Xia-Gibbs syndrome

Inspired by a patient

Shirai H, Oitani Y, Nishi E, Haraguchi K, Nakamura T, Ichinose F, Sanefuji M, Hattori A, Yanagi K, Shimojima Yamamoto K, Okamoto N, Matsuo M, Saitoh S, Yoshiura KI, Kaname T, Yamamoto T. Clinical and molecular profiles of patients with Xia-Gibbs syndrome: a cohort in Japan. Brain Dev. 2026 Apr;48(2):104509. doi: 10.1016/j.braindev.2026.104509. Epub 2026 Feb 6. PMID: 41653504.

Abstract

Background: Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT-hook DNA binding motif containing 1 (AHDC1) gene. More than 100 patients with XGS have been reported. In this study, we describe the findings from a Japanese cohort of patients with XGS. To enhance understanding, we also conducted a systematic literature review of XGS.

Methods: We collected clinical and genetic information from seven new Japanese patients with XGS which were diagnosed through comprehensive genetic analysis. A systematic literature review was also conducted using PubMed.

Results: All Japanese patients carried premature truncation variants or deletions. The core clinical features were global developmental delay and hypotonia, which were consistent with those observed in the 106 previously reported patients identified in our literature review. In one patient with a frameshift variant, escape from nonsense-mediated mRNA decay was confirmed using the patient's sample.

Conclusion: The clinical and molecular profiles of Japanese patients with XGS were analyzed and compared with those of previously reported patients from other countries, confirming the consistent characteristics of XGS. This study provides direct evidence of nonsense-mediated mRNA decay escape. A comprehensive understanding of this expanding phenotype is crucial for accurate diagnosis and management.

Jiang N, Zhang L, Zheng Z, Du H, Chen S, Pan H. Phenotypic subtypes of Xia-Gibbs syndrome: a latent class analysis. Eur J Hum Genet. 2025 Dec;33(12):1558-1566. doi: 10.1038/s41431-024-01754-0. Epub 2024 Dec 9. Erratum in: Eur J Hum Genet. 2026 Jun;34(6):886-892. doi: 10.1038/s41431-025-01825-w. PMID: 39648204; PMCID: PMC12669642.

Abstract

Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder with considerable clinical heterogeneity. To further characterize the syndrome's heterogeneity, we applied latent class analysis (LCA) on reported cases to identify phenotypic subtypes. By searching PubMed, Embase, China National Knowledge Infrastructure and Wanfang databases from inception to February 2024, we enrolled 97 cases with nonsense, frameshift or missense variants in the AHDC1 gene. LCA was based on the following 6 phenotypes with moderate occurrence and low missingness: ataxia, seizure, autism, sleep apnea, short stature and scoliosis. After excluding cases with missing data on all LCA variables or with unmatched phenotype-genotype information, a total of 85 cases were selected for LCA. Models with 1-5 classes were compared based on Akaike Information Criterion, Bayesian Information Criterion, Sample-Size Adjusted BIC and entropy. We used multinomial logistic regression (MLR) analyses to investigate the phenotype-genotype association and potential predictors for class membership. LCA revealed 3 distinct classes labeled as Ataxia subtype (n = 11 [12.9%]), Sleep apnea & short stature subtype (n = 23 [27.1%]) and Neuropsychological subtype (n = 51 [60.0%]). The commonest Neuropsychological subtype was characterized by high estimated probabilities of seizure, ataxia and autism. By adjusting for sex, age and variant type, MLR showed no significant association between phenotypic subtype and variant position. Age and variant type were identified as predictors of class membership. The findings of this review offer novel insights for different presentations of XGS. It is possible to deliver targeted monitoring and treatment for each subtype in the early stage.

Romano F, Falco M, Cappuccio G, Brunetti-Pierri N, Lonardo F, Torella A, Digilio MC, Dentici ML, Alfieri P, Agolini E, Novelli A, Garavelli L, Accogli A; TUDP; Striano P, Scarano G, Nigro V, Scala M, Capra V. Genotype-phenotype spectrum and correlations in Xia-Gibbs syndrome: Report of five novel cases and literature review. Birth Defects Res. 2022 Aug 1;114(13):759-767. doi: 10.1002/bdr2.2058. Epub 2022 Jun 18. PMID: 35716097; PMCID: PMC9545659.

Abstract

Background: Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT-hook DNA-binding motif-containing 1 gene (AHDC1), encoding a protein with a crucial role in transcription and epigenetic regulation, axonogenesis, brain function, and neurodevelopment. AHDC1 variants possibly act through a dominant-negative mechanism and may interfere with DNA repair processes, leading to genome instability and impaired DNA translesion repair. Variants affecting residues closer to the N-terminal are thought to determine a milder phenotype with better cognitive performances. However, clean-cut genotype-phenotype correlations are still lacking.

Cases: In this study, we investigated five subjects with XGS in whom exome sequencing led to the identification of five novel de novo pathogenic variants in AHDC1. All variants were extremely rare and predicted to cause a loss of protein function. The phenotype of the reported patients included developmental delay, hypotonia, and distinctive facial dysmorphisms. Additionally, uncommon clinical features were observed, including congenital hypothyroidism and peculiar skeletal abnormalities.

Conclusions: In this study, we report uncommon XGS features associated with five novel truncating variants in AHDC, thus expanding the genotype and phenotypic spectrum of this complex condition. We also compared our cases to previously reported cases, discussing the current status of genotype-phenotype correlations in XGS.

Cinelli G, Della Vecchia S, Bergonzini P, Caramaschi E, Spezia E, Parenti C, Madeo SF, Lucaccioni L, Francesca C, Pugliese M, Raviglione F, Colonna C, Calabrese O, Stanghellini I, Marongiu MC, Biagioni E, Ferrari AR, Battini R, Iughetti L. Clinical, Behavioral and Neuroradiological Phenotype in an Italian Cohort of Patients With Xia Gibbs Syndrome: A Multicenter Cross-Sectional Study and Systematic Literature Review. Am J Med Genet A. 2026 Sep;200(9):2067-2079. doi: 10.1002/ajmg.a.70163. Epub 2026 Apr 30. PMID: 42059486.

Abstract

Heterozygous variants in the AHDC1 gene are associated with Xia Gibbs Syndrome (XGS), a genetic disorder with a highly variable phenotype. Cognitive impairment, motor delay, language delay, neonatal hypotonia, and sleep apnea are considered "cardinal" signs of the disease. In a multicenter cross-sectional study, we analyzed the genetic, epileptological, behavioral, and neuroradiological features of 15 patients with XGS harboring heterozygous variants in AHDC1. The phenotype of our patient cohort is almost overlapping with that already reported in the literature. Seizures begin between 2 and 9 years, while EEG is generally characterized by normal background activity with paroxysmal abnormalities in the posterior areas increased by sleep. We systematically analyzed brain imaging findings as the most frequent brain alteration: the thinning of the corpus callosum, followed by posterior fossa malformation and lateral ventricle morphology abnormalities. Regarding psychiatric disorders, we observed neurodevelopmental disorders such as ID, language disorders, Autism spectrum disorders (ASD), and ADHD in preschoolers, followed by a prevalence of externalizing problems during childhood and adolescence. Our study showed that epilepsy and brain anomalies are very common among XGS individuals. MRI changes are nonspecific, but their association with other clinical features of the syndrome can guide early diagnosis. EEG abnormalities are present in all epileptic patients in the temporal-occipital regions with the same characteristics, so we could hypothesize that these abnormalities could represent a recognizable EEG pattern of XGS. Behavioral disorders represent an important problem, and longitudinal evaluations are needed to improve the classification of the psychopathological spectrum in XGS.

Juvenile-onset ALS

See: https://childnervoussystem.blogspot.com/2015/06/mystery-illness.html

Esther and Rivka Herzfeld are members of an inspirational and beloved family that are well-known in the Teaneck community. Active members at Congregation Beth Aaron, all four children in the Herzfeld family have been diagnosed with juvenile-onset ALS, a neuromuscular degenerative disease. Esther’s husband (Rivka’s father) also suffers from a version of this disease, which developed in adulthood. The story of the Herzfelds has been featured in The Jewish Link in the past, particularly in 2015 during their successful quest for a van to allow their family mobility (“Herzfeld Family Gets Their Van,” July 9, 2015, https://jewishlink.news/herzfeld-family-gets-their-van/).

What always strikes people who get to know the Herzfelds is how they stubbornly refuse to allow their challenges to define them, or to hold them back. While one of the siblings, Rivka, works 40 hours a week, another, Racheli, is pursuing a master’s degree in social work. As they are all in their 20s and early 30s, they also have special interests, activities and friends. They are also highly intelligent critical thinkers who are focused on staying as active as possible so that when a cure is found for their condition, they will be ready to benefit from it.

However, as time has gone on, the needs of the family have increased manifold, even though they have their van and now live in a fully accessible house all on one floor. With communal assistance, they are putting together a fundraiser with the aim of allowing them to pay for an immense shortfall in their bills for the long term.

That’s why the mother and daughter are embarking on a speaking tour called “Life Rewritten,” planning to demonstrate their immense strength as a family and their hope for a better, more supportive future. As Esther explained: “I’m an English teacher, and storytelling is important to me. I emphasize the role of strong women and the role they play in the life cycle of a whole family, and I thought about the irony of my inability to control my own story.” She emphasized that this is the case for many families. “Many people plan a life, and their lives are then derailed. We’re not the only ones.”

Juvenile-onset ALS, an extremely rare condition, affects limb strength, breath support and swallowing, among other basic functions. “Everyone knows about ALS because of Lou Gehrig and Stephen Hawking, and that type of ALS shows up for people in their 50s, 60s, or even 70s. That type of ALS is fatal,” Esther explained. The type of ALS her children and husband have is different, and much less well-known, even among doctors. “My children were studied by neurologists for years and given multiple wrong diagnoses. Finally, right before COVID, they started honing in on what neurons were affected, and because it was similar to ALS, they decided to call it juvenile-onset ALS. Baruch Hashem, it’s not fatal, but it affects daily living.” Of about 100 known cases, the Herzfelds make up five.

Because the condition wasn’t identified until recently, it was a process of years to figure out why the Herzfeld children couldn’t live life as normal. “At first, they were just tripping and falling and dropping things. In retrospect, we realize this was the beginning of the degeneration of the muscles.”

Esther and Rivka recounted that each child developed symptoms at a different stage in their life. While Tzipora was the first to mention that something felt wrong at age 6, Rivka didn’t experience symptoms until her senior year of high school. “I remember saying to my parents, ‘Do you think I have what Tzipora has?’ and they sort of quietly chuckled and said, ‘Yeah, of course you have what Tzipora has.’”

To explain the mechanisms of the condition, Rivka analogized the story of Bavel. “Our sphingolipids, the messengers from the brain to the muscles, are being sent in English. But the muscles are reading the messages from the neurons in Sanskrit. Our muscles can sometimes do the actions, but more slowly, and sometimes can’t do them at all, because they don’t understand Sanskrit.” Rivka clarified, however, that “it doesn’t impact our intellectual capability and our thinking, which is such a bracha.” In her mother’s words, “You’re not fast in your legs, but you’re fast in your mind.”

At this point in time, all four Herzfeld children are wheelchair- or scooter-bound. In their first family house on Schley Place in Teaneck, which they lived in until recently, it was nearly impossible for everyone to fit in the house at a time. “It was like putting corks in a dam that was going to burst,” said Esther. “We got a stairlift, and a ramp, and another ramp, but it was brutally uncomfortable.”

A few years ago, thanks to a previous campaign, the Herzfelds were able to move into a house on Queen Anne Road, which “took the pressure out of the pressure cooker,” said Esther. “There was no need to be fighting over who could get the door or pass each other in the hallway.” According to Rivka, “It’s such a mechaye [relief] to not worry about the house being an obstacle.”

However, the obstacles of navigation within the home are only a small challenge to the Herzfeld family. Between the cost of the electricity, the medical equipment, therapy required that isn’t covered by insurance, and the staggering cost of having multiple aides for 22 hours a day, the family is struggling financially.

Unfortunately, government funding only pays for 40 hours a week for home care per person, which is not enough to cover the needs of the family, which has five members who require full care 22 hours each day. It means, they have to pay cash to their aides to the tune of close to $6,000 each week.

While many have asked the Herzfelds why the government can’t stretch more to help them, Rivka believes that her case specifically is confusing for a disability office to make space for, and possibly out of their comfort zone. For example: “I am a working person, but I have a full disability that is congenital, but didn’t occur until I was 17. All of those things make it extremely complicated for people to understand, especially the government. There’s a $25,000-a-month need, every single month. This is critical to the maintenance of our family.”

Beyond that, all family members take physical and other types of therapy with hand specialists and others at not-insignificant costs, which insurances can often limit or not cover because “they’re not getting better.”

With “Life Rewritten,” the Herzfelds are hoping to take their lives back into their own hands. Currently, they only have enough money for another few weeks of therapy. “I’m afraid to look at the fund total,” Esther said. “I’m just taking out the money. I’m hoping that December 28th will help.” Rivka added: “It’s Kislev, and it should be a month of light. It should be a month in which people can see the light that we can give and not just take. A month of miracles.”

Rabbi Daniel Fridman of the Jewish Center of Teaneck is helping to spearhead the campaign. He shared his thoughts on the importance of helping the Herzfelds. “Chazal describe the Jewish people as possessed of certain indelible characteristics. Amongst these are our status as rachmanim, merciful people, and gomlei chasadim, active purveyors of loving kindness. We invite the entire community to join us to learn about the story of the Herzfeld family, and in doing so, to express these two qualities.”

On Dec. 28, the “Life Rewritten” campaign begins. Please join at Jewish Center of Teaneck, where Esther and Rivka will tell their story and ask for help, allowing them to begin to rewrite their life story. They also recently appeared on The Jewish Link “Pitch Meeting” podcast: youtube.com/watch?v=tTQ7jRrreuw&t=4s. To donate to the campaign, visit thechesedfund.com/herzfeld/the-herzfeld-family.

Eliana Birman

https://jewishlink.news/herzfeld-family-launches-life-rewritten-speaking-tour-and-dec-28-fundraiser/

Gene replacement therapy for SURF1-related Leigh syndrome.

Ling Q, Rioux M, Hu Y, Lee M, Gray SJ. Adeno-associated viral vector serotype 9-based gene replacement therapy for SURF1-related Leigh syndrome. Mol Ther Methods Clin Dev. 2021 Sep 7;23:158-168. doi: 10.1016/j.omtm.2021.09.001. PMID: 34703839; PMCID: PMC8517205.

Abstract

SURF1 (surfeit locus protein 1)-related Leigh syndrome is an early-onset neurodegenerative disorder, characterized by reduction in complex IV activity, resulting in disrupted mitochondrial function. Currently, there are no treatment options available. To test our hypothesis that adeno-associated viral vector serotype 9 (AAV9)/human SURF1 (hSURF1) gene replacement therapy can provide a potentially meaningful and long-term therapeutic benefit, we conducted preclinical efficacy studies using SURF1 knockout mice and safety evaluations with wild-type (WT) mice. Our data indicate that with a single intrathecal (i.t.) administration, our treatment partially and significantly rescued complex IV activity in all tissues tested, including liver, brain, and muscle. Accordingly, complex IV content (examined via MT-CO1 protein expression level) also increased with our treatment. In a separate group of mice, AAV9/hSURF1 mitigated the blood lactic acidosis induced by exhaustive exercise at 9 months post-dosing. A toxicity study in WT mice showed no adverse effects in either the in-life portion or after microscopic examination of major tissues up to a year following the same treatment regimen. Taken together, our data suggest a single dose, i.t. administration of AAV9/hSURF1 is safe and effective in improving biochemical abnormalities induced by SURF1 deficiency with potential applicability for SURF1-related Leigh syndrome patients.

Mitochondrial transfer therapy

Nakai, R., Varnum, S., Field, R.L. et al. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome. Nat Metab 6, 1886–1896 (2024). https://doi.org/10.1038/s42255-024-01125-5

Abstract

Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4−/− peritoneal macrophages. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations, and mitochondria transplantation was shown to minimize ischaemic damage to the heart, brain and limbs. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4−/− mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4−/− mice, whereas mitochondria from Ndufs4−/− mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4−/− mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.

15q26.3 deletions

Inspired by a patient

Sivakumaran TA, Grebe TA. 15q26.3 deletions distal to IGF1R cause growth retardation, congenital heart defect and skeletal anomalies: Case report and review of literature. Am J Med Genet A. 2023 Sep;191(9):2392-2397. doi: 10.1002/ajmg.a.63350. Epub 2023 Jul 12. PMID: 37434556.

Abstract

15q26 deletion is a rare genomic disorder characterized by intrauterine and postnatal growth retardation, microcephaly, intellectual disability, and congenital malformations. Here, we report a 4-month-old female with intrauterine growth retardation, short stature, pulmonary hypertension, atrial septal defect and congenital bowing of long bones of the legs. Chromosomal microarray analysis showed a de novo deletion of approximately 2.1 Mb at 15q26.3 region that does not include IGF1R. Our analysis of patients documented in the literature and the DECIPHER database with 15q26 deletions distal to IGF1R, including 10 patients with de novo pure deletions, allowed us to define the smallest region of overlap to 686 kb. This region includes ALDH1A3, LRRK1, CHSY1, SELENOS, SNRPA1, and PCSK6. We propose haploinsufficiency of one or more genes, besides IGF1R, within this region may contribute to the clinical findings in patients with 15q26.3 deletion.

Dincer BT, Ozdemir EM, Cetincelik U, Ucar A. Drayer Syndrome due to Chromosome 15q26.3 Deletion: Response to Growth Hormone Treatment. Sisli Etfal Hastan Tip Bul. 2024 Dec 24;58(4):521-523. doi: 10.14744/SEMB.2024.01879. PMID: 39816431; PMCID: PMC11729826.

Abstract

Chromosome 15q26 deletion is a rare condition that causes short stature and is associated with intrauterine growth restriction (IUGR), failure to thrive, congenital heart disease and many congenital malformations. The insulin growth factor receptor (IGF-1R) on chromosome 15 has many important roles, especially in growth regulation. Our case is an 18-month-old small for gestational age girl who presented with severe short stature, microcephaly and minor dysmorphic features. Chromosome microarray revealed 15q26 deletion including the IGF1R gene. Recombinant growth hormone (rGH) has been used in patients with IGF-1R defects with variable treatment responses. The reason for rGH unresponsiveness in some patients with terminal chromosome 15q deletion is still unclear. Herein we discuss the use of rGH in a patient with heterozygous IGF1R deletion and emphasize the need for further follow-up regarding other endocrine disorders.

Benbouchta Y, De Leeuw N, Amasdl S, Sbiti A, Smeets D, Sadki K, Sefiani A. 15q26 deletion in a patient with congenital heart defect, growth restriction and intellectual disability: case report and literature review. Ital J Pediatr. 2021 Sep 16;47(1):188. doi: 10.1186/s13052-021-01121-5. PMID: 34530895; PMCID: PMC8447573.

Abstract

Background: 15q26 deletion is a relatively rare chromosomal disorder, and it is described only in few cases. Patients with this aberration show many signs and symptoms, particularly pre- and postnatal growth restriction, developmental delay, microcephaly, intellectual disability and various congenital malformations.

Case presentation: We report on a girl, 4 years old, of consanguineous parents, with a 15q26 deletion. Clinical manifestations included failure to thrive, developmental delay, microcephaly, dysmorphic facies with broad forehead, hypertelorism, narrowed eyelid slits and protruding columella. The patient also showed skeletal abnormalities, especially clinodactyly of the 5th finger, varus equine right foot and left club foot. Additionally, she had teething delay and divergent strabismus. Heart ultrasound displayed two atrial septal defects with left-to-right shunt, enlarging the right cavities. Routine cytogenetic analysis revealed a shortened 15q chromosome. Subsequent array analysis disclosed a terminal 9.15 Mb deletion at subband 15q26.1-q26.3. Four candidate genes associated with 15q26 deletion phenotype were within the deleted region, i.e. IGF1R, NR2F2, CHD2 and MEF2A.

Poot M, Verrijn Stuart AA, van Daalen E, van Iperen A, van Binsbergen E, Hochstenbach R. Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases. Eur J Med Genet. 2013 Jul;56(7):346-50. doi: 10.1016/j.ejmg.2013.04.001. Epub 2013 Apr 16. PMID: 23603061.

Abstract

Patients with trisomy or tetrasomy of distal 15q show a recognizable overgrowth syndrome, whereas patients with a monosomy of 15q26 share some degree of pre- and postnatal growth retardation, but differ with respect to facial and skeletal dysmorphisms, congenital heart disease and intellectual development. By reviewing 16 cases with losses of 15q26 we found that the size of the deletion was also not a predictor of the breadth of the phenotypic spectrum, the severity of disease or prognosis of the patient. Although monosomies of 15q26 do not represent a classical contiguous gene syndrome, a few candidate genes for selected features such as proportional growth retardation and cardiac abnormalities have been identified. In 11 out of 16 patients with monosomy of distal 15q variable neurobehavioral phenotypes, including learning difficulties, seizures, attention-deficit-hyperactivity disorder, hearing loss and autism, have been found. We discuss clinical ramifications for cases with a loss of 15q26 detected by prenatal array-CGH.

O'Riordan AM, McGrath N, Sharif F, Murphy NP, Franklin O, Lynch SA, O'Grady MJ. Expanding the clinical spectrum of chromosome 15q26 terminal deletions associated with IGF-1 resistance. Eur J Pediatr. 2017 Jan;176(1):137-142. doi: 10.1007/s00431-016-2802-y. Epub 2016 Nov 8. PMID: 27826649.

Abstract

Haploinsufficiency of the insulin-like growth factor-1 receptor (IGF1R) gene on chromosome 15q26.3 is associated with impaired prenatal and postnatal growth, developmental delay, dysmorphic features and skeletal abnormalities. Terminal deletions of chromosome 15q26 arising more proximally may also be associated with congenital heart disease, epilepsy, diaphragmatic hernia and renal anomalies. We report three additional cases of 15q26 terminal deletions with novel features which may further expand the spectrum of this rarely reported contiguous gene syndrome. Phenotypic features including neonatal lymphedema, aplasia cutis congenita and aortic root dilatation have not been reported previously. Similarly, laboratory features of insulin-like growth factor 1 (IGF-1) resistance are described, including markedly elevated IGF-1 of up to +4.7 SDS. In one patient, the elevated IGF-1 declined over time and this coincided with a period of spontaneous growth acceleration.

Conclusion: Deletions of 15q26 are a potential risk factor for aortic root dilatation, neonatal lymphedema and aplasia cutis in addition to causing growth restriction. What is Known: • Terminal deletions of chromosome 15q26 are associated with impaired prenatal and postnatal growth, developmental delay, dysmorphic features and skeletal abnormalities. What is New: • Neonatal lymphedema, aplasia cutis congenita and aortic root dilatation have not been previously described in 15q26 terminal deletions and may represent novel features. • IGF-1 levels may be increased up to 4.7 SDS.

Infantile spasms--therapeutic thoughts

Wang M, Zhao F, Sun L, Yu Y, Zhang H. Ketogenic diets therapy in the management of epileptic spasms syndrome. Front Pediatr. 2024 Nov 6;12:1472982. doi: 10.3389/fped.2024.1472982. PMID: 39568784; PMCID: PMC11576165.

Abstract

Infantile Epileptic Spasm Syndrome (IESS) is a group of infantile spasm syndromes of various etiologies that typically present in early infancy, predispose to refractory epilepsy, and leave intellectual disability. Ketogenic diet therapy (KDT) is a non-pharmacologic treatment modality for medically refractory IESS. Recent scientific evidence supported the efficacy, safety, and tolerability of KDT for the treatment of IESS. KDT not only reduces the frequency of seizures in infants with IESS, but also improve their cognition and long-term prognosis. Recently, it has also received increasing attention as a potential treatment for neurological disorders. This reviewed the recent research progress of KDTs for the treatment of IESS, and discussed the different types and the mechanisms of KDTs, the expansion of KDT applications, the influencing factors, and future research issues.

Reyes Valenzuela G, Gallo A, Calvo A, Chacón S, Fasulo L, Galicchio S, Adi J, Fortini PS, Caraballo R. Purified cannabidiol as add-on therapy in children with treatment-resistant infantile epileptic spasms syndrome. Seizure. 2024 Feb;115:94-99. doi: 10.1016/j.seizure.2024.01.010. Epub 2024 Jan 15. PMID: 38237316.

Abstract

Objective: The aim of this study was to assess efficacy, safety, and tolerability of highly purified cannabidiol oil (CBD) as add-on therapy for the treatment of a series of patients with infantile epileptic spasms syndrome (IESS) who were resistant to antiseizure medications and ketogenic dietary therapy.

Material and methods: We conducted a retrospective analysis of the medical records of 28 infants with treatment-resistant IESS aged 6 to 21 months who received highly purified CBD between July 2021 and June 2023. Data were collected on neurological examinations, EEG, Video-EEG and polygraphic recordings, imaging studies, laboratory testing, and seizure frequency, type, and duration, and adverse effects. As the primary outcome, a reduction of frequency of epileptic spasms (ES) was assessed. ES freedom was considered after a minimal time of 1 month without ES.

Results: Sixteen male and 12 female patients, aged 6-21 months, who received CBD for treatment-resistant IESS were included. The etiology was structural in 10, Down syndrome in seven, genetic in nine, and unknown in two. Initial CBD dose was 2 mg/kg/day, which was uptitrated to a median dose of 25 mg/kg/day (range, 2-50). Prior to CBD initiation, patients had a median of 69 ES in clusters per day (range, 41-75) and of 10 focal seizures per week (range, 7-13). After a mean and median follow-up of 15 and 12.5 months (range, 6-26 months), seven patients were ES free and 12 had a >50 % ES reduction. Five of seven patients (71 %) with Down syndrome and 3/5 (60 %) with cerebral palsy responded well. Adverse effects were mild. EEG improvements correlated with ES reductions.

Conclusion: In this study evaluating the use of CBD in children with IESS, 19/28 (67.8 %) had a more than 50 % ES reduction with good tolerability.

Matsuura R, Hamano SI, Hirata Y, Takeda R, Takeuchi H, Koichihara R, Kikuchi K, Oka A. Long-term analysis of adrenocorticotropic hormone monotherapy for infantile epileptic spasms syndrome with periventricular leukomalacia. Seizure. 2023 Jul;109:40-44. doi: 10.1016/j.seizure.2023.05.012. Epub 2023 May 16. PMID: 37207538.

Abstract

Purpose: Infantile epileptic spasms syndrome (IESS) with periventricular leukomalacia (PVL) has a poor neurological prognosis. Adrenocorticotropic hormone (ACTH) and vigabatrin therapies are the recommended first-line treatments for IESS. However, ACTH monotherapy for IESS with PVL has not been studied in detail. We analysed long-term outcomes of ACTH monotherapy for IESS with PVL.

Methods: We retrospectively examined 12 patients with IESS and PVL at Saitama Children's Medical Center between January 1993 and September 2022. We evaluated seizure outcomes 3 months post-ACTH therapy and at the last visit. We also assessed electroencephalography findings and developmental outcomes. A positive response was defined as complete remission of epileptic spasms, no other seizure types, and hypsarrhythmia resolution post-ACTH therapy.

Results: The median onset age of epileptic spasms was 7 (range: 3-14) months. The median age at initiation of ACTH therapy was 9 (7-17) months. Seven of 12 patients (58.3%) showed a positive response. The median age at the last visit was 5 years and 6 months (1 year and 5 months-22 years and 2 months). At the last visit, only 2 of 7 initial responders remained seizure-free who demonstrated normal electroencephalography findings within 1-month post-ACTH therapy. Patients with epileptic discharge in the parieto-occipital region within 1-month post-ACTH therapy showed relapse of epileptic spasms or other seizure types.

Conclusion: Patients having epileptic discharge in the parietal or occipital regions on electroencephalography within 1-month post-ACTH therapy may be at a high risk of epileptic spasm recurrence or other seizure types in the long term.

Snyder HE, Jain P, RamachandranNair R, Jones KC, Whitney R. Genetic Advancements in Infantile Epileptic Spasms Syndrome and Opportunities for Precision Medicine. Genes (Basel). 2024 Feb 21;15(3):266. doi: 10.3390/genes15030266. PMID: 38540325; PMCID: PMC10970414.

Abstract

Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, 60% of cases are thought to be structural, metabolic or infectious in nature, with the remainder genetic or of unknown cause. Epilepsy genetics is a growing field, and over 28 copy number variants and 70 single gene pathogenic variants related to IESS have been discovered to date. While not exhaustive, some of the most commonly reported genetic aetiologies include trisomy 21 and pathogenic variants in genes such as TSC1, TSC2, CDKL5, ARX, KCNQ2, STXBP1 and SCN2A. Understanding the genetic mechanisms of IESS may provide the opportunity to better discern IESS pathophysiology and improve treatments for this condition. This narrative review presents an overview of our current understanding of IESS genetics, with an emphasis on animal models of IESS pathogenesis, the spectrum of genetic aetiologies of IESS (i.e., chromosomal disorders, single-gene disorders, trinucleotide repeat disorders and mitochondrial disorders), as well as available genetic testing methods and their respective diagnostic yields. Future opportunities as they relate to precision medicine and epilepsy genetics in the treatment of IESS are also explored.

SETD1A mutations

Inspired by a patient

Lan M, Wang Y, Li S, Zhao L, Liu P, Hu W. Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome. Front Neurol. 2023 Oct 19;14:1278035. doi: 10.3389/fneur.2023.1278035. PMID: 37928142; PMCID: PMC10620521.

Abstract

Infantile epileptic spasms syndrome (IESS) is one of the most common epileptic encephalopathies of infancy, with typical clinical features defined by a triad of epileptic spasms, hypsarrhythmia, and developmental delay. Genetic factors are important causes of IESS. The SETD1A (SET Domain Containing 1A) gene encodes a histone lysine methyltransferase that activates gene transcription through histone H3 lysine K4 methylation. Mutations in the SETD1A gene have been associated with schizophrenia, and some have been reported to cause seizures. Herein, we report a case of IESS caused by a SETD1A gene mutation. Video electroencephalography showed hypsarrhythmia. No specific findings were obtained after brain MRI and metabolic work-up. The seizures disappeared after treatment with adrenocorticotropic hormone, vitamin B6, and valproic acid during hospitalization. Genetic testing revealed that the child had a variant (NM_014712.3:c.3005_3,006 delAG, p.Glu1002Glyfs*20) in exon 12 of the SETD1A gene, representing a de novo mutation. There have been no previous reports on the SETD1A gene causing infantile spasms. We also summarize the existing literature on SETD1A gene-related epilepsy to provide a reference for clinical diagnosis and treatment.

Lease R, Oshone RT, Ahmed Y, Ali S, Arjona S, Choe J, Colantuoni C, Cortes-Gutierrez M, Herb BR, Humphries EM, Mocci E, O'Hara-Payne R, Kuehner R, Damcott C, Sampath H, Shaub S, Woelfel K, Wolford C, Ahn K, Detera-Wadleigh S, Markx S, Gogos JA, Kochunov P, Pollin TI, Postolache T, Shuldiner AR, McMahon FJ, Hong LE, Mitchell BD, Ament SA. Clinical, cellular, and genomic consequences of a population-enriched SETD1A missense variant. Res Sq [Preprint]. 2026 Jul 13:rs.3.rs-9900286. doi: 10.21203/rs.3.rs-9900286/v1. PMID: 42523465; PMCID: PMC13405502.

Abstract

Rare variants in SETD1A, encoding a histone H3K4 methyltransferase, are among the strongest genetic risk factors for schizophrenia. Exome sequencing (n=3,736) revealed a population-enriched SETD1A missense variant (P596L) in the Lancaster Old Order Amish founder population, presenting a unique opportunity to elucidate variant-specific, multi-scale mechanisms. Psychiatric and cognitive phenotyping revealed nearly two-fold increased risk for bipolar disorder, accompanied by allele dose-dependent cognitive deficits in adulthood. Induced pluripotent stem cells (iPSCs) from homozygous carriers exhibited signatures of SETD1A hypofunction, including reduced proliferation and heightened susceptibility to replication stress and DNA double-strand breaks. During forebrain-directed differentiation, homozygous mutant cells displayed premature activation of neurodevelopmental transcriptional programs but impaired neural rosette formation, reduced neurite complexity, and early progenitor senescence. Multi-omic profiling revealed dysregulation of gene modules converging on replication stress pathways and neuronal regulatory networks enriched for autism and psychiatric risk genes. Pharmacologic inhibition of the H3K4 demethylase KDM5 partially rescued replication stress and neurite deficits, supporting an epigenetic mechanism and suggesting therapeutic tractability. Together, these findings link a population-enriched missense variant to disrupted chromatin regulation, genome stability, and neurodevelopmental timing, bridging human genetic risk with cellular pathophysiology.

Lee S, Menzies L, Hay E, Ochoa E, Docquier F, Rodger F, Deshpande C, Foulds NC, Jacquemont S, Jizi K, Kiep H, Kraus A, Löhner K, Morrison PJ, Popp B, Richardson R, van Haeringen A, Martin E, Toribio A, Li F, Jones WD, Sansbury FH, Maher ER. Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders. Hum Mol Genet. 2023 Nov 3;32(22):3123-3134. doi: 10.1093/hmg/ddad079. PMID: 37166351; PMCID: PMC10630252.

Abstract

Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.

Eising E, Vino A, Mabie HL, Campbell TF, Shriberg LD, Fisher SE. Genome Sequencing of Idiopathic Speech Delay. Hum Mutat. 2024 Mar 28;2024:9692863. doi: 10.1155/2024/9692863. PMID: 40225914; PMCID: PMC11918988.

Abstract

Genetic investigations of people with speech and language disorders can provide windows into key aspects of human biology. Most genomic research into impaired speech development has so far focused on childhood apraxia of speech (CAS), a rare neurodevelopmental disorder characterized by difficulties with coordinating rapid fine motor sequences that underlie proficient speech. In 2001, pathogenic variants of FOXP2 provided the first molecular genetic accounts of CAS aetiology. Since then, disruptions in several other genes have been implicated in CAS, with a substantial proportion of cases being explained by high-penetrance variants. However, the genetic architecture underlying other speech-related disorders remains less well understood. Thus, in the present study, we used systematic DNA sequencing methods to investigate idiopathic speech delay, as characterized by delayed speech development in the absence of a motor speech diagnosis (such as CAS), a language/reading disorder, or intellectual disability. We performed genome sequencing in a cohort of 23 children with a rigorous diagnosis of idiopathic speech delay. For roughly half of the sample (ten probands), sufficient DNA was also available for genome sequencing in both parents, allowing discovery of de novo variants. In the thirteen singleton probands, we focused on identifying loss-of-function and likely damaging missense variants in genes intolerant to such mutations. We found that one speech delay proband carried a pathogenic frameshift deletion in SETD1A, a gene previously implicated in a broader variable monogenic syndrome characterized by global developmental problems including delayed speech and/or language development, mild intellectual disability, facial dysmorphisms, and behavioural and psychiatric symptoms. Of note, pathogenic SETD1A variants have been independently reported in children with CAS in two separate studies. In other probands in our speech delay cohort, likely pathogenic missense variants were identified affecting highly conserved amino acids in key functional domains of SPTBN1 and ARF3. Overall, this study expands the phenotype spectrum associated with pathogenic SETD1A variants, to also include idiopathic speech delay without CAS or intellectual disability, and suggests additional novel potential candidate genes that may harbour high-penetrance variants that can disrupt speech development.