Schinzel-Giedion syndrome redux

Inspired by a patient

Duis J, Agresta L, Bennett WE Jr, Chambers H, Clarke A, Fairhurst C, Hoover-Fong J, Murphy F, Noritz G, Schwantes S, Shreve M, Thusang K, Weidemann D, Beale R, Mehta A, Wilhelmsen A, Summerfield N. International Expert Opinion on Standard of Care for Patients With Schinzel-Giedion Syndrome: A Modified Delphi Study. Am J Med Genet A. 2025 Jun;197(6):e64015. doi: 10.1002/ajmg.a.64015. Epub 2025 Feb 19. PMID: 39967563.

Abstract

Schinzel-Giedion Syndrome (SGS) is an ultra-rare, multisystem, genetic developmental disorder caused by gain-of-function pathogenic variants in the SETBP1 gene. No standard of care (SoC) recommendations currently exist. To assess expert opinion on SoC for individuals with SGS using a modified Delphi method. A multidisciplinary panel of 21 experts from the USA and Europe was assembled. Experts responded to a two-round questionnaire, with a subgroup participating in a virtual workshop, through which recommendations pertaining to the diagnosis, monitoring, treatment, and management of SGS were iteratively developed. Consensus was defined as ≥ 70% of respondents demonstrating agreement/disagreement with 6-point Likert scale questions, or ≥ 70% of respondents selecting a given multiple-choice question option. Overall, 81/94 statements achieved consensus. Experts agreed that the recommendations should be considered applicable to any individual with confirmed SGS or an indicative phenotype and any SETBP1 gain-of-function mutation. Key considerations included early and sustained involvement of a multidisciplinary team, routine monitoring for common tumors, neurologic, renal, genitourinary, pulmonary, musculoskeletal and gastrointestinal manifestations/complications, and facilitation of shared decision-making processes. These recommendations should help guide clinicians and families/caregivers in care decisions to enhance quality and duration of life for individuals with SGS and facilitate shared decision-making.

Takeuchi A, Okamoto N, Fujinaga S, Morita H, Shimizu J, Akiyama T, Ninomiya S, Takanashi J, Kubo T. Progressive brain atrophy in Schinzel-Giedion syndrome with a SETBP1 mutation. Eur J Med Genet. 2015 Aug;58(8):369-71. doi: 10.1016/j.ejmg.2015.05.006. Epub 2015 Jun 19. PMID: 26096993.

Abstract

Schinzel-Giedion syndrome is a rare congenital malformation syndrome. Recently, SETBP1 was identified as the causative gene. Herein, we present a Japanese boy with Schinzel-Giedion syndrome resulting from a novel mutation in SETBP1 in order to establish the clinical features and serial MRI findings associated with the syndrome. On the third day of life, the boy was referred to our hospital because of facial abnormalities and feeding difficulty. Midfacial retraction, frontal bossing, deep groove under the eyes, upturned nose, low-set ears, bilateral cryptorchidism, and generalized hypertrichosis were identified on admission. At the age of 7 months, epileptic spasms in series occurred. Based on characteristic facial and skeletal abnormalities and severe developmental delay, we clinically diagnosed him with Schinzel-Giedion syndrome. Direct sequencing of the SETBP1 gene revealed a heterozygous mutation (p.Ile871Ser) in exon 4. Although neither cardiac defect nor choanal stenosis were present in our case, the phenotype of our case was nearly identical to those of previously reported cases confirmed by genetic analysis. Serial MRI from the age of 1 month-3 years revealed progressive brain atrophy, especially in the white matter and basal ganglia. However, myelination was age-appropriate and no obvious abnormal signals in the white matter were seen. Diffusion weighted imaging revealed no abnormal findings. Accumulation of MRI data including diffusion weighted imaging from Schinzel-Giedion syndrome cases is needed to understand the mechanism underlying progressive brain atrophy in this syndrome.

Leone MP, Palumbo P, Palumbo O, Di Muro E, Chetta M, Laforgia N, Resta N, Stella A, Castellana S, Mazza T, Castori M, Carella M, Bukvic N. The recurrent SETBP1 c.2608G > A, p.(Gly870Ser) variant in a patient with Schinzel-Giedion syndrome: an illustrative case of the utility of whole exome sequencing in a critically ill neonate. Ital J Pediatr. 2020 May 27;46(1):74. doi: 10.1186/s13052-020-00839-y. PMID: 32460883; PMCID: PMC7254667.

Abstract

Background: Schinzel-Giedion syndrome (SGS) is a multiple malformation syndrome mainly characterized by severe intellectual disability, distinctive facial features, and multiple congenital anomalies, including skeletal abnormalities, genitourinary and renal malformations, cardiac defects, as well as an increased pediatric cancer risk. Recently, SGS has been associated with de novo heterozygous deleterious variants in the SETBP1 gene; to date, nine different variants, clustering in exon 4 of SETBP1, have been identified in 25 patients.

Case presentation: In this study, by using Whole Exome Sequencing (WES), we identified a patient with a recurrent missense mutation in SETBP1, the c.2608G > A, p.(Gly870Ser) variant, previously reported as likely pathogenic. This finding allowed us to confirm the suspected clinical diagnosis of SGS. Clinical features of patients carrying the same variant, including our patient, were evaluated by a review of medical records.

Conclusions: Our study confirms SGS as a severe disorder potentially presenting at birth as a critically ill neonate and demonstrates the causal role of the c.2608G > A, p.(Gly870Ser) variant in the etiology of the syndrome. Moreover, although the cohort of SETBP1-patients reported in the literature is still small, our study reports for the first time the prevalence of the variant (about 27%, 7/26). Finally, given the heterogeneity of clinical presentations of affected patients hospitalized in Neonatal Intensive Care Units (NICU) and/or Pediatric Intensive Care Units (PICU), in agreement with emerging data from the literature, we suggest that WES should be used in the diagnosis of unexplained syndromic conditions, and even as part of a standard first-line diagnostic approach, as it would allow a better diagnosis, counseling and management of affected patients and their families.

See: https://childnervoussystem.blogspot.com/2026/05/schinzel-giedion-syndrome.html

Child Neurology Society statement on Dobbs v Jackson and my response

Dobbs v Jackson

A Statement from the Child Neurology Foundation (CNF) & Child Neurology Society (CNS)

The Child Neurology Foundation (CNF) and the Child Neurology Society (CNS) work on behalf of children and families living with neurologic conditions within the United States, and the child neurologists who care for them. As the leading organizations representing
the child neurology community, we stand firm in our commitment that all have access to safe, equitable and quality healthcare, including medical termination of pregnancy-abortion. We are persistent in our belief of the essential and critical relationship between a patient and their health care professional, and boldly guard against any intrusion.

Medical decisions are intricate and complex, particularly when neurological conditions are involved. Our community faces care decisions related to pregnancies affected by congenital, genetic, life-threatening anomalies, or in persons with intellectual and developmental impairment who live with a higher risk for sexual assault. Moreover, our health care professionals commonly manage medicines known to be correlated with a higher risk of birth defects. We affirm that all medical decisions should occur between the health care professional, patient, and their caregiver. Therefore, we are deeply concerned with a growing number of states reacting to the Dobbs v. Jackson Women’s Health Organization decision with legislation that impedes health care professionals from optimally and equitably serving their patients and caregivers.

Guided by compassion and medical expertise, we remain steadfast in our support of the child neurology community – keeping our patients and their families at the center of our work.

Anup Patel, MD

President

Child Neurology Foundation

Bruce Cohen, MD

President

Child Neurology Society


My response:

From: Galen Breningstall
Sent: Thursday, July 21, 2022 12:02 PM
To: bcohen@akronchildrens.org <bcohen@akronchildrens.org>; anup.patel@nationwidechildrens.org <anup.patel@nationwidechildrens.org>
Subject: Dobbs v Jackson statement

I cannot in good conscience accept the Dobbs v Jackson statement of the Child Neurology Society or remain a member of an organization where this is the official position of the organization. "As the leading organizations representing the child neurology community, we stand firm in our commitment that all have access to safe, equitable and quality healthcare, including medical termination of pregnancy - abortion. We are persistent in our belief of the essential and critical relationship between a patient and their health care professional, and boldly guard against any intrusion."  I do not believe that the "essential and critical relationship between a patient and their health care professional" should be protected "against any intrusion". In recent political discussion regarding the abortion issue it has been abundantly clear than any mother who wishes to kill her baby, for whatever frivolous reason and at whatever gestation, will find a medical professional willing to accommodate her. This is an abomination and warrants legal protection for the unborn child.

immunosuppressive therapy discontinuation in patients with myelin oligodendrocyte glycoprotein antibody-associated disease

Boudot de la Motte M, Gavoille A, Papeix C, et al. Treatment Discontinuation in Patients With Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease. JAMA Neurol. 2026;83(5):490–498. doi:10.1001/jamaneurol.2026.0268

Key Points

Question What is the impact of maintenance therapy discontinuation on relapse risk in patients with myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD)?

Findings In this cohort study of 705 adult patients with MOGAD, 83 discontinuations were analyzed, with a1-year relapse risk of 8.7%. Relapse risk was significantly decreased in patients with a prior treatment duration greater than 1 year and a time since last relapse greater than 2 years.

Meaning The findings suggest that treatment discontinuation may be considered in selected adult patients with MOGAD.

Abstract

Importance Therapeutic deescalation strategies are increasingly considered in demyelinating diseases to mitigate the risks associated with prolonged immunosuppression. The impact of treatment discontinuation in myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) is not established.

Objective To assess the relapse risk following treatment discontinuation in adult patients with MOGAD and to evaluate factors associated with disease reactivation.

Design, Setting, and Participants This retrospective cohort study including 41 centers was conducted using the French NOMADMUS database. Adult patients with MOGAD diagnosed between January 2013 and April 2024 were included. Data were extracted on July 1, 2024. A total of 1047 patients with MOGAD were screened, and 705 patients fulfilled the inclusion criteria. Among them, 319 (45.2%) received at least 1 maintenance therapy.

Exposure All instances of treatment discontinuation were collected and categorized according to their underlying reasons. Only discontinuations that were scheduled or related to adverse events were analyzed.

Main Outcomes and Measures Time to first relapse was estimated using Kaplan-Meier survival curves, and differences between groups were assessed using the log-rank test.

Results A total of 83 patients (median [IQR] age, 42.7 [28.9-53.3] years; 52 [63.7%] female) discontinued either oral immunosuppressants (azathioprine or mycophenolate mofetil) or rituximab in 60 (72.1%) and 23 (27.7%) individuals, respectively. Discontinuations were scheduled (n = 54 [65.1%]) or related to adverse events (n = 29 [34.9%]). After discontinuation, 7 patients relapsed, with a median (IQR) time to relapse of 0.5 (0.1-1.4) years. The Kaplan-Meier estimated cumulative incidence of relapse at 1 year after discontinuation was 8.7% (95% CI, 1.0-15.9). Severity of relapses was mild, with a median (IQR) change in the Expanded Disability Status Scale score of 0 (0-1) points. Factors associated with an increased relapse risk were a treatment duration of less than 1 year (7 relapses [19.4%] vs 0 relapses; log-rank P = .002) and a time since last relapse of less than 2 years (7 relapses [15.9%] vs 0 relapses; log-rank P = .01).

Conclusions and Relevance The low risk of disease reactivation found in this study suggests that discontinuing treatment may be considered in selected adult patients with MOGAD. Future clinical trials are necessary to confirm these results and establish guidelines in this situation.

Kang YR, Ju H, Kim KH, Choo SH, Ju W, Kim SM, Kim S, Sohn E, Nam TS, Oh SY, Yoon BA, Kim JK, Kim H, Lee EJ, Lim YM, Kwon YN, Kim SW, Shin HY, Kim JE, Joo IS, Park M, Lee HS, Kim BJ, Park JW, Lee SY, Kim W, Hyun JW, Kim SH, Min JH, Kim HJ. Outcomes of immunosuppressive therapy discontinuation in patients with myelin oligodendrocyte glycoprotein antibody-associated disease. Mult Scler. 2025 Aug;31(9):1102-1109. doi: 10.1177/13524585251320046. Epub 2025 Apr 28. PMID: 40296497.

Abstract

Background: Research on the optimal duration of immunosuppressive therapy (IST) and the outcome upon its discontinuation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remains limited.

Objective: To evaluate the outcomes following IST discontinuation in MOGAD.

Methods: This multicenter retrospective study collected data from 333 MOGAD patients in Korea. Among 273 patients who received IST, 41 who discontinued IST were analyzed.

Results: The median age at disease onset was 38.3 years (interquartile range (IQR), 27.6-53.1). Before IST withdrawal, 21 (51%) patients exhibited relapsing courses. Over a median follow-up of 23.5 months (IQR, 12.1-39.5) after discontinuation, 10 patients (24.4%) relapsed after a median of 8.2 months (IQR, 6.3-11.5). All relapses occurred in patients with a prior relapsing course (10/21, 47.6%); none with prior monophasic courses relapsed. Among 21 prior relapsing patients, relapse after discontinuation group had a shorter IST duration than non-relapse group (median, 9.4 vs 50.9 months, p = 0.036). None of the 41 patients had severe disability (Expanded Disability Status Scale (EDSS) score ⩾ 4.0 or Visual Functional System score ⩾ 5) at the last visit.

Conclusion: IST discontinuation did not necessarily lead to relapse and could be considered with an individualized approach based on factors such as disease course and IST duration.

Yeh WZ, Francis A, Cooper S, Rashid W, Martin R, Hobart J, Halfpenny C, Williams V, O'Sullivan E, Hemingway C, Hacohen Y, Dobson R, Waters P, Sharma SM, Butzkueven H, Geraldes R, Ramdas S, Leite MI, Palace J. Optimal strategies for treatment discontinuation in MOG antibody-associated disease. Brain. 2026 Feb 4:awag006. doi: 10.1093/brain/awag006. Epub ahead of print. PMID: 41637110.

Abstract

It is not known what the relapse risk is after immunomodulatory treatment discontinuation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Evidence suggests "at least" 3 months of oral corticosteroids reduces the relapse risk after a single attack and that it may be possible to stop maintenance treatment in relapsing stable disease but the optimal duration of treatment is unknown. We therefore aimed to investigate relapse outcomes following maintenance treatment discontinuation. We conducted a cohort study of MOGAD patients seen in the Oxford Neuromyelitis Optica Highly Specialised Service between January 2010 and May 2025. Patients with MOGAD, at least 12 months follow-up, and who commenced and then discontinued maintenance treatment were included. Associations of factors including treatment duration prior to discontinuation, disease course at discontinuation (after a single attack/monophasic or relapsing course) and MOG IgG1 status on live cell-based assay were investigated. Primary outcome was time-to-relapse following treatment discontinuation. Cox regression was used. We included 190 MOGAD patients with 236 discontinued treatment intervals. 150 (63.6%) discontinuations were after a single attack and before a first relapse when disease course was monophasic, and 86 (36.4%) discontinuations occurred in patients who had a relapsing disease course. Most patients used corticosteroids alone (84.7% IT intervals), and non-steroid IT were used in 15.2% of IT intervals either alone or in combination with steroids. Post-discontinuation relapse occurred after 92 (39.0%) discontinuations at a median time of 5.4 (interquartile range 1.4-20.1) months after treatment cessation. Those who relapsed were more likely to have a relapsing course at time of discontinuation (50% vs 27.8%, P=0.001) and a positive/low positive pre-discontinuation MOG IgG1 result (89.8% vs 71.5%, P=0.005). In multivariable analysis, a relapsing course at time of discontinuation was associated with an elevated relapse risk (hazard ratio 1.95, 95% confidence interval 1.25-3.06, P=0.003). Overall, prolonged treatment durations prior to discontinuation beyond 3 months significantly reduced relapse risk. Optimal treatment durations were estimated as at least 10-18 months for patients treated after their onset attack and 20-30 months for relapsing patients, following which treatment discontinuation could be considered in patients who were relapse-free on treatment. Identifying the relapse risk when discontinuing maintenance immunomodulatory treatment in MOGAD should aid management decisions in patients presenting with their first attack and also in those on longer-term treatment for relapsing disease. Our findings, from a cohort predominantly treated with steroids, provide evidence to inform joint decision-making for stable patients who are considering treatment cessation.

Efficacy of pyridostigmine in myasthenia gravis

Remijn-Nelissen L, Bakker WR, van den Hout WB, van Gelder T, Ruiter AM, Campman YJM, Badrising UA, Straathof CSM, Verschuuren JJGM, Tannemaat MR. Efficacy of Pyridostigmine in Myasthenia Gravis: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial. Neurology. 2026 Apr 28;106(8):e214865. doi: 10.1212/WNL.0000000000214865. Epub 2026 Apr 7. PMID: 41945881.

Abstract

Background and objectives: Pyridostigmine, an acetylcholinesterase inhibitor, is a symptomatic drug approved for the treatment of myasthenia gravis (MG), but no randomized controlled trials substantiate its widespread use. We aimed to assess the efficacy and cost utility of pyridostigmine in patients with anti-acetylcholine receptor-positive MG (AChR MG).

Methods: A randomized, double-blind, placebo-controlled crossover trial was conducted at Leiden University Medical Center, a tertiary center for the treatment of MG in the Netherlands. Main eligibility criteria were current use of pyridostigmine and a stable dose of other MG treatments. Participants were assigned to a sequence of 2 treatment periods for 5 days separated by a 2-day washout, in which patients either first received placebo and then pyridostigmine, or vice versa. Pyridostigmine dosing matched each participant's prestudy regimen. The primary outcome was change in the Myasthenia Gravis Impairment Index (MGII) score. Secondary efficacy outcome measures included the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale, the Quantitative Myasthenia Gravis (QMG) score, and the revised 15-item Myasthenia Gravis Quality of Life (MG-QOL15r) questionnaire. For the post hoc cost-utility analysis, a mathematical model was developed to translate the observed study results into long-term annual effect on societal costs and quality-adjusted life years (QALYs).

Results: A total of 19 patients (median age 59 years, 58% female) were recruited between March 23, 2023, and February 21, 2024. The estimated mean difference in the MGII score between pyridostigmine and placebo interventions was 5.3 (95% CI 1.9-8.7, p = 0.004). Secondary efficacy outcome measures showed estimated mean differences of 1.4 (95% CI 0.5-2.3) for the QMG score, 1.2 (95% CI 0.5-1.8) for the MG-ADL score, and 2.0 (95% CI 0.03-3.91) for the MG-QoL15r score. The post hoc cost-utility analysis showed lower annual societal costs (€6,565, 95% CI €328-€15,945) and annual improved QALYs (0.106, 95% CI 0.019-0.210) for patients using pyridostigmine.

Discussion: This trial showed that, in patients with AChR MG chronically treated with pyridostigmine, pyridostigmine demonstrated benefit over placebo across all efficacy outcome measures and substantially reduced societal costs.

Trial registration information: The trial was registered at EudraCT (2021-004110-20, registration date: July 12, 2022) and ClinicalTrials.gov (NCT05919407, registration date: June 16, 2023). First patient enrolled: March 23, 2023.

Classification of evidence: This study provides Class I evidence that, in adults with AChR ab-positive ocular or generalized MG on stable standard-of-care therapy and currently using pyridostigmine, pyridostigmine improves MG symptoms compared with placebo.

____________________________________________________________

Experts Weigh In

Ricardo Roda, MD, PhD, assistant professor of neurology and director of the Myasthenia Gravis Center at Johns Hopkins Medicine, said the complementary scales strengthened the study's design.

“Even if the results were mixed, that kind of thoughtful measurement framework gives clinicians a much more reliable picture of what the drug is actually doing,” he said.

Other leading MG clinicians also thought the study was useful.

“Even after decades of use, having structured, quantifiable evidence like this helps establish a clear benchmark for clinicians and future therapies,” said A. Gordon Smith, MD, FAAN, professor of neurology and endowed distinguished chair in clinical and translational research at Virginia Commonwealth University.

The trial's results align closely with the limited data available for other symptomatic agents in MG. Small randomized studies of Beta2-adrenergic agonists such as terbutaline, as well as ephedrine and investigational chloride channel (ClC-1) inhibitors, have reported QMG improvements in the range of 1 to 3 points.

“While these trials demonstrate consistent statistical significance, the improvements in efficacy outcome scores with all symptomatic therapies remain modest,” Dr. Remijn-Nelissen said. “It is noteworthy that these changes appear to be comparable across different agents.”

Reinforcing Dose Optimization

The study also provided updated data on tolerability. Side effects were reported in 63 percent of patients receiving pyridostigmine compared with 37 percent of those in the placebo group. In the cross-sectional cohort, 91 percent of patients reported side effects during treatment with pyridostigmine, compared with 54 percent of the control group.

Most adverse events were mild to moderate and consistent with cholinergic effects, including gastrointestinal symptoms, such as flatulence and diarrhea; increased secretions; muscle-related complaints; and fatigue. No serious or unexpected adverse events emerged, and the overall safety profile aligned with longstanding clinical experience.

“We've always appreciated that pyridostigmine has gastrointestinal side effects, but much of that understanding has been based on clinical impression rather than rigorous data,” Dr. Kaminksi said. “This study allows us to move beyond anecdote and actually quantify the side effect profile in a meaningful, evidence-based way.”

The frequency of adverse effects, typically cholinergic in nature, underscores the importance of careful dose titration. Although it is already common practice to titrate the dose of pyridostigmine based on clinical effect and side effects, and to taper the medication once symptoms are stable, reporting the high frequency of side effects may further increase clinicians' awareness of the importance of using the lowest effective dose of pyridostigmine and discontinuing it when patients are clinically stable.
Cost-Effective in Modern Care

Beyond clinical endpoints, the study incorporated a post-hoc cost-utility analysis, using modeling to estimate long-term societal impact. The researchers found that use of pyridostigmine was associated with an estimated annual cost savings of approximately 6,565 Euros, or about $7,000, per patient and a gain of 0.106 quality-adjusted life years (QALYs). The projected savings were largely driven by improved functional status, which may reduce health care use and productivity losses.

“Although the magnitude of the effect was relatively modest, pyridostigmine nevertheless demonstrated clear cost-effectiveness, which will likely contribute to its continued role as an important component of the treatment of MG,” Dr. Remijn-Nelissen said.

The results suggest that pyridostigmine use is associated with gains in QALYs and reduced overall costs—findings that could be relevant in health policy discussions, particularly as newer, high-cost biologics and targeted therapies reshape the MG treatment landscape.

“The inclusion of economic and societal metrics is a real strength; it's valuable to understand not just how well the drug works but also how it affects patients' lives on a broader scale,” Dr. Smith said.
Dr. Roda echoed that perspective, noting the findings were somewhat unexpected.

“What surprised me most was seeing a clear economic signal from such a simple, inexpensive drug,” he said. “We tend to think of cost-effectiveness in the context of newer, high-cost therapies, but this shows that even a symptomatic treatment like pyridostigmine can deliver measurable value.”

He pointed out that “what the cost-utility analysis captures is something we don't always measure well in clinic—how patients actually function and feel day to day. Even modest symptomatic improvements can translate into meaningful gains, and that's important because it gives us a benchmark for evaluating the value of the next generation of often much more expensive treatments.”

Reassuring Data—With Caveats

For neurologists, the IMPACT-MG trial offers both validation and recalibration. It confirms that pyridostigmine does, in fact, provide symptomatic benefit, something long assumed but never rigorously proven. At the same time, it tempers expectations about the magnitude of that benefit at the population level.

“This was never intended to change how we treat patients overnight; it was meant to be foundational: to finally validate a therapy we've relied on for decades, to quantify its benefits and risks, and to create a more rigorous framework for future research,” Dr. Kaminski said. “In that sense, the real value isn't that the results were surprising but that we've finally put structure and numbers around what clinicians have long understood from experience.”

Perhaps most importantly, the study highlights a methodological gap: the lack of validated thresholds for clinically meaningful change in trials of symptomatic therapies.

“That represents one of the key insights gained from this trial,” said Dr. Remijn-Nelissen, suggesting that future studies may need to redefine how efficacy is measured in this context. “However, until additional studies are conducted, pyridostigmine's role in MG management remains well established, backed not only by decades of clinical experience but also by this new randomized trial evidence.”
In terms of future studies, Dr. Remijn-Nelissen said that an ideal clinical trial would be conducted to evaluate the effect of pyridostigmine in patients who have never previously used the drug.
“However, due to feasibility concerns, we deliberately chose not to pursue this approach in our study, as recruiting a sufficient number of patients would likely have required a multicenter, and potentially even multinational, study,” he said.

https://neurologytoday.aan.com/doi/10.1097/01.wnt.0001197708.37587.e7

MRI findings in YIF1B-related neurodevelopmental disorder (Kaya-Barakat-Masson syndrome)

 

Minimal prominence of the subarachnoid spaces diffusely. Markedly small size of the corpus callosum (bottom) . There is a mild white matter FLAIR hyperintensity of the cerebral white matter, (top) with T1 hyperintensity involving the bilateral internal capsule and lateral thalami second from top). Additional intrinsic T1 hyperintensity in the brain stem evaluated to better effect on MP-RAGE imaging (third from top).

See: https://childnervoussystem.blogspot.com/2026/01/yif1b-related-neurodevelopmental.html

Sunflower syndrome potpourri

Inspired by patients

Sourbron J, Ayub N, Luo Y, Thiele EA. Ictal EEG in sunflower syndrome: Provoked or unprovoked seizures? Epilepsy Behav. 2020 Dec;113:107470. doi: 10.1016/j.yebeh.2020.107470. Epub 2020 Oct 15. PMID: 33070054.

Abstract

Sunflower syndrome (SS) is a rare, photosensitive epilepsy characterized by an attraction to light and highly stereotyped seizures with associated hand-waving (HW). It is controversial whether HW is part of the seizure or a provoking factor; therefore, we aimed to characterize the ictal electroencephalogram (EEG) in patients with SS. Video-EEG (vEEG) and charts of five patients with SS with HW during vEEG from Massachusetts General Hospital's Pediatric Epilepsy Program were reviewed and analyzed. In four out of five patients, the ictal EEG showed high amplitude (500-700 μV) 3-4 Hz generalized spike/polyspike-and-slow wave discharges, lasting 1.63-24.41 s. One hundred and twelve of 126 HW episodes, correlating to epileptiform activity (vEEG), had a lag time of less than 1.00 s (88.89%) between onset of HW and appearance of epileptiform activity. This suggests that HW does not induce seizure activity. Awareness of the ictal EEG features of this syndrome is important, as patients are frequently described as "self-inducing" their seizures.

Belcastro V, Striano P. Self-induction seizures in sunflower epilepsy: a video-EEG report. Epileptic Disord. 2014 Mar;16(1):93-5. doi: 10.1684/epd.2014.0630. PMID: 24556582.

Abstract

Seizures triggered by visual stimuli are the most common type of reflex seizure. Self-induced seizures produced by stimulation of natural light are rare and self-induction is a mode of seizure precipitation employed by either intellectually disabled or healthy photosensitive individuals. Absences and myoclonic jerks are the most common seizure types in self-induction. We report on a girl with normal intelligence who self-induced seizures by waving her outspread fingers in front of a bright light. This situation is called sunflower epilepsy.

Nava E, Mori AC, Striano P, Ramantani G. Atypical presentation of sunflower epilepsy featuring an EEG pattern of continuous spike waves during slow-wave sleep. Epileptic Disord. 2021 Dec 1;23(6):927-932. doi: 10.1684/epd.2021.1353. PMID: 34704936.

Abstract

Sunflower epilepsy is a rare photosensitive and commonly pharmacoresistant reflex epilepsy characterized by stereotyped seizures involving turning of the head towards light, similar to a sunflower turning towards the sun, and waving of the hands in front of the eyes, sometimes followed by absence seizures, myoclonic jerks, and tonic-clonic seizures. In the original description, seizures in sunflower epilepsy have been perceived as self-induced, but contemporary case series suggest that hand waving corresponds to an ictal phenomenon and not to a precipitating factor. We describe a nine-year-old girl featuring absence seizures with eye rolling or fluttering associated with hand waving movements. The chronological sequence of events based on a video-EEG-documented episode of our patient adds to the controversy surrounding the hypothesis of "self-induced" epileptic seizures in sunflower epilepsy. Shortly after epilepsy diagnosis, our patient presented with an EEG pattern of continuous spike waves in slow-wave sleep, an EEG feature that has not been described before and may relate to the cognitive deficit observed in some patients with sunflower epilepsy. Continuous spike waves in slow-wave sleep resolved, and lasting seizure freedom was achieved by a combination of ethosuximide and lamotrigine, which may be a possible alternative to valproic acid, particularly in girls and women of childbearing age. However, an attempt to taper anti-seizure drugs two years later led to seizure recurrence. We suggest performing sleep EEG recordings for sunflower epilepsy, particularly in patients with developmental stagnation or regression, to timely diagnose and treat continuous spike waves in slow-wave sleep syndrome.

Mazzone S, Landolina L, Utili A, Belcastro V, Striano P, Cordelli DM, Russo A. Neuropsychological analysis in sunflower syndrome suggests the involvement of the ventral attention network on right visual dorsal stream. Epileptic Disord. 2025 Apr;27(2):280-286. doi: 10.1002/epd2.20330. Epub 2025 Feb 7. PMID: 39918374.

Abstract

Sunflower syndrome, a rare photosensitive epilepsy characterized by handwaving episodes and fixation on light sources, remains poorly understood, especially regarding its neuropsychological profile. This study provides a detailed cognitive evaluation of two patients, revealing a likely disruption in the visual dorsal stream, with particular involvement of the ventral attention network (VAN). Despite normal overall intellectual functioning, both patients exhibited significant deficits in Processing Speed Index and inhibitory control, indicating selective executive dysfunction. Coupled with EEG anomalies predominantly in the right frontal lobe, these findings suggest right hemisphere involvement, potentially along the VAN pathway. This study highlights the need for further research, particularly functional neuroimaging, to better understand the neurocognitive aspects of sunflower syndrome and its impact on patients' quality of life.

See: https://childnervoussystem.blogspot.com/2026/03/sunflower-syndrome-redux.html

https://childnervoussystem.blogspot.com/2026/03/sunflower-syndrome-ocular-treatment.html

https://childnervoussystem.blogspot.com/2021/10/epilepsy-in-sunflower-syndrome.html

https://childnervoussystem.blogspot.com/2021/03/more-sunflowers.html

https://childnervoussystem.blogspot.com/2021/01/sunflower-syndrome.html

SPG50 mutation and treatment

A family in Queensland, Australia, is faced with selling their dream home to raise funds for their daughter’s life-saving therapy, which will cost a staggering $3 million.

Tallulah Moon, 5, has been diagnosed with SPG56, a degenerative brain disease that is caused by a rare gene mutation.

Tallulah was a healthy, happy baby until shortly after her first birthday, when she suddenly began to lose her motor skills.

"She was hitting all of her milestones, and then suddenly she experienced a really steep regression — her abilities sort of fell like an avalanche off the cliff, and it was terrifying," Golden Whitrod, Tallulah Moon’s mother, told Fox News Digital during an on-camera interview.

"She went from a little girl who was walking and talking to suddenly not even being able to sit up on her own, not being able to lift her arms above her shoulders or hold up her neck," Whitrod said.

Swallowing and choking also became a concern.

"We'd gone from watching this beautiful child thrive at 14 months, to regressing to the abilities of a 4-month-old," Whitrod recalled.

Tallulah Moon was also terrified, unable to comprehend the loss of her abilities.

"I remember her looking at us as if to say, ‘Why can't you help me?’" her mother said. "And I could feel that as a parent. I just didn't know what to do."

A devastating diagnosis

At first, Whitrod hoped there would be an easy fix for whatever was causing Tallulah's decline.

After six months of testing and scans, doctors performed a genetic study known as whole genome sequencing (WGS), leading to Tallulah Moon’s diagnosis of SPG56 in August 2020.

SPG56 is a type of hereditary spastic paraplegia (HSP) that usually begins around age 1 or 2 and worsens over time, causing muscle weakness and gradually robbing children of the ability to walk, talk, stand and sit up, as seen in past cases.

In later stages, the disease can cause cognitive decline, seizures and even an inability to swallow.

SPG56 is one of the rarest types of HSP, affecting fewer than one in every million children, statistics show.

"We'd gone from watching this beautiful child thrive at 14 months, to regressing to the abilities of a 4-month-old."

There is currently no cure for the disease.

"The doctors told us, ‘just love your baby,’" Whitrod said. "They said there was nothing they could do — that there were no treatments."

A mother’s determination

After "coming out of the fog" post-diagnosis, Whitrod immersed herself in research, making connections with other families whose children were also living with rare genetic diseases.

One of those was Terry Pirovolakis, a Canadian father whose son was diagnosed with SGP50, a disease that is very similar to Tallulah Moon’s SPG56.

Pirovolakis immediately started researching to find a gene therapy that could help his son.

After meeting with experts from around the world, he liquidated his life savings and paid a team of researchers to start developing the therapy. In 2022, after massive fundraising efforts, his son received the one-time treatment, which halted progression of the disease.

Following Pirovolakis’ lead, Whitrod met with scientists at genetic institutes and carefully built her own research team.

Over a three-year period, the team created an experimental gene therapy for SPG56, which Whitrod calls a "massive win."

The next step is for the therapy to go through clinical trials to make sure it's safe and effective for the children who need it — but the cost is too high for the vast majority of families to cover.

It will require $3 million to manufacture the medication before it can be administered to Tallulah Moon in a clinical trial, according to Whitrod.

"Unfortunately, the big pharmaceutical companies just aren't interested in funding the research for these rare diseases, even though the treatments are possible," she said.

"We realized that we have to fund this on our own if we want to do this."

Walter Gaman, MD, founder of Executive Medicine of Texas, emphasized the financial burden that often comes with rare diseases.

"Rare diseases, by nature, account for a small market share, meaning that there are few customers to absorb the cost of bringing effective drugs to market," Gaman, who is not affiliated with the Whitrod family, told Fox News Digital.

"We realized that we have to fund this on our own if we want to do this."

In 2003, Deloitte reported that the average cost of bringing a drug to market exceeded $2 billion, according to Gaman.

"One of the most significant wins for orphan drugs came in 2017, when President Trump signed the Food and Drug Administration Reauthorization Act (FDARA) into law," he noted.

"This was a huge win for orphan therapies because it expanded the FDA Rare Disease Program and also expedited the review process. As a result, 2018 saw a record 59 orphan drugs greenlighted. We need to build that momentum up once again."

In 2003, the average cost of bringing a drug to market exceeded $2 billion.

There is still a lot of work to do, he noted.

"We need to bring orphan drugs to market, but we also need to look at ways of making these drugs more affordable to the end user," Gaman said.

Some potential ideas are to offer tax breaks to companies that champion such drugs, or to have a tax on pharmaceutical companies that goes directly to the FDA Rare Disease Program, he suggested.

A ‘much bigger dream’

"We're standing at the precipice of there being a treatment for Tallulah and for children in her position," Whitrod said.

"We feel like we're almost there. But, of course, $3 million for a little Aussie family is quite a lot."

The Whitrods have launched a charitable foundation called Genetic Cures for Kids, with a fundraising initiative called Our Moon’s Mission.

The family has raised some funds through GoFundMe donations, but it’s only a fraction of what is needed to treat Tallulah Moon — hence their decision to sell their home.

The house, which is located in the suburb of Stuart Park, is scheduled to go up for auction this week.

"We'd hoped that some miracle would happen and we wouldn't need to sell it, and that help would come before we needed to come to this crunch point," Whitrod said.

"But in the end, we realized that's our last asset that we have, and that could help us get to the finish line."

While they are sacrificing their family’s "dream home," Whitrod says they are now aspiring to a "much bigger dream."

"That is to give Tallulah the life she deserves — and we're all in for that."

Meanwhile, Whitrod said, Tallulah Moon is working to fight the neurodegenerative disease through physiotherapy, occupational therapy and speech therapy.

While she is intent on saving her daughter, Whitrod has also set her sights on a wider goal — to help other families whose children are facing similar challenges.

"What we're creating is not just a treatment for Tallulah that ends with the kids with SPG56 — we’re creating a replicable framework, so the researchers can go on to create treatments for other similar diseases," she said.

"If we can get there in time, then we can help Tallulah live the life she deserves — and not just her, but also lots of children just like her."

For more information on Our Moon's Mission or to donate, people can visit https://ourmoonsmission.org/donate/.

Melissa Rudy

https://www.foxnews.com/health/family-selling-dream-home-fund-life-saving-treatment-daughter

Dowling JJ, Pirovolakis T, Devakandan K, Stosic A, Pidsadny M, Nigro E, Sahin M, Ebrahimi-Fakhari D, Messahel S, Varadarajan G, Greenberg BM, Chen X, Minassian BA, Cohn R, Bonnemann CG, Gray SJ. AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nat Med. 2024 Jul;30(7):1882-1887. doi: 10.1038/s41591-024-03078-4. Epub 2024 Jun 28. PMID: 38942994; PMCID: PMC11271397.

Abstract

There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .