Genetic link to autism Identified on X chromosome

Summary: Researchers identified variants in the DDX53 gene, located on the X chromosome, as contributors to autism spectrum disorder (ASD). These genetic variants, found predominantly in males, provide critical insights into the biological mechanisms behind autism’s male predominance.

The study also uncovered another potential gene, PTCHD1-AS, near DDX53, linked to autism, emphasizing the complexity of ASD’s genetic architecture. This research highlights the importance of the X chromosome in ASD and opens avenues for more precise diagnostics and therapeutics.

The findings challenge current models, urging a re-evaluation of how autism is studied. These discoveries mark a significant step in understanding the genetic underpinnings of autism.

Key Facts:

Gene Discovery: Variants in the DDX53 gene on the X chromosome are associated with ASD, particularly in males.

Additional Insight: PTCHD1-AS, another gene near DDX53, may also contribute to autism’s genetic basis.

Research Impact: Findings suggest sex chromosomes play a pivotal role in autism and call for new models to study these genetic pathways.

Source: Hospital for Sick Children

New research published in The American Journal of Human Genetics has identified a previously unknown genetic link to autism spectrum disorder (ASD).

The study found that variants in the DDX53 gene contribute to ASD, providing new insights into the genetic underpinnings of the condition.

ASD, which affects more males than females, encompasses a group of neurodevelopmental conditions that result in challenges related to communication, social understanding and behaviour.

While DDX53, located on the X chromosome, is known to play a role in brain development and function, it was not previously definitively associated with autism.

In the study published today, researchers from The Hospital for Sick Children (SickKids) in Canada and the Istituto Giannina Gaslini in Italy clinically tested 10 individuals with ASD from 8 different families and found that variants in the DDX53 gene were maternally inherited and present in these individuals.

Notably, the majority were male, highlighting the gene’s potential role in the male predominance observed in ASD.

“By pinpointing DDX53 as a key player, particularly in males, we can better understand the biological mechanisms at play and improve diagnostic accuracy for individuals and their families,” says senior author Dr. Stephen Scherer, Senior Scientist, Genetics & Genome Biology and Chief of Research at SickKids, and Director of the McLaughlin Centre at the University of Toronto.

“Identifying this new gene as a confirmed contributor to ASD underscores the complexity of autism and the need for comprehensive genetic analysis.”

At the same location on the X chromosome, the researchers found evidence that another gene, PTCHD1-AS, might be involved in autism. The study highlights a case where a boy and his mother, both with autism with little support needs, had a specific gene deletion involving the DDX53 gene and parts of PTCHD1-AS.

The study cohort was assembled through an international collaborative effort, involving several renowned clinical and research institutions from Canada, Italy and the U.S. Further analysis of large autism research databases, including Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, identified 26 more individuals with ASD who had similar rare DDX53 variants to the study participants.

“This gene has long eluded us, not previously linked to any neuropsychiatric condition. Our findings support a direct link between DDX53 and autism, which is not only crucial for future clinical genetic testing, but its discovery suggests that the pathway it affects is related to the behavioural traits of autism, opening a whole new area of exploration,” says lead author Dr. Marcello Scala, researcher in Medical Genetics at the Istituto Giannina Gaslini, affiliated with the University of Genoa (Department of Neuroscience).

In another paper published today in the same journal, Scherer and lead author Dr. Marla Mendes, a research fellow at SickKids, identified 59 genetic variants on the X chromosome significantly associated with ASD.

The variants were found in genes linked to autism, including PTCHD1-AS (near to DDX53), DMD, HDAC8, PCDH11X, and PCDH19 beside novel ASD-linked candidates ASB11 and ASB9. Additionally, the FGF13 gene was highlighted as being related to ASD, with sex-specific differences, adding more evidence to the role of sex chromosomes in the condition.

“These findings provide new insights into the biology of the X chromosome in ASD, providing additional evidence for the involvement of certain genes like DDX53 and FGF13, and suggesting they should be investigated further,” says Scherer.

The team notes that the absence of a similar gene like DDX53 in commonly used mouse models may require future researchers to reconsider how they study ASD. Since it lacks a functional equivalent in these models, findings in DDX53 cannot be easily replicated.

“Insights from this study could significantly influence the design and interpretation of autism research, particularly in developing new models. Identifying these variants is an important step towards developing more precise diagnostics and therapeutics for patients and families with ASD,” says Scherer.

Scherer also added “both studies provide even more evidence that complex neurobehavioral conditions like autism can sometimes have simple biologic (genetic) underpinnings.”

https://neurosciencenews.com/genetics-ddx53-autism-28276/

Marcello Scala, Clarrisa A. Bradley, Jennifer L. Howe, Brett Trost, Nelson Bautista Salazar, Carole Shum, Marla Mendes, Miriam S. Reuter, Evdokia Anagnostou, Jeffrey R. MacDonald, Sangyoon Y. Ko, Paul W. Frankland, Jessica Charlebois, Mayada Elsabbagh, Leslie Granger, George Anadiotis, Verdiana Pullano, Alfredo Brusco, Roberto Keller, Sarah Parisotto, Helio F. Pedro, Laina Lusk, Pamela Pojomovsky McDonnell, Ingo Helbig, Sureni V. Mullegama, Emilie D. Douine, Rosario Ivetth Corona, Bianca E. Russell, Stanley F. Nelson, Claudio Graziano, Maria Schwab, Laurie Simone, Federico Zara, Stephen W. Scherer. Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus. The American Journal of Human Genetics, 2024, ISSN 0002-9297,

https://doi.org/10.1016/j.ajhg.2024.11.003.

Summary

Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD.

Mendes M, Chen DZ, Engchuan W, Leal TP, Thiruvahindrapuram B, Trost B, Howe JL, Pellecchia G, Nalpathamkalam T, Alexandrova R, Salazar NB, McKee EA, Alfaro NR, Lai MC, Bandres-Ciga S, Roshandel D, Bradley CA, Anagnostou E, Sun L, Scherer SW. Chromosome X-Wide Common Variant Association Study (XWAS) in Autism Spectrum Disorder. medRxiv [Preprint]. 2024 Jul 18:2024.07.18.24310640. doi: 10.1101/2024.07.18.24310640. PMID: 39108515; PMCID: PMC11302709.

Abstract

Autism Spectrum Disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD. The "female protective effect" in ASD suggests that females may require a higher genetic burden to manifest similar symptoms as males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leave them underrepresented in genome-wide studies. Here, we conducted an X chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Cohort SSC, and Simons Foundation Powering Autism Research SPARK, alongside 8,981 population controls (43% males). We analyzed 418,652 X-chromosome variants, identifying 59 associated with ASD (p-values 7.9×10-6 to 1.51×10-5), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on chrXp22.2 (lead SNP=rs12687599, p=3.57×10-7) harboring ASB9/ASB11, and another encompassing DDX53/PTCHD1-AS long non-coding RNA (lead SNP=rs5926125, p=9.47×10-6). When mapping genes within 10kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD (GRPR, AP1S2, DDX53, HDAC8, PCDH19, PTCHD1, PCDH11X, PTCHD1-AS, DMD, SYAP1, CNKSR2, GLRA2, OFD1, CDKL5, GPRASP2, NXF5, SH3KBP1). FGF13 emerged as a novel X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant new insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation.

More on Down syndrome regression disorder

Courtesy of a colleague

Santoro JD, Filipink RA, Baumer NT, Bulova PD, Handen BL. Down syndrome regression disorder: updates and therapeutic advances. Curr Opin Psychiatry. 2023 Mar 1;36(2):96-103. doi: 10.1097/YCO.0000000000000845. Epub 2022 Dec 29. PMID: 36705008.

Abstract

Purpose of review: Down syndrome regression disorder (DSRD) is a symptom cluster consisting of neuropsychiatric regression without cause. Although knowledge of this condition has accelerated over the last decade, prior studies have been limited by heterogenous nomenclature, diagnostic approaches and therapeutic interventions. This review highlights recent advances in the diagnosis and clinical approach to DSRD and reviews the most up-to-date literature on therapeutic interventions for this condition.

Recent findings: Several multicentre studies have reported exciting findings on the presence of neurodiagnostic study abnormalities and responses to a variety of therapeutics, including psychotropics (including benzodiazepines), electroconvulsive therapy and immunotherapy. Differential response rates have been observed in the presence and absence of a variety of clinical and diagnostic factors.

Summary: Individuals with DSRD are responsive to a variety of psychiatric pharmacotherapy and immunotherapy underscoring this phenotype may have multiple causes. Multidisciplinary care is helpful in the evaluation and management of individuals with this condition.

Rosso M, Fremion E, Santoro SL, Oreskovic NM, Chitnis T, Skotko BG, Santoro JD. Down Syndrome Disintegrative Disorder: A Clinical Regression Syndrome of Increasing Importance. Pediatrics. 2020 Jun;145(6):e20192939. doi: 10.1542/peds.2019-2939. PMID: 32471843.

Abstract

Down syndrome disintegrative disorder (DSDD), a developmental regression in children with Down syndrome (DS), is a clinical entity that is characterized by a loss of previously acquired adaptive, cognitive, and social functioning in persons with DS usually in adolescence to early adulthood. Initially reported in 1946 as "catatonic psychosis," there has been an increasing interest among the DS community, primary care, and subspecialty providers in this clinical area over the past decade. This condition has a subacute onset and can include symptoms of mood lability, decreased participation in activities of daily living, new-onset insomnia, social withdrawal, autistic-like regression, mutism, and catatonia. The acute phase is followed by a chronic phase in which baseline functioning may not return. No strict criteria or definitive testing is currently available to diagnose DSDD, although a comprehensive psychosocial and medical evaluation is warranted for individuals presenting with such symptoms. The etiology of DSDD is unknown, but in several hypotheses for regression in this population, psychological stress, primary psychiatric disease, and autoimmunity are proposed as potential causes of DSDD. Both psychiatric therapy and immunotherapies have been described as DSDD treatments, with both revealing potential benefit in limited cohorts. In this article, we review the current data regarding clinical phenotypes, differential diagnosis, neurodiagnostic workup, and potential therapeutic options for this unique, most disturbing, and infrequently reported disorder.

Santoro JD, Patel L, Kammeyer R, Filipink RA, Gombolay GY, Cardinale KM, Real de Asua D, Zaman S, Santoro SL, Marzouk SM, Khoshnood M, Vogel BN, Tanna R, Pagarkar D, Dhanani S, Ortega MDC, Partridge R, Stanley MA, Sanders JS, Christy A, Sannar EM, Brown R, McCormick AA, Van Mater H, Franklin C, Worley G, Quinn EA, Capone GT, Chicoine B, Skotko BG, Rafii MS. Assessment and Diagnosis of Down Syndrome Regression Disorder: International Expert Consensus. Front Neurol. 2022 Jul 15;13:940175. doi: 10.3389/fneur.2022.940175. PMID: 35911905; PMCID: PMC9335003.

Abstract

Objective: To develop standardization for nomenclature, diagnostic work up and diagnostic criteria for cases of neurocognitive regression in Down syndrome.

Background: There are no consensus criteria for the evaluation or diagnosis of neurocognitive regression in persons with Down syndrome. As such, previously published data on this condition is relegated to smaller case series with heterogenous data sets. Lack of standardized assessment tools has slowed research in this clinical area.

Methods: The authors performed a two-round traditional Delphi method survey of an international group of clinicians with experience in treating Down syndrome to develop a standardized approach to clinical care and research in this area. Thirty-eight potential panelists who had either previously published on neurocognitive regression in Down syndrome or were involved in national or international working groups on this condition were invited to participate. In total, 27 panelists (71%) represented nine medical specialties and six different countries reached agreement on preliminary standards in this disease area. Moderators developed a proposed nomenclature, diagnostic work up and diagnostic criteria based on previously published reports of regression in persons with Down syndrome.

Results: During the first round of survey, agreement on nomenclature for the condition was reached with 78% of panelists agreeing to use the term Down Syndrome Regression Disorder (DSRD). Agreement on diagnostic work up and diagnostic criteria was not reach on the first round due to low agreement amongst panelists with regards to the need for neurodiagnostic testing. Following incorporation of panelist feedback, diagnostic criteria were agreed upon (96% agreement on neuroimaging, 100% agreement on bloodwork, 88% agreement on lumbar puncture, 100% agreement on urine studies, and 96% agreement on "other" studies) as were diagnostic criteria (96% agreement).

Conclusions: The authors present international consensus agreement on the nomenclature, diagnostic work up, and diagnostic criteria for DSRD, providing an initial practical framework that can advance both research and clinical practices for this condition.

Santoro JD, Spinazzi NA, Filipink RA, Hayati-Rezvan P, Kammeyer R, Patel L, Sannar EA, Dwyer L, Banerjee AK, Khoshnood M, Jafarpour S, Boyd NK, Partridge R, Gombolay GY, Christy AL, Real de Asua D, Del Carmen Ortega M, Manning MA, Van Mater H, Worley G, Franklin C, Stanley MA, Brown R, Capone GT, Quinn EA, Rafii MS. Immunotherapy responsiveness and risk of relapse in Down syndrome regression disorder. Transl Psychiatry. 2023 Aug 8;13(1):276. doi: 10.1038/s41398-023-02579-z. PMID: 37553347; PMCID: PMC10409776.

Abstract

Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation. A prospective, multi-center, non-randomized, observational study was performed. Patients met criteria for DSRD and were treated with IVIg. All patients underwent a standardized wean-off therapy after 9-12 months of treatment. Baseline, on-therapy, and relapse scores of the Neuropsychiatric Inventory Total Score (NPITS), Clinical Global Impression-Severity (CGI-S), and the Bush-Francis Catatonia Rating Scale (BFCRS) were used to track clinical symptoms. Eighty-two individuals were enrolled in this study. Patients had lower BFCRS (MD: -6.68; 95% CI: -8.23, -5.14), CGI-S (MD: -1.27; 95% CI: -1.73, -0.81), and NPITS scores (MD: -6.50; 95% CI: -7.53, -5.47) while they were on therapy compared to baseline. Approximately 46% of the patients (n = 38) experienced neurologic relapse with wean of IVIg. Patients with neurologic relapse were more likely to have any abnormal neurodiagnostic study (χ2 = 11.82, P = 0.001), abnormal MRI (χ2 = 7.78, P = 0.005), and abnormal LP (χ2 = 5.45, P = 0.02), and a personal history of autoimmunity (OR: 6.11, P < 0.001) compared to patients without relapse. IVIg was highly effective in the treatment of DSRD. Individuals with a history of personal autoimmunity or neurodiagnostic abnormalities were more likely to relapse following weaning of immunotherapy, indicating the potential for, a chronic autoimmune etiology in some cases of DSRD.

Rachubinski AL, Patel LR, Sannar EM, Kammeyer RM, Sanders J, Enriquez-Estrada BA, Worek KR, Fidler DJ, Santoro JD, Espinosa JM. JAK inhibition in Down Syndrome Regression Disorder. J Neuroimmunol. 2024 Oct 15;395:578442. doi: 10.1016/j.jneuroim.2024.578442. Epub 2024 Aug 22. PMID: 39216159; PMCID: PMC11533451.
Abstract


Down Syndrome Regression Disorder (DRSD) is an uncommon but devastating condition affecting primarily adolescents and young adults with Down syndrome (DS). Individuals with DS display a dysregulated immune system associated with hyperactive interferon signaling, which is associated with a high incidence of autoimmune conditions. While the cause of DSRD is unknown, increasing evidence indicates that it may have an immune basis, and some individuals with DSRD have responded to intravenous immunoglobulin therapy. This case series describes three individuals with probable DSRD who received the JAK inhibitor tofacitinib and saw improvement in DSRD symptoms across multiple domains of neurological function.

Treatment for Down syndrome regression disorder

Kelley BJ, Bailey KJ, Hubregsen JJ. Clinical Response to Electroconvulsive Therapy in a Young Adult With Down Syndrome Regression Disorder. J ECT. 2024 Dec 3. doi: 10.1097/YCT.0000000000001093. Epub ahead of print. PMID: 39652068.

Abstract

Down syndrome regression disorder (DSRD) is a condition in which individuals with Down syndrome experience a decline in social and adaptive functioning in adolescence to early adulthood. Initially described as catatonic psychosis and later designated Down syndrome disintegrative disorder (DSDD), the etiology for DSRD remains unclear but has been hypothesized to relate to autoimmune function, stress, and psychiatric disease. DSRD presents heterogeneously and has no clearly established diagnostic criteria, which can complicate treatment recommendations. ECT has been used to successfully treat DSRD, but the number of reported cases remains low, especially when it is unclear whether there are comorbid catatonic features. Here, we present a case of successful use of ECT in an individual with DSRD in which catatonic features were difficult to ascertain, and we make recommendations for the use of ECT in the treatment of DSRD.

Rachubinski AL, Patel LR, Sannar EM, Kammeyer RM, Sanders J, Enriquez-Estrada BA, Worek KR, Fidler DJ, Santoro JD, Espinosa JM. JAK inhibition in Down Syndrome Regression Disorder. J Neuroimmunol. 2024 Oct 15;395:578442. doi: 10.1016/j.jneuroim.2024.578442. Epub 2024 Aug 22. PMID: 39216159; PMCID: PMC11533451.

Abstract

Down Syndrome Regression Disorder (DRSD) is an uncommon but devastating condition affecting primarily adolescents and young adults with Down syndrome (DS). Individuals with DS display a dysregulated immune system associated with hyperactive interferon signaling, which is associated with a high incidence of autoimmune conditions. While the cause of DSRD is unknown, increasing evidence indicates that it may have an immune basis, and some individuals with DSRD have responded to intravenous immunoglobulin therapy. This case series describes three individuals with probable DSRD who received the JAK inhibitor tofacitinib and saw improvement in DSRD symptoms across multiple domains of neurological function.

Santoro JD, Jafarpour S, Khoshnood MM, Boyd NK, Vogel BN, Nguyen L, Saucier LE, Partridge R, Tiongson E, Ramos-Platt L, Nagesh D, Ho E, Rosser T, Ahsan N, Mitchell WG, Rafii MS. Safety and tolerability of intravenous immunoglobulin infusion in Down syndrome regression disorder. Am J Med Genet A. 2024 May;194(5):e63524. doi: 10.1002/ajmg.a.63524. Epub 2024 Jan 2. PMID: 38169137.

Abstract

Three large multi-center studies have identified the clinical utility of intravenous immunoglobulin (IVIg) in the treatment of Down syndrome regression disorder (DSRD). Yet the tolerability of infusions in individuals with DS and the safety of IVIg remains unknown in this population. This study sought to evaluate the safety and tolerability of IVIg in individuals with DSRD compared to a real-world cohort of individuals with pediatric onset neuroimmunologic disorders. A single-center, retrospective chart review evaluating clinically documented infusion reactions was performed for individuals meeting international consensus criteria for DSRD and having IVIg infusions between 2019 and 2023. Infusion reactions were evaluated for severity and need for alterations in infusion plan. This cohort was compared against an age and sex matched cohort of children with neuroimmunologic conditions who had also received IVIg infusions. In total, 127 individuals with DSRD and 186 individuals with other neuroimmunologic disorders were enrolled. There was no difference in the overall rate of adverse reactions (AEs) between the DSRD and general neuroimmunology cohorts (p = 0.31, 95% CI: 0.80-2.00), but cardiac-related AEs specifically were more common among the DSRD group (p = 0.02, 95% CI: 1.23-17.54). When AEs did occur, there was no difference in frequency of pharmacologic intervention (p = 0.12, 95% CI: 0.34-1.13) or discontinuation of therapy (p = 0.74, 95% CI: 0.06-7.44). There was a higher incidence of lab abnormalities on IVIG among the general neuroimmunology cohort (p = 0.03, 95% CI: 0.24-0.94) compared to the DSRD cohort. Transaminitis was the most common laboratory abnormality in the DSRD group. In a large cohort of individuals with DSRD, there were no significant differences in the safety and tolerability of IVIg compared to a cohort of children and young adults with neuroimmunologic conditions.

Santoro JD, Khoshnood MM, Nguyen L, Vogel BN, Boyd NK, Paulsen KC, Rafii MS. Alternative Diagnoses in the Work Up of Down Syndrome Regression Disorder. J Autism Dev Disord. 2023 Aug 16. doi: 10.1007/s10803-023-06057-9. Epub ahead of print. PMID: 37584771.

Abstract

Purpose: Down Syndrome Regression Disorder (DSRD) is a diagnosis of exclusion. Psychiatric and neuroimmunologic etiologies have been proposed although the exact etiology remains unknown. This study sought to review non-DSRD diagnoses at a large quaternary medical center specializing in the diagnosis of DSRD and compare clinical characteristics between those diagnosed with DSRD and those with non-DSRD diagnoses.

Methods: The authors performed a single-center retrospective, chart-based, review of referrals for developmental regression in individuals with Down syndrome.

Results: Two hundred and sixty-six individuals were evaluated for DSRD and of these, 54 (20%) ultimately had alternative diagnoses. Individuals with DSRD were more likely to have shorter nadir to clinical symptoms (p = 0.01, 95% CI: 0.36-0.47) and have preceding triggers (p < 0.001, 95% CI: 1.13-1.43) compared to those with alternative diagnoses. Individuals with non-DSRD diagnoses were more likely to be born premature (p = 0.01, 95% CI: 0.51-0.87) and have a history of epilepsy (p = 0.01, 95% CI: 0.23-0.77) but were also less likely to have a history of cytokine abnormalities on bloodwork (p < 0.001, 95% CI: 1.19-1.43) and have catatonia (p < 0.001, 95% CI: 1.54-2.17). The majority of alternative diagnoses (41/54, 76%) were autism spectrum disorder. In these cases, symptoms were more likely to be longstanding (symptoms > 12 months) and earlier onset (median 8 years, IQR: 6-11). Other diagnoses included epilepsy (5/54, 9%), Celiac disease (5/54, 9%), cerebrovascular disease (3/54, 6%).

Conclusions: This study identifies that 20% of individuals referred with concerns for DSRD have alternative diagnoses. The majority of these diagnoses were autism, but rare treatable conditions were also identified, highlighting the importance of a thorough neurodiagnostic assessment.

Male fertility in Down syndrome

Jazayeri O, Gorjizadeh N. A male Down syndrome with two normal boys: Cytogenetic, paternity and andrological investigations. Andrologia. 2020 Apr;52(3):e13521. doi: 10.1111/and.13521. Epub 2020 Jan 31. PMID: 32003054.

Abstract

Down syndrome is the most common autosomal chromosome anomaly with several medical abnormalities and intellectual disability, occurring in about of 1:1,000 to 1:1,100 infants. Many pregnancies in women with Down syndrome produce children both with normal and with trisomy 21, whereas males are infertile. However, Down syndrome males are not always infertile and this is not global. Here we reported a 36-year-old man with proved nonmosaic trisomy 21 fathered two normal boys. Paternity analysis using 26 microsatellite loci confirmed that Down syndrome male is the biological father of his two normal boys. Serum LH, FSH, testosterone and 17-OH progesterone were all in the normal range in this father with Down syndrome. To the best of our knowledge, this is the second report of one man with Down syndrome who has two normal children in the world. The current study not only supports the rare evidence of the fertility of males with Down syndrome but also highlights the caution in advising people responsible for the care of adults with this condition about possible fertility and transmission of sexual diseases as well.

Pradhan M, Dalal A, Khan F, Agrawal S. Fertility in men with Down syndrome: a case report. Fertil Steril. 2006 Dec;86(6):1765.e1-3. doi: 10.1016/j.fertnstert.2006.03.071. Epub 2006 Nov 13. PMID: 17094988.

Abstract

Objective: To inform clinicians about fertility in males with Down syndrome.

Design: Case report.

Setting: Medical Genetics Department of a tertiary-care hospital.

Patient(s): A 26-year-old man with confirmed nonmosaic trisomy 21.

Intervention(s): Karyotype, amniocentesis, paternity testing using microsatellite markers.

Main outcome measure(s): Confirmed paternity in the son of a male with nonmosaic trisomy 21.

Result(s): A male with nonmosaic Down syndrome fathered a normal son, and the paternity was proven by microsatellite marker analysis.

Conclusion(s): Although Down syndrome males have been reported to be infertile, it may not always be true. Infertility in males has been attributed to defective spermatogenesis, but ignorance of the sexual act may be one of the contributing factors. It is important to advise postpubertal Down syndrome males on contraceptive measures.

Euthanasia in Canada

Canada is experiencing a significant surge in deaths by euthanasia, according to a report released this week by the Canadian government.

Health Canada’s medical assistance in dying (MAID) report, its fifth annual one, shows euthanasia accounting for nearly five percent of total deaths in the country last year.

Medical officials euthanized an astonishing 15,343 people in Canada in 2023, an increase of 15.8 percent over 2022.

In a bit of irony worthy of the Babylon Bee, the report states that “Health Canada is the federal department responsible for helping the people of Canada maintain and improve their health.”

Health Canada “is committed to improving the lives of all of Canada’s people and to making this country’s population among the healthiest in the world as measured by longevity, lifestyle and effective use of the public health care system,” it adds.

It also declares that the government has laid out “strict eligibility criteria to determine who can receive MAID, and robust safeguards to ensure that MAID is safely provided,” a stipulation some may find self-contradictory.

One of the criteria for eligibility set out by the government states that a patient must have a natural death that is “reasonably foreseeable,” perhaps the lowest bar imaginable since no one has ever been known to live forever.

In its attempt to assess the remarkable growth in euthanasia’s popularity among Canadians, the report points to a number of factors, including greater social acceptance of government-assisted killing.

“An increased awareness of MAID within the care continuum, population aging, and the associated patterns of illness or disease, personal beliefs, and societal acceptance, as well as the availability of practitioners who provide MAID, may all influence the rate of provisions,” the report said.

The report also said that assisted killing “appears to be becoming an area of focused expertise for some healthcare workers,” noting that a small group of 89 practitioners were responsible for 35.1 percent of all Track 1 and 28.6 percent of all Track 2 deaths respectively, the latter group being those whose natural deaths were not “reasonably foreseeable.”

The total number of those who have died under Canada’s euthanasia law since its legalization in 2016 is now is 60,301, the report revealed.

https://www.breitbart.com/health/2024/12/14/canada-maid-euthanasia-deaths-spike-by-16-percent-in-just-one-year/

Poor sleep and glymphatic function in adolescents

MRIs of healthy adolescents who experienced poor sleep quality, particularly in the NREM or slow-wave sleep stages, tended to have larger perivascular spaces, a factor associated with cognitive decline, according to an abstract presented in November at the Child Neurology Society annual meeting in San Diego. Neurologists said this research could open the door to looking at the impact of poor sleep quality on both adolescent and long-term health issues.

Researchers said the finding shows that a non-invasive, structural, and longitudinally trackable marker of glymphatic functions could help determine if impairments in NREM sleep quality impact brain health not only in people with neurodegenerative diseases or aging brains but also in healthy adolescents. But they cautioned that the data was collected after a single night's sleep, and longer studies will be needed.

“We suspect that everyone sits on their own perivascular growth trajectory that is influenced by both physiologic and pathophysiologic factors, and in turn influences their ability to clear cerebral waste as well as engage in other impor­­tant glymphatic functions. These results suggest that sleep during adolescence—something that can be targeted and modified—may be one of these factors," said Seva G. Khambadkone, MD, PhD, lead author of the study and a child neurology resident at Oregon Health & Science University.

“A lot of work remains to be done, and we have a lot of questions, but I think one takeaway is that maybe one day we will start thinking about pediatric glymphatic health in a similar way that we think about childhood obesity."

The glymphatic system is primarily active during NREM sleep and is critical for clearing waste produced by the brain, sort of like a brain sewage system, said Dr. Khambadkone. Although most research has focused on older adults, glymphatic clearance is established early in life and perivascular spaces—the network through which glymphatic clearance occurs—can be seen on pediatric MRIs, she added.

The new study focused on the relationship between MRI-visible perivascular space (MV-PVS) volume and polysomnographic (PSG) measures of sleep in a healthy pediatric population, ages 12 to 21 years. The analysis included data from 111 participants from the sleep arm of the National Consortium on Alcohol and Neurodevelopment in Adolescence, a multisite, cohort-sequential, longitudinal study. Participants had a mean age of 15.3, and 47 were female. They underwent PSG studies and brain MRIs and were analyzed according to age, sex, body-mass index, and study site.

​The study found that male participants had a “significantly" greater mean MV-PVS volume than females (7.57 +/- 1.22 vs. 6.72 +/- 1.22, p<0.001). MV-PVS volume in the white matter was negatively associated with delta EEG power in NREM2 sleep, and MV-PVS volume in the basal ganglia was negatively associated with delta EEG power in NREM3 sleep. Researchers did not observe any associations between MV-PVS volumes and PSG measures of wake after sleep onset, sleep efficiency, or time spent in NREM2 or NREM3 sleep.

The results highlighted the “potential physiologic relevance of MV-PVS in healthy adolescents and young adults," the study authors wrote. Dr. Khambadkone said studying healthy adolescents will allow them to research implications for neurologic impacts. One of the next steps is to address youth who have had a traumatic brain injury—which often is associated with severe sleep disturbances—looking at the relationship between TBI, sleep, and perivascular spaces.

“While a huge focus of this field has been in neurodegeneration and aging, we can't stop thinking about what role this system could have in mediating neurodevelopment and neurologic health and function across the lifespan, and how we can intervene to both mitigate risk and promote resilience—for example, by targeting sleep health," Dr. Khambadkone said.

Temitayo Oyegbile-Chidi, MD, PhD, FAAN, FAES, FANA, an associate professor of neurology who is certified in pediatric neurology, epilepsy, and sleep medicine at the University of California, Davis, said researchers are just beginning to understand the role of sleep in neurologic disorders. She was excited that the study focused on adolescent brains, which opened possibilities to study how sleep impacts development.

“This was one of the first studies investigating the role of sleep-related glymphatic function and neurodevelopmental brain health in an adolescent population. Prioritizing sleep to optimize daytime function as well as short-term and long-term neurologic health is crucial in the pediatric population and not just in older adults," said Dr. Oyegbile-Chidi, noting that it would be interesting to further investigate the impact of glymphatic function in sleep on neurologic disorders of childhood, such as autism, epilepsy, and attention deficit disorders.

​“Traditionally, it has been believed that glymphatic dysfunction related to cumulative poor sleep is a problem of older adults and is associated with the development of cognitive impairment including dementias," she added. “But this study indicates that glymphatic dysfunction can be observed in very early developmental stages. Future studies are necessary to clearly characterize this dysfunction in the pediatric population and the long-term consequences. Regardless, this study adds to the accumulating evidence that sleep is very important for optimal brain development and brain health in the pediatric population."

https://journals.lww.com/neurotodayonline/blog/NeurologyTodayConferenceReportersCNSAnnualMeeting/pages/post.aspx?PostID=63&utm_source

Child Neurology Society Abstract PL1-7: Khambadkone SG, Yamamoto EA, Koike S, et al. Delta power during sleep is associated with MRI-visible perivascular space volume in adolescents and young adults.

OBJECTIVE: Enlarged, MRI-visible perivascular spaces (MV-PVS) are putative markers of impaired glymphatic function, and are increasingly recognized in the general pediatric population. The significance of MV-PVS in the developing brain remains unknown. In adults, slow-wave sleep has been shown to mediate glymphatic function, and poor sleep quality is associated with larger MV-PVS volume. The aim of this study was to determine the relationship between MV-PVS volume and polysomnographic (PSG) and electroencephalographic (EEG) measures of sleep in a healthy pediatric population. METHODS: Data were analyzed from 111 participants (age range:12-21 years of age, mean: 15.3
2.2 years, 47 female) enrolled in a sleep arm of the National Consortium on Alcohol and Neurodevelopment in Adolescence, a multisite, cohort-sequential, longitudinal study. Participants underwent PSG studies and brain MRI scans at study entry. MV-PVS volume/white matter (WM; mm3/cm3) was quantified using an automated detection algorithm. Associations between MV-PVS volume and PSG and EEG measures (log transformed) were analyzed by linear regression including age, sex, BMI, and study site as covariates. RESULTS: Males had significantly greater mean MV-PVS volume/WM than females (7.57
1.22 vs 6.72
1.22, p<0.001). MV-PVS volume/WM was negatively associated with delta EEG power in Stage N2 sleep (β=-0.50, SE=0.23, p=0.035), but not in Stage N3 sleep. There were no associations observed between MV-PVS volume/WM and PSG measures of wake after sleep onset, sleep efficiency, or time spent in N2 or N3 sleep. CONCLUSIONS: Lower delta power in N2 sleep was associated with larger MV-PVS volume, highlighting potential physiologic relevance of MV-PVS in healthy adolescents and young adults.

Charcot-Marie-Tooth disease in children

Saylam, E., Ramani, P.K., Duvuru, R., Haley, B. and Veerapandiyan, A. (2024), Charcot-Marie-Tooth disease in children. Ann Child Neurol Soc. https://doi.org/10.1002/cns3.20093

Abstract

Charcot-Marie-Tooth (CMT) disease represents a diverse group of inherited neuropathies with a broad spectrum of symptoms. It is the most prevalent inherited neuropathy, with an estimated prevalence ranging from 9.7 to 82 cases per 100,000 individuals. Despite this, CMT comprises only 118 of 853 inherited neuropathy entries in the Online Mendelian Inheritance in Man (OMIM) database. This comprehensive review offers a thorough examination of CMT's clinical features, subtypes, genetic underpinnings, and pathomechanisms in pediatric cases. CMT typically manifests as progressively worsening muscle weakness and atrophy, primarily affecting the distal extremities. Patients may also experience foot and ankle deformities, hand atrophy, and other systemic issues. To accurately diagnose CMT, a detailed family history, comprehensive clinical evaluation, nerve conduction studies, and relevant genetic testing are essential. Importantly, establishing a differential diagnosis is crucial during evaluation to rule out other conditions with similar presentations. This review aims to provide clinicians with a valuable resource for diagnosing and managing CMT, emphasizing the need for a streamlined and standardized approach considering advancements in genetic testing and the identification of various subtypes.

Preventative treatment of tuberous sclerosis complex with sirolimus

Capal, J.K., Ritter, D.M., Franz, D.N., Griffith, M., Currans, K., Kent, B., Martina Bebin, E., Northrup, H., Koenig, M.K., Mizuno, T., Vinks, A.A., Galandi, S.L., Zhang, W., Setchell, K.D.R., Kremer, K.M., Prada, C.M., Greiner, H.M., Holland-Bouley, K., Horn, P.S. and Krueger, D.A. (2024), Preventative treatment of tuberous sclerosis complex with sirolimus: Phase I safety and efficacy results. Ann Child Neurol Soc, 2: 106-119. https://doi.org/10.1002/cns3.20070

Abstract

Objective

Tuberous sclerosis complex (TSC) results from overactivity of the mechanistic target of rapamycin (mTOR). Sirolimus and everolimus are mTOR inhibitors that treat most facets of TSC but are understudied in infants. We sought to understand the safety and potential efficacy of preventative sirolimus in infants with TSC.
Methods

We conducted a phase 1 clinical trial of sirolimus, treating five patients until 12 months of age. Enrolled infants had to be younger than 6 months of age with no history of seizures and no clinical indication for sirolimus treatment. Adverse events (AEs), tolerability, and blood concentrations of sirolimus measured by tandem mass spectrometry were tracked through 12 months of age, and clinical outcomes (seizure characteristics and developmental profiles) were tracked through 24 months of age.
Results

There were 92 AEs, with 34 possibly, probably, or definitely related to treatment. Of those, only two were grade 3 (both elevated lipids) and all AEs were resolved by the age of 24 months. During the trial, 94% of blood sirolimus trough levels were in the target range (5–15 ng/mL). Treatment was well tolerated, with less than 8% of doses held because of an AE (241 of 2941). Of the five patients, three developed seizures (but were well controlled on medications) at 24 months of age. Of the five patients, four had normal cognitive development for age. One was diagnosed with possible autism spectrum disorder.
Interpretation

These results suggest that sirolimus is both safe and well tolerated by infants with TSC in the first year of life. Additionally, the preliminary work suggests a favorable efficacy profile compared with previous TSC cohorts not exposed to early sirolimus treatment. Results support sirolimus being studied as preventive treatment in TSC, which is now underway in a prospective phase 2 clinical trial (TSC-STEPS).

Efgartigimod in generalized myasthenia gravis

Blair HA. Efgartigimod: A Review in Generalised Myasthenia Gravis. Drugs. 2024 Nov;84(11):1463-1474. doi: 10.1007/s40265-024-02101-9. Epub 2024 Nov 7. PMID: 39511131.

Abstract

Efgartigimod (Vyvgart®; Vyvgart® Hytrulo) is a neonatal fragment crystallizable receptor (FcRn) antagonist indicated for the treatment of generalised myasthenia gravis (gMG) in adults who are acetylcholine receptor (AChR) antibody positive (Ab+). Efgartigimod is approved for both intravenous (IV) and subcutaneous (SC) use. In a pivotal phase III trial, IV efgartigimod was associated with significant and clinically meaningful improvements in myasthenia gravis symptoms and reductions in disease burden. The beneficial effects of IV efgartigimod were reproducible, durable and maintained over the long term. IV efgartigimod also improved health-related quality of life (HRQOL). In another phase III trial, SC efgartigimod PH20 was noninferior to IV efgartigimod in reducing total immunoglobulin G levels. Clinical improvement with SC efgartigimod PH20 was consistent with that of IV efgartigimod and was reproducible over the long term. Efgartigimod was generally well tolerated; the most common adverse events were headache and infections (with IV efgartigimod) and injection-site reactions (with SC efgartigimod PH20). Although further long-term data are required, IV and SC formulations of efgartigimod provide effective, generally well-tolerated and flexible treatment options for adults with AChR Ab+ gMG.

Smith AG, Wolfe GI, Habib AA, Qi CZ, Yang H, Du M, Chen X, Gelinas D, Brauer E, Phillips G, Saccà F. Risk-Benefit Analysis of Novel Treatments for Patients with Generalized Myasthenia Gravis. Adv Ther. 2024 Dec;41(12):4628-4647. doi: 10.1007/s12325-024-03014-5. Epub 2024 Oct 29. PMID: 39470879; PMCID: PMC11550228.

Abstract

Introduction: This study used network meta-analysis (NMA) to inform and compare the number needed to treat (NNT), number needed to harm (NNH), and cost per improved outcome (CPIO) associated with more recently approved treatments for anti-acetylcholine receptor antibody-positive (anti-AChR Ab+) generalized myasthenia gravis (gMG).

Methods: Clinical trials of neonatal Fc receptor (FcRn) inhibitors, efgartigimod intravenous (IV) and rozanolixizumab, and complement inhibitors, ravulizumab and zilucoplan, versus placebo (with background conventional treatment) were included in the primary NMA to compare efficacy and safety outcomes. The outputs from the NMAs were used to estimate NNT and NNH of each treatment versus placebo. CPIO (2024 USD) was estimated for a ≥ 3- or ≥ 5-point reduction from baseline in Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores. Sensitivity analyses were performed adding efgartigimod PH20 subcutaneous (SC) and eculizumab to the NMA.

Results: Efgartigimod IV had the lowest NNT versus placebo for achieving a ≥ 3- and ≥ 5-point reduction in QMG, as well as a ≥ 5-point reduction in MG-ADL, whereas rozanolixizumab had the lowest NNT for a ≥ 3-point reduction in MG-ADL. The NNH versus placebo was similar across comparator treatments. Efgartigimod IV had the lowest CPIO among all treatments for all assessed efficacy outcomes. Sensitivity analyses yielded results consistent with primary analysis and indicated that efgartigimod PH20 SC had comparable NNT and CPIO values to efgartigimod IV, whereas eculizumab had comparable NNT and higher CPIO values compared to other complement inhibitors.

Conclusions: FcRn inhibitors and complement inhibitors assessed in this study all demonstrated clinical benefit in terms of NNT as well as an acceptable safety profile in terms of NNH. Within the limitations of this meta-analysis, efgartigimod was associated with a favorable benefit-risk profile as well as a better economic value compared to ravulizumab, rozanolixizumab, and zilucoplan as treatments for anti-AChR Ab+ gMG.

Dewilde S, Griffiths A, Qi CZ, Phillips G, Gelinas D, Brauer E, Mantegazza R, Howard JF Jr. Post-hoc analyses from the ADAPT clinical study demonstrate aggregate sustained benefit of Efgartigimod in generalized myasthenia gravis. J Neurol Sci. 2024 Nov 15;466:123264. doi: 10.1016/j.jns.2024.123264. Epub 2024 Oct 4. PMID: 39426360.

Abstract

Objectives: This post-hoc analysis evaluates the long-term efficacy of efgartigimod versus placebo in adult patients with generalized myasthenia gravis (gMG) with acetylcholine-receptor autoantibodies (AChR-Ab+), based on data from the ADAPT RCT and its open-label extension ADAPT+.

Methods: Changes from baseline in Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores were assessed by treatment group over the ADAPT (up to 20 weeks) and ADAPT+ time horizon (extended to 64 weeks for efgartigimod group patients). Response to treatment was defined as 5-point reduction in QMG or 3-point reduction in MG-ADL vs. baseline values.

Results: AChR-Ab+ patients treated with efgartigimod spent a substantially greater percentage of time in response in ADAPT based on at least a 5-point change in QMG compared to the placebo group (44 % versus 13 % respectively, p = 0.0034). Analyses based on a 3-point change in MG-ADL in ADAPT showed the percentage of time in response was nearly double for efgartigimod versus placebo (59 % versus 30 % respectively, p = 0.010). These trends were also maintained using different response definitions, as well as in patients with and without prior immune therapy exposure and by time from diagnosis (<7 years versus ≥7 years).

Conclusions: The clinical benefit of efgartigimod was sustained over repeat treatment cycles and maintained over the long term. Response to treatment was consistent regardless of response definition and was repeated in different patient subgroups. Overall, the results of this analysis indicate that efgartigimod is an effective therapeutic option, demonstrating a robust benefit among AChR-Ab+ patients with gMG.

Empowering epilepsy care: opportunities in managing rare epilepsy syndromes

Matsumoto JH, Wirrell EC. Empowering epilepsy care: opportunities for neurologists and pediatricians in managing rare epilepsy syndromes. Practical Neurology (US). 2024;23(9):43-46.

To help educate adult and pediatric neurologists on the management of epilepsy syndromes, Practical Neurology’s Publisher, Wendy Terry, spoke with two epileptologists, Joyce H. Matsumoto, MD, University of California, Los Angeles, David Geffen School of Medicine, and Elaine C. Wirrell, MD, Mayo Clinic Alix School of Medicine, about their experiences diagnosing and treating patients with rare forms of epilepsy.

This article emphasizes the critical role of general neurologists and pediatricians in recognizing and diagnosing rare epilepsy syndromes, highlighting the importance of thorough patient history, video documentation, genetic testing, and collaboration with epilepsy specialists to improve patient outcomes and management strategies.

Why Should General Neurologists and Pediatricians Take the Time to Diagnose Patients Living with Rare Forms of Epilepsy Syndromes?

Dr. Wirrell: For many neurologists, there’s a perception that persons diagnosed with early life epilepsies, particularly one of the developmental and epileptic encephalopathies (DEE) such as Lennox-Gastaut syndrome (LGS), have a drug-resistant epilepsy, and there’s not a lot of treatment options available. Clinicians may ask themselves, “So what am I really going to do to make a difference with this patient?” I would argue that we now have a number of new therapies that have been shown to be efficacious in clinical studies. I believe we can make a difference in reducing seizure burden in these patients, although the individual may not be seizure-free altogether.

Dr. Matsumoto: I would add that as we are gaining more knowledge of the different rare genetic conditions that can lead to epilepsy, clarifying the genetic diagnosis can, in unexpected ways, help identify other organ systems that may be involved. These details can help guide treatment and management options.

The more information we gather from these patients and their loved ones about their experience, the more we learn about these conditions. This understanding can lead to better treatments and outcomes for these patients. It’s also helpful for us to be better able to explain to family members what might happen during the course of their life with this illness. Of course, it’s always important to clarify to family members that not everything that they read about the condition is going to happen with their child. But it can be validating for them to be able to say, “Okay, other people have experienced this. And it’s not that we’re doing anything wrong.” So I think that it does help to have as much information as possible, including genetic test results. It can help even older patients who have been living with epilepsy for a long time. When we have been able to do genetic testing for people where it wasn’t available years ago when they were going through the initial diagnostic journey and we find a genetic diagnosis, it helps them.

Can We Walk Through the Overall Diagnosis Process for Patients and the Challenges Associated with that Process?

Dr. Wirrell: In terms of diagnosis, one of the challenges is that some of our DEEs, such as LGS, really take time to evolve. Research has shown that LGS, for example, often takes 2 to 3 years to evolve and for the patient to manifest all of the diagnostic criteria. This can be a tough time for families, as they see their child having a lot of seizures and not progressing developmentally. We know the seizure activity will likely be challenging, and we’re certainly concerned that they’re possibly moving towards a LGS diagnosis, but they’re very young, and they haven’t met the clinical criteria. So, it can be extraordinarily difficult sometimes to provide an accurate early diagnosis.

Additionally, some rare epilepsies will change as the child ages. For example, with Dravet syndrome, there is a dramatic difference in how this syndrome appears when you compare a 1-year-old child with this condition with a 20-year-old young adult. For a child with Dravet syndrome at 1 years old, they’re having prolonged convulsive seizures, often hemi-convulsive, switching sides from one seizure to the next. Although the seizures may not be that frequent, every time they have a seizure, it’s prolonged or it’s status epilepticus.

Then, as the patient moves forward into their teens or in their twenties, you don’t see those prolonged seizures very frequently, if at all. You often see more frequent, but briefer, tonic-clonic seizures or convulsive seizures that happen during sleep. So we do see that sort of evolution with time as well. That can be challenging for some of the general neurologists to appreciate certain characteristic features unless you have knowledge of that early patient history and familiarity with the varied presentations seen with genetic and rarer epilepsies.

Dr. Matsumoto: The diagnostic process can be challenging in situations involving the reevaluation of patient records to ensure diagnostic accuracy. For older patients, it is difficult to obtain electroencephalogram (EEG) test results from a long time ago when a lot of the findings might have been more obvious, especially if you’re dealing with an older child. There is also sometimes a challenge in cases in which the initial EEG tests or initial evaluations were performed by somebody who’s not familiar with LGS or familiar with children who have epilepsy that is difficult to control.

The reports alone may not describe the patient history, test results, and presentation in the way that we would expect them to. So sometimes it can be difficult to read between the lines and say, “Oh, this is what they were probably seeing,” because getting the raw data can be very difficult.

How Can the Diagnostic Process Be Improved for Patients Living with Rare Forms of Epilepsy?

Dr. Wirrell: What’s important to recognize is that for most patients, their first contact after they develop seizures is going to be with a general neurologist. So, it is essential that general neurologists are empowered to recognize relevant clues found in children with DEEs. They don’t necessarily need to recognize the features associated with every rare genetic epilepsy but they need to recognize what appears to be a DEE: children coming in with early life or early onset seizures, with seizures that are very frequent, seizures that appear drug resistant, and with certain types of seizures like spasms or tonic seizures or atonic seizures.

Additionally, children with DEEs often have very abnormal EEG test results, with marked slowing, high amplitude, and frequent discharges. Children have onset of developmental disabilities that may predate or certainly can worsen when seizures become more frequent. So, I think seeing children and looking for all of those clues and putting that together and saying, “Boy, this looks like a child with a DEE.”

Dr. Matsumoto: When we talk about trying to empower general neurologists, it’s also important to realize that a lot of these patients may not be seen by child neurologists for some of their initial evaluations. They may be seen by an adult epileptologist who is trying to do their best because of the shortage of pediatric specialists. What is important for all involved, whether general neurologists or pediatricians, is to understand some of the warning signs so that they can be empowered to say, “Okay, in this patient, there’s something very wrong, and they need to be seen more urgently.”

I believe that it’s important for us as epileptologists to be in contact with pediatricians and general neurologists and be able to say, “Hey, these are the things that you really need to tell us about,” because time is of the essence.

Helping our colleagues understand what we are looking for, and identifying concerns that we need to evaluate quickly are a couple of the biggest things that they can do to help the diagnostic process. This includes patients with developmental regression with a patient history that would predispose them to perhaps having a higher risk of seizures, a history of a challenging birth or hypoxic injury, and presentations that involve documented movements that happen very similarly in clusters around the same time of day or in certain situations that cannot be explained otherwise.

Dr. Wirrell: I think the other thing that can be helpful is to ask parents to record a video. Many times, we will get called by outside providers who will send a video, and they’ll say, “Geez, I’m a little worried about this kid.” And you look at the video, and say “Yes, that’s clearly spasms and we need to prioritize that child,” or “No, we don’t really need to worry about that, that looks more like shuddering or more like a tic.” Videos can be very helpful tools that can easily be sent around and reviewed.

What Recommendations Would You Share with General Neurologists or Pediatricians Who Are Unsure How to Best Manage a Patient’s Symptoms Once Confirming a Diagnosis?

Dr. Matsumoto: Initiate the referral process early and establish a collaborative relationship with an epilepsy center or a specialist who frequently manages complex cases. This partnership can enhance your ability to provide comprehensive care for patients with epilepsy. Although referral to a specialized center is crucial for certain cases, maintaining continuity of care at the local level is equally important. Many families prefer having a local physician they can consult regularly. As you follow these patients over time, you may not always feel comfortable making all treatment decisions, but you can monitor their progress, familiarize yourself with various medications, and understand the range of available interventions.

By combining local follow-up with specialized care, you can provide more comprehensive and coordinated management for your patients with epilepsy. This approach allows you to gain experience with complex cases while ensuring your patients receive optimal care.

Dr. Wirrell: Effective management of pediatric epilepsy often requires a collaborative approach involving a pediatric epileptologist and local neurologist. This multidisciplinary partnership is crucial for providing comprehensive care, especially for medically fragile children who may find long travel times for frequent visits challenging. Although telemedicine has alleviated some of these challenges, having a local neurologist familiar with the patient’s case remains critical for everything from managing potential seizure emergencies to providing timely interventions.

General neurologists should recognize that epilepsy management extends beyond seizure control. Yes, seizure reduction is a primary goal, but addressing comorbidities is equally important. When considering treatment modifications, clinicians should carefully weigh the potential benefits against possible risks and strive to achieve an optimal balance that considers the patient’s overall well-being. These should not only focus on seizure control but also prioritize the child’s cognitive function, learning potential, and overall quality of life for both the patient and their family. By considering these factors, clinicians can develop a more holistic treatment plan that addresses the complex needs of pediatric epilepsy patients.

What Diagnostic Tools or Tests Are Available for General Neurologists or Pediatricians to Identify Patients with Rare Forms of Seizure Disorders More Easily?

Dr. Matsumoto: I think that genetic testing is an important tool to know about and understand. It keeps evolving, and the availability keeps on improving. Exome sequencing, for example, is much more readily available than in the past. I think that genetic testing has really helped us in trying to better categorize people and to understand conditions, such as LGS, better.

Dr. Wirrell: With respect to EEG, I think one of the challenges is that the younger the child or infant, the tougher the EEG can be to interpret, because general neurologists may be more familiar with reading adult EEG tests in which there’s a lot less variability. It’s important to appreciate what is normal and what is abnormal and have the confidence if there is a pattern like hypsarrhythmia present to really recognize that and call it out. Identifying such patterns will then alert everyone to think about a potential diagnosis of infantile spasms. For infants who have potential for DEEs if they’re having frequent seizures or there’s developmental regression or presentations like that, it’s important to have the EEG test results reviewed by someone with expertise in pediatric epilepsy.

If We Improve the Diagnostic Process, What’s the Impact for the Patient and the Caregiver?

Dr. Wirrell: One of the impacts of genetic testing as a first-line test for those with unexplained epilepsy is that it can lead to an earlier diagnosis. With an earlier diagnosis, we can then select the most efficacious therapy for the specific condition, avoiding trial and error with medications that are contraindicated or that may potentially worsen seizures. Early intervention can mitigate the impact of frequent seizures on a child’s development. Although some developmental issues may be related to the underlying cause of epilepsy, others are related to the epileptic process itself, including frequent seizures and EEG discharges. Controlling seizures earlier can mean 6 months or even 1 year of less damage on the brain caused by seizures, potentially leading to better long-term developmental outcomes for the child.

With respect to genetic testing, having a definitive diagnosis provides parents with answers, alleviating guilt and reducing frustration. You can give the parents an answer and say, “Here is what caused this. It doesn’t relate to anything you did or didn’t do during the pregnancy.” It helps them understand their child’s condition and be able to connect with support networks for others with rare epilepsies.

By addressing these factors through early diagnosis and appropriate treatment, we can potentially improve both seizure control and overall developmental outcomes for children with epilepsy.

Dr. Matsumoto: I agree with Dr. Wirrell that improving the diagnostic process in epilepsy can have significant benefits, especially for parents. It can reduce parental frustration, for example. Validating parents’ concerns and instincts when they notice something is wrong with their child can be tremendously helpful. This is especially important if they were previously told not to worry about certain movements they have been observing. An earlier diagnosis also can help parents avoid feelings of guilt or regret for not bringing up concerns sooner. Lastly, an accurate and timely diagnosis helps set realistic expectations for both parents and healthcare providers regarding treatment efficacy and prognosis.

I want to underscore Dr. Wirrell’s comments about an early diagnosis leading to earlier treatment initiation, more targeted treatments, and better long-term outcomes. There is evidence supporting better outcomes when definitive treatment begins sooner. Although treatments may not work for everyone, having the opportunity to try appropriate interventions earlier is valuable.

Conclusion

In conclusion, the diagnosis and management of rare forms of epilepsy syndromes present significant challenges for healthcare providers. However, with advancements in genetic testing, improved diagnostic tools, and a growing understanding of these conditions, there is hope for better patient outcomes. For example, the Refractory Epilepsy Screening Tool for LGS (REST-LGS) is a validated screening tool that can help healthcare providers who don’t encounter many LGS patients identify and diagnose the condition.

General neurologists and pediatricians play a crucial role in recognizing early signs and symptoms, and collaboration with epilepsy specialists is essential. The importance of thorough patient history, video documentation of seizures, and appropriate EEG interpretation cannot be overstated. As research progresses and new therapies emerge, including potential disease-modifying treatments, the outlook for patients with rare epilepsies continues to improve. By staying informed about the latest developments and guidelines, healthcare providers can make a meaningful difference in the lives of these patients and their families.

Maternal prenatal psychological distress and the development of epilepsy in offspring

Arai Y, Okanishi T, Masumoto T, Noma H, Maegaki Y; Japan Environment and Children’s Study Group. The impact of maternal prenatal psychological distress on the development of epilepsy in offspring: The Japan Environment and Children's Study. PLoS One. 2024 Nov 13;19(11):e0311666. doi: 10.1371/journal.pone.0311666. PMID: 39536042; PMCID: PMC11560057.

Abstract

The relationship between maternal prenatal psychological distress and epilepsy development in offspring has not yet been clarified. Herein, we used a dataset obtained from the Japan Environment and Children’s Study, a nationwide birth cohort study, to evaluate the association between six-item Kessler Psychological Distress Scale (K6) scores and epilepsy among 1–3 years old. The data of 97,484 children were retrospectively analyzed. The K6 was administered to women twice: during the first half (M-T1) and second half (M-T2) of pregnancy. M-T1 ranged from 12.3–18.9 (median 15.1) weeks, and M-T2 ranged from 25.3–30.1 (median 27.4) weeks. Participants were divided into six groups based on K6 scores of two ranges (≤4 and ≥5) at M-T1 and M-T2. The numbers of children diagnosed with epilepsy at the ages of 1, 2, and 3 years were 89 (0.1%), 129 (0.2%), and 149 (0.2%), respectively. A maternal K6 score of ≥5 at both M-T1 and M-T2 was associated with epilepsy diagnosis ratios among 1-, 2-, and 3-year-old children in the univariate analysis. Moreover, multivariate analysis revealed that a maternal K6 score of ≥5 at both M-T1 and M-T2 was associated with epilepsy diagnosis ratios among 1-, 2-, and 3-year-olds. Continuous moderate-level maternal psychological distress from the first to the second half of pregnancy is associated with epilepsy among 1-, 2-, and 3-year-old children. Hence, environmental adjustments to promote relaxation such as mindfulness in pregnant women might be necessary.

Chromosome 2q12.3-q13 copy number variants in patients with neurodevelopmental disorders

Inspired by a patient

Aarabi M, Baumann J, Babcock M, Kessler E, Sebastian J, Madan-Khetarpal S, Hu J, Ou Z, Yatsenko S. Chromosome 2q12.3-q13 copy number variants in patients with neurodevelopmental disorders: genotype-phenotype correlation and new hotspots. Psychiatr Genet. 2022 Oct 1;32(5):171-177. doi: 10.1097/YPG.0000000000000319. Epub 2022 Jul 15. PMID: 35837682.

Abstract

Introduction: The complex structure of the chromosome 2q12.3-q13 region provides a high chance of recombination events between various low copy repeats (LCRs). Copy number variants (CNV) in this region are present in both healthy populations and individuals affected with developmental delay, autism and congenital anomalies. Variable expressivity, reduced penetrance and limited characterization of the affected genes have complicated the classification of the CNVs clinical significance.

Methods: Chromosomal microarray analysis data were reviewed for 10 298 patients with neurodevelopmental disorders referred to the UPMC Medical Genetics and Genomics Laboratories. A genotype-phenotype correlation was performed among the patients harboring the 2q12.3-q13 CNVs with overlapping genomic intervals.

Results: We identified 17 (1 in ~600) individuals with rare CNVs in the 2q12.3-q13 region, including nine patients with deletions, seven individuals with duplications and one patient who had both a deletion and a duplication. Likely pathogenic CNVs with the breakpoints between LCRs encompassing the potential dosage-sensitive genes BCL2L11, BUB1, FBLN7 and TMEM87B were the most common. CNVs were also observed between LCRs surrounding the RANBP2 and LIMS1 genes.

Conclusion: Our study provides evidence for pathogenic CNV hotspots within the chromosome 2q12.3-q13 region. We suggest CNV classification based on the affected interval and the involvement of potential dosage-sensitive genes in these patients.

Huynh MT, Gérard M, Ranguin K, Pichon O, Ghesh L, Alfallaj K, Joubert M, Bézieau S, Bénéteau C. Novel interstitial 2q12.3q13 microdeletion predisposes to developmental delay and behavioral problems. Neurogenetics. 2021 Jul;22(3):195-206. doi: 10.1007/s10048-021-00653-6. Epub 2021 Jun 16. PMID: 34132911.

Abstract

Microarray-based comparative genomic hybridization (aCGH) is being increasingly applied to delineate novel genomic disorders and related syndromes in patients with developmental delay. In this study, detailed clinical and cytogenetic data of three unrelated patients with interstitial 2q12.3q13 microdeletion were described and compared with thirteen 2q12.3q13 microdeletion patients, gathered from the medical literature and public databases. 60 K aCGH analysis revealed three overlapping 2q12.3q13 microdeletions measuring 1.88 Mb in patient 1, 1.25 Mb in patient 2, and 0.41 Mb in patient 3, respectively. Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative real-time PCR. Variable clinical features of 2q12.3q13 microdeletion including microcephaly, prenatal growth retardation, developmental delay, short stature, behavioral problems, learning difficulties, skeletal anomalies, congenital heart defects, and features of ectodermal dysplasia were observed. The boundaries and sizes of the 2q12.3q13 deletions in the sixteen patients were different, but an overlapping region of 249 kb in 2q12.3 was defined. The SRO (smallest region of overlap) encompasses four genes, including LIMS1, RANBP2, CCDC138, and EDAR. Among these genes, RANBP2 is a strong candidate gene for neurological phenotype and genetic susceptibility to viral infections. To our knowledge, this is the first published report of 2q12.3q13 microdeletion syndrome and our observations strongly suggest that these recurrent CNVs may be a novel risk factor for developmental delay with variable expressivity and incomplete penetrance.

Favorable outcomes with givinostat in Duchenne muscular dystrophy

Givinostat (Duvyzat) had favorable outcomes in both functional tests and histological findings in patients with Duchenne muscular dystrophy (DMD) but not in those with the less severe form of the disease, Becker muscular dystrophy (BMD), according to a systematic review of drug trials presented in November at the Child Neurology Society annual meeting.

The drug, which the US Food and Drug Administration approved in February, is used to treat patients 6 years and older.

Three clinical trials—two of which tested the efficacy of givinostat in DMD and the other in BMD—included 250 total participants in the review, which was led by Roba Al Shouli of Al Qassimi Women and Children Hospital in United Arab Emirates. In the pivotal phase 3 EPIDYS trial involving DMD, which led to the drug's approval, patients treated with givinostat showed significantly less decline on the primary endpoint, the standard timed four-stair climb test, compared with the placebo group after 18 months of treatment. The mean change from baseline to month 18 in time to climb four stairs was 1.25 seconds for patients receiving givinostat compared with 3.03 seconds for patients receiving placebo. The givinostat cohort also experienced less worsening on the secondary efficacy endpoint, the change from baseline to month 18 in physical function as assessed by the North Star Ambulatory Assessment, but that difference did not reach statistical significance.

“Without the dystrophin protein, the muscle cell membranes are vulnerable to injury, and over time, the inflammatory process within injured muscle tissue results in replacement by fat and fibrosis. As a consequence of this, boys with DMD experience relentlessly progressive muscle weakness. Since the 1970s, we have been treating boys with DMD with prednisone in an attempt to decrease this inflammation and slow the progression of muscle weakness," said Jessica Nance, MD, assistant professor of neurology and director of the pediatric neuromuscular clinical trials group at Johns Hopkins University in Baltimore, who was not involved in the study. “

Because prednisone has a lot of undesirable systemic side effects, research has focused on finding other drugs that decrease muscle degeneration and slow the progression of weakness in a more targeted way. Givinostat is a histone deacetylase inhibitor that appears to target the pathways that promote replacement of muscle with fat and fibrosis in Duchenne muscular dystrophy."

That theory is supported by additional findings from EPIDYS, which also included MR spectroscopy studies in a subset of patients and found reduced fat fraction of the vastus lateralis muscle in patients treated with givinostat. It also correlated with findings from another 2016 study included in the review, which primarily investigated givinostat's histological effect in DMD and found that it increased the fraction of muscle tissue by 29.1 percent and cross-sectional area by 77 percent while reducing the amount of necrosis by 43.5 percent and fatty replacement by 37.5 percent.

“This is striking data in support of the medicine helping to decrease muscle degeneration," Dr. Nance said. “Anything we can do to slow the progression of weakness is beneficial. In doing so, we may allow boys to walk longer, and it may give families more time to prepare emotionally and practically for the transition to a power wheelchair."

The systematic review noted that an additional 2023 trial of givinostat in BMD found no effect on mean total fibrosis, which did not change in either the treatment or placebo group. The two groups did not differ at month 12 (least squares mean difference 1.04 percent; p=0.8282). But this partly may be because of the relatively slow progression of BMD as well as its much more variable presentation.

“It's a milder form of the disease and a much broader phenotype," Dr. Nance said. “Because progression of weakness may be slower in Becker, you may not be able to demonstrate efficacy over the same period of time that you can with Duchenne. Given the combination of the functional and imaging results showing the drug's efficacy, and the fact that the overall underlying pathophysiologic process is the same in BMD as in DMD, I think it's reasonable to assume we can extrapolate efficacy. The difficulty is often related to medication side effects; for drugs with a more problematic side effect profile—like the significant weight gain, osteopenia, and behavioral issues associated with long-term prednisone treatment —those side effects might outweigh any potential benefit."

But givinostat has a much more limited side effect profile, with the most commonly reported adverse events being gastrointestinal in nature, typically loose stools and diarrhea. “That is something more inconvenient than dangerous, and it can usually be ameliorated by dose adjustments," Dr. Nance said. High levels of triglycerides and the potential for low platelet counts are the other side effects of most concern with givinostat and require close monitoring. “Overall, this might be a good drug for Becker, but we need to think about how we can better demonstrate its efficacy," she added.

However, givinostat's average annual cost of $700,000 is a major shift from the extremely inexpensive prednisone. “Getting this medication approved by insurance is labor intensive, requiring prior authorization and often multiple appeals, but it's worth it if we can help these boys stay even a little bit stronger for longer," Dr. Nance said. “Though we are not yet able to provide a cure for Duchenne muscular dystrophy, it's been satisfying to be on this frontier. Because of these new therapies, my conversations with patients and their parents are much more hopeful than they were five or 10 years ago."

Child Neurology Society Abstract 295: Al Shouli R, Sohal A. The efficacy of givinostat in patients with muscular dystrophy: A systematic review.​

https://journals.lww.com/neurotodayonline/blog/NeurologyTodayConferenceReportersCNSAnnualMeeting/pages/post.aspx?PostID=66

Clinical factors associated with genetic diagnosis in suspected neurogenetic disorders

Wong NR, Klomhaus A, Adams DJ, Schneider BN, Mehta S, DiStefano C, Wilson RB, Martinez-Agosto JA, Jeste SS, Besterman AD. Clinical factors associated with genetic diagnosis in suspected neurogenetic disorders in a tertiary care clinic. Genet Med. 2024 Oct 10:101252. doi: 10.1016/j.gim.2024.101252. Epub ahead of print. PMID: 39395029.

Abstract

Purpose: This study aimed to identify phenotypic factors associated with genetic diagnoses in patients with neurodevelopmental disorders and generate a decision tree to assist clinicians in identifying patients most likely to receive a positive result on genetic testing.

Methods: We retrospectively reviewed the charts of 316 patients evaluated in a neurodevelopmental clinic between 2014 and 2019. Patients were categorized based on genetic test results. Analyses were performed to identify variables that discriminate between patients with and without a genetic diagnosis.

Results: Patients with a genetic diagnosis were more likely to be female and have a history of motor delay, hypotonia, congenital heart disease, and early intervention. Classification and regression tree analysis revealed that 75% of patients with motor delay had a genetic diagnosis. In patients without motor delay, hypotonia, age of walking, and age at initial evaluation were important indicators of a genetic diagnosis.

Conclusion: Our findings suggest that motor delay and hypotonia are associated with genetic diagnoses in children with neurodevelopmental disorders. The decision tree highlights patient subsets at greater risk and suggests possible phenotypic screens. Future studies could develop validated decision trees based on phenotypic data to assist clinicians in stratifying patients for genetic testing.  

___________________________________________________________________

Article In Brief

A chart review of 316 children and adolescents revealed that mild to severe motor delays and being female strongly predicted that testing would show the existence of a genetic mutation. And while genetic testing is now more common, disparities in access to those tests remain.

Children with neurodevelopmental delays who tested positive for a genetic mutation were more likely to be female and have a history of motor delays, low muscle tone, congenital heart disease, and a history of early interventions, according to an Oct.10 study in Genetics in Medicine.

Neurodevelopmental specialists at the Care and Research in Neurogenetics (CARING) Clinic at the University of California, Los Angeles, who carried out the chart review of 316 children and adolescents, said that genetic testing of children with these phenotypic factors is important in understanding the cause of their delays. These children also could be referred to clinical studies of these rare genetic variations that could ultimately lead to targeted treatments.

“One of the goals in neurodevelopmental medicine is to move into a more personal approach for each of our patients,” said Aaron D. Besterman, MD, health sciences associate clinical professor in the department of psychiatry at the University of California in San Diego. He was previously a neurodevelopmental genetics fellow at UCLA, where the work was carried out. A child and adolescent psychiatrist, Dr. Besterman is now a clinical investigator at the Rady Children's Institute for Genomic Medicine.

“Genetic testing allows us to identify a specific genetic cause,” he said, adding it is now standard of practice to order genetic testing and family counseling for children with developmental disorders. But insurance companies still have a say in what genetic tests they will pay for, and there remains a lot of variability in genetic testing, he noted.

The children and young adults ultimately seen at the CARING clinic are sicker and have complex histories, said Dr. Besterman. The families are desperate and welcome a detailed genetic screen to figure out the cause of their child's disabilities.

“Initially, the question we asked ourselves was whether we were recruiting patients into the CARING clinic because we thought they had a genetic disorder or whether there were clinical characteristics in children with an identified genetic disorder,” he said.

They were able to identify unique factors in those who tested positive on a genetic screen, which he said “should help clinicians decide who should be prioritized for genetic testing.”

It is now suspected that at least 30 percent of children with a neurodevelopmental disorder, including autism, intellectual disability, and global developmental delay, would have a positive genetic test. Hundreds of rare genetic variants are tied to these disorders. Genetic testing is now more common, but disparities in access to testing remain.

Chromosomal microarray (CMA) can identify copy-number variants, which seem responsible for 10 to 20 percent of children with neurodevelopmental problems. Exome sequencing (ES) also identifies single-nucleotide variants and can bring a diagnostic yield of more than 40 percent if both tests are ordered. Patients with a genetic disorder often have other medical problems, including gastrointestinal mobility, epilepsy, heart disease, and kidney/urinary problems, that factor into the level of care they require. This is the first study looking at risk factors for a genetic diagnosis conducted in tertiary care centers, said Dr. Besterman.

“There have been other studies that tested a broader population of children with neurodevelopmental disabilities, and our small study replicated the findings from these larger studies. Motor delays, mild to severe, and being female strongly predicted a positive genetic finding,” the child psychiatrist said.
Study Design, Findings

The UCLA team conducted a chart review on 316 patients seen at the CARING clinic from 2014 to 2019, separating children and young adults based on the results—positive or negative—of their genetic tests. Then, the scientists used a computer model to identify phenotypic variables in those with and without a genetic diagnosis. (There was incomplete genetic testing in 70 patients, and they were not part of the analysis.) Their charts included information on when the children sat up, crawled, and walked. They looked for language delays, including when the children said their first word (after a year) and phrase (after two years); whether the electronic medical record included a history of motor delay, hypotonia, seizures, congenital heart, any neurological diagnosis, ADHD, macrocephaly, microcephaly, or abnormal head circumference; and whether they were referred for early intervention and if they were younger than 3 years old at the time.

Of the 246 patients with completed genetic testing, 152 patients (61.8 percent) were found to have a genetic variant. There were 62 genetic diagnoses based on the testing. Only a dozen genetic conditions were shared by two or more patients.

The most robust differences between those who tested positive and those who didn't were being female and having a history of motor delays. In this population, 75 percent of patients with motor delays had a genetic diagnosis. Even without having a formal motor delay, those with hypotonia, the age at which they started walking, and an earlier age of intervention were also important indicators of a positive genetic test. (The scientists created three cohorts: those who tested positive, those who tested negative, and others who tested negative if they had CMA and ES genetic tests.) The genetic tests varied in the cohort, including CMA, FMR1 CGG repeat analysis, metabolic testing, PTEN testing, mitochondrial DNA testing, and MECP2 testing. Thirty-three of the negative cohort group also had ES testing. Interestingly, for every month's delay in walking (recalled by the caregiver), the child's chance of having a positive genetic test increased by 5 to 11 percent. A history of hypotonia, congenital heart disease, and early intervention also independently increased the odds of having a positive genetic test. Language delays were also associated with a higher risk for a genetic mutation.

The scientists did not observe differences between the two negative cohorts. When they looked at the genetic tests, they found that people living in lower socioeconomic neighborhoods were less likely to have had an ES test. This test is more expensive, insurance companies might deny coverage, and the families might not have the means to pay for genetic testing.

The CARING clinic was launched by Julian Antonio Martinez, MD, PhD, associate professor in the department of human genetics and the department of pediatrics at UCLA, and Shafali Spurling Jeste, MD, chief of the division of neurology and co-director of the Neurological Institute at Children's Hospital Los Angeles, to offer more help to children with neurodevelopmental problems. Dr. Jeste also is a professor of neurology and pediatrics at the Keck School of Medicine of the University of Southern California.

The clinician-scientists said a more extensive prospective study is necessary to replicate the findings. If genetic testing resources are limited, then knowing who is at higher risk—in this case, girls with motor deficits—will help decide who would benefit most from genetic testing. Now, whole genome sequencing is available, and older tests might not be necessary.

Neurodevelopmental specialists believe that knowing that there is a genetic explanation for their child's symptoms is important for families. “Clinicians can explain to families that there is a genetic reason why their child has the symptoms they do. While insurance companies by law can't discriminate against a genetic illness, life insurance companies can,” Dr. Besterman said. He recommends that families who want life insurance make arrangements before genetic testing.

https://journals.lww.com/neurotodayonline/fulltext/2024/12050/clinical_factors_that_preclude_genetic_testing_in.3.aspx/?cid=eTOC+Issues.2024-neurotodayonline

GM3 synthase deficiency

Inspired by a patient

Cruz V, Xin B, Wang H. GM3 Synthase Deficiency. 2023 Jul 20. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 37471511.

Excerpt

Clinical characteristics: Early clinical features of GM3 synthase deficiency include infantile onset of severe irritability with feeding difficulties, early and intractable seizures, growth failure with acquired microcephaly, sensorineural hearing impairment, hypotonia, and poor visual function. Over time, affected individuals experience severe-to-profound developmental delay and intellectual disability, can develop dystonia with hyperkinetic movements, and may develop pigmentary skin changes of the hands and feet. Affected individuals often have frequent ear infections and pneumonia without evidence of immune dysfunction.

Diagnosis/testing: The diagnosis of GM3 synthase deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in ST3GAL5 identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment for new-onset or worsening irritability is based on identification of inciting factors; for example, motility agents for constipation, antibiotic treatment of infections, and standard therapies for GERD, such as proton pump inhibitors. Seizures are treated with anti-seizure medication (ASM), although the majority of electrographic seizures in affected children are clinically silent. No ASM has been demonstrated effective for this condition specifically, ASM treatment may be only partially effective, and multiple ASMs may be required. Feeding therapy may be useful, with consideration of gastrostomy tube placement for persistent poor feeding / growth failure. Hearing aids may be helpful on a case-by-case basis. There is no specific treatment for optic atrophy or cortical blindness, although referral to low vision services is recommended. Dystonia, developmental delay / intellectual disability, sleep disturbances, infectious illnesses, and scoliosis are treated per standard methods.

Surveillance: At each visit: measure growth parameters, evaluate status and safety of oral intake, monitor for new manifestations (seizures, changes in tone, movement disorders), monitor developmental progress, assess for behavioral changes (new-onset or worsening irritability; aggressive or self-injurious behaviors), monitor for constipation/GERD/emesis, monitor for signs/symptoms of pneumonia, and obtain a non-invasive SpO2. Annually: physical exam for signs/symptoms of scoliosis. As clinically indicated: Audiologic evaluation, ophthalmologic evaluation, and assessment of mobility, physical medicine, and OT/PT needs.

Therapies under investigation: Oral supplementation with GM3 gangliosides did not alter disease course and demonstrated only modest short-term benefit to affected individuals.

Genetic counseling: GM3 synthase deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ST3GAL5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the ST3GAL5 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Yang H, Brown RH Jr, Wang D, Strauss KA, Gao G. Rescue of GM3 synthase deficiency by spatially controlled, rAAV-mediated ST3GAL5 delivery. JCI Insight. 2023 May 8;8(9):e168688. doi: 10.1172/jci.insight.168688. PMID: 37014712; PMCID: PMC10243808.

Abstract

GM3 synthase deficiency (GM3SD) is an infantile-onset epileptic encephalopathy syndrome caused by biallelic loss-of-function mutations in ST3GAL5. Loss of ST3GAL5 activity in humans results in systemic ganglioside deficiency and severe neurological impairment. No disease-modifying treatment is currently available. Certain recombinant adeno-associated viruses (rAAVs) can cross the blood-brain barrier to induce widespread, long-term gene expression in the CNS and represent a promising therapeutic strategy. Here, we show that a first-generation rAAV-ST3GAL5 replacement vector using a ubiquitous promoter restored tissue ST3GAL5 expression and normalized cerebral gangliosides in patient-derived induced pluripotent stem cell neurons and brain tissue from St3gal5-KO mice but caused fatal hepatotoxicity when administered systemically. In contrast, a second-generation vector optimized for CNS-restricted ST3GAL5 expression, administered by either the intracerebroventricular or i.v. route at P1, allowed for safe and effective rescue of lethality and behavior impairment in symptomatic GM3SD mice up to a year. These results support further clinical development of ST3GAL5 gene therapy.

Wang AS, Kilbane C. Dystonia Due to GM3 Synthase Deficiency. Mov Disord Clin Pract. 2022 Jan 5;9(2):236-239. doi: 10.1002/mdc3.13399. PMID: 35146061; PMCID: PMC8810422.

Abstract

Background: Gangliosides are expressed in neuronal membranes, and play roles in neuronal differentiation and cell regulation during brain development. The ST3GAL5 gene encodes the enzyme GM3 synthase, and its deficiency causes a rare condition described to cause refractory epilepsy, profound intellectual disability, quadriplegia, choreoathetosis, and pigmentary skin changes. GM3 synthase deficiency is rarely reported to cause dystonia. We report five cases of GM3 synthase deficiency involving a dystonic phenotype.

Cases: The five reported individuals were born of unaffected consanguineous parents from Old Order Amish families. They all developed refractory epilepsy and developmental regression within the first few months of life. They exhibit variable degrees of extrapyramidal movements, including orofacial, cervical, and limb dystonia, as well as choreoathetosis.

Conclusions: We report five individuals with GM3 synthase deficiency who developed dystonic features. Dystonia has previously been reported in only one case of GM3 synthase deficiency.

Heide S, Jacquemont ML, Cheillan D, Renouil M, Tallot M, Schwartz CE, Miquel J, Bintner M, Rodriguez D, Darcel F, Buratti J, Haye D, Passemard S, Gras D, Perrin L, Capri Y, Gérard B, Piton A, Keren B, Thauvin-Robinet C, Duffourd Y, Faivre L, Poe C, Pervillé A, Héron D, Thévenon J, Arnaud L, LeGuern E, La Selva L, Vetro A, Guerrini R, Nava C, Mignot C. GM3 synthase deficiency in non-Amish patients. Genet Med. 2022 Feb;24(2):492-498. doi: 10.1016/j.gim.2021.10.007. Epub 2021 Nov 30. PMID: 34906476.

Abstract

Purpose: Biallelic loss-of-function variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD) responsible for Amish infantile epilepsy syndrome. All Amish patients carry the homozygous p.(Arg288Ter) variant arising from a founder effect. To date only 10 patients from 4 non-Amish families have been reported. Thus, the phenotypical spectrum of GM3SD due to other variants and other genetic backgrounds is still poorly known.

Methods: We collected clinical and molecular data from 16 non-Amish patients with pathogenic ST3GAL5 variants resulting in GM3SD.

Results: We identified 12 families originating from Reunion Island, Ivory Coast, Italy, and Algeria and carrying 6 ST3GAL5 variants, 5 of which were novel. Genealogical investigations and/or haplotype analyses showed that 3 of these variants were founder alleles. Glycosphingolipids quantification in patients' plasma confirmed the pathogenicity of 4 novel variants. All patients (N = 16), aged 2 to 12 years, had severe to profound intellectual disability, 14 of 16 had a hyperkinetic movement disorder, 11 of 16 had epilepsy and 9 of 16 had microcephaly. Other main features were progressive skin pigmentation anomalies, optic atrophy or pale papillae, and hearing loss.

Conclusion: The phenotype of non-Amish patients with GM3SD is similar to the Amish infantile epilepsy syndrome, which suggests that GM3SD is associated with a narrow and severe clinical spectrum.

Dravet syndrome gene therapy shows reduction in motor seizure frequency

A new gene therapy treatment for Dravet syndrome, a severe developmental and epileptic encephalopathy in children, is the first to show a reduction in motor seizure frequency, according to findings presented in November at the Child Neurology Society annual meeting in San Diego.

The study of an antisense oligonucleotide (ASO) therapy, which involved an increasing dose of STK-001 (Zorevunersen), produced encouraging results that offer hope to patients and their loved ones, the researchers said.

The phase 1/2a study was designed to allow participants to receive the treatment in a dose-escalating manner to ensure safety and tolerability as the primary endpoint, said lead author Joseph E. Sullivan, MD, FAES, professor of neurology and pediatrics at the University of California, San Francisco. The first dose started at 10 mg and then increased in a stepwise manner up to 70 mg, he said.

Researchers analyzed the safety, tolerability, and clinical impact of intrathecally (IT) administered STK-001 in 81 patients with DS between ages 2 and 18 years with recurrent seizures and a confirmed SCN1A variant. Their seizures were resistant to standard treatments, with ongoing convulsive seizures occurring despite the fact that 85 percent of participants took at least three antiseizure medications and 54 percent took four or more.

According to a press release from Stoke Therapeutics, which developed the treatment, there were median reductions of 85 percent (n=10) at three months and 74 percent (n=9) at six months after the last dose. Single and multiple doses of up to 70 mg of STK-001 were generally well tolerated, researchers wrote.

Patients treated with at least one initial dose of 70 mg “demonstrated substantial and sustained reductions in convulsive seizure frequency," according to the study abstract. Children receiving ongoing treatment in an open label extension demonstrated both reductions in seizure frequency and “clinically meaningful improvements" in both cognition and behavior measures after a year. Researchers hoped STK-001 would have this kind of impact, Dr. Sullivan said.

“There was hope based on the pre-clinical data in the mouse model that if we can up-regulate the amount of functioning NAV 1.1 channel, that not only would that translate into a significant reduction in seizures but also start to show some improvements in some of the other non-seizure related comorbidities as well as survival," he said.

In his presentation at CNS, Dr. Sullivan acknowledged that 30 percent of the patients experienced a study drug-related adverse event, most commonly elevated cerebrospinal fluid proteins (13.6 percent) and procedural vomiting (4.9 percent); 22% of patients experienced a treatment-emergent serious adverse event, although all but one were unrelated to the study drug.

The results could have important implications for other disorders, said Orrin Devinsky, MD, FAAN, a professor in the departments of neurology, neurosurgery, and psychiatry at NYU Grossman School of Medicine and an epileptologist at the Comprehensive Epilepsy Center at NYU Langone Health, who was not involved in the study.

“The initial data is very promising, and since this ASO promises to address the underlying problem—too little of the Nav1.1 protein produced by the SCN1A gene—it has the potential to be truly disease-modifying and provide benefits beyond seizure control, in other domains such as cognition and coordination," he wrote in an email. “Stopping seizures can improve cognition. Fenfluramine is a very effective drug to reduce convulsive seizures in Dravet syndrome patients and, likely through this reduction in seizures, led to significant improvements in cognition and behavior in many patients."

The next stage is a phase 3 trial with a larger cohort and a sham procedure in which patients will receive a lumbar puncture but no drug, said Dr. Sullivan. With most conventional anti-ASM trials, it takes about three months to know if the intervention is effective. It may take longer for the gene upregulation and protein production to happen with the ASO treatment, so it could take longer to understand the full benefit from a seizure and non-seizure comorbidity standpoints in the next phase of the study, he said.

“The primary endpoint is focused on seizure reduction, but we also want to understand if the development also improves in the group that's being treated, and that's also informing the clinical trial design in terms of the duration of the clinical trial," he said.

David A. Gloss, MD, FAAN, a neurologist specializing in epilepsy and neurophysiology at the NeuroMedical Center in Baton Rouge, LA, said that using STK-100 to replace a missing/malfunctioning protein makes a lot of sense physiologically, as it tries to improve the underlying abnormality. The challenge with ASO treatments is that they have not been tested on the wider population, focusing mainly on patients with rare diseases, so the true frequency and seriousness of adverse effects are not known very well.

However, he said, caregivers of those with Dravet syndrome should feel hopeful.

“There may be a new drug on the horizon," Dr. Gloss said by email. “This presentation combined four phase 1/2 trials, showing relative safety, but there are no guarantees that it will be able to come to market eventually."

Dr. Devinsky said many families are waiting and hoping for the next stage of the trial.

“The Dravet community of patients, families, physicians, and scientists are all rooting hard for this gene therapy to transform the landscape of care for this terrible and potentially deadly disease," he said.

https://journals.lww.com/neurotodayonline/blog/NeurologyTodayConferenceReportersCNSAnnualMeeting/pages/post.aspx?PostID=62

PL1-1. Safety and Clinical Effects of STK-001, an Antisense Oligonucleotide (ASO), in Children and Adolescents with Dravet Syndrome: Phase 1/2a End of-Study and Open-label Extension (OLE) Data Sullivan J (San Francisco, CA), Cross H, Laux L, Perry S, Desurkar A, Schreiber J, Roberts C, Knupp K, Wheless J, Wirrell E, Wang F, Parkerson K, Ticho B.

OBJECTIVE: DS is a severe and progressive genetic epilepsy that is typically caused by spontaneous, heterozygous loss of-function SCN1A gene mutations, which encode the Nav1.1 protein. STK-001 is an investigational ASO that exploits modulation of pre-mRNA to upregulate functional brain Nav1.1 expression by leveraging the wild-type copy of SCN1A to restore physiological protein levels. 

METHODS: Phase 1/2a studies, MONARCH (US) and ADMIRAL (UK), with the SWALLOWTAIL (US) and LONGWING (UK), assessed safety, tolerability, plasma pharmacokinetics, CSF exposure, and clinical effect of intrathecally (IT) administered STK-001 in patients with DS aged 2-18y. Patients have disease onset <12 months old with recurrent seizures and confirmed SCN1A variant. Adverse Events were monitored continuously. 

RESULTS: 81 patients received ≥1 dose of STK-001 (10-70mg/dose). Patients were highly refractory to standard treatments with ongoing convulsive seizures despite 85% taking ≥3 ASMs and 54% taking ≥4 ASMs. Patients treated with ≥1 initial dose of 70mg demonstrated substantial and sustained reductions in convulsive seizure frequency. Patients receiving ongoing OLE treatment (30 or 45mg/4 months) demonstrated durable reductions in convulsive seizure frequency and clinically meaningful improvements in multiple measures of cognition and behavior through month 12. Single and multiple doses of up to 70 mg STK-001 was generally well-tolerated across these studies. 

CONCLUSIONS: STK-001 has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome.