Clinical signatures of genetic epilepsies precede diagnosis in electronic medical records

Galer PD, Parthasarathy S, Xian J, McKee JL, Ruggiero SM, Ganesan S, Kaufman MC, Cohen SR, Haag S, Chen C, Ojemann WKS, Kim D, Wilmarth O, Vaidiswaran P, Sederman C, Ellis CA, Gonzalez AK, Boßelmann CM, Lal D, Sederman R, Lewis-Smith D, Litt B, Helbig I. Clinical Signatures of Genetic Epilepsies Precede Diagnosis in Electronic Medical Records of 32 000 Individuals. Genet Med. 2024101211. doi:10.1016/j.gim.2024.101211. PMID: 39011766

Purpose: An early genetic diagnosis can guide the time-sensitive treatment of individuals with genetic epilepsies. However, most genetic diagnoses occur long after disease onset. We aimed to identify early clinical features suggestive of genetic diagnoses in individuals with epilepsy through large-scale analysis of full-text electronic medical records (EMRs). Methods: We extracted 89 million time-stamped standardized clinical annotations using Natural Language Processing from 4,572,783 clinical notes from 32 112 individuals with childhood epilepsy, including 1925 individuals with known or presumed genetic epilepsies. We applied these features to train random forest models to predict SCN1A-related disorders and any genetic diagnosis. Results: We identified 47 774 age-dependent associations of clinical features with genetic etiologies a median of 3.6 years prior to molecular diagnosis. Across all 710 genetic etiologies identified in our cohort, neurodevelopmental differences between 6 and 9 months increased the likelihood of a later molecular diagnosis fivefold (P < .0001, 95% CI = 3.55-7.42). A later diagnosis of SCN1A-related disorders (AUC = 0.91) or an overall positive genetic diagnosis (AUC = 0.82) could be reliably predicted using random forest models. Conclusion: Clinical features predictive of genetic epilepsies precede molecular diagnoses by up to several years in conditions with known precision treatments. An earlier diagnosis facilitated by automated EMR analysis has the potential for earlier targeted therapeutic strategies in the genetic epilepsies.

Commentary on the above:

Li Y. Predicting Pediatric Genetic Epilepsy Through Electronic Medical Records: A Data-Driven Biomarker Discovery Approach. Epilepsy Currents. 2024;0(0). doi:10.1177/15357597241290322

With the goal to identify key clinical features linked to genetic epilepsy syndromes and predict genetic diagnoses, Galer et al extracted clinical notes from the electronic medical record (EMR) system of 32 112 individuals diagnosed with childhood epilepsy, including 1925 individuals with known or presumed genetic epilepsies at the Children's Hospital of Philadelphia Care Network between 2010 and 2022. A customized natural language processing (NLP) pipeline was utilized to help extract clinical features in the form of Language System codes. These features were subsequently mapped onto the Human Phenotype Ontology and segmented into 3-month age bins for analysis. A conservative framework was developed to analyze only clinical notes before an individual's genetic diagnosis, with additional analysis using cumulative time binning. Furthermore, validation was conducted by collecting phenotype data from individuals with SCN1A-related epilepsy disorders and control groups in two different cohorts, analyzing the most significant neurological phenotypes associated with SCN1A-related epilepsy and employing random forest models for prediction. In their study, causative genetic etiologies were found in 38% of individuals with known or presumed genetic epilepsy, involving 271 unique genes, with 87 occurring in two or more individuals. The median time from the first neurological abnormality to genetic diagnosis was 1.4 years in their cohort. The earliest clinical feature associated with a genetic diagnosis occurred a median of 3.62 years before the median age of genetic diagnosis. Furthermore, broad clinical features that predict positive genetic diagnoses independent of molecular etiology were identified, including muscular hypotonia between 1 and 1.25 years, neurodevelopmental abnormality between 6 and 9 months, and neurodevelopmental delay between 6 and 9 months.
The study offers valuable insights into the clinical applicability of predictive models for genetic diagnoses in epilepsy. The utilization of NLP allows for the extraction of data from real-world observations, facilitating the mapping of clinical phenotype trajectories in genetic epilepsies over time. This not only tracks the natural history overtime but also enables the identification of novel pathognomonic clinical features. Such an approach is especially beneficial for rare genetic disorders, enabling the discovery of unprecedented details that may have been previously overlooked. Additionally, the study highlights the promising combination of NLP with machine learning models to identify significant clinical phenotypes. This integrated approach may aid in predicting genetic diagnoses at an earlier age, offering potential for the application of precision medicine in epilepsy care.
Early recognition of diagnosis and optimized treatment has been one of the fundamental objectives in medical care to improve patient outcomes and enhance overall healthcare cost-effectiveness. Large-scale modeling of EMR trajectories have been developed for various common medical conditions such as sepsis, heart failure, and cancer, among others. These models leverage current advancements in large language models and deep learning technologies to drive forward the field of precision medicine. While early diagnosis of genetic epilepsies is crucial for timely treatment, the practicality and cost-effectiveness of such an approach would need further research. It is anticipated that clinical features or a combination thereof could be utilized to identify patients highly likely to have a genetic cause, prompting further genetic testing for confirmation or even consideration of empirical treatment when genetic testing is not an option in resource-limited scenarios. However, there is a need for ongoing evaluation of the potential for false positive identifications within EMR systems based on this proposed algorithm. Additionally, the cost implications and overall cost-effectiveness of these approaches warrant further investigation.
Furthermore, when considering the application of these discoveries beyond SCN1A syndromes, integrating them into clinical practice may encounter limitations in generalizability resulting from data heterogeneity or data insufficiency, which is one of the common challenges for prediction models based on EMR trajectories. The algorithms trained on pediatric epilepsy patients within a tertiary center network may present variations in specific terms or syndromes compared to the documentation practices of general neurologists or adult neurologists. These discrepancies could be from less detailed history reviews by general providers or inadequate data due to recall bias among patients and their guardians, ultimately leading to underdocumented clinical symptoms. For instance, specific symptoms like muscular hypotonia at a younger age between 1 and 1.25 years, identified as an independent clinical biomarker for genetic epilepsy diagnosis in this study, might not be consistently recorded due to recall bias related to their remote occurrence within families in adult neurology practice. Additionally, adult-onset genetic epilepsies exhibit unique genetic mutations and clinical features that can notably differ from those observed in childhood epilepsy cases. Therefore, further expansion of the training and application of similar methodologies across diverse populations holds significant promise in offering valuable insights in the field.

The role of default mode network connectivity in the onset of FCD-related focal epilepsy

Macdonald-Laurs E, Warren AEL, Leventer RJ, Harvey, AS. Why Did My Seizures Start Now? Influences of Lesion Connectivity and Genetic Etiology on Age at Seizure Onset in Focal Epilepsy. Epilepsia, 2024,65(6):1644–1657. https://doi.org/10.1111/epi.17947

Objective: Patients with focal, lesional epilepsy present with seizures at variable ages. Larger lesion size and overlap with sensorimotor or default mode network (DMN) have been associated with younger age at seizure onset in cohorts with mixed types of focal cortical dysplasia (FCD). Here, we studied determinants of age at seizure onset in patients with bottom-of-sulcus dysplasia (BOSD), a discrete type of FCD with highly localized epileptogenicity. Methods: Eighty-four patients (77% operated) with BOSD were studied. Demographic, histopathologic, and genetic findings were recorded. BOSD volume and anatomical, primary versus association, rostral versus caudal, and functional network locations were determined. Normative functional connectivity analyses were performed using each BOSD as a region of interest in resting-state functional magnetic resonance imaging data of healthy children. Variables were correlated with age at seizure onset. Results: Median age at seizure onset was 5.4 (interquartile range = 2–7.9) years. Of 50 tested patients, 22 had somatic and nine had germline pathogenic mammalian target of rapamycin (mTOR) pathway variants. Younger age at seizure onset was associated with greater BOSD volume (p = .002), presence of a germline pathogenic variant (p = .04), DMN overlap (p = .04), and increased functional connectivity with the DMN (p < .05, false discovery rate corrected). Location within the sensorimotor cortex and networks was not associated with younger age at seizure onset in our relatively small but homogenous cohort. Significance: Greater lesion size, pathogenic mTOR pathway germline variants, and DMN connectivity are associated with younger age at seizure onset in small FCD. Our findings strengthen the suggested role of DMN connectivity in the onset of FCD-related focal epilepsy and reveal novel contributions of genetic etiology.

Recurrent status epilepticus episodes

Bauer K, Rosenow F, Knake S, Willems LM, Kämppi L, Strzelczyk A. Clinical Characteristics and Outcomes of Patients With Recurrent Status Epilepticus Episodes. Neurol Res Pract. 2023;5(1):34. doi:https://doi.org/10.1186/s42466-023-00261-9

Abstract

Background:
Multiple studies have focused on medical and pharmacological treatments and outcome predictors of patients with status epilepticus (SE). However, a sufficient understanding of recurrent episodes of SE is lacking. Therefore, we reviewed recurrent SE episodes to investigate their clinical characteristics and outcomes in patients with relapses.
Methods:
In this retrospective, multicenter study, we reviewed recurrent SE patient data covering 2011 to 2017 from the university hospitals of Frankfurt and Marburg, Germany. Clinical characteristics and outcome variables were compared among the first and subsequent SE episodes using a standardized form for data collection.
Results:
We identified 120 recurrent SE episodes in 80 patients (10.2% of all 1177 episodes). The mean age at the first SE episode was 62.2 years (median 66.5; SD 19.3; range 21–91), and 42 of these patients were male (52.5%). A mean of 262.4 days passed between the first and the second episode. Tonic–clonic seizure semiology and a cerebrovascular disease etiology were predominant in initial and recurrent episodes. After subsequent episodes, patients showed increased disability as indicated by the modified Rankin Scale (mRS), and 9 out of 80 patients died during the second episode (11.3%). Increases in refractory and super-refractory SE (RSE and SRSE, respectively) were noted during the second episode, and the occurrence of a non-refractory SE (NRSE) during the first SE episode did not necessarily provide a protective marker for subsequent non-refractory episodes. An increase in the use of intravenous-available anti-seizure medication (ASM) was observed in the treatment of SE patients. Patients were discharged from hospital with a mean of 2.8 ± 1.0 ASMs after the second SE episode and 2.1 ± 1.2 ASMs after the first episode. Levetiracetam was the most common ASM used before admission and on discharge for SE patients.
Conclusions:
This retrospective, multicenter study used the mRS to demonstrate worsened outcomes of patients at consecutive SE episodes. ASM accumulations after subsequent SE episodes were registered over the study period. The study results underline the necessity for improved clinical follow-ups and outpatient care to reduce the health care burden from recurrent SE episodes.

Commentary on the above:

Gaspard N. Double, Double Toil and Trouble: Recurrent Episodes of Status Epilepticus Are Associated With Increasingly Worse Outcomes. Epilepsy Currents. 2024;24(5):316-317. doi:10.1177/15357597231223587

The first key finding is that 10% of patients with a first episode of SE are at risk of suffering from a recurrent episode of SE, half of them within 6 months of the first episode. This figure is roughly in line with the available literature, which provides an estimate of recurrence ranging from 7.6% to 32%. Thus, the annual risk of a second episode of SE after having suffered from a first is at least 250 to 1000 times higher than the annual incidence of SE in the general population. Even though half of the episodes of SE occur in patients with epilepsy, a 10% annual risk is still higher than the risk of SE in patients with epilepsy.
This indicates an intrinsic predisposition of a subgroup of patients for their seizures to present as SE. The International League Against Epilepsy defines SE as “a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures.” While these mechanisms still elude us, an individual’s predisposition for SE suggests that this could be identified by investigating patients with recurrent episodes, at the neuroanatomical, neurophysiological, and, perhaps, genetic levels. The mean age of patients in the cohort was 62 years at the time of the first episode and 63 years at the time of the second episode. This is not surprising as SE incidence peaks after 60 years. Part of it is explained by the higher incidence of acute brain injuries, such as ischemic strokes and cerebral hemorrhages, that can cause SE after 60 years. Since most patients in this cohort, and in other cohorts of recurrent SE, had remote epilepsy, it is also possible that this higher risk of SE and of SE recurrence is also in part explained by the aging of the brain, which could be accompanied by a decrease in the efficiency of the mechanisms responsible for seizure termination. The risk of SE is also higher in patients with drug-resistant epilepsy and uncontrolled seizures than in patients with controlled epilepsy. Whether this also affects the risk of recurrence is unclear, although a prior study found that recurrent episodes of SE were more likely in patients who took more anti-seizure medications (ASMs).
A few patients in the cohort suffered 3 or more episodes of SE. From the data presented in the article, it can be estimated that the risk of third, fourth, or fifth episode approximates 50%, which is even greater than the risk of a first recurrence. This might mean that some individuals have a particularly strong intrinsic predisposition for SE. Another possible explanation is that each SE episode durably tampers the epileptic network to make it more prone to subsequent episodes. After all, the epileptogenic effects of SE are well-known: experimental SE, by chemical or electrical mean, is a classical way to cause epilepsy in animal models and acute symptomatic SE in acute brain injuries carries a greater risk of long-term post-injury epilepsy than single acute symptomatic seizures.
The second key finding of the study is that recurring episodes of SE are associated with increasingly worse outcomes. Compared to a first episode, a second episode of SE carries a higher risk of functional decline and dependency. It also leads to an increase in the burden of anti-seizure medications, including with medications that have a less desirable profile of side effects in the elderly, such as phenytoin and valproate. However, at the time of the second episode, the mean number of ASMs taken was lower than immediately after the first episode. Although this was not formally assessed in this study, ASM withdrawal was previously identified a precipitating factor of recurrent SE. The authors thus rightfully warn us against the temptation to quickly withdraw the ASM used to manage SE. Given the risk of recurrence, seizure action plans that could be used in the out-of-hospital setting should be discussed with patients and caregivers. Such plans may include fats-acting benzodiazepines for prolonged seizures.
There was also a trend toward increasing refractoriness at the time of the second episode. Of note, this has not been found in all other studies, perhaps owing to the difference in inclusion criteria mentioned above. A prior study found that the risk of refractoriness was higher if SE episodes recurred within 6 months of the first episode, but this was probably explained a greater proportion of acute and progressive etiologies in this subgroup.

See the cerebral dysplasia?

 

Radiprodil for seizures in children with GRIN-related neurodevelopmental disorders

Treatment with radiprodil (GRIN Therapeutics, New York, NY), a selective, potent negative allosteric modulator of the N-methyl-D-aspartate receptor subtype SB (NR2B or GluN2B), was well tolerated and associated with a significant reduction in seizure frequency in children with GRIN-related neurodevelopmental disorders. Following the reporting of findings from the phase 1b Honeycomb clinical study (NCT05818943), GRIN Therapeutics announced the initiation of the phase 1b/2b Astroscape clinical study (NCT06392009), which will investigate the safety and efficacy of radiprodil treatment for children with tuberous sclerosis (TSC) or focal cortical dysplasia (FCD) type II.

The multicenter phase 1b Honeycomb trial enrolled 15 patients aged ≥6 months to ≤12 years with gain-of-function (GoF) mutations in the GRIN1, GRIN2A, or GRIN1B genes. Participants were split into 2 cohorts, with Cohort 1 assessed for the frequency of countable motor seizures (CMS) within a 28-day screening period, and Cohort 2 assessed for baseline severity of nonseizure behavioral symptoms. The study included 2 periods, with participants who completed Part A being eligible for continued study treatment in Part B, consisting of an ongoing open-label extended treatment period.In Part A, participants treated with radiprodil showed an 86% reduction from baseline in seizure frequency. 71% of participants in Part A experienced a >50% reduction in CMS, 43% experienced a >90% reduction, and 1 participant was seizure free.

Radiprodil appeared generally well tolerated throughout Part A and Part B of the study to date.
Treatment emergent adverse events (TEAEs) included pyrexia, diarrhea, respiratory tract infection, abnormal behavior, agitation, cough, dystonia, fatigue, and gastroenteritis, which were associated with infections or underlying disease symptoms.

Astroscape is an open-label phase 1b/2b study that will evaluate radiprodil treatment at different doses for a targeted enrollment of 20 participants aged 6 months to 18 years with TSC or FCD type II with treatment-resistant seizures. Primary endpoints will include safety parameters, tolerability, and pharmacokinetic measures with key secondary endpoints assessing the effect of treatment on epileptic seizure frequency and severity and symptoms related to behavior, sleep, and quality of life. Participants who complete the treatment period may have the option to enroll in a long-term extension study.

"The initiation of treatment in the first patients enrolled in this landmark study is an important milestone for the TSC and FCD communities," said Dr. Manuel Toledo, MD, PhD, Head of the Epilepsy Unit at Vall d'Hebron University Hospital, Barcelona, Spain, who enrolled the first patient in the study. "We appreciate GRIN Therapeutics' commitment to making a positive difference for patients and families impacted by these serious conditions and we look forward to completing this clinical trial and reporting results as quickly as possible."

https://practicalneurology.com/news/favorable-results-for-radiprodil-tx-for-grin-disorders-leads-to-launch-of-study-to-test-treatment-in-those-with-tuberous-sclerosis-or-focal-cortical-dysplasia?

Newly presented data from the phase 1 Honeycomb study (NCT05818943) showed that treatment with investigational radiprodil (GRIN Therapeutics) was generally well tolerated, with significant impacts on seizure frequency in patients with GRIN-related neurodevelopmental disorder. Overall, the data support the continued development of radiprodil, selective and potent negative allosteric modulator of the N-methyl-D-aspartate receptor subtype 2B (NR2B or GluN2B), in this patient population.

At the July 15th cut-off date, 15 patients with GRIN-related disorder with a gain-of-function (GoF) variant in GRIN1, GRIN2A, 2GRINB, or GRIN2D were included for analysis. The study was designed as a 2-part trial, with Part A included a screening period (35 days), titration period (approximately 51 days), and maintenance period (up to 53 days). At the end of the maintenance period, there is an additional overnight stay when the participant is invited to take part in Part B or enter the tapering (15 days) and safety follow-up period (14 days).

Patients were escalated from a starting dose of 0.05 mg/kg based on tolerability, pharmacokinetics, and predicted GluN2B receptor occupancy to a dose level to be maintained through an 8-week maintenance period. During Part A, patients treated with radiprodil showed a median reduction of 86% in seizure frequency, a secondary end point, relative to baseline.

During this same period, 71% of treated patients experienced at least a 50% reduction in countable motor seizures (CMS), with 43% who saw a greater than 90% reduction. Notably, 1 patient was considered seizure free following treatment. In addition, clinician and caregiver-related scales generally assessed patients as improved clinically throughout the trial.

“GRIN-related neurodevelopmental disorder is a devastating disease for which there are no FDA-approved treatments,” Bruce Leuchter, MD, president and chief executive officer at Neurvati Neurosciences and GRIN Therapeutics, told NeurologyLive®. “Ongoing research, including the promising results from our Honeycomb clinical trial, are deepening our understanding of the disorder and how best to help patients, families and caregivers. Our team is very excited about these results and the opportunity to advance a potential first-in-class ​therapy into a pivotal Phase 3 clinical trial. We are looking forward to working with regulatory authorities and the patient and caregiver communities to advance the development of radiprodil.”

The study was divided into 2 cohorts based on the frequency of CMS experienced during the 28-day screening period (cohort 1) and baseline severity of non-seizure behavioral symptoms. While demographics and baseline disease characteristics were generally balanced between the cohorts, there was a higher level of seizure activity at baseline in cohort 1, as explained by a mean CMS of 37.0 and median CMS of 25.5 per patient (range of 4.8 to 85.9). At baseline, there were no CMS observed in cohort 2.

GRIN-related neurodevelopmental disorder is part of a larger family of genetic diseases related to ionotropic glutamate receptors and is caused by a change in one of 7 GRIN genes including GRIN1, GRIN2A, GRIN2B, and GRIN2D. These genes contain the code to create NMDA receptors, which are essential for learning and memory. To date, there have been several research studies conducted in the search for possible treatments targeting the NMDA receptors; however, there have been no FDA-approved treatments of GRIN disorders yet.

In Honeycomb, there were no deaths, and the most common treatment-emergent adverse events (TEAEs) related to radiprodil were those associated with infections or underlying disease symptoms. These included pyrexia, diarrhea, respiratory tract infection, abnormal behavior, agitation, cough, dystonia, fatigue, and gastroenteritis. Investigators observed 3 serious AEs, which were obstructive bronchitis, viral pneumonia, and adenovirus infection, each found in 1 patient. None of these were considered related to the study treatment and none met the study criteria for stopping treatment.

Part B of Honeycomb, an open-label extended treatment period for patients who completed Part A and were eligible for continued study treatment, remains ongoing. During this period, there will be 4 visits per year, 2 of which require overnight stays. At the end of the long-term treatment period, patients will enter a 15-day tapering period, and 14-day safety follow-up period.

Despite increased efforts, there are still no approved treatments for GRIN-related neurodevelopmental disorder. Memantine, an NMDAR antagonist, has been tested in various GoF variants and has been shown to reduce the frequency of seizures in some patients. L-Serine is a NMDAR agonist that has been shown to improve motor impairments, cognition, and communication in patients with a GRIN2B loss-of-function variant. In a published phase 2a study (NCT04646447), treatment with L-serine was associated with significant improvement in the median Gross Motor Function-88 total score (P = .002) and the mean Pediatric Quality of Life total score (P = .00068) regardless of disease severity.

https://www.neurologylive.com/view/radiprodil-significantly-reduces-seizure-frequency-phase-1b-honeycomb-study-grin-related-neurodevelopmental-disorderstudy-grin-related-neurodevelopmental-disorder

Bertocchi I, Cifarelli L, Oberto A, Eva CE, Sprengel R, Mirza NR, Muglia P. Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation. Br J Pharmacol. 2024 Jun;181(12):1886-1894. doi: 10.1111/bph.16361. Epub 2024 Mar 26. PMID: 38529699.

Abstract

Background and purpose: GRIN-related disorders are neurodevelopmental disorders caused by mutations in N-methyl-D-aspartate receptor (NMDAR) subunit genes. A large fraction of these mutations lead to a 'gain of function' (GoF) of the NMDAR. Patients present with a range of symptoms including epilepsy, intellectual disability, behavioural and motor. Controlling seizures is a significant unmet medical need in most patients with GRIN-related disorders. Although several hundred GRIN mutations have been identified in humans, until recently none of the mouse models carrying Grin mutations/deletions showed an epileptic phenotype. The two recent exceptions both carry mutations of GluN2A. The aim of this study was to assess the efficacy of radiprodil, a selective negative allosteric modulator of GluN2B-containing NMDARs, in counteracting audiogenic seizures (AGS) in a murine model carrying the GluN2A(N615S) homozygous mutation (Grin2aS/S mice).

Experimental approach: Grin2aS/S mice were acutely treated with radiprodil at different doses before the presentation of a high-frequency acoustic stimulus commonly used for AGS induction.

Key results: Radiprodil significantly and dose-dependently reduced the onset and severity of AGS in Grin2aS/S mice. Surprisingly, the results revealed a sex-dependent difference in AGS susceptibility and in the dose-dependent protection of radiprodil in the two genders. Specifically, radiprodil was more effective in female versus male mice.

Conclusion and implications: Overall, our data clearly show that radiprodil, a GluN2B selective negative allosteric modulator, may have the potential to control seizures in patients with GRIN2A GoF mutations. Further studies are warranted to better understand the sex-dependent effects observed in this study.

BCL11A intellectual developmental disorder

Peron A, D'Arco F, Aldinger KA, Smith-Hicks C, Zweier C, Gradek GA, Bradbury K, Accogli A, Andersen EF, Au PYB, Battini R, Beleford D, Bird LM, Bouman A, Bruel AL, Busk ØL, Campeau PM, Capra V, Carlston C, Carmichael J, Chassevent A, Clayton-Smith J, Bamshad MJ, Earl DL, Faivre L, Philippe C, Ferreira P, Graul-Neumann L, Green MJ, Haffner D, Haldipur P, Hanna S, Houge G, Jones WD, Kraus C, Kristiansen BE, Lespinasse J, Low KJ, Lynch SA, Maia S, Mao R, Kalinauskiene R, Melver C, McDonald K, Montgomery T, Morleo M, Motter C, Openshaw AS, Palumbos JC, Parikh AS, Perilla-Young Y, Powell CM, Person R, Desai M, Piard J, Pfundt R, Scala M, Serey-Gaut M, Shears D, Slavotinek A, Suri M, Turner C, Tvrdik T, Weiss K, Wentzensen IM, Zollino M, Hsieh TC; C4RCD Research Group; Telethon Undiagnosed Disease Program (TUDP); University of Washington Center for Mendelian Genomics (UW-CMG); de Vries BBA, Guillemot F, Dobyns WB, Viskochil D, Dias C. BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations. Eur J Hum Genet. 2024 Oct 24. doi: 10.1038/s41431-024-01701-z. Epub ahead of print. PMID: 39448799.

Abstract

An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11A's role in brain development.

Peron A, Bradbury K, Viskochil DH, Dias C. BCL11A-Related Intellectual Disability. 2019 Sep 26. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 31556984.

Excerpt

Clinical characteristics: BCL11A-related intellectual disability (BCL11A-ID) is characterized by developmental delay / intellectual disability of variable degree, neonatal hypotonia, microcephaly, distinctive but variable facial characteristics, behavior problems, and asymptomatic persistence of fetal hemoglobin. Growth delay, seizures, and autism spectrum disorder have also been reported in some affected individuals.

Diagnosis/testing: The diagnosis of BCL11A-ID is established in a proband with suggestive clinical and laboratory findings and a heterozygous pathogenic variant in BCL11A identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is primarily supportive and dictated by symptoms. Standard anti-seizure medication for seizure disorder; standard treatment for abnormal vision and/or strabismus, sleep disturbance, scoliosis, joint laxity, gastroesophageal reflux disease (GERD), constipation, and developmental issues.

Surveillance: Assessment of growth parameters, feeding difficulties, GERD, constipation, scoliosis, developmental progress, and behavior at each visit. Monitor seizures as clinically indicated. Assessment of vision and eye alignment as needed.

Genetic counseling: BCL11A-ID is inherited in an autosomal dominant manner; however, most affected individuals have the disorder as the result of a de novo BCL11A pathogenic variant. Once the BCL11A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Alobar holoprosencephaly

Madysen Wilcox, 29, was just six weeks pregnant when she began having complications, including bleeding and spotting that her doctors initially suspected may be a sign of miscarriage.

"However, when we got our ultrasound, they discovered I had what was called a subchorionic hematoma," Wilcox, of Utah, tells PEOPLE in an exclusive interview. According to the Cleveland Clinic, it is a condition in which "blood forms between a baby's amniotic sac and the uterine wall."

While it can be threatening to pregnancy depending on the location and size of the hematoma, doctors said Wilcox's "was small and in a spot that wasn't concerning." So they recommended pelvic rest, telling her to pause exercising and refrain from staying on her feet for long periods of time, or lifting anything heavier than 10 pounds.

"I did that for two weeks and my hematoma resolved and everything seemed fine," Wilcox says.

Once she entered her second trimester, the spotting began again.

"I was 15 weeks pregnant and my midwife wanted to do an ultrasound to figure out if the spotting was due to the hematoma or if there were issues with my placenta," she says. "So they checked again and found another subchorionic hematoma — but this time they also found that the baby's brain was not properly forming and they had a hard time locating a nasal bone."

Doctors then advised Wilcox to undergo a genetic blood test screening and a more in-depth ultrasound, suspecting that her baby might have Down syndrome. The blood test came back negative for any genetic disorder, but Wilcox's midwife still wanted a second opinion from a specialist based on her ultrasound images.

At 18 weeks pregnant, on May 29, 2024, Wilcox learned that her unborn baby — a boy she and her husband Darin had already named Charlie — had Alobar Holoprosencephaly, a rare condition in which the brain does not separate into two hemispheres.

https://people.com/woman-who-is-pregnant-with-a-baby-with-terminal-diagnosis-opens-up-exclusive-8717611

The condition, she learned, is fatal.

"The outcomes that doctors [gave] us are very grim," Wilcox says, noting that she saw four separate doctors after receiving the diagnosis. While each physician offered a somewhat different answer when asked about exact life expectancy, they all offered the same outlook: Charlie would not live long, and had a high likelihood of not even making it to birth.

However, Wilcox and Charlie defied some of the odds. "Most babies with this condition end in a miscarriage before the second trimester," she says. "Those who survive the first trimester, do not live past 24 weeks gestation."

But at 34 weeks pregnant, Charlie's heartbeat remained strong.

As she explains to PEOPLE, Wilcox was told that only one out of 10,000 pregnancies with Alobar Holoprosencephaly make it to a live birth, but she remained optimistic, sharing details of the condition, and her pregnancy, on TikTok.

She also made an effort to speak about Charlie as much as she could throughout her pregnancy, both with her husband and their two other children.

"Carrying a baby with a terminal diagnosis is an emotional roller coaster to say the least," she says. "I call it emotional chaos. It's a mixture of love, gratitude, compassion, joy, grief, fear, despair, guilt, and apathy, all at once. In the same day I can feel all of these emotions ten times over."

Though she adds, "I love this baby more than life," she admits "it’s also painful to get attached, because once I do, the grief and despair set in."

As the couple got closer to delivery day, they met with their doctors to plan how best to handle Charlie’s arrival, making "plans for every possible scenario," Wilcox says.

While Wilcox's due date was Oct. 27, doctors had planned to induce her on Oct. 4, just one day shy of a full-term pregnancy.

But on Oct. 4, the hospital was too full to accommodate her inducement — and she gave birth on Oct. 5 as she had hoped.

Ahead of his due date, Wilcox's plan was to "cherish the little time we get with our son, just getting to know him and holding him in our arms, where he is warm and knows he is loved," she shares.

In the end, they got to do just that. In a video posted to TikTok, Wilcox explained that Charlie "made his debut on the morning of October 5, 2024. We spent 41 beautiful minutes with him until he peacefully passed in our arms. Charlie's life was brief but perfect ... he only knew love and the warmth of his parents' arms."

For Wilcox, the moments she spent with Charlie were life-changing.

"It’s been the most beautiful and the most painful experience I’ve ever gone through in my life," she tells PEOPLE. "It’s hard to prepare to say goodbye to a person you’ve never met, but that you've also carried for nine months."

https://people.com/woman-who-is-pregnant-with-a-baby-with-terminal-diagnosis-opens-up-exclusive-8717611