ARHGEF9 mutations

Inspired by a patient with recurrent febrile seizures.

Yang H, Liao H, Gan S, Xiao T, Wu L. ARHGEF9 gene variant leads to developmental and epileptic encephalopathy: Genotypic phenotype analysis and treatment exploration. Mol Genet Genomic Med. 2022 Jul;10(7):e1967. doi: 10.1002/mgg3.1967. Epub 2022 May 31. PMID: 35638461; PMCID: PMC9266599.

Abstract

Background: The ARHGEF9 gene variants have phenotypic heterogeneity, the number of reported clinical cases are limited and the genotype-phenotype relationship is still unpredictable.

Methods: Clinical data of the patients and their family members were gathered in a retrospective study. The exome sequencing that was performed on peripheral blood samples was applied for genetic analysis. We used the ARHGEF9 gene as a key word to search the PubMed database for cases of ARHGEF9 gene variants that have previously been reported and summarized the reported ARHGEF9 gene variant sites, their corresponding clinical phenotypes, and effective treatment.

Results: We described five patients with developmental and epileptic encephalopathy caused by ARHGEF9 gene variants. Among them, the antiepileptic treatment of valproic acid and levetiracetam was effective in two cases individually. The exome sequencing results showed five children with point mutations in the ARHGEF9 gene: p.R365H, p.M388V, p.D213E, and p.R63H. So far, a total of 40 children with ARHGEF9 gene variants have been reported. Their main clinical phenotypes include developmental delay, epilepsy, epileptic encephalopathy, and autism spectrum disorders. The variants reported in the literature, including 22 de novo variants, nine maternal variants, and one unknown variant. There were 20 variants associated with epileptic phenotypes, of which six variants are effective for valproic acid treatment.

Conclusion: The genotypes and phenotypes of ARHGEF9 gene variants represent a wide spectrum, and the clinical phenotype of epilepsy is often refractory and the prognosis is poor. The p.R365H, p.M388V, p.D213E, and p.R63H variants have not been reported in the current literature, and our study has expanded the genotype spectrum of ARHGEF9 gene. Our findings indicate that levetiracetam and valproic acid can effectively control seizures in children with epileptic phenotype caused by ARGHEF9 gene variations. These findings will help clinicians improve the level of diagnosis and treatment of the genetic disease.

Scala M, Zonneveld-Huijssoon E, Brienza M, Mecarelli O, van der Hout AH, Zambrelli E, Turner K, Zara F, Peron A, Vignoli A, Striano P. De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females. Neurogenetics. 2021 Mar;22(1):87-94. doi: 10.1007/s10048-020-00622-5. Epub 2020 Sep 17. PMID: 32939676.

Abstract

Individuals harboring pathogenic variants in ARHGEF9, encoding an essential submembrane protein for gamma-aminobutyric acid (GABA)-ergic synapses named collybistin, show intellectual disability (ID), facial dysmorphism, behavioral disorders, and epilepsy. Only few affected females carrying large chromosomal rearrangements involving ARHGEF9 have been reported so far. Through next-generation sequencing (NGS)-based panels, we identified two single nucleotide variants (SNVs) in ARHGEF9 in two females with neurodevelopmental features. Sanger sequencing revealed that these variants were de novo. The X-inactivation pattern in peripheral blood cells was random. We report the first affected females harboring de novo SNVs in ARHGEF9, expanding the genotypic and phenotypic spectrum of ARHGEF9-related neurodevelopmental disorder in females.

Klein KM, Pendziwiat M, Eilam A, Gilad R, Blatt I, Rosenow F, Kanaan M, Helbig I, Afawi Z; Israeli-Palestinian Epilepsy Family Consortium. The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures. J Neurol. 2017 Jul;264(7):1421-1425. doi: 10.1007/s00415-017-8539-3. Epub 2017 Jun 15. PMID: 28620718.

Abstract

Mutations or structural genomic alterations of the X-chromosomal gene ARHGEF9 have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of ARHGEF9 by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2-3 years and intellectual disability. Three developed afebrile seizures between age 7-17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel ARHGEF9 variant (c.967G>A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in ARHGEF9 may be more common than previously assumed in patients with intellectual disability and mild epilepsy.

DHX37 gene variants and ribosomopathy

Menetrey A, Tarnopolsky M, Yoganathan S, Shroff M, Gorodetsky C. Child Neurology: Clinical and Imaging Findings in a Child With DHX37 Gene Variant: A Ribosomopathy Masquerading as Cerebral Palsy. Neurology. 2025 Oct 7;105(7):e214126. doi: 10.1212/WNL.0000000000214126. Epub 2025 Sep 11. PMID: 40934457.

Abstract

DEAH-Box helicase 37 (DHX37) gene, encoding an RNA-helicase, is essential for ribosome biogenesis. Pathogenic variants in the DHX37 gene result in a spectrum of ribosomopathies ranging from neurodevelopmental disorders with possible brain, vertebral, and/or cardiac anomalies (NEDBAVC syndrome, OMIM #618731) as well as disorders of sex development. Here, we describe a young boy with DHX37-related neurodevelopmental disorder with clinical and imaging findings masquerading as cerebral palsy. A 7.5-year-old boy presented with global developmental delay and generalized chorea of 6 months duration. He was born at 37 weeks gestation after an uneventful pregnancy with a birth weight of 2668 g. He had primary microcephaly and intractable epilepsy from infancy. Examination revealed microcephaly, spastic quadriparesis, generalized choreoathetosis and dystonia. MRI of the brain revealed T2-weighted hyperintensity in bilateral corticospinal tracts, posterior limb of the internal capsule (PLIC), corona radiata, external capsule, periventricular and deep white matter, as well as subcortical cysts. Diffusion-weighted images showed high signal in bilateral corticospinal tract and PLIC. As there were red flags pointing away from cerebral palsy such as primary microcephaly, refractory seizures, late-onset movement disorder, and persistent high signal on diffusion-weighted imaging, whole genome sequencing (WGS) was sent. WGS revealed a homozygous variant c.2417G>A (p.Ser806Asn) in the DHX37 gene. He was managed with antiseizure medications and clonazepam. DHX37-related neurodevelopmental disorder should be included in the differential for cerebral palsy mimic as affected children have global developmental delay, primary microcephaly, seizures, and movement disorders and thus may masquerade as sequel of hypoxic ischemic encephalopathy.

McElreavey K, Pailhoux E, Bashamboo A. DHX37 and 46,XY DSD: A New Ribosomopathy? Sex Dev. 2022;16(2-3):194-206. doi: 10.1159/000522004. Epub 2022 Jul 14. PMID: 35835064.

Abstract

Recently, a series of recurrent missense variants in the RNA-helicase DHX37 have been reported associated with either 46,XY gonadal dysgenesis, 46,XY testicular regression syndrome (TRS), or anorchia. All affected children have non-syndromic forms of disorders/differences of sex development (DSD). These variants, which involve highly conserved amino acids within known functional domains of the protein, are predicted by in silico tools to have a deleterious effect on helicase function. DHX37 is required for ribosome biogenesis in eukaryotes, and how these variants cause DSD is unclear. The relationship between DHX37 and human congenital disorders is complex as compound heterozygous as well as de novo heterozygous missense variants in DHX37 are also associated with a complex congenital developmental syndrome (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies; OMIM 618731), consisting of microcephaly, global developmental delay, seizures, facial dysmorphia, and kidney and cardiac anomalies. Here, we will give a brief overview of ribosome biogenesis and the role of DHX37 in this process. We will discuss variants in DHX37, their contribution to human disease in the general context of human ribosomopathies, and the possible disease mechanisms that may be involved.

Jiang W, Yu J, Mao Y, Tang Y, Cao L, Du Q, Li J, Yang J. Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development. Mol Genet Genomic Med. 2024 May;12(5):e2453. doi: 10.1002/mgg3.2453. PMID: 38769888; PMCID: PMC11106588.

Abstract

Background: 46,XY sex reversal 11 (SRXY11) [OMIM#273250] is characterized by genital ambiguity that may range from mild male genital defects to gonadal sex reversal in severe cases. DHX37 is an RNA helicase that has recently been reported as a cause of SRXY11. So far, a total of 21 variants in DHX37 have been reported in 58 cases with 46,XY disorders of sex development (DSD).

Methods: Whole exome sequencing (WES) was conducted to screen for variations in patients with 46,XY DSD. The subcellular localization of mutant DHX37 proteins was detected by immunofluorescence. And the levels of mutant DHX37 proteins were detected via Western blotting.

Results: A novel pathogenic variant of DHX37 was identified in a patient with 46,XY DSD c.2012G > C (p.Arg671Thr). Bioinformatics analysis showed that the protein function of the variant was impaired. Compared with the structure of the wild-type DHX37 protein, the number of hydrogen bonds and interacting amino acids of the variant protein were changed to varying degrees. In vitro assays revealed that the variant had no significant effect on the intracellular localization of the protein but significantly reduced the expression level of the protein.

Conclusions: Our finding further expands the spectrum of the DHX37 variant and could assist in the molecular diagnosis of 46,XY DSD patients.

Medicine only goes so far

As her husband, Rabbi Meshulom Weiss, shared with JEM’s My Encounter:

When we went to see the Rebbe for a blessing a few days before our wedding, she started to cry and asked that I leave the room so she could speak to the Rebbe alone. Puzzled, I complied.

After twenty minutes, she came out no longer crying, and she said nothing to me about it until after we were married. Then she confessed, “I hope that you won’t be upset about what I told the Rebbe. I had wanted to call the wedding off because I am very impatient and have a bad temper; I feared that my temperament made me unsuitable to be a wife and mother. I told the Rebbe that I would rather not get married than to get married only to get divorced. But the Rebbe just smiled at me and said, ‘G-d will bless you with many children, and these children will teach you patience. Meanwhile, do volunteer work – preferably in a hospital with children – and you will find your patience growing. But don’t call off the wedding.”

Having the Rebbe’s promise of many children, we looked forward to starting our family, but months came and went, and my wife – who was eighteen at the time we got married – did not get pregnant. When we sought the advice of a gynecologist, she was informed that she had an undeveloped womb – what is called an “infantile uterus” – which meant she could not bear children. My wife was absolutely devastated to hear this, so we went to get a second opinion and a third opinion, both of which only confirmed the first.

Then we called New York and reported this news to the Rebbe. His response was to reiterate the promise of many children and to give us a blessing. A month later my wife became pregnant with our first child, a boy whom we named Mordechai. And as it turned out, he was the first of fifteen!

After our sixth or seventh child was born, the doctor called me in and said, “Listen, your wife is having a child every year. This is not good for her body. You must give her a rest.” He scared the daylights out of me. I came home and reported this to my wife, who said, “Let’s consult a rabbi. We need to know what the opinion of Jewish law in a case such as ours.”

The rabbi we consulted ruled that, if the doctor said my wife’s life was in danger, we had to listen to him and take a break from having children. Maybe have no more kids at all.

We accepted that decision, but shortly thereafter, we had an opportunity to be in New York, and my wife decided to pose this question to the Rebbe. She told him about the doctor’s opinion and the rabbi’s opinion. She also said, “Despite these opinions, I don’t want to stop having children. But my husband has been scared by the doctor and he fears something might happen to me.”

Hearing that, the Rebbe called me in and said, “Meshulom, don’t mix in G-d’s business. If your wife is not supposed to have any more children, she won’t. And if she is, she will. It’s not up to you.”

Even though the Rebbe usually referred people to a rabbinic authority in such situations, he made an exception in our case. With that we continued and had a total of fifteen beautiful children, thank G-d, each of whom is a tremendous blessing.

But there is postscript to the story.

Years later, when my wife was older, she went to see a gynecologist again. He examined her and said, “You must be very disappointed – as a religious woman, you undoubtedly wanted many children, but with your infantile uterus you obviously never could have any.”

My wife said nothing, but she went out the door laughing. When she came home and told me about it, we had a good laugh together. And I said to her, “All those doctors could not have been wrong. But something amazing happened. The Rebbe promised you that you would have many children and gave you a blessing. Without the Rebbe’s blessing, without his advice and foresight, none of our children would be here!”

https://anash.org/mrs-eileen-weiss-86-ah/

Sunflower syndrome redux

Inspired by patients

Capobianco F 3rd, Beal R, Vemuri P, Bhatia S. A Girl Who Seeks the Light: Diagnosis of Sunflower Syndrome and Review of Management Options. Neurol India. 2025 Mar 1;73(2):346-348. doi: 10.4103/neurol-india.Neurol-India-D-23-00564. Epub 2025 Apr 3. PMID: 40176229.

Abstract

Sunflower syndrome (SS) is a rare self-induced, reflexive epilepsy with photic triggers having highly unique and specific clinical features as patients will characteristically flap their fingers in front of their eyes upon exposure to bright light. Many clinicians are perhaps unaware of this entity, making SS prone to infrequent consideration and misdiagnosis. The purpose of this case is to increase awareness of this diagnosis. We present an adolescent girl in whom this diagnosis was missed/delayed and discuss workup/management in hopes of minimizing holdup in care for individuals affected by this syndrome.

Baumer FM, Julich K, Friedman J, Nespeca M, Thiele EA, Bhatia S, Joshi C. Sunflower Syndrome: A Survey of Provider Awareness and Management Preferences. Pediatr Neurol. 2024 Mar;152:177-183. doi: 10.1016/j.pediatrneurol.2023.11.013. Epub 2023 Nov 30. PMID: 38295719; PMCID: PMC10936539.

Abstract

Background: Sunflower syndrome is a rare photosensitive pediatric epilepsy characterized by stereotyped hand-waving in response to bright lights. These stereotyped movements with maintained awareness can be mistaken for a movement disorder. This study assessed neurology providers' diagnostic reasoning, evaluation, and treatment of Sunflower syndrome.

Methods: A 32-question anonymized electronic survey, including a clinical vignette and video of hand-waving in sunlight, was distributed to child neurology providers to assess (1) initial diagnosis and evaluation based on clinical information, (2) updated diagnosis and management after electroencephalography (EEG), and (3) prior experience with Sunflower syndrome.

Results: Among 277 viewed surveys, 211 respondents provided information about initial diagnosis and evaluation, 200 about updated diagnosis, 191 about management, and 189 about prior clinical experience. Most providers (135, 64%) suspected seizure, whereas fewer suspected movement disorders (29, 14%) or were unsure of the diagnosis (37, 22%). EEG was recommended by 180 (85%). After EEG, 189 (95%) diagnosed epilepsy, 111 of whom specifically diagnosed Sunflower syndrome. The majority (149, 78%) recommended antiseizure medications (ASMs) and sun avoidance (181, 95%). Only 103 (55%) had managed Sunflower syndrome. Epileptologists and those with prior clinical experience were more likely to suspect a seizure, order an EEG, and offer ASMs than those without prior experience.

Conclusions: Although many providers had not managed Sunflower syndrome, the majority recognized this presentation as concerning for epilepsy. Epilepsy training and prior clinical experience are associated with improved recognition and appropriate treatment. Educational initiatives that increase awareness of Sunflower syndrome may improve patient care.

Sourbron J, Proost R, Vandenneucker J, Ticcinelli V, Roelens F, Schoonjans AS, Sercu E, Verhelst H, Jansen K, Lagae L. Seizure quantification in sunflower syndrome by a wrist-worn device. Epileptic Disord. 2025 Apr;27(2):219-227. doi: 10.1002/epd2.20318. Epub 2024 Dec 5. PMID: 39636535.

Abstract

Objective: Sunflower syndrome is a rare photosensitive childhood-onset epilepsy, featuring repetitive handwaving events (HWE) triggered by light. Objective documentation of these HWE can be difficult due to the numerous events occurring daily and/or caregivers who document the seizures but are not always present. Hence, seizure diaries can be underreporting.

Methods: We performed a feasibility study in three Belgian Sunflower syndrome individuals to assess the possibility to quantify the HWE by a wrist-worn wearable device (Axivity AX6). We conducted a structured exercise aiming to capture patterns of possible confounders in a controlled environment. Subsequently, patients wore the device for three to six consecutive days and nights at home. Spectral power analyses were performed to characterize the frequency signature of the different movements.

Results: The HWE of patient A and B showed homogeneity and narrow-band frequencies. Patient C did not experience any HWE at the start of the study due to proper seizure control. Regarding HWE, there was a higher spectral power for Gyroscope Z (Gz) compared to Gy. The inter-subject variability for HWE frequency peaks was in the 3-6 Hz range. Computer analysis by visual annotation, without checking the seizure diary, detected 71% of the HWE if the HWE lasted for longer than 5 s (sensitivity 64%). For shorter HWE duration, the detection rate was 50% but seemed to be higher if there was a concordant change of eye movement (63%) (sensitivity 36%). The most obvious confounder was toothbrushing (TB). However, TB showed a different pattern: that is, higher or comparable spectral power for Gy compared to Gz. There was also a higher or comparable spectral power for Gy compared to Gz for "waving hello".

Significance: We show that the wearable movement sensor Axivity AX6 can detect HWE in Sunflower syndrome individuals and distinguish them from confounders in a real-world setting.

Sunflower syndrome: ocular treatment

Inspired by patients

Geenen KR, Yap SV, Tsega L, Cantrell S, Bruno PL, Thiele EA. Efficacy and tolerability of blue-tinted contact lenses in the treatment of Sunflower syndrome: A questionnaire-based study. Epilepsy Behav. 2026 Mar;176:110921. doi: 10.1016/j.yebeh.2026.110921. Epub 2026 Jan 31. PMID: 41621154.

Abstract

Aim: The goal of this study was to assess the efficacy and tolerability of the Cantrell Notch Filtering soft contact lens as a treatment for patients with Sunflower syndrome.

Methods: A questionnaire was distributed to patients with Sunflower syndrome that were being treated with the Cantrell Notch Filtering contact lenses. The survey was hosted on REDCap, and covered topics pertaining to the respondent's history of Sunflower syndrome, including frequency of seizures, tolerability of the lenses, and the perceived benefit of the lenses with regard to reduction of handwaving episodes.

Results: Nineteen people participated in this study. Sixteen of the 19 respondents provided numerical data regarding the frequency of handwaving episodes with and without contact lenses. At the time of survey completion, the average length of time that patients reported wearing the contact lenses was 11.5 months (range: 1 week-2 years 6 months). There was an average 72.9% reduction in handwaving episodes with the use of the contact lenses. Many respondents were able to reduce the use of other non-pharmacological interventions, such as hats and sunglasses, while wearing the contact lenses. However, 10 respondents (52.6%) reported difficulty with tolerability of the contact lenses, including stinging, burning, and color distortion. Of note, these contact lenses filter light between 250 and 650 nm, compared to a Zeiss Z1 lens which filters light between 550 and 700 nm.

Conclusion: The Cantrell Notch Filtering contact lens for Sunflower syndrome may be a beneficial non-pharmacological treatment option for some patients with Sunflower syndrome, although many patients have difficulty with tolerability.

Geenen KR, Yap SV, Tsega L, Dowless D, Bruno PL, Thiele EA. Eye patches and seizure frequency in young people with Sunflower syndrome. Dev Med Child Neurol. 2026 Jan 10. doi: 10.1111/dmcn.70140. Epub ahead of print. PMID: 41518217.

Abstract

The goal of this study was to assess the impact of wearing an eye patch on seizure frequency in patients with Sunflower syndrome, a reflex photosensitive epilepsy. Caregivers were instructed to record the number of handwaving episodes (HWEs) that occurred per hour under each of the following conditions: (1) no eye patch, (2) wearing an eye patch on the eye ipsilateral to the hand involved in handwaving, and (3) wearing an eye patch on the eye contralateral to the hand involved in handwaving. Patients performed each trial three times, for a total of nine 1-hour trials. Seven patients (five females, two males; age range 8 years 10 months-21 years 5 months, median age = 11 years 2 months) participated in this study. All patients experienced a decrease in HWEs while wearing an eye patch on either eye. Across all patients, the median frequency of HWEs with no eye patch (baseline) was 136 HWEs/hour. When patching the contralateral eye, the median frequency was 26 HWEs/hour. When patching the ipsilateral eye, the median frequency was 23 HWEs/hour. The findings in this study suggest that blocking sensory input to one eye may significantly reduce seizure frequency in patients with Sunflower syndrome. This may inform theories around the pathophysiology of Sunflower syndrome and provide insight into more effective treatment options.

Congenital CMV story

Courtesy of my daughter

Jess Markins' daughter was just a little over 24 hours old when her whole world was rocked.

The mom and content creator, who has been sharing her 2-year-old daughter Caroline's journey on TikTok, tells PEOPLE that she first learned that something might be wrong with Caroline during her pregnancy at her 20-week anatomy scan.

"Doctors noticed growth restriction and some abnormalities on the ultrasound," she explains. "We went through additional testing and very close monitoring for the rest of my pregnancy, but I was mostly told that she was just small."

Markins says that she was told Caroline would be evaluated more thoroughly once she was born, since nothing stood out strongly enough to give a clear diagnosis. And for the first 24 hours of Caroline's life, everything was relatively normal.

"After that, everything changed. A routine brain ultrasound showed calcifications, and she was diagnosed with microcephaly," says Markins. "That led to an MRI, which revealed more extensive abnormalities in her brain."

"Around the same time, she failed her newborn hearing screening. Because of [the state of] Virginia's guidelines, that meant she needed to be tested for congenital CMV — something I had never even heard of before."

According to the CDC, cytomegalovirus (CMV) is a common virus that infects people of all ages. However, when a baby is born after being infected with CMV during pregnancy, it is called congenital CMV. About 1 in 200 babies are born with congenital CMV infection, and about 1 in 5 babies with congenital CMV infection will have birth defects or other long-term health issues.

"When Caroline was one week old, we got the results: she tested positive for congenital CMV," says Markins. "My first reaction was fear — there were so many unknowns. I clung to the hope that she might be one of the children who test positive, but remain asymptomatic.

But as Markins and her partner Chris began meeting with specialists, it became clear that Caroline was symptomatic and would need significant medical support. She began antiviral medication during her first weeks of life, and early intervention began shortly after. Caroline had physical therapy at 2 months old, occupational therapy at 6 months and speech therapy by her first birthday.

"At first, I think I was in a bit of denial, hoping things might not be as serious as they seemed," she says. "But I also knew that giving Caroline every available resource could only help her. Early intervention became something I was incredibly passionate about right from the start. Even in the middle of fear and uncertainty, I knew action was something I could control."

Now two years later, Caroline's days are very structured. Markins says her daughter gets up very early — sometimes around 2 a.m. — and will watch a few TV shows while she tries to sleep a little more. They officially begin the day at 6:30 or 7 a.m., where Caroline gets her first G-tube (gastronomy tube) of the day.

"Caroline sees multiple specialists and has therapy every week, so some days are very busy and involve a lot of driving and time at clinics," says Markins. "On days we're home, we focus on movement and play. She spends time stretching, using her swing and doing floor activities like assisted sitting and rolling."

"She also uses supportive equipment like her activity chair and stander, depending on her energy level that day. Throughout the day, we incorporate her eye-gaze device so she can communicate and make choices," she continues.

Caroline is able to communicate through her eye-gaze device, which is a form of augmentative and alternative communication (AAC) that uses eye tracking. She can select words or phrases on a screen by just looking at them.

"Her communication journey has been incredible to watch. We started when she was about a year old with simple buttons, which gave her very limited ways to express herself. But the more she worked in speech therapy, the more we realized she had a lot to say," explains Markins.

"We moved to picture boards, where she began communicating with her eyes, and as she got older, she had a formal eye-gaze evaluation. She did so well that she now uses her eye-gaze device as her primary way to communicate."

Markins says that Caroline's vocabulary is "constantly growing" and that they are always adding new words and updating her device to match her growing interests and personality.

"And trust me, she has a big personality. Caroline is funny, sassy and very opinionated," says the proud mom. "If you don't understand what she's saying, she will absolutely repeat herself until you do."

Right now, Markins says some of her daughter's favorite things to say are "watch" followed by the name of a television program, and she's been asking for "drink water" because she enjoys taking small sips by mouth.

Caroline also has an About Me page on her device, where she can share her name, age and birthday. Markins says Caroline loves to tell people all about herself, and adds that her favorite button right now is "big news." She's set to become a big sister this summer.

"She tells anyone and everyone, and she is so proud and excited," says Markins.

When they don't have the eye-gaze device, Markins and her family use head taps to help her make choices. But even without any tools, she says that Caroline is incredibly expressive.

"You can see what she's feeling just by watching her face. Her smile is warm and contagious, and she makes it very clear what she thinks," says Markins. "For us, communication is about giving her as much autonomy and voice as possible — and watching her personality shine through has been one of the greatest gifts."

Throughout this journey, Markins says she and her husband have been very fortunate to rely on a strong support system around them. Both of their families live within 30 minutes, and they've been leaning on their local community recently.

"We’re currently fundraising for adaptive equipment and a wheelchair-accessible van for Caroline, and the way people have rallied around her has been overwhelming in the best way," she says. "Seeing how much love and care people have for her truly blows me away."

"Day to day, my husband is my biggest teammate. He works incredibly hard — seven days a week — to support our family financially so I can stay home and be Caroline’s full-time caregiver and be present for both of our girls," she continues. "That kind of partnership makes everything we do possible."

Caroline also has a big sister named Emersynn, who is only 13 months older than her. The two sisters have grown up together, and Emersynn has never known life without medical equipment, therapy visits and extra care for Caroline.

"What amazes me most is how naturally Emersynn has adapted. From the time she was very little, we never had to constantly tell her 'don’t touch' or worry about her interfering with Caroline’s equipment," says Markins. "When Caroline had feeding tubes taped to her face, Emersynn didn’t pull at them. With her feeding pump or medical supplies, she’s always been curious but respectful. Even with Caroline’s hearing aids, she asks questions but doesn’t try to grab or remove them."

"Emersynn just wants to be involved. She watches closely, asks questions, and cheers Caroline on in the sweetest ways. When Caroline uses her eye-gaze device, takes a sip of water, or activates a toy, Emersynn is right there clapping and cheering her on. She is truly one of Caroline’s biggest supporters."

Since sharing Caroline's story on TikTok, Markins says she's found a community online from other parents who are walking the same path as her. She's also been able to advocate for her daughter and provide an example of a medically complex and disabled child.

"When Caroline was first diagnosed, I found myself searching for other parents who were living this kind of life. Watching medical moms and disability parents share their experiences made me feel less alone," Markins tells PEOPLE. "Seeing how they adapted their homes, routines, and expectations to give their children full, meaningful lives was incredibly powerful for me."

"At some point, I realized I wanted to be that person for someone else. I wanted to be the mom I wish I had been able to watch when I was newly navigating diagnoses, equipment, and a completely different version of parenthood than I had imagined," she says. "There’s also such a lack of representation for medically complex and disabled children. Our world is built for able-bodied people, and families like ours often have to fight and advocate just to access basic opportunities."

Markins says she feels a responsibility to share their family's story to help create more awareness, more understanding and more inclusion for kids like Caroline.

"I want people to see that disability is not something to hide away — it’s a part of life, and these children deserve to be seen, supported, and celebrated," she says. "I would choose Caroline in every lifetime, a hundred times over. What I would change is not her — it’s the way society views and supports people with disabilities. If sharing our story helps even one person better understand or shift their perspective, then it’s worth it."

Hannah Sacks

https://people.com/2-year-old-girl-communicates-with-eye-gaze-device-exclusive-11913019

Compassion in the UK

February 5

Dear Shmuly,

Today we attended a full-day meeting to work out the legal aspects surrounding your care. Here in England, they don’t place a high value on life that isn’t “productive.” Under UK law, if a patient is dependent on life-sustaining treatment without the prospect of significant recovery, it’s often judged to be not “in their best interests” to continue. These life-or-death decisions end up in the hands of NHS trusts and the courts. So even though every breath you took — with the help of the ventilator — meant the world to us, we knew we wouldn’t be able to fight the NHS forever.We didn’t want a court case, so Tatty and I, along with our legal team, went to many meetings as we tried to work out an agreement with the hospital administration through the courts.

Today I had to join an in-person meeting.

Last night I slept at home and noticed an empty picture frame I’d bought before Tatty and I got married. The placeholder paper read: Today is a good day. And I thought, Today is a good day, but tomorrow can’t be.

But tonight, after ten long, long hours of discussion, migraines, exhaustion, and the brick wall of a quickly-going-nowhere back-and-forth, I looked at that frame again and realized: Good is relative. Our situation isn’t great, and it looks like we’re going to have to take your case to court, but there are moments of goodness and even humor and laughter laced through all the frustration.

I’ve tried to notice the small hugs Hashem sends. That moment of sunlight on your face. The nurse who gave me a birthday card with your footprints. The friend who texts at exactly the right time.

Small hugs, but when I look for them, I find them.

Love, Mommy

June 30

Dear Shmuly,

The court process dragged on longer than we expected; hearings were postponed, and dates kept getting moved as we struggled to reach an agreementabout your long-term care — with the hospital denying that you had quality of life, and we insisting that your very existence was valuable.

First the hearing was pushed off until after Pesach. Then after Shavuos. When I heard about the latest delay, I said, “It looks like Shmuly’s going to livethrough all the Yamim Tovim!” It was another hug from Hashem, a confirmation of your life.

But I knew the end was coming, and instead of feeling robbed, I felt grateful. You could have died right away, Shmuly. Or much earlier. Every extra day was agift. And we chose to accept it.

The finalized legal decisions included one week so we could say goodbye properly. The family came. Grandparents. Siblings. Aunts. Uncles. Friends. Wecaptured those moments with you.

But the uncertainty was crushing. We didn’t know what would happen once the ventilator was removed. Would it be peaceful, or would our time together bepunctuated by alarms ringing as you struggled to breathe? Would it be minutes? Hours? How long would we have to cherish the last few moments?

Nothing was certain. But I bought you a final set of soft, cuddly pajamas, and you stayed in them until the end.

By the time Monday came, I was prepared — at least intellectually — to give you back. Nothing could prepare my emotions. The pain I carried in my heartwas excruciating, stealing my breath at the thought of losing you. But we’d been living in the shadow of this goodbye for months, and I wanted the momentto be as perfect as possible. Tatty and I were in the room with you, and everything was calm and gentle.

The hospital wanted to extubate you, but doing that could have caused you to die immediately. We needed to make sure you had a chance, so we worked tocreate a plan that would reduce your support gradually and safely. With the help of our supporters, the court honored the Torah way of doing this transition,avoiding immediate death.

The doctors switched your ventilator to a CPAP mask (a machine that gently pushes air into your lungs to help you breathe) and helped keep your airwayopen. They reduced your breathing support slowly and carefully, only when they thought you could handle it.

In the end, you surprised everyone, Shmuly. You breathed on your own for nearly ten hours.

For the first eight hours, you were perfectly calm. I held you the entire time, listening to each breath. For the first time since you were a newborn, I could seeyour whole face… no tubes or machinery covering you. And that’s the picture I remember.

One striking detail about your life is that the timing of your birth, cardiac arrest, and passing, all took place at night, the start of the new Jewish day. Every dayof your life was complete. The 16 days before the hospital and the 307 days in the hospital, 323 days in total, were all whole.

In the final two hours, you struggled for breath. I held your hand and stroked you as the sun set and the sky turned pink behind you. I whispered Shema,faltered through Hamalach, and sang softly.

And then, peacefully, you passed away.

I was there the whole time. I was always there.

We fought for you all the way, Shmuly. And in the end, you fought for yourself.

Love, Mommy

See: https://mishpacha.com/23-million-seconds/