the need for individualized assessment. Grouping variants into heterogeneous categories may obscure clinically relevant differences. Moreover, our patient carries a recurrent MECP2 variant and a class 3 VoUS in GABBR1, presenting a complex neurodevelopmental disorder with overlapping RTT and TS features. GABBR1 encodes a subunit of the GABA_B _BB​ receptor, essential for neuronal inhibition. Monoallelic GABBR1 variants have been linked to motor/language delay of varying severity, with one case of epilepsy. Additional features include intellectual disability, learning difficulties, autism, ADHD, oppositional defiant disorder, sleep disturbances, and hypotonia (31–35). In this context, the coexistence of a recurrent MECP2 variant and a GABBR1 VoUS in our patient supports the hypothesis of a potential additive or modifying effect of GABBR1, particularly through GABAergic signaling pathways already known to be impaired in MECP2 deficiency. Although functional validation is still lacking, this dual-genotype framework may help explain the atypical features observed and guide more individualized therapeutic strategies. Further studies are needed to clarify genotype-phenotype correlations and refine pharmacological and psychosocial interventions, tailoring them to the patient's and family's needs to improve clinical outcomes.