Recommendations for the management of gastrointestinal comorbidities with or without trofinetide use in Rett syndrome.

INTRODUCTION: Although gastrointestinal (GI) comorbidities are experienced by over 90% of individuals with Rett syndrome (RTT), a neurodevelopmental disorder associated with mutations in the MECP2 gene, many neurologists and pediatricians do not rank the management of these comorbidities among the most important treatment goals for RTT. Trofinetide, the first approved pharmacologic treatment for RTT, confers improvements in RTT symptoms but is associated with adverse GI events, primarily diarrhea and vomiting. Treatment strategies for GI comorbidities and drug-associated symptoms in RTT represent an unmet clinical need. AREAS COVERED: This perspective covers GI comorbidities experienced by those with RTT, either with or without trofinetide treatment. PubMed literature searches were undertaken on treatment recommendations for the following conditions: constipation, diarrhea, vomiting, aspiration, dysphagia, gastroesophageal reflux, nausea, gastroparesis, gastritis, and abdominal bloating. EXPERT OPINION: The authors recommend a proactive approach to management of symptomatic GI comorbidities and drug-associated symptoms in RTT to enhance drug tolerance and improve the quality of life of affected individuals. Management strategies for common GI comorbidities associated with RTT are reviewed based on authors' clinical experience and augmented by recommendations from the literature.

Electroencephalographic Correlates of Clinical Severity in the Natural history study of RTT and Related Disorders.

OBJECTIVE: This study was undertaken to characterize quantitative electroencephalographic (EEG) features in participants from the Natural history study of RTT and Related Disorders and to assess the potential for these features to act as objective measures of cortical function for Rett syndrome (RTT). METHODS: EEG amplitude and power features were derived from the resting EEG of 60 females with RTT (median age = 10.7 years) and 26 neurotypical females (median age = 10.6 years). Analyses focus on group differences and within the RTT group, associations between the EEG parameters and clinical severity. For a subset of participants (n = 20), follow-up data were available for assessing the reproducibility of the results and the stability in the parameters over 1 year. RESULTS: Compared to neurotypical participants, participants with RTT had greater amplitude variability and greater low-frequency activity as reflected by greater delta power, more negative 1/f slope, and lower theta/delta, alpha/delta, beta/delta, alpha/theta, and beta/theta ratios. Greater delta power, more negative 1/f slope, and lower power ratios were associated with greater severity. Analyses of year 1 data replicated the associations between 1/f slope and power ratios and clinical severity and demonstrated good within-subject consistency in these measures. INTERPRETATION: Overall, group comparisons reflected a greater predominance of lower versus higher frequency activity in participants with RTT, which is consistent with prior clinical interpretations of resting EEG in this population. The observed associations between the EEG power measures and clinical assessments and the repeatability of these measures underscore the potential for EEG to provide an objective measure of cortical function and clinical severity for RTT. ANN NEUROL 2024;96:175-186.

Comparison of evoked potentials across four related developmental encephalopathies.

BACKGROUND: Developing biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies. METHODS: Visual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1-17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study. RESULTS: As reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome (n = 43) and CDKL5 deficiency disorder (n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome (n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome (n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome (n = 14) and FOXG1 syndrome (n = 6) compared to individuals with Rett syndrome (n = 51) and CDKL5 deficiency disorder (n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome. CONCLUSIONS: There are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions.

Distribution of hand function by age in individuals with Rett syndrome.

Objective: To determine the longitudinal distribution of hand function skills in individuals with classic Rett Syndrome (RTT), an X-linked dominant neurodevelopmental disorder, and correlate with MECP2 variants. Method: We conducted a longitudinal study of 946 girls and young women with typical RTT seen between 2006 and 2021 in the US Natural History Study (NHS) featuring a structured clinical evaluation to assess the level of hand function skills. The specific focus in this study was to assess longitudinal variation of hand skills from age 2 through age 18 years in relation to specific MECP2 variant groups. Results: Following the initial regression period, hand function continues to decline across the age spectrum in individuals with RTT. Specific differences are noted with steeper declines in hand function among those with milder variants (Group A: R133C, R294X, R306C, and C-terminal truncations) compared to groups composed of individuals with more severe variants. Conclusions: These temporal variations in hand use represent specific considerations which could influence the design of clinical trials that test therapies aiming to ameliorate specific functional limitations in individuals with RTT. Furthermore, the distinct impact of specific MECP2 variants on clinical severity, especially related to hand use, should be considered in such interventional trials.

Electrophysiological biomarkers of brain function in CDKL5 deficiency disorder.

CDKL5 deficiency disorder is a debilitating developmental and epileptic encephalopathy for which no targeted treatment exists. A number of promising therapeutics are under development for CDKL5 deficiency disorder but a lack of validated biomarkers of brain function and clinical severity may limit the ability to objectively assess the efficacy of new treatments as they become available. To address this need, the current study quantified electrophysiological measures in individuals with CDKL5 deficiency disorder and the association between these parameters and clinical severity. Visual and auditory evoked potentials, as well as resting EEG, were acquired across 5 clinical sites from 26 individuals with CDKL5 deficiency disorder. Evoked potential and quantitative EEG features were calculated and compared with typically developing individuals in an age- and sex-matched cohort. Baseline and Year 1 data, when available, were analysed and the repeatability of the results was tested. Two clinician-completed severity scales were used for evaluating the clinical relevance of the electrophysiological parameters. Group-level comparisons revealed reduced visual evoked potential amplitude in CDKL5 deficiency disorder individuals versus typically developing individuals. There were no group differences in the latency of the visual evoked potentials or in the latency or amplitude of the auditory evoked potentials. Within the CDKL5 deficiency disorder group, auditory evoked potential amplitude correlated with disease severity at baseline as well as Year 1. Multiple quantitative EEG features differed between CDKL5 deficiency disorder and typically developing participants, including amplitude standard deviation, 1/f slope and global delta, theta, alpha and beta power. Several quantitative EEG features correlated with clinical severity, including amplitude skewness, theta/delta ratio and alpha/delta ratio. The theta/delta ratio was the overall strongest predictor of severity and also among the most repeatable qEEG measures from baseline to Year 1. Together, the present findings point to the utility of evoked potentials and quantitative EEG parameters as objective measures of brain function and disease severity in future clinical trials for CDKL5 deficiency disorder. The results also underscore the utility of the current methods, which could be similarly applied to the identification and validation of electrophysiological biomarkers of brain function for other developmental encephalopathies.

Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. METHODS: Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. RESULTS: Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). CONCLUSION: Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. TRIAL REGISTRATION: NCT00299312 and NCT02738281.

Analysis of X-inactivation status in a Rett syndrome natural history study cohort.

BACKGROUND: Rett syndrome (RTT) is a rare neurodevelopmental disorder associated with pathogenic MECP2 variants. Because the MECP2 gene is subject to X-chromosome inactivation (XCI), factors including MECP2 genotypic variation, tissue differences in XCI, and skewing of XCI all likely contribute to the clinical severity of individuals with RTT. METHODS: We analyzed the XCI patterns from blood samples of 320 individuals and their mothers. It includes individuals with RTT (n = 287) and other syndromes sharing overlapping phenotypes with RTT (such as CDKL5 Deficiency Disorder [CDD, n = 16]). XCI status in each proband/mother duo and the parental origin of the preferentially inactivated X chromosome were analyzed. RESULTS: The average XCI ratio in probands was slightly increased compared to their unaffected mothers (73% vs. 69%, p = .0006). Among the duos with informative XCI data, the majority of individuals with classic RTT had their paternal allele preferentially inactivated (n = 180/220, 82%). In sharp contrast, individuals with CDD had their maternal allele preferentially inactivated (n = 10/12, 83%). Our data indicate a weak positive correlation between XCI skewing ratio and clinical severity scale (CSS) scores in classic RTT patients with maternal allele preferentially inactivated XCI (rs  = 0.35, n = 40), but not in those with paternal allele preferentially inactivated XCI (rs  = -0.06, n = 180). The most frequent MECP2 pathogenic variants were enriched in individuals with highly/moderately skewed XCI patterns, suggesting an association with higher levels of XCI skewing. CONCLUSION: These results extend our understanding of the pathogenesis of RTT and other syndromes with overlapping clinical features by providing insight into the both XCI and the preferential XCI of parental alleles.

Anthropometric Measures Correspond with Functional Motor Outcomes in Females with Rett Syndrome.

OBJECTIVE: To characterize growth and anthropometric measurements in females with Rett syndrome and compare these measurements with functional outcomes. STUDY DESIGN: We obtained longitudinal growth and anthropometric measurements from 1154 females with classic and atypical Rett syndrome seen between 2006 and 2019 in the US Natural History Study. We calculated the Clinical Severity Score, Motor Behavior Assessment score, and arm and leg muscle areas and recorded the functional assessments of arm and hand use and ambulation. We compared growth and anthropometric variables from females with Rett syndrome in regard to normative data. We analyzed Clinical Severity Score, Motor Behavior Assessment, and anthropometric measurements in regard to functional assessments. RESULTS: Growth and anthropometric measurements were significantly lower in females with classic and severe atypical Rett syndrome compared with those classified as mild atypical Rett syndrome and deviated from normative patterns among all 3 groups. Suprailiac skinfold measurements correlated with body mass index measurements in each group. Lower leg muscle area measurements were significantly greater among females in all 3 Rett syndrome groups who ambulated independently compared with those who did not. In females with classic Rett syndrome, arm, thigh, and lower leg muscle area measurements increased significantly over time and were significantly greater among those who had purposeful arm and hand use and independent ambulation compared with those who did not. CONCLUSIONS: The pattern of growth and anthropometric measures in females with Rett syndrome differs from normative data and demonstrates clear differences between classic and mild or severe atypical Rett syndrome. Anthropometric measures correspond with functional outcomes and could provide markers supporting efficacy outcomes in clinical trials.

Lethal Pediatric Cerebral Vasculitis Triggered by Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: We report the clinical, radiological, laboratory, and neuropathological findings in support of the first diagnosis of lethal, small-vessel cerebral vasculitis triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric patient. PATIENT DESCRIPTION: A previously healthy, eight-year-old Hispanic girl presented with subacute left-sided weakness two weeks after a mild febrile illness. SARS-CoV-2 nasopharyngeal swab was positive. Magnetic resonance imaging revealed an enhancing right frontal lobe lesion with significant vasogenic edema. Two brain biopsies of the lesion showed perivascular and intraluminal lymphohistiocytic inflammatory infiltrate consistent with vasculitis. Despite extensive treatment with immunomodulatory therapies targeting primary angiitis of the central nervous system, she experienced neurological decline and died 93 days after presentation. SARS-CoV-2 testing revealed positive serum IgG and positive cerebrospinal fluid IgM. Comprehensive infectious, rheumatologic, hematologic/oncologic, and genetic evaluation did not identify an alternative etiology. Postmortem brain autopsy remained consistent with vasculitis. CONCLUSION: This is the first pediatric presentation to suggest that SARS-CoV-2 can lead to a fatal, postinfectious, inflammatory small-vessel cerebral vasculitis. Our patient uniquely included supportive cerebrospinal fluid and postmortem tissue analysis. While most children recover from the neurological complications of SARS-CoV-2, we emphasize the potential mortality in a child with no risk factors for severe disease.

Multisite Study of Evoked Potentials in Rett Syndrome.

OBJECTIVE: The aim of the current study was to evaluate the utility of evoked potentials as a biomarker of cortical function in Rett syndrome (RTT). As a number of disease-modifying therapeutics are currently under development, there is a pressing need for biomarkers to objectively and precisely assess the effectiveness of these treatments. METHOD: Yearly visual evoked potentials (VEPs) and auditory evoked potentials (AEPs) were acquired from individuals with RTT, aged 2 to 37 years, and control participants across 5 sites as part of the Rett Syndrome and Related Disorders Natural History Study. Baseline and year 1 data, when available, were analyzed and the repeatability of the results was tested. Two syndrome-specific measures from the Natural History Study were used for evaluating the clinical relevance of the VEP and AEP parameters. RESULTS: At the baseline study, group level comparisons revealed reduced VEP and AEP amplitude in RTT compared to control participants. Further analyses within the RTT group indicated that this reduction was associated with RTT-related symptoms, with greater severity associated with lower VEP and AEP amplitude. In participants with RTT, VEP and AEP amplitude was also negatively associated with age. Year 1 follow-up data analyses yielded similar findings and evidence of repeatability of EPs at the individual level. INTERPRETATION: The present findings indicate the promise of evoked potentials (EPs) as an objective measure of disease severity in individuals with RTT. Our multisite approach demonstrates potential research and clinical applications to provide unbiased assessment of disease staging, prognosis, and response to therapy. ANN NEUROL 2021;89:790-802.

Well-woman care and HPV vaccination rates in women with Rett syndrome.

BACKGROUND: Lifespan has increased in individuals with Rett syndrome (RTT), but little is currently known about the provision of well-woman care to these individuals. OBJECTIVE: To collect data on well-woman examinations and human papillomavirus (HPV) vaccination rates in women with RTT to understand the current state of women's healthcare in individuals with RTT. METHODS: A retrospective cross-sectional chart review and prospective survey of 77 patients with Rett syndrome who were cared for at a single specialty clinic over five years was conducted to collect data on women's health examinations and HPV vaccination rates. RESULTS: The following percentages represent women with RTT who have met the recommendations of ACOG for well-woman examinations: breast examinations- 40.3%, pelvic examinations- 51.2%, mammograms- 75.0%, external genitourinary examinations -31.6%. Many of these women also had delayed exams. 22.9% of women who were eligible for the HPV vaccine have received it. CONCLUSIONS: Many women with RTT do not undergo well-woman examinations and HPV vaccinations as recommended by ACOG. Since these women are not usually sexually active, many guardians believe the HPV vaccine is unnecessary. However, like other women with disabilities, RTT females are at risk for sexual abuse and disparities in access to women's health services, so these topics should be discussed with caretakers.

Phenotypic features in MECP2 duplication syndrome: Effects of age.

BACKGROUND: MECP2 Duplication syndrome (MDS) is a rare X-linked genomic disorder that is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Although phenotypic features in MDS have been described, there is a limited understanding of the range of severity of these features, and how they evolve with age. METHODS: The cross-sectional results of N = 69 participants (ages 6 months-33 years) enrolled in a natural history study of MDS are presented. Clinical severity was assessed using a clinician-report measure as well as a parent-report measure. Data was also gathered related to the top 3 concerns of parents as selected from the most salient symptoms related to MDS. The Child Health Questionnaire was also utilized to obtain parental reports of each child's quality of life to establish disease burden. RESULTS: The results of linear regression from the clinician-reported measure show that overall clinical severity scores, motor dysfunction, and functional skills are significantly worse with increasing age. Top concerns rated by parents included lack of effective communication, abnormal walking/balance issues, constipation, and seizures. Higher levels of clinical severity were also related to lower physical health quality of life scores as reported by parents. CONCLUSIONS: The data suggest that increasing levels of clinical severity are noted with older age, and this is primarily attributable to motor dysfunction, and functional skills. The results provide an important foundation for creating an MDS-specific severity scale highlighting the most important domains to target for treatment trials and will help clinicians and researchers define clinically meaningful changes.

Features of Menstruation and Menstruation Management in Individuals with Rett Syndrome.

STUDY OBJECTIVE: To describe features of menstruation, menstrual-related symptoms, and menstrual management in females with Rett syndrome (RTT) to help develop a clinical approach to these parameters in RTT. DESIGN: Retrospective cross-sectional chart review and prospective survey. SETTING: Cincinnati Children's Hospital Medical Center, Rett Syndrome and Related Spectrum Disorders Clinic. PARTICIPANTS: Females with RTT (12-55 years of age) and their caregivers. MAIN OUTCOME MEASURES: Descriptive data on features of menstruation and menstrual-related symptoms in individuals with Rett syndrome; prevalence, types, reason for use/discontinuation, and efficacy of hormonal treatment in females with RTT. RESULTS: Age at menarche, menstrual cycle length, and menstrual period length in females with RTT are comparable to those in typically developing females and females with other neurodevelopmental disabilities. Dysmenorrhea and emotional lability are common menstrual cycle-related changes among females with RTT; 22.1% of participants also reported catamenial seizures. Oral progestin, combined oral contraceptive pill, and depot-medroxyprogesterone acetate (DMPA) were effectively used to suppress or regulate menstruation and to manage menstrual-related symptoms. CONCLUSIONS: Characteristics of menstruation in females with RTT are comparable to those of typically developing females, with the exception of increase in catamenial seizure activity. Hormonal treatments are used for management of menstruation, dysmenorrhea, and seizures. Choice of hormonal treatment is influenced by bone health and immobility in females with RTT.

A Psychometric Evaluation of the Motor-Behavioral Assessment Scale for Use as an Outcome Measure in Rett Syndrome Clinical Trials.

Rett syndrome (RTT) is a neurodevelopmental disorder that primarily affects females. Recent work indicates the potential for disease modifying therapies. However, there remains a need to develop outcome measures for use in clinical trials. Using data from a natural history study (n = 1,075), we examined the factor structure, internal consistency, and validity of the clinician-reported Motor Behavior Assessment scale (MBA). The analysis resulted in a five-factor model: (1) motor dysfunction, (2) functional skills, (3) social skills, (4) aberrant behavior, and (5) respiratory behaviors. Item Response Theory (IRT) analyses demonstrated that all items had acceptable discrimination. The revised MBA subscales showed a positive relationship with parent reported items, age, and a commonly used measure of clinical severity in RTT, and mutation type. Further work is needed to evaluate this measure longitudinally and to add items related to the RTT phenotype.

Multisystem comorbidities in classic Rett syndrome: a scoping review.

BACKGROUND: Rett syndrome (RTT) is a severe, progressive neurodevelopmental disorder with multisystem comorbidities that evolve across a patient's lifespan requiring attentive coordination of subspecialty care by primary care providers. A comprehensive, up-to-date synthesis of medical comorbidities in RTT would aid care coordination and anticipatory guidance efforts by healthcare providers. Our objective was to review and summarise published evidence regarding prevalence of RTT medical comorbidities across all relevant organ systems. METHODS: Search of PubMed from January 2000 to July 2019 was performed using the search terms (Rett and MECP2 AND patient) OR (Rett and MECP2 AND cohort). Articles reporting the prevalence of clinical findings in RTT were assessed with respect to the size and nature of the cohorts interrogated and their relevance to clinical care. RESULTS: After review of over 800 records, the multisystem comorbidities of RTT were summarised quantitatively from 18 records comprising both retrospective and prospective cohorts (31-983 subjects). Neurological comorbidities had the highest prevalence, occurring in nearly all individuals with gastrointestinal and orthopaedic concerns almost as prevalent as neurological. With the exception of low bone mineral content which was relatively common, endocrine comorbidities were seen in only around one-third of patients. Although more prevalent compared with the general population, cardiac conduction abnormalities were the least common comorbidity in RTT. CONCLUSIONS: Effective care coordination for RTT requires knowledge of and attention to multiple comorbidities across multiple unrelated organ systems. Many issues common to RTT can potentially be managed by a primary care provider but the need for sub-specialist referral can be anticipated. Since the median life expectancy extends into the sixth decade with evolving subspecialty requirements throughout this time, paediatric providers may be tasked with continued coordination of these comorbidities or transitioning to adult medicine and specialists with experience managing individuals with complex medical needs.

Consensus guidelines on managing Rett syndrome across the lifespan.

BACKGROUND: Rett syndrome (RTT) is a severe neurodevelopmental disorder with complex medical comorbidities extending beyond the nervous system requiring the attention of health professionals. There is no peer-reviewed, consensus-based therapeutic guidance to care in RTT. The objective was to provide consensus on guidance of best practice for addressing these concerns. METHODS: Informed by the literature and using a modified Delphi approach, a consensus process was used to develop guidance for care in RTT by health professionals. RESULTS: Typical RTT presents early in childhood in a clinically recognisable fashion. Multisystem comorbidities evolve throughout the lifespan requiring coordination of care between primary care and often multiple subspecialty providers. To assist health professionals and families in seeking best practice, a checklist and detailed references for guidance were developed by consensus. CONCLUSIONS: The overall multisystem issues of RTT require primary care providers and other health professionals to manage complex medical comorbidities within the context of the whole individual and family. Given the median life expectancy well into the sixth decade, guidance is provided to health professionals to achieve current best possible outcomes for these special-needs individuals.

Characterizing the phenotypic effect of Xq28 duplication size in MECP2 duplication syndrome.

Individuals with methyl CpG binding protein 2 (MECP2) duplication syndrome (MDS) have varying degrees of severity in their mobility, hand use, developmental skills, and susceptibility to infections. In the present study, we examine the relationship between duplication size, gene content, and overall phenotype in MDS using a clinical severity scale. Other genes typically duplicated within Xq28 (eg, GDI1, RAB39B, FLNA) are associated with distinct clinical features independent of MECP2. We additionally compare the phenotype of this cohort (n = 48) to other reported cohorts with MDS. Utilizing existing indices of clinical severity in Rett syndrome, we found that larger duplication size correlates with higher severity in total clinical severity scores (r = 0.36; P = 0.02), and in total motor behavioral assessment inventory scores (r = 0.31; P = 0.05). Greater severity was associated with having the RAB39B gene duplicated, although most of these participants also had large duplications. Results suggest that developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism are common in MDS. This is the first study to show that duplication size is related to clinical severity. Future studies should examine whether large duplications which do not encompass RAB39B also contribute to clinical severity. Results also suggest the need for creating an MDS specific severity scale.

The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2.

Mutations in the X-linked gene MECP2 are associated with a severe neurodevelopmental disorder, Rett syndrome (RTT), primarily in girls. It had been suspected that mutations in Methyl-CpG-binding protein 2 (MECP2) led to embryonic lethality in males, however such males have been reported. To enhance understanding of the phenotypic spectrum present in these individuals, we identified 30 males with MECP2 mutations in the RTT Natural History Study databases. A wide phenotypic spectrum was observed, ranging from severe neonatal encephalopathy to cognitive impairment. Two males with a somatic mutation in MECP2 had classic RTT. Of the remaining 28 subjects, 16 had RTT-causing MECP2 mutations, 9 with mutations that are not seen in females with RTT but are likely pathogenic, and 3 with uncertain variants. Two subjects with RTT-causing mutations were previously diagnosed as having atypical RTT; however, careful review of the clinical history determined that an additional 12/28 subjects met criteria for atypical RTT, but with more severe clinical presentation and course, and less distinctive RTT features, than females with RTT, leading to the designation of a new diagnostic entity, male RTT encephalopathy. Increased awareness of the clinical spectrum and widespread comprehensive genomic testing in boys with neurodevelopmental problems will lead to improved identification.

A Case of An Unusual Bell's Palsy Mimic.

We discuss the case of a 5-year-old boy who presented with an isolated left-sided cranial nerve 7 palsy that was initially magnetic resonance imaging negative. Owing to continued symptoms, repeat magnetic resonance imaging was performed and showed a temporal bone encephalocele. A review of the differential diagnosis of cranial nerve 7 palsy, warning signs signaling the need for additional workup, and a discussion of temporal lobe encephaloceles is provided in this case report. It is important to recognize that structural lesions can closely mimic idiopathic Bell's palsy, despite initial negative imaging.

An Atypical Rett Syndrome Phenotype Due to a Novel Missense Mutation in CACNA1A.

BACKGROUND: Some typical and atypical Rett syndrome patients lack known genetic mutations. Mutations in the P/Q type calcium channel CACNA1A have been implicated in epileptic encephalopathy, familial hemiplegic migraine, episodic ataxia 2, and spinocerebellar ataxia 6, but not Rett syndrome. Patient Description: The authors describe a female patient with developmental regression and a de novo, likely pathogenic mutation in CACNA1A who meets 3 of 4 main criteria (stereotypic hand movements, loss of purposeful hand movements, gait disturbance), and 6 of 11 supportive criteria (impaired sleep, abnormal tone, vasomotor disturbance, scoliosis, growth retardation, and screaming spells) for atypical Rett syndrome. Furthermore, she resembles the early seizure variant of Rett syndrome. Previously, 3 children with similar CACNA1A mutations have been reported, but a Rett syndrome phenotype has not been described. CONCLUSION: CACNA1A mutations should be considered in children presenting with an atypical Rett syndrome phenotype, specifically, the early seizure variant.