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.