CSNK2B-related neurodevelopmental syndrome (Poirier-Bienvenu) 2

Li D, Zhou B, Tian X, Chen X, Wang Y, Hao S, Zhang C, Hui L. Genetic analysis and literature review of a Poirier-Bienvenu neurodevelopmental syndrome family line caused by a de novo frameshift variant in CSNK2B. Mol Genet Genomic Med. 2024 Jan;12(1):e2327. doi: 10.1002/mgg3.2327. Epub 2023 Nov 30. PMID: 38037515; PMCID: PMC10767686.

Abstract

Background: Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) is a rare autosomal dominant neurologic disorder caused by a heterozygous variant of CSNK2B, which is characterized by early onset epilepsy, hypotonia, varying degrees of intellectual disability (ID), developmental delay (DD), and facial dysmorphism. This study clarifies the molecular diagnosis and causative factors of a Chinese boy with POBINDS.

Methods: The clinical phenotypes and ancillary laboratory tests were collected and analyzed by trio whole exome sequencing (WES) and copy number variant sequencing (CNV-seq) in the follow-up proband's families. The candidate variant was validated by Sanger sequencing and bioinformatics software was used to further explore the effect of the de novo frameshift variant on the protein structure.

Results: The proband carries a de novo frameshift variant c.453_c.454insAC (p.H152fs*76) in CSNK2B. According to the ACMG genetic variant classification criteria and guidelines, the locus is a pathogenic variant (PVS1+PS2+PM2) and the associated disease was POBINDS. Protein structure prediction suggests significant differences in amino acid sequences before and after mutation.

Conclusion: A rare case of POBINDS caused by a novel frameshift variant in CSNK2B was diagnosed. The novel variant extends the variation spectrum of CSNK2B, which provides guidance for early clinical diagnosis, genetic counseling and treatment of this family. A review of the currently reported cases of POBINDS further enriches and summarizes the relationship between genotype and phenotype of POBINDS.

Trivisano M, Dominicis A, Stregapede F, Quintavalle C, Micalizzi A, Cappelletti S, Dentici ML, Sinibaldi L, Calabrese C, Terracciano A, Vigevano F, Novelli A, Specchio N. Refining of the electroclinical phenotype in familial and sporadic cases of CSNK2B-related Neurodevelopmental Syndrome. Epilepsy Behav. 2023 Oct;147:109436. doi: 10.1016/j.yebeh.2023.109436. Epub 2023 Sep 15. PMID: 37717460.

Abstract

CSNK2B encodes a regulatory subunit of casein kinase II, which is highly expressed in the brain. Heterozygous pathogenic variants in CSNK2B are associated with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) (OMIM #618732), characterized by facial dysmorphisms, seizures, intellectual disability, and behavioral disturbances. We report ten new patients with CSNK2B-related Neurodevelopmental Syndrome associated with heterozygous variants of CSNK2B. In three patients, a pathogenic variant was inherited from an affected parent. We describe both molecular and clinical features, focusing on epileptic and neurodevelopmental phenotypes. The median age at follow-up was 8.5 years (range 21 months-42 years). All patients had epilepsy, with onset at a median age of 10.5 months range 6 days-10 years). Seizures were both focal and generalized and were resistant to anti-seizure medications in two out of ten patients. Six patients had mild to moderate cognitive delays, whereas four patients had no cognitive disability. Although all previously reported patients had a de novo CSNK2B pathogenic variant, here we report, for the first time, two familial cases of CSNK2B-related Neurodevelopmental Syndrome. We confirmed the highly variable expressivity of the disease among both interfamilial and intrafamilial cases. Furthermore, this study provides information about the long-term outcome in adult patients and underlines the importance of detailed family history collection before performing genetic testing in patients with epilepsy and neurodevelopmental disorders.

Drive through awake kidney transplant

Kidney transplants are not uncommon — the kidney is actually the most frequently transplanted organ in the U.S. — but a Chicago man recently received his in a highly unusual way.

John Nicholas, 28, was awake during the entire procedure, which was performed on May 24 at Northwestern Medicine Hospital. He was discharged the very next day.

Doctors administered a spinal anesthesia shot — similar to what is used for a Cesarean section — instead of general anesthesia, according to a press release from the hospital.

"This is the first case at Northwestern Medicine where a patient was awake during an entire kidney transplant procedure and went home the next day, basically making this an outpatient procedure," said Satish Nadig, M.D., PhD, transplant surgeon and director of the Northwestern Medicine Comprehensive Transplant Center, in the release.

"Inside the operating room, it was an incredible experience being able to show a patient what their new kidney looked like before placing it inside the body," he added.

"It was incredibly simple and uneventful."

This type of "awake transplant" could reduce surgical risks and shorten the length of the patient’s hospitalization, doctors say.

"It was an incredible experience, being able to show a patient what their new kidney looked like before placing it inside the body."

It could also increase access to care for patients who are considered high-risk or have phobias surrounding general anesthesia.

He was considered an ideal patient for awake surgery due to his young age, his otherwise good health and his "eagerness to participate," per the release.

"It was a pretty cool experience to know what was happening in real time and be aware of the magnitude of what they were doing," said Nicholas in a statement to Northwestern.

"At one point during surgery, I recall asking, ‘Should I be expecting the spinal anesthesia to kick in?’ They had already been doing a lot of work and I had been completely oblivious to that fact. Truly, no sensation whatsoever."

Although Nicholas did receive sedation for comfort, he said he was still aware of what was going on.

"Especially when they called out my name and told me about certain milestones they had reached," he noted.

Nicholas walked out of the hospital on May 25, the day after surgery.

Nicholas’ kidney issues began at age 16 when he was diagnosed with Crohn’s disease, the release stated.

After a few years of managing the condition with medication, his kidney function worsened and he required a transplant.

Nicholas’ mother originally planned to donate her kidney, but a breast cancer diagnosis prevented her from doing so, the hospital relayed.

It was Nicholas’ best friend from elementary school, 29-year-old Pat Wise in Alexandria, Virginia, who ultimately donated the life-saving kidney.

Dr. Marc Siegel, clinical professor of medicine at NYU Langone Medical Center and a Fox News medical contributor, was not involved in the surgery but shared his input.

"My opinion is that in most cases, spinal anesthesia presents a reasonable alternative for those at high risk of general anesthesia complications," Siegel told Fox News Digital.

"Having said that, general anesthesia would be preferred whenever possible for major surgery like this," said Dr. Siegel, "because control of the airway and breathing is essential, and is much easier if the patient is asleep and on the ventilator."

The doctors at Northwestern credit the patient for helping to advance the field of transplant medicine.

"When John agreed to be the first known patient at Northwestern Medicine to undergo an awake kidney transplant and be discharged home the next day, he knew the benefits outweighed the risks, and … he’s now helping to move the field of transplantation forward," said Vinayak Rohan, M.D., transplant surgeon at Northwestern Memorial Hospital, in the release.

"He is an extremely compliant patient who was in tune with his body and willing to push the envelope," stressing that the patient had faith in the doctors and they, in turn, had faith in him.

The hospital now plans to establish the AWAKE Program (Accelerated Surgery Without General Anesthesia in Kidney Transplantation) for patients who want or need to pursue surgery without general anesthesia.

"It really opens up a whole new door and is another tool in our toolbelt for the field of transplantation," Nadig added.

https://www.foxnews.com/health/chicago-man-receives-kidney-transplant-fully-awake-goes-home-next-day

Posterior reversible encephalopathy syndrome in children with malignancies

Kiermasz A, Zapała M, Zwiernik B, Stręk-Cholewińska A, Machnikowska-Sokołowska M and Mizia-Malarz A (2023) Posterior reversible encephalopathy syndrome in children with malignancies – a single-center retrospective study. Front. Neurol. 14:1261075. doi: 10.3389/fneur.2023.1261075

Background: Posterior reversible encephalopathy syndrome (PRES) diagnosis relies on clinical and radiological characteristics. Clinical manifestations include focal neurologic deficits, hemiparesis, seizures with symptoms of intracranial hypertension, headache, nausea, vomiting, and visual field disturbances. The majority of patients have typical changes in magnetic resonance imaging. The epidemiology and outcomes of PRES in the pediatric cancer population have not been well described. Most of the available data are from retrospective analyses.

Objective: The aim of our study was to evaluate the clinical and radiological presentation as well as the outcome of PRES in children treated for cancers in a single center.

Methods: We analyzed data from 1,053 patients diagnosed with malignancies in a single center over 15 years to determine the incidence of PRES.

Results: 19/1053 (1.8%) patients developed PRES. The diagnosis was accompanied by a range of clinical symptoms including hypertension, seizures, altered mental status, and headaches. Magnetic resonance imaging was performed in all patients, and 14/19 (73.7%) exhibited typical findings consistent with PRES. Four patients (21.0%) required treatment in the Intensive Care Unit.

Conclusion:

1. Posterior reversible encephalopathy syndrome (PRES) is a rare but significant complication in children with cancer.

2. There is a clear need to establish clinical criteria for PRES to improve the diagnosis and treatment of patients with PRES, particularly in the pediatric oncological population.

3. Further studies are needed to identify the risk factors for recurrent PRES, particularly in pediatric cancer patients undergoing chemotherapy or immunosuppressive treatment.

Martin Pistorius 3

https://www.youtube.com/watch?v=JtLw5KXm09U

https://www.youtube.com/watch?v=WD1IX1AFRZg

https://www.youtube.com/watch?v=GaAp7Q-fFiw

See: https://childnervoussystem.blogspot.com/2018/07/martin-pistorius-2.html

https://childnervoussystem.blogspot.com/2015/04/an-aromatherapist-saw-something-in-his.html

Recommendations for the assessment and management of idiopathic intracranial hypertension in children

Amin S, Monaghan M, Forrest K, Harijan P, Mehta V, Moran M, Mukhtyar B, Muthusamy B, Parker A, Prabhakar P, Whitehouse WP, Krishnakumar D. Consensus recommendations for the assessment and management of idiopathic intracranial hypertension in children and young people. Arch Dis Child. 2024 May 9:archdischild-2023-326545. doi: 10.1136/archdischild-2023-326545. Epub ahead of print. PMID: 38724065.

Abstract

Background: Idiopathic intracranial hypertension (IIH) is a potentially disabling condition. There is a lack of evidence and national guidance on how to diagnose and treat paediatric IIH, leading to variation in clinical practice. We conducted a national Delphi consensus via the Children's Headache Network to propose a best-practice diagnostic and therapeutic pathway.

Methods: The Delphi process was selected as the most appropriate methodology for examining current opinion among experts in the UK. 104 questions were considered by 66 healthcare professionals, addressing important aspects of IIH care: assessment, diagnosis, treatment, follow-up and surveillance. General paediatricians, paediatric neurologists, ophthalmologists, opticians, neuroradiologists and neurosurgeons with a clinical interest or experience in IIH, were invited to take part.

Results: The Delphi process consisted of three rounds comprising 104 questions (round 1, 67; round 2, 24; round 3 (ophthalmological), 13) and was completed between March 2019 and August 2021. There were 54 and 65 responders in the first and second rounds, respectively. The Delphi was endorsed by the Royal College of Ophthalmologists, which engaged 59 ophthalmologists for round 3.

Conclusions: This UK-based Delphi consensus process reached agreement for the management of paediatric IIH and has been endorsed by the Children's Headache Network and more broadly, the British Paediatric Neurology Association. It provides a basis for a pragmatic clinical approach. The recommendations will help to improve clinical care while minimising under and over diagnosis.

From the article:

Management: therapeutic LP

CSF pressure, if over 28 cm CSF (21 mm Hg) should be reduced down to 20–25 cm CSF (15–18 mm Hg).

The maximum number of (therapeutic) LPs a patient should have over the course of their illness is five, as other therapeutic options should be instigated before this point.

Management: weight management

A dietetic service should be available for weight management for patients with IIH.

Overweight or obese patients with IIH should be referred to a dietician for weight management or to a weight management team.

Management: first-line therapy in patients with IIH who do not have visual impairment

There was no consensus on medical management but the most selected answer by 46% of responders was that acetazolamide should be considered for all patients as first-line medical treatment, regardless of their BMI. This did not reach the threshold for consensus. The leading answer after ‘acetazolamide’ (46%) or ‘other’ (26%) was ‘information, general advice, safety netting but no drug treatment for now’ (18%). A minority of respondents supported topiramate (4%), no intervention (4%) or surgical approaches (2%).

Management: first-line therapy in patients with new visual impairment/loss of vision

If a patient is taking acetazolamide, blood urea, electrolytes and bicarbonate levels should be checked. Bicarbonate should be corrected when the value is equal to or lower than 18 mmol/L.

Management: second line

Repeated therapeutic LP should be offered when visual changes progress and there is a threat to vision on medical management and/or when symptoms are not responsive to medical management.

Management: neurosurgical

ICP bolt monitoring for 48 hours should be considered for patients with persistently raised LP opening pressure measurements (on two LPs) and papilloedema.

VSS should be considered if there is evidence of stenosis of the dominant venous sinus.

Recommendations for the assessment and management of Individuals With CDKL5 deficiency disorder

Amin S, Monaghan M, Aledo-Serrano A, Bahi-Buisson N, Chin RF, Clarke AJ, Cross JH, Demarest S, Devinsky O, Downs J, Pestana Knight EM, Olson H, Partridge CA, Stuart G, Trivisano M, Zuberi S, Benke TA. International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder. Front Neurol. 2022 Jun 20;13:874695. doi: 10.3389/fneur.2022.874695. PMID: 35795799; PMCID: PMC9251467.

Abstract

CDKL5 Deficiency Disorder (CDD) is a rare, X-linked dominant condition that causes a developmental and epileptic encephalopathy (DEE). The incidence is between ~ 1:40,000 and 1:60,000 live births. Pathogenic variants in CDKL5 lead to seizures from infancy and severe neurodevelopmental delay. During infancy and childhood, individuals with CDD suffer impairments affecting cognitive, motor, visual, sleep, gastrointestinal and other functions. Here we present the recommendations of international healthcare professionals, experienced in CDD management, to address the multisystem and holistic needs of these individuals. Using a Delphi method, an anonymous survey was administered electronically to an international and multidisciplinary panel of expert clinicians and researchers. To provide summary recommendations, consensus was set, a priori, as >70% agreement for responses. In the absence of large, population-based studies to provide definitive evidence for treatment, we propose recommendations for clinical management, influenced by this proposed threshold for consensus. We believe these recommendations will help standardize, guide and improve the medical care received by individuals with CDD.

From the article:

There were many areas of consensus recommendations identified. The majority of these are for completion at baseline. There is an emphasis upon holistic care, such as the monitoring of systemic functions and educational needs, with certain areas recommended to be reviewed, not only at baseline, but also annually and if clinically indicated. These included the monitoring of growth, the need for a regular review of feeding and swallowing, and non-specialist screening for respiratory difficulties.

A comprehensive neurological assessment is encouraged at baseline. The consensus recommendations are for the individual with CDD to be reviewed by a pediatric neurologist with experience in managing epilepsy, clinician discussion to inform families about the risk of SUDEP, completion of a baseline MRI and EEG, consideration for epilepsy surgery, screening for the presence of a movement disorder, registration with the CDKL5 international registry and a review of the individual's sleep. Despite limited published evidence on the use of novel antiseizure drugs for CDD in the literature, Ganaxolone and Epidiolex are encouraged to be offered for epilepsy associated with CDD, if clinically indicated, dependent on FDA and EMA approvals and legal and regulatory requirements, respectively.

Discussion

CDD is a debilitating condition where there is an urgent need for further development of management options. To achieve these necessary advances will require large scale and international, collaborative efforts to evaluate potentially effective interventions in sufficiently powered clinical trials. Progress will rely heavily on cooperation between international medical and scientific professionals, affected families, industry and funding organizations. The extensive experience of the author group includes those with direct experience in CDD management including authors of a clinically relevant CDD severity assessment tool. We hope that this survey adds to the current knowledge base concerning clinical aspects of care and provides a useful proposed standard of care elucidated by the agreed areas of consensus. These recommendations can support clinicians with less experience of CDD and act as a catalyst for further research that would aim to increase capacity for evidence-based management in CDD.

Dell'Isola GB, Antonella F, Francesco P, Mario M, Cordelli DM, Piero P, Pasquale P, Alessandro F, Operto FF, Maurizio E, Marco C, Dario P, Sara M, Elisabetta S, Alberto S, Giovanna S, Savasta S, Paolo P, Di Cara G, Fruttini D, Vincenzo S, Pasquale S, Alberto V. CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy. J Neurol. 2024 Jun 14. doi: 10.1007/s00415-024-12421-1. Epub ahead of print. PMID: 38874638.

Abstract

CDKL5 deficiency disorder (CDD) is a complex clinical condition resulting from non-functional or absent CDKL5 protein, a serine-threonine kinase pivotal for neural maturation and synaptogenesis. The disorder manifests primarily as developmental epileptic encephalopathy, with associated neurological phenotypes, such as hypotonia, movement disorders, visual impairment, and gastrointestinal issues. Its prevalence is estimated at 1 in 40,000-60,000 live births, and it is more prevalent in females due to the lethality of germline mutations in males during fetal development. This Italian multi-center observational study focused on 34 patients with CDKL5-related epileptic encephalopathy, aiming to enhance the understanding of the clinical and molecular aspects of CDD. The study, conducted across 14 pediatric neurology tertiary care centers in Italy, covered various aspects, including phenotypic presentations, seizure types, EEG patterns, treatments, neuroimaging findings, severity of psychomotor delay, and variant-phenotype correlations. The results highlighted the heterogeneity of seizure patterns, with hypermotor-tonic-spasms sequence seizures (HTSS) noted in 17.6% of patients. The study revealed a lack of clear genotype-phenotype correlation within the cohort. The presence of HTSS or HTSS-like at onset resulted a negative prognostic factor for the presence of daily seizures at long-term follow-up in CDD patients. Despite extensive polypharmacotherapy, including medications such as valproic acid, clobazam, cannabidiol, and others, sustained seizure freedom proved elusive, affirming the inherent drug-resistant nature of CDD. The findings underscored the need for further research to explore response rates to different treatments and the potential role of non-pharmacological interventions in managing this challenging disorder.

Benke TA, Demarest S, Angione K, Downs J, Leonard H, Saldaris J, Marsh ED, Olson H, Haviland I. CDKL5 Deficiency Disorder. 2024 Apr 11. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 38603524.

Excerpt

Clinical characteristics: CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe early-onset intractable epilepsy and motor, cognitive, visual, and autonomic disturbances. Movement disorders include chorea, dystonia, and stereotypical hand and leg movements.

Although females are more commonly affected than males (female-to-male ratio is approximately 4:1), the severity of manifestations in heterozygous females and hemizygous males can be equivalent. However, the severity of the phenotype can vary depending on the type and position of the CDKL5 pathogenic variant, pattern of X-chromosome inactivation in females, and presence of postzygotic mosaicism in males or females, who can have mild manifestations.

Diagnosis/testing: The diagnosis of CDD is established in a female proband with suggestive clinical findings and a heterozygous CDKL5 pathogenic variant identified by molecular genetic testing.

The diagnosis of CDD is established in a male proband with suggestive clinical findings and a hemizygous CDKL5 pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations: International consensus recommendations for the assessment and management of individuals with CDD have been published. The management of individuals with CDD is complex and requires multiple specialty evaluations; referral to a CDKL5 Center of Excellence may allow families to coordinate care more easily for affected individuals.

Targeted therapy: Ztalmy® (ganaxolone) is a targeted therapy for the treatment of epilepsy associated with CDD in individuals aged two years and older. This is the first approved treatment for seizures associated with CDD and the first treatment specifically for CDD.

Supportive care: Multidisciplinary care by specialists in the fields of pediatric neurology including pediatric epilepsy, feeding and nutrition, sleep disorders, behavioral disorders, orthopedics, physical therapy, occupational therapy, speech-language disorders, and genetic counseling.

Surveillance: Annual assessments by a medical home / primary care physician and specialists.

Genetic counseling: CDD is inherited in an X-linked manner. Approximately 99% of affected individuals represent simplex cases (i.e., a single occurrence in the family). The majority of individuals who represent simplex cases have the disorder as the result of a de novo germline or (rarely) postzygotic CDKL5 pathogenic variant. Rarely, an individual with CDD has the disorder as the result of a CDKL5 pathogenic variant inherited from a heterozygous or mosaic mother. If the mother of the proband has a CDKL5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype. Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected. Once the CDKL5 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

See: https://childnervoussystem.blogspot.com/2019/10/cdkl5-genetic-disorder.html

Electrographic seizures and EEG background features in pediatric neuro-oncology patients admitted to the pediatric intensive care unit

Pickup EES, Keenan JS, Packer RJ, Wells EM, Conley C, Staso K, Harrar DB, Sansevere AJ. Electrographic seizures and EEG background features in pediatric neuro-oncology patients admitted to the pediatric intensive care unit. Neuro Oncol. 2024 Jun 18;26(Suppl 4):0. doi: 10.1093/neuonc/noae064.682. PMCID: PMC11183668.

Abstract

BACKGROUND

Electrographic seizures (ES) are common in critically ill children with the incidence of ES ranging from 10-50%. Continuous EEG (cEEG) is frequently obtained in children with brain tumors due to encephalopathy or concern for seizures. Despite this, little is known about the incidence of ES, EEG background features, or the impact of EEG on clinical management in this population.

METHODS

This is a prospective single center study of critically ill children with brain tumors admitted to the pediatric intensive care unit (PICU) from July 2021 to July 2023. Patients with new or known primary brain tumors and cEEG completed during their admission were included. We excluded patients with planned admissions for EEG. Clinical variables included age, sex, oncologic diagnosis, tumor grade and location, indication for EEG, EEG features, and changes in management.

RESULTS

Thirty-six patients were identified who met the inclusion criteria. 21 patients were female. The median age was 11.0 years (IQR 6.6– 15.4 years). The most common indication for EEG was encephalopathy in 42% followed by clinical seizure in 31%. ES were captured in 19% (7/36) with the majority being subclinical; in patients with acute encephalopathy, ES were captured in 20% (3/15). The EEG background was abnormal in 97% of cases. The most common EEG background was slow disorganized with background asymmetry seen in in 74%. EEG background features met criteria for the ictal-interictal continuum in 14%. A higher rate of ES was seen in patients with disseminated tumors (p=0.03) and severe encephalopathy on EEG (p=0.006). EEG led to a change in management in 31% of patients.

CONCLUSIONS

ES are common in critically ill children with brain tumors and would go undetected without cEEG. EEG findings often led to a change in clinical management and is a vital tool for the evaluation of this population.

Acute disseminated encephalomyelitis

Background

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory demyelinating condition that predominately affects the white matter of the brain and spinal cord. The disorder manifests as an acute-onset encephalopathy associated with polyfocal neurologic deficits and is typically self-limiting. ADEM bears a striking clinical and pathological resemblance to other acute demyelinating syndromes (ADS) of childhood, including multiple sclerosis (MS). ADEM in children is readily distinguishable from alternative diagnoses on the basis of clinical features and findings on neuroimaging and laboratory investigations. However, given that ADEM lacks a specific identified biological marker rendering a reliable laboratory diagnosis, long-term follow-up is important as there are instances where an illness initially diagnosed as ADEM is ultimately replaced with a diagnosis of MS.

The onset of ADEM usually occurs in the wake of a clearly identifiable febrile prodromal illness or immunization and in association with prominent constitutional signs and encephalopathy of varied degrees. ADEM is typically a monophasic disease of pre-pubertal children; whereas, MS is typically a chronic relapsing and remitting disease of young adults. Abnormalities of findings on cerebrospinal fluid (CSF) immunoglobulin studies are less common in ADEM. However, the division between these processes is indistinct, suggesting a clinical continuum. Moreover, other conditions along the suggested continuum include optic neuritis, transverse myelitis, and neuromyelitis optica - clinical entities that may occur as manifestations of either MS or ADEM. Other boundaries of ADEM merge indistinctly with a wide variety of inflammatory encephalitic and vasculitic illnesses as well as monosymptomatic, postinfectious illnesses that should remain distinctfromADEM, such as acute cerebellar ataxia (ACA). A further indistinct boundary is shared by ADEM and Guillain-Barré syndrome as manifested in cases of Miller-Fisher syndrome and encephalomyeloradiculoneuropathy (EMRN).

Susceptibility to either ADEM or MS is likely the product of multiple factors, including a complex interrelationship of genetics and exposure to infectious agents and other environmental factors. Of particular interest are the indications that susceptibility to either condition is in part age-related. Most cases of ADEM possibly occur as the result of an inflammatory response provoked by pre-pubertal infection with a virus, vaccine, or other infectious agent. Typically, the manifestations of ADEM occur quickly after this pre-pubertal febrile systemic illness and are monophasic. In a minority of cases, patients with ADEM experience one or two pre-pubertal recurrences followed by remission. MS, on the other hand, typically manifests as a relapsing-remitting illness in ensuing adolescence or young adulthood, a significant and unexplained latency of effect with apparent permanency of immune dysregulation. Bouts of MS occur without a febrile prodrome. Uncommonly, MS develops in pre-pubertal individuals and ADEM develops in post-pubertal individuals. In very rare instances, individuals manifest pre-pubertal ADEM and, after long latency, MS in adolescence.

See more at: https://emedicine.medscape.com/article/1147044-overview

DEA training mandate: 8 hours of my life I'd like back

It's time to renew two of my three narcotic prescribing licenses. For the first time in my career, I've waffled on whether the financial outlay to the US Drug Enforcement Agency (DEA) is worth it. 

At $888 each, I've considered letting two licenses lapse because I only work part-time in Montana. But several friends advised me to keep a "spare" in case I transfer to a new location. 

I thought about just paying the fees until I could do a little more research, but there is no mechanism for a refund unless I die within the first year of the 3-year cycle, provide incorrect credit card digits, or accidentally duplicate payments.

The renewal fee is just part of the issue.

I also received an alert about the requirement for more "narcotics prescribing education" thanks to the Medication Access and Training Expansion Act (MATE). 

The requirement seems counterintuitive because opioid prescribing has decreased for the 10th consecutive year, according to the AMA Overdose Epidemic Report. The continuing rise in overdose deaths is largely due to illegitimate manufacturing of synthetic opioids. 

I've written zero outpatient narcotics prescriptions in the past 6 years, and I've written very few in my 33 years of practice. My use is limited to intravenous morphine for flash pulmonary edema or refractory angina, but unless you graduated from a training program within 5 years of the June 2023 mandate or are boarded in addiction medicine, there is no way to escape the 8-hour education requirement.

The problem is that these courses are never just 8 hours in duration. After signing up for one such CME course that cost $150, I was still dying of boredom and at risk for DVT 4 days later. That's how long it took to sit through.

Instead of the 30 seconds it should have taken to review the simple instructions to deliver Narcan, there were scores of screens followed by juvenile quizlets and cartoons. All but about 2 hours out of the 4 days is now relegated to that category of "hours of my life that I can never get back." Additionally, none of that mandatory "education" will change my prescribing habits one whit. 

Of course, I would always be truthful when asked to check the box on the DEA renewal application attesting to my having completed the required education. On the outside chance that you plan to check the yes box without completing the relevant courses, those found guilty of such false claims could be fined up to $250,000 and subject to "not more than four years in prison," or both. Yikes! 

Larry Houck, a former DEA investigator, explained that "[t]here are lot of people who are coming up for renewal and log on but still don't know this is a requirement." Neither ignorance nor complacency is an acceptable defense. 

The only good thing that came of those 4 long days of opioid education was a motivation to drive change in our current licensing and educational experience. Why not use this opportunity to reform the DEA-physician/prescriber relationship? 

The educational requirements should be curtailed for those of us who do not provide outpatient narcotic prescriptions even if we use inpatient opioids. Meds with low abuse potential should be rescheduled to minimize who gets caught in the broad net of the education requirement. 

We should reduce overregulation of the legitimate prescribers by lowering, instead of increasing, licensing fees. We should change to a single license number that covers every state. In this digital age, there is no legitimate excuse to prevent this from happening. 

After all, the settlements from opioid manufacturers and distributors will in time total $50 billion. It seems that at least some of the responsibilities of the DEA could shift to states, cities, and towns. 

My friend Siamak Karimian, MD, who provides locum services in multiple states, pays for seven active DEA licenses every 3 years. He pointed out the hypocrisy in the current regulatory system: "It's funny that you can have only one DEA or state license and work for the government in all other states or territories with no limits, including the VA, Indian healthcare systems, or prison systems."

All other prescribers require a separate DEA number for every state. Ultimately, you'd think tracking prescriptions for a single DEA number should be far simpler than tracking someone with seven. 

Competent physicians not guilty of criminal overprescribing seem to be the last to be considered in nearly every healthcare endeavor these days. It would be refreshing if they would reduce our fees and prevent this waste of our time. 

And while we are at it, perhaps a more fitting punishment is due for Richard Sackler and all the Purdue Pharma–affiliated family members. The Sacklers will pay out $6 billion in exchange for immunity against civil litigation. That doesn't seem like much when they are worth $11 billion. 

Perhaps they should be made to take an 8-hour course on opioid prescribing, annually and in perpetuity. Let's see them complete a few quizlets and sit through screens of instruction on how to administer Naloxone. Of course, that would be a mild punishment for those who manufactured a drug that killed hundreds of thousands. But it would be a start. 

https://www.medscape.com/viewarticle/dea-training-mandate-8-hours-my-life-id-back-2024a1000avg

Auto-brewery syndrome 2

While some people might have experienced the feeling of "being drunk" the morning after they consumed excessive amounts of alcohol, is it possible to feel intoxicated without ever drinking an alcoholic beverage?

Although it’s extremely rare, experts say it can happen.

The phenomenon is called auto-brewery syndrome, or ABS, according to Dr. Douglas Dieterich, M.D., director of the Institute for Liver Medicine at the Mount Sinai Health System in New York City.

The syndrome occurs when a patient’s gut gets colonized by a fungus that metabolizes carbohydrates and sugar into alcohol through fermentation, the doctor told Fox News Digital.

Before diagnosing a patient with ABS, Dieterich said that doctors "should always rule out other causes and make sure the patient is not drinking surreptitiously."

Here's a deeper dive.

A real-life case of auto-brewery syndrome

In one recent case study published in the Canadian Medical Association Journal, a 50-year-old woman had not consumed alcohol. Yet she continually had symptoms associated with intoxication, including the smell of alcohol on her breath, slurred speech and elevated blood alcohol levels during several emergency department visits.

The woman had a history of recurrent urinary tract infections that were treated with several courses of antibiotics, along with medications to reduce stomach acid.

Eventually the patient was diagnosed with auto-brewery syndrome, according to the published report.

"ABS carries paramount medical, legal, social and financial consequences for patients and their loved ones," Dr. Rahel Zewude, lead author of the study and an infectious diseases and microbiology fellow at University of Toronto in Canada, told Fox News Digital.

"Therefore, awareness of this rare syndrome in the medical community, as well as in the general public, can be instrumental in reducing delays in diagnosis."

"ABS carries paramount medical, legal, social and financial consequences for patients and their loved ones."

The woman in the case study saw her physician and visited the emergency department at least seven times over a two-year period. She complained of excessive sleepiness, slurred speech, falls and alcohol smells on her breath.

During her first ED visit, she was diagnosed with alcohol intoxication after having an elevated blood alcohol limit at 39 mmol/L (normal is 2 mmol/L or less) — despite her reports of not consuming alcoholic drinks, which family members verified.

The woman’s liver enzymes were normal and a computed tomography (CT) scan of her head revealed no acute findings, the study said.

Throughout the woman’s various visits to the emergency department, three psychiatrists provided addiction-related care, even though she scored a zero on the CAGE (Cut, Annoyed, Guilty and Eye) screening test, which assesses patients for alcohol use disorder.

(A total score of 2 or higher is considered clinically significant, according to the American Addiction Centers website.)

After experiencing episodes every one to two months, the woman was diagnosed — upon her seventh visit to the ED — with possible auto-brewery syndrome. She was prescribed an antifungal medication called fluconazole and referred to a gastroenterologist.

She completed a one-month course of fluconazole and adhered to a low-carb diet — and her symptoms began to resolve.

After four months, though, symptoms began to come back when she ramped up her carbohydrate intake, the study said.

After another course of fluconazole and a return to a low-carb diet, the symptoms resolved.

A course of probiotics was also prescribed to help foster better gut health.

Several factors contribute to ABS, according to Zewude.

"The disease likely presents when these factors emerge simultaneously alongside a high-carbohydrate diet," she told Fox News Digital.

One of the main factors is disruption of the gut microbiome, which is the population of microorganisms in the gut.

"In ABS, the fungi that ferment alcohol overpopulate our gut ahead of other non-fermenting bacteria," Zewude said.

"This gut microbiome disruption can occur due to frequent or prolonged courses of antibiotics."

Diabetes as well as gastrointestinal illnesses such as Crohn’s, liver disease and ulcerative colitis can also be risk factors for ABS, Zewude said.

Genetic predispositions that affect how the body metabolizes and clears ethanol can also play a role.

One way to test for ABS is to perform an oral glucose challenge in a supervised setting, where a patient first measures their fasting blood alcohol level.

This baseline level should be undetectable if the person had fasted for eight hours and did not consume any alcohol, according to Zewude.

"Diet modification is an extremely important part of reducing or resolving symptoms of auto-brewery disease."

The patient then ingests a high load of glucose, and their alcohol level is measured in 30-minute, one-hour, two-hour, four-hour, eight-hour and 24-hour increments.

"If their alcohol level begins to rise after ingestion of glucose, that can help confirm gut fermentation of alcohol from carbohydrates, which is ABS," Zewude told Fox News Digital.

The test should be conducted in a monitored clinic to ensure that the patient is not consuming alcohol, and to ensure safety in the event that the patient does become intoxicated, the expert advised.

The rare condition requires a multidisciplinary approach that may include a liver specialist or gastroenterologist, primary care physician, infectious diseases specialist and registered dietitian, health experts told Fox News Digital.

It is typically treated with antifungal medications and a low-carb diet, as noted in the case study mentioned earlier.

"Diet modification is an extremely important part of reducing or resolving symptoms of auto-brewery disease," Simone Gmuca, a registered dietitian who works with patients in Douglaston, New York, told Fox News Digital.

"A sugar-free, low-carb diet has been shown to be effective in managing symptoms — the fewer carbohydrates ingested, the less chance that carbohydrate fermentation will occur in the gut," added Gmuca, who was not affiliated with the study.

Patients should avoid simple carbohydrates like breads, pastas, crackers, sugary beverages, potato chips and fruit juices during treatment, the doctor said.

"Increasing lean protein, heart-healthy fats and low-starch vegetables can help promote satiation and reduce the risk of nutrient deficiencies," Gmuca added.

Patients with ABS should also incorporate plenty of lean meats, fish, avocados, olive oil, nuts, seeds and leafy green vegetables into their diet, she recommended.

Although ABS has been described in medical literature for over 50 years, the condition still remains misunderstood — with limited information regarding diagnosis and treatment, according to health experts.

https://www.foxnews.com/health/can-you-become-drunk-without-drinking-alcohol-could-happen

Rahel T. Zewude, Kenneth Croitoru, Ronit Das, Brian Goldman, Isaac I. Bogoch. Auto-brewery syndrome in a 50-year-old woman. CMAJ Jun 2024, 196 (21) E724-E727; DOI: 10.1503/cmaj.231319

KEY POINTS

Auto-brewery syndrome involves endogenous alcohol fermentation by fungi in the gut.

Diagnostic evaluation includes collateral history, ethanol level measurements with an oral glucose challenge, and, potentially, fungal culture and susceptibility testing of gastrointestinal secretions.

Management involves longitudinal, multidisciplinary care involving specialists in primary care, gastroenterology, infectious diseases, and mental health, as well as dietitians, with a strategy of antifungal therapy and a low-carbohydrate diet.

Auto-brewery syndrome may carry substantial social, legal, occupational, and medical consequences for patients, and awareness of this syndrome is essential for clinical diagnosis and management.

Ehlers-Danlos syndrome linked to small-fiber neuropathy 2

Igharo D, Thiel JC, Rolke R, Akkaya M, Weis J, Katona I, Schulz JB, Maier A. Skin biopsy reveals generalized small fibre neuropathy in hypermobile Ehlers-Danlos syndromes. Eur J Neurol. 2023 Mar;30(3):719-728. doi: 10.1111/ene.15649. Epub 2022 Dec 13. PMID: 36437696.

Abstract

Background and purpose: Ehlers-Danlos syndromes are hereditary disorders of connective tissue that are characterized by joint hypermobility, skin hyperextensibility and tissue fragility. The most common subtype is the hypermobile type. In addition to symptoms of small fibre neuropathy (SFN) due to damage to the small peripheral nerve fibres, with degeneration of the distal nerve endings, autonomic disorders such as postural tachycardia syndrome (PoTS) are frequently reported features in patients with hypermobile Ehlers-Danlos syndrome (hEDS). To date, the underlying pathophysiological mechanisms are still not completely understood.

Study purpose: To better understand pathophysiological mechanisms of small fiber neuropathy and autonomic neuropathy in hypermobile Ehlers-Danlos Syndromes.

Methods: We prospectively investigated 31 patients with hEDS compared to 31 healthy controls by using skin biopsy, quantitative sensory testing, tilt-table testing, the painDetect, Small Fibre Neuropathy Screening List and the COMPASS-31 (Composite Autonomic Symptom Score 31) questionnaire.

Results: Nineteen (61%) patients with hEDS were diagnosed with SFN, and 10 (32%) fulfilled the criteria for PoTS. Patients with hEDS had significantly higher heart rates than controls. According to quantitative sensory testing, these patients had generalized thermal and tactile hypesthesia. Skin biopsy revealed significantly reduced intraepithelial nerve fibre density proximally (thigh) and distally (lower leg) in patients compared to controls. This was consistent with various complaints of pain and sensory disturbances in both the proximal and distal body regions.

Conclusion: These results confirm histologically proven SFN as a common feature in patients with hEDS, revealing a generalized distribution of nerve fibre loss. Regarding the frequently reported autonomic and neuropathic dysfunctions, the findings support SFN as an important, but not the only, underlying pathomechanism.

Cook MK, Jordan M. Autoimmune Small Fiber Neuropathy Associated With Ehlers-Danlos Syndrome Treated With Intravenous Immunoglobulins. J Clin Neuromuscul Dis. 2021 Mar 1;22(3):160-163. doi: 10.1097/CND.0000000000000341. PMID: 33596000.

Abstract

Patients with Ehlers-Danlos syndrome (EDS) have many associated symptoms of unclear cause, most recently suggested to be due to small fiber neuropathy (SFN). Small fiber neuropathies are sorely underestimated and with minimal treatment options. We report 2 cases of patients with EDS with presumed immune-mediated SFN, successfully treated with IV immunoglobulins. There is a stark need for further investigational studies into immunosuppressant treatments for immune-mediated SFN as well as the link between EDS and immune-mediated SFN.

Ghasemi M, Rajabally YA. Small fiber neuropathy in unexpected clinical settings: a review. Muscle Nerve. 2020 Aug;62(2):167-175. doi: 10.1002/mus.26808. Epub 2020 Feb 4. PMID: 31943276.

Abstract

Small fiber neuropathy (SFN) is being recognized with increasing frequency in neuromuscular practice due to improved diagnostic techniques. Although there are some common etiologies, up to one-third of cases are considered idiopathic. In recent years, several disorders have unexpectedly been reported in association with SFN, on clinical grounds and complementary investigations, including quantitative sensory testing, intraepidermal nerve fiber density and confocal corneal microscopy. Knowledge of these disorders is important in clinical practice as increased awareness enables prompt diagnosis of SFN in these settings and early optimal therapeutic management of affected patients. Furthermore, these new developments may lead to a better understanding of the pathophysiologic mechanisms underlying SFN in these different disorders as well as, in some cases, an expanded spectrum of affected organs and systems. This article reviews these reported associations, their possible pathophysiologic bases, and the potential resulting management implications.

PIK3CA mutations

A 2-year-old boy was diagnosed with CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies/scoliosis). He was delivered via cesarean section at 38 weeks of gestation, presenting with a thoraco-abdominal lymphatic malformation. At birth, physical examination revealed hypertrophy in the right hand and the right foot, specifically affecting toes III, IV, and V, along with a capillary malformation overlaying the thoracic lymphatic malformation. MRI of the chest and abdomen identified a large macrocystic lymphatic malformation accompanied by multiple dorsal lipomas. After recurrent infections, a significant lymphatic malformation was surgically excised at 15 months of age, during which toes III, IV, and V were also disarticulated. Additionally, surgical debulking of the dorsal lipomas was undertaken to alleviate patient comorbidity.

Further Evaluation

Whole-exome sequencing conducted on genomic DNA extracted from the resected lymphangioma tissue revealed the presence of a PIK3CA (NM_006218) c.3140A>G (H1047R) gain-of-function mutation with 11% mosaicism. This finding led to the diagnosis of CLOVES syndrome, a phenotype in the PIK3CA-related overgrowth spectrum (PROS). The patient's treatment regimen included alpelisib, which significantly reduced the size of the dorsal lipomas and the residual, unresectable thoracic lymphatic malformation. This intervention also enhanced the patient's mobility and overall functional status.

Discussion

PROS is a complex and heterogeneous condition caused by somatic variations in the PIK3CA gene. PROS is characterized by a wide range of clinical presentations, reflecting the diversity of affected tissues and the extent of overgrowth. Phenotypes within PROS are diverse and can range from a single lesion (eg, solitary macrodactyly) to systemic diseases (eg, Klippel-Trenaunay syndrome and CLOVES syndrome). CLOVES (syndrome is a recently described overgrowth syndrome. The phenotypes included in PROS, all of which are caused by a pathogenic PIK3CA variant, are:

Fibroadipose hyperplasia (also called fibroadipose overgrowth)

CLOVES syndrome

Klippel-Trenaunay syndrome

Megalencephaly-capillary malformation syndrome

Hemihyperplasia-multiple lipomatosis syndrome

Dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia

Facial infiltrating lipomatosis (a congenital disorder that causes overgrowth of one side of the face)

CLAPO syndrome (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry and partial/generalized overgrowth)

This heterogeneity is primarily due to the timing of the onset of the somatic causative PIK3CA pathogenic variants during embryonic and fetal development, influencing the degree of mosaicism and the combination of tissues involved (eg, neural progenitor cell pathogenic variants can lead to postnatal megalencephaly and hydrocephalus). Moreover, different gain-of-function variants in PIK3CA lead to varying levels of hyperactivation of the PI3K/AKT/mTOR pathway, resulting in diverse severity of abnormal proliferation of mesodermal and ectodermal tissues from embryogenesis onwards. The pathogenesis of CLOVES syndrome has been attributed to somatic (postzygotic) mutations in the PIK3CA gene that result in increased AKT cell signaling and excess cell proliferation.

In general, PROS is marked by segmental overgrowth of multiple tissues, including:

Lipomatosis overgrowth: with or without regional reduction of adipose tissue on the trunk and limbs.

Vascular malformations: Capillary, venous, arteriovenous, or lymphatic types, which are common and occur in about 43% of patients. These abnormalities can contribute to additional complications, including swelling, pain, and increased risk for bleeding.

Skeletal findings: Polydactyly, macrodactyly, macrodontia, and scoliosis or other spinal abnormalities.

Overgrowth of tissues and organs: Excessive and asymmetric overgrowth can affect the skin, bones, muscles, and other structures, leading to disfigurement and functional impairments. The overgrowth typically follows a distal-to-proximal pattern, mostly unilateral and affecting the lower limbs.

Isolated lymphatic malformation: Dilated vascular channels lined by lymphatic endothelial cells may lead to fluid-filled cysts that usually grow proportionally with the growth of the affected person and may cause pain or significant morbidity if they are infiltrative.

Epidermal nevi and pigmentary anomalies: These are common and include thickened epidermal nevi or pigmentary anomalies, such as hyperpigmentation or hypopigmentation. These skin manifestations can be early signs of PROS and aid in diagnosis.

It is estimated that each of these conditions has a prevalence rate of less than 1 in 1,000,000.

Differential Diagnosis

Several syndromes may be considered when diagnosing PROS. These syndromes share common clinical features such as overgrowth, hemihyperplasia, vascular anomalies, skin abnormalities, scoliosis, tumors and others. However, these other overgrowth syndromes have more distinctive features and specific genetic causes that set them apart from PROS. These syndromes include:

Proteus syndrome (somatic AKT1 gene variant);

Linear sebaceous nevus syndrome (somatic HRAS, NRAS, KRAS gene variants);

Mosaic KRAS-related disorder;

PTEN-hamartoma tumor syndrome (somatic and germline PTEN gene variant); and

Neurofibromatosis type 1 (somatic and germline NF1 gene variant).

Diagnostic Testing

Testing for PROS generally requires genetic testing of affected tissue with either tissue or skin biopsy to look for a somatic PIK3CA mutation in patients with high clinical suspicion. It is difficult to identify the tissue with the highest probability of carrying the mutation because biopsies from PROS patients often show low levels of mosaicism, as is seen in this patient. Molecular genetic testing for diagnosing PROS requires a tissue sample from an affected area, preferably obtained through dermal biopsy or surgical procedures. PIK3CA mutations can be detected in affected tissues or cultured cells at varying levels; however, testing blood or DNA isolated from blood is not yet recommended because PIK3CA mutations have not been detected in blood samples.

The types of assays and their respective sensitivities are shown in the Table.


MALDI-TOF = matrix-assisted laser desorption/ionization time-of-flight; NA = not applicable; PCR = polymerase chain reaction; RFLP = restriction fragment length polymorphism

It is essential to interpret the findings of a particular assay and the tissue sampled. A mosaic mutation can help diagnose a PROS disorder; however, there is no direct correlation between the mutation level and disease manifestation or severity of the patient's symptoms.

Management

The available management strategies for PROS-related complications includes debulking of lipomatous lesions; scoliosis and leg-length discrepancy may require orthopedic care and surgical intervention. Neurologic complications (eg, obstructive hydrocephalus, increased intracranial pressure, progressive and/or symptomatic cerebellar tonsillar ectopia or Chiari malformation, and epilepsy in those with brain overgrowth or malformations) may warrant neurosurgical intervention. Depending on the type of vascular malformation, sclerotherapy, laser therapy, or oral medications such as sirolimus may be used. Similarly, lymphatic malformations may be treated with oral medications or careful surgical debulking, preferably by a vascular anomalies team. For patients experiencing pain, evaluation for the source of pain and treatment of the underlying cause is recommended.

Sirolimus, an mTOR inhibitor, has been used with modest success to reduce overgrowth and symptoms in patients with PROS. However, patients do not always respond to this treatment and sometimes experience disease progression while on it.

Miransertib, a pan-protein kinase B (AKT) inhibitor, was clinically evaluated and was available under expanded access. However, it is no longer available because efficacy was not demonstrated in the MOSAIC trial.

Taselisib, a beta-sparing PI3K inhibitor evaluated for PROS in the TOTEM trial, was discontinued from further clinical development owing to an unfavorable safety profile that precluded long-term use, despite providing functional improvements.

Alpelisib, an orally bioavailable alpha-selective PI3K inhibitor, directly targets the molecular driver of PROS pathology. Efficacy was evaluated using real-world data from EPIK-P1, a single-arm clinical study in patients aged 2 years or older with PROS who received alpelisib as part of an expanded access program for compassionate use. In primary findings from EPIK-P1, 37.5% of patients(n = 12/32) showed at least a 20% reduction in target lesion volume after 24 weeks. As a result, alpelisib received accelerated approval from the FDA US Food and Drug Administration on April 6, 2022, for the treatment of adult and pediatric patients at least 2 years of age with severe manifestations of PROS who require systemic therapy.

Prognosis

The prognosis for individuals with PROS varies widely, depending on the areas of the body affected and the severity of the symptoms. The condition can lead to significant morbidity and disability, particularly in those with extensive neurologic involvement or complex lymphatic anomalies, who tend to have a poorer prognosis. Patients with severe cases of PROS, especially those with critical functional impairments, often do not survive into adulthood, highlighting the spectrum's potential impact on lifespan and quality of life.

Comprehensive and regular monitoring is essential to address the diverse and evolving clinical manifestations of PROS. During each medical visit, it is essential to measure growth parameters, including head circumference and the length of arms, hands, legs, and feet. This assessment helps identify any new neurologic symptoms, such as seizures, changes in muscle tone, or signs of Chiari malformation. Monitoring the patient's developmental progress, behavior, and motor skills is similarly recommended.

Clinical Takeaways

It is crucial to ensure an early and accurate diagnosis of PROS (CLOVES and other component syndromes) to allow the initiation of appropriate treatments that have been shown to significantly affect overall functional status. Identifying the PIK3CA mutation through genetic testing from the affected tissue is essential for confirming the diagnosis, as seen in this case with the discovery of a PIK3CA gain-of-function mutation. Confirming diagnosis is important because CLOVES syndrome and other PROS can present with a wide range of symptoms and complications that require tailored management strategies to prevent further complications and improve quality of life.

Management of CLOVES and other PROS syndromes requires a multidisciplinary approach owing to their systemic and diverse manifestations, including overgrowths, vascular malformations, and potential for recurrent infections. Surgical interventions may be necessary to remove or reduce overgrowth and alleviate comorbidities; however, they are not curative and regrowth is common. Thus, systemic therapies such as alpelisib that target the molecular basis of the disease offer a promising addition to the management strategies.

https://www.medscape.com/viewarticle/1000430?src=flex_916_medscape.com

Gerasimenko A, Baldassari S, Baulac S. mTOR pathway: Insights into an established pathway for brain mosaicism in epilepsy. Neurobiol Dis. 2023 Jun 15;182:106144. doi: 10.1016/j.nbd.2023.106144. Epub 2023 May 4. PMID: 37149062.

Abstract

The mechanistic target of rapamycin (mTOR) signaling pathway is an essential regulator of numerous cellular activities such as metabolism, growth, proliferation, and survival. The mTOR cascade recently emerged as a critical player in the pathogenesis of focal epilepsies and cortical malformations. The 'mTORopathies' comprise a spectrum of cortical malformations that range from whole brain (megalencephaly) and hemispheric (hemimegalencephaly) abnormalities to focal abnormalities, such as focal cortical dysplasia type II (FCDII), which manifest with drug-resistant epilepsies. The spectrum of cortical dysplasia results from somatic brain mutations in the mTOR pathway activators AKT3, MTOR, PIK3CA, and RHEB and from germline and somatic mutations in mTOR pathway repressors, DEPDC5, NPRL2, NPRL3, TSC1 and TSC2. The mTORopathies are characterized by excessive mTOR pathway activation, leading to a broad range of structural and functional impairments. Here, we provide a comprehensive literature review of somatic mTOR-activating mutations linked to epilepsy and cortical malformations in 292 patients and discuss the perspectives of targeted therapeutics for personalized medicine.

Dobyns WB, Mirzaa GM. Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT-MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR. Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):582-590. doi: 10.1002/ajmg.c.31736. Epub 2019 Aug 23. PMID: 31441589.

Abstract

Megalencephaly (MEG) is a developmental abnormality of brain growth characterized by early onset, often progressive, brain overgrowth. Focal forms of megalencephaly associated with cortical dysplasia, such as hemimegalencephaly and focal cortical dysplasia, are common causes of focal intractable epilepsy in children. The increasing use of high throughput sequencing methods, including high depth sequencing to more accurately detect and quantify mosaic mutations, has allowed us to identify the molecular etiologies of many MEG syndromes, including most notably the PI3K-AKT-MTOR related MEG disorders. Thorough molecular and clinical characterization of affected individuals further allow us to derive preliminary genotype-phenotype correlations depending on the gene, mutation, level of mosaicism, and tissue distribution. Our review of published data on these disorders so far shows that mildly activating variants (that are typically constitutional or germline) are associated with diffuse megalencephaly with intellectual disability and/or autism spectrum disorder; moderately activating variants (that are typically high-level mosaic) are associated with megalencephaly with pigmentary abnormalities of the skin; and strongly activating variants (that are usually very low-level mosaic) are associated with focal brain malformations including hemimegalencephaly and focal cortical dysplasia. Accurate molecular diagnosis of these disorders is undoubtedly crucial to more optimally treat children with these disorders using PI3K-AKT-MTOR pathway inhibitors.

Moloney PB, Cavalleri GL, Delanty N. Epilepsy in the mTORopathies: opportunities for precision medicine. Brain Commun. 2021 Sep 25;3(4):fcab222. doi: 10.1093/braincomms/fcab222. PMID: 34632383; PMCID: PMC8495134.

Abstract

The mechanistic target of rapamycin signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mechanistic target of rapamycin cascade funnels through mechanistic target of rapamycin complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mechanistic target of rapamycin complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mechanistic target of rapamycin regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mechanistic target of rapamycin pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mechanistic target of rapamycin complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively, the mTORopathies are characterized by excessive mechanistic target of rapamycin pathway activation and drug-resistant epilepsy. In the first large-scale precision medicine trial in a genetically mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5-related epilepsy and focal cortical dysplasia type II. This review outlines a personalized medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mechanistic target of rapamycin pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mechanistic target of rapamycin inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.

BrainBridge

https://www.youtube.com/watch?v=szXbuUlUhQ4

The internet has been set ablaze with a mind-bending video depicting a futuristic "head transplant machine" called BrainBridge. The footage, which has amassed hundreds of thousands of views, shows robotic arms swiftly removing a person's head and attaching it to a healthy body. 

The idea is to give people with severe disabilities a new lease on life by using artificial intelligence algorithms to direct robotic arms to remove a head and attach it to a new torso.

While the concept may seem straight out of a B-grade horror flick, it has ignited a fiery debate about the ethics and feasibility of such a procedure. Is BrainBridge a genuine biomedical endeavor or an elaborate hoax designed to provoke discussion?

The mastermind behind the viral sensation

As it turns out, BrainBridge is not a real company. The video is the brainchild of Hashem Al-Ghaili, a Yemeni science communicator and film director known for blurring the lines between reality and science fiction. Al-Ghaili's previous viral hit, "EctoLife," depicted artificial wombs and left journalists scrambling to separate fact from fiction.

While the BrainBridge video may be a work of fiction, it serves as a provocative billboard for a controversial scheme gaining traction among some life-extension proponents and entrepreneurs — head transplantation, or as some prefer to call it, "body transplantation."

The pursuit of radical life extension

For those dedicated to achieving radical life extension, the idea of head transplantation holds an alluring promise — the ability to bypass aging by transferring one's head onto a younger, healthier body. Proponents argue that while anti-aging medicine has yet to achieve significant breakthroughs, a head transplant could offer a comparatively straightforward solution, at least as long as the brain remains functional.

However, the concept raises a host of ethical and practical concerns. Where would the donor bodies come from? Would it be ethical to use a body to benefit only one person when its organs could save multiple lives? These are just a few of the thorny questions that have emerged in the wake of the BrainBridge video.

Kurt's key takeaways

While the public reaction to the BrainBridge video has been largely negative, with many decrying the idea as "disgusting" and "immoral," Al-Ghaili remains undeterred. He claims to have received inquiries from potential investors and individuals seeking relief from personal health challenges.

As the debate rages on, one thing is clear. The BrainBridge video has challenged our perceptions of what is possible and forced us to confront the ethical implications of pushing the boundaries of science and technology in the pursuit of longevity.

https://www.foxnews.com/tech/real-story-behind-creepy-head-swapping-operations-robotic-surgeons

EBF3 neurodevelopmental disorder

Inspired by a patient

Ignatius E, Puosi R, Palomäki M, Forsbom N, Pohjanpelto M, Alitalo T, Anttonen AK, Avela K, Haataja L, Carroll CJ, Lönnqvist T, Isohanni P. Duplication/triplication mosaicism of EBF3 and expansion of the EBF3 neurodevelopmental disorder phenotype. Eur J Paediatr Neurol. 2022 Mar;37:1-7. doi: 10.1016/j.ejpn.2021.12.012. Epub 2021 Dec 26. PMID: 34999443.

Abstract

Deleterious variants in the transcription factor early B-cell factor 3 (EBF3) are known to cause a neurodevelopmental disorder (EBF3-NDD). We report eleven individuals with EBF3 variants, including an individual with a duplication/triplication mosaicism of a region encompassing EBF3 and a phenotype consistent with EBF3-NDD, which may reflect the importance of EBF3 gene-dosage for neurodevelopment. The phenotype of individuals in this cohort was quite mild compared to the core phenotype of previously described individuals. Although ataxia tended to wane with age, we show that cognitive difficulties may increase, and we recommend that individuals with EBF3-NDD have systematic neuropsychological follow-up.

Deisseroth CA, Lerma VC, Magyar CL, Pfliger JM, Nayak A, Bliss ND, LeMaire AW, Narayanan V, Balak C, Zanni G, Valente EM, Bertini E, Benke PJ, Wangler MF, Chao HT. An Integrated Phenotypic and Genotypic Approach Reveals a High-Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain. Ann Neurol. 2022 Jul;92(1):138-153. doi: 10.1002/ana.26359. Epub 2022 Apr 16. PMID: 35340043.

Abstract

Objective: Collier/Olf/EBF (COE) transcription factors have distinct expression patterns in the developing and mature nervous system. To date, a neurological disease association has been conclusively established for only the Early B-cell Factor-3 (EBF3) COE family member through the identification of heterozygous loss-of-function variants in individuals with autism spectrum/neurodevelopmental disorders (NDD). Here, we identify a symptom severity risk association with missense variants primarily disrupting the zinc finger domain (ZNF) in EBF3-related NDD.

Methods: A phenotypic assessment of 41 individuals was combined with a literature meta-analysis for a total of 83 individuals diagnosed with EBF3-related NDD. Quantitative diagnostic phenotypic and symptom severity scales were developed to compare EBF3 variant type and location to identify genotype-phenotype correlations. To stratify the effects of EBF3 variants disrupting either the DNA-binding domain (DBD) or the ZNF, we used in vivo fruit fly UAS-GAL4 expression and in vitro luciferase assays.

Results: We show that patient symptom severity correlates with EBF3 missense variants perturbing the ZNF, which is a key protein domain required for stabilizing the interaction between EBF3 and the target DNA sequence. We found that ZNF-associated variants failed to restore viability in the fruit fly and impaired transcriptional activation. However, the recurrent variant EBF3 p.Arg209Trp in the DBD is capable of partially rescuing viability in the fly and preserved transcriptional activation.

Interpretation: We describe a symptom severity risk association with ZNF perturbations and EBF3 loss-of-function in the largest reported cohort to date of EBF3-related NDD patients. This analysis should have potential predictive clinical value for newly identified patients with EBF3 gene variants. ANN NEUROL 2022;92:138-153.

Zhu J, Li W, Yu S, Lu W, Xu Q, Wang S, Qian Y, Guo Q, Xu S, Wang Y, Zhang P, Zhao X, Ni Q, Liu R, Li X, Wu B, Zhou S, Wang H. Further delineation of EBF3-related syndromic neurodevelopmental disorder in twelve Chinese patients. Front Pediatr. 2023 Mar 3;11:1091532. doi: 10.3389/fped.2023.1091532. PMID: 36937983; PMCID: PMC10020332.

Abstract

Neurodevelopmental disorders (NDDs) have heterogeneity in both clinical characteristics and genetic factors. EBF3 is a recently discovered gene associated with a syndromic form of NDDs characterized by hypotonia, ataxia and facial features. In this study, we report twelve unrelated individuals with EBF3 variants using next-generation sequencing. Five missense variants (four novel variants and one known variant) and seven copy number variations (CNVs) of EBF3 gene were identified. All of these patients exhibited developmental delay/intellectual disability. Ataxia was observed in 33% (6/9) of the patients, and abnormal muscle tone was observed in 55% (6/11) of the patients. Aberrant MRI reports were noted in 64% (7/11) of the patients. Four novel missense variants were all located in the DNA-binding domain. The pathogenicity of these variants was validated by in vitro experiments. We found that the subcellular protein localization of the R152C and F211L mutants was changed, and the distribution pattern of the R163G mutant was changed from even to granular. Luciferase assay results showed that the four EBF3 mutants' transcriptional activities were all significantly decreased (p < 0.01). Our study further expanded the gene mutation spectrum of EBF3-related NDD.

Bilateral gene therapy in children with autosomal recessive deafness 9

Five children who were born completely deaf have had some reversal of hearing loss after receiving a "groundbreaking" gene therapy.

The clinical trial, which was co-led by Mass Eye and Ear in Boston and the Eye & ENT Hospital of Fudan University in Shanghai, was the first in the world to apply gene therapy to children in both ears, according to the researchers.

The research has just been published in Nature Medicine on June 5.

In addition to regaining their hearing, the children participating in the trial — who ranged in age from 1 to 11 years old — were also able to identify the origins and locations of sounds, even in noisy environments, researchers said.

This was a follow-up to an earlier trial that began in Dec. 2022, in which the research team successfully performed the gene therapy in just one ear. This new study showed that treating both ears led to even greater benefits.

All the children in the study had a hereditary form of deafness called DFNB9, which is caused by mutations in the OTOF gene.

The condition occurs when the OTOF gene is unable to produce a protein called otoferlin, which is essential for transmitting sound signals from the ear to the brain.

As a result, the children could not hear or speak.

"The children were chosen because they would benefit most from early intervention of gene therapy, especially in speech acquisition," study author Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear in Boston, told Fox News Digital in an interview.

"From a safety standpoint, however, it is more risky for children."

How the procedure works

During the "minimally invasive" surgical procedure, the doctors administered an injection of the human OTOF gene into the children’s inner ears.

The children remained in the hospital for around seven to 10 days for observation.

"After four weeks, the kids showed hearing perception in tests, and then gradually they gained the ability to speak," Chen said.

Within the families, response to sound was noticed within two to three weeks.

"All five patients have restoration of hearing, speech perception improvements, and sound source perception in noisy environments," Chen said.

The participants experienced only low-grade adverse effects, such as fever and vomiting.

"This is the first time in history that hearing loss is being reversed by gene therapy."

"There were no serious adverse effects," he said. "They all recovered without any intervention."

The gene therapy is intended to be a one-time treatment and will not need to be repeated, the researchers said, although the children will likely require speech therapy.

Until now, there has not been any single treatment for hearing loss, other than cochlear implants, according to researcher Yilai Shu M.D., PhD, director of the Diagnosis and Treatment Center of Genetic Hearing Loss at Fudan Hospital in Shanghai.

"This is the first time in history that hearing loss is being reversed by gene therapy," Shu told Fox News Digital. "And, of course, we believe this will have a profound impact on children's lives."

Chang Yiyi, a mother in Shanghai whose 3-year-old son, Zhu Yangyang, participated in the trial, spoke to Fox News Digital about the experience.

"When Zhu couldn’t speak at 2 years old and didn’t have a response to sound, we realized there was a problem," she said.

After hearing tests, it was determined that Yiyi’s son had total deafness.

"It was unbelievable — the best feeling. It was like a miracle."

"He would get very frustrated because he couldn’t understand, couldn’t speak, couldn’t hear," she said.

Twenty-three days after receiving the gene therapy, the boy first responded to someone calling out to him.

"It was unbelievable — the best feeling," Yiyi told Fox News Digital. "It was like a miracle."

"Now he can say ‘Mommy’ and ‘I want’ and some simple sentences."

Approximately 430 million people worldwide have disabling hearing loss, including 34 million children, according to the World Health Organization.

Gene therapy is promising but limitations exist, expert says

Dr. Amy Sarow, the Michigan-based lead audiologist at Soundly, a hearing health care marketplace, noted that gene therapy has had some success in the treatment of cancer and eye disease, along with other emerging areas.

"It is exciting to think about how gene therapy could impact millions of individuals with hearing loss worldwide," Sarow, who was not involved in the experimental gene therapy, told Fox News Digital.

"However, it is essential to emphasize that there are many causes of hearing loss, and one type of gene therapy will not be right for every type."

Even among genetic causes of deafness, different genes may cause abnormalities or dysfunction that affect different auditory pathways, according to Sarow.

"Thus, development of specific treatment interventions is dependent on causality and will still take time to develop."

Additionally, Sarow noted, a "reversal" of hearing loss does not mean that an individual will have normal hearing ability fully restored.

"The first three years of life are very important to language acquisition, and although these children would be behind their normal-hearing peers (having spent the first few years of life profoundly deaf), they would still have the possibility to ‘catch up’ to some degree," she said.

"Research tells us that the younger the intervention, the better for potential language development."

As with any intervention, there can be risks with gene therapy. "One potential risk is that treatment may not be successful in every case," Sarow said.

"Another potential risk is that the targeted gene therapy may not work in the targeted region."

What’s next?

The next step is to follow the trial patients for a longer time period to ensure that the positive results are stable, Shu said.

Based on the results of the first study, the researchers expect that the patients’ hearing abilities will continue to improve over time.

"Then we want to expand to older patients, and gauge how the treatment works for aging adults," he said.

"Ultimately, we want the patient to have a choice about which treatment option they want to go with."

The researchers also plan to start the process of seeking FDA approval to bring the gene therapy to the U.S.

"We are working to bring this to people outside China, including the U.S., as quickly as possible," Shu Fox News Digital.

The researchers also hope to extend this type of gene therapy to treat other types of deafness in the future.

https://www.foxnews.com/health/children-total-deafness-regain-hearing-groundbreaking-gene-therapy-miracle

Wang, H., Chen, Y., Lv, J. et al. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nat Med (2024). https://doi.org/10.1038/s41591-024-03023-5

Abstract

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181.

It's not the size that matters

A small, unassuming fern-like plant has something massive lurking within: the largest genome ever discovered, outstripping the human genome by more than 50 times.

The plant (Tmesipteris oblanceolata) contains a whopping 160 billion base pairs, the units that make up a strand of DNA. That’s 11 billion more than the previous record holder, the flowering plant Paris japonica, and 30 billion more than the marbled lungfish (Protopterus aethiopicus), which has the largest animal genome. The findings were published today in iScience.

Study co-author Jaume Pellicer, an evolutionary biologist at the Botanical Institute of Barcelona in Spain, who also co-discovered P. japonica’s gargantuan genome, had thought that the earlier discovery was close to the genome size limit. “But the evidence has once again surpassed our expectations,” he says.

Genomic giants

The world’s genomic champion, which is native to New Caledonia and neighbouring archipelagos in the South Pacific, is a species of plant called a fork fern. Its colossal number of base pairs raises questions as to how the plant manages its genetic material. Only a small proportion of DNA is made of protein-coding genes, leading study co-author Ilia Leitch, an evolutionary biologist at London’s Royal Botanic Gardens, Kew, to wonder how the plant’s cellular machinery accesses those bits of the genome “amongst this huge morass of DNA. It’s like trying to find a few books with the instructions for how to survive in a library of millions of books — it’s just ridiculous.”

There’s also the question of how and why an organism evolved to have so many base pairs. Generally, having more base pairs leads to higher demand for the minerals that comprise DNA and for energy to duplicate the genome with every cell division, Leitch says. But if the organism lives in a relatively stable environment with little competition, a gargantuan genome might not come with a high cost, she adds.

That could help to provide an explanation — although a rather boring one — for the fork fern’s large genome: it might be neither detrimental nor particularly helpful for the plant’s ability to survive and reproduce, so the fork fern has gone on accumulating base pairs over time, says Julie Blommaert, a genomicist at the New Zealand Institute for Plant and Food Research in Nelson.

For now, researchers can only speculate on answers to these questions. The largest genome to be sequenced and assembled belongs to the European mistletoe (Viscum album), with about 90 billion base pairs. Modern techniques might not be sufficient to do the same for the fork fern’s genome: even if it’s sequenced, there’s still the computational challenge of taking the data and “sticking them together in a way that biologically reflects what’s going on”, Leitch says.

Finding ways to analyse enormous genomes could yield crucial insights into how genome size influences where organisms can grow, how they are able to flourish in their environments and their resilience to climate change, independent of their specific DNA sequence, she adds. Pellicer says it’s remarkable that a tiny, non-flowering plant that most people “wouldn’t bother to stop and look at” could offer such important lessons. “The beauty of the plant is inside.”

https://www.nature.com/articles/d41586-024-01567-7

Kozlov M. Biggest genome ever found belongs to this odd little plant. Nature. 2024 May 31. doi: 10.1038/d41586-024-01567-7. Epub ahead of print. PMID: 38822106.

Researchers identify a genetic cause of intellectual disability affecting tens of thousands

Researchers at the Icahn School of Medicine at Mount Sinai and others have identified a neurodevelopmental disorder, caused by mutations in a single gene, that affects tens of thousands of people worldwide. The work, published in the May 31 online issue of Nature Medicine, was done in collaboration with colleagues at the University of Bristol, UK; KU Leuven, Belgium; and the NIHR BioResource, currently based at the University of Cambridge, UK.

The findings will improve clinical diagnostic services for patients with neurodevelopmental disorders.

Through rigorous genetic analysis, the researchers discovered that mutations in a small non-coding gene called RNU4-2 cause a collection of developmental symptoms that had not previously been tied to a distinct genetic disorder. Non-coding genes are parts of DNA that do not produce proteins. The investigators used whole-genome sequencing data in the United Kingdom's National Genomic Research Library to compare the burden of rare genetic variants in 41,132 non-coding genes between 5,529 unrelated cases with intellectual disability and 46,401 unrelated controls.

The discovery is significant, as it represents one of the most common single-gene genetic causes of such disorders, ranking second only to Rett syndrome among patients sequenced by the United Kingdom's Genomic Medicine Service. Notably, these mutations are typically spontaneous and not inherited, providing important insights into the nature of the condition.

"We performed a large genetic association analysis to identify rare variants in non-coding genes that might be responsible for neurodevelopmental disorders," says the study's first author Daniel Greene, PhD, Assistant Professor of Genetics and Genomics Sciences at Icahn Mount Sinai and a Visitor at the University of Cambridge. "Nowadays, finding a single gene that harbors genetic variants responsible for tens of thousands of patients with a rare disease is exceptionally unusual. Our discovery eluded researchers for years due to various sequencing and analytical challenges."

More than 99 percent of genes known to harbor mutations that cause neurodevelopmental disorders encode proteins. The researchers hypothesized that non-coding genes, which don't produce proteins, could also host mutations leading to intellectual disability. Neurodevelopmental disorders, which often appear before grade school, involve developmental deficits affecting personal, social, academic, or occupational functioning. Intellectual disability specifically includes significant limitations in intellectual functioning (e.g., learning, reasoning, problem-solving) and adaptive behavior (e.g., social and practical skills).

"The genetic changes we found affect a very short gene, only 141 units long, but this gene plays a crucial role in a basic biological function of cells, called gene splicing, which is present in all animals, plants and fungi," says senior study author Ernest Turro, PhD, Associate Professor of Genetics and Genomic Sciences at Icahn Mount Sinai and a Visitor at the University of Cambridge. "Most people with a neurodevelopmental disorder do not receive a molecular diagnosis following genetic testing. Thanks to this study, tens of thousands of families will now be able to obtain a molecular diagnosis for their affected family members, bringing many diagnostic odysseys to a close."

Next, the researchers plan to explore the molecular mechanisms underlying this syndrome experimentally. This deeper understanding aims to provide biological insights that could one day lead to targeted interventions.

"What I found remarkable is how such a common cause of a neurodevelopmental disorder has been missed in the field because we've been focusing on coding genes," says Heather Mefford, MD, PhD, of the Center for Pediatric Neurological Disease Research at St. Jude Children's Research Hospital who was not involved with the research. "This study's discovery of mutations in non-coding genes, especially RNU4-2, highlights a significant and previously overlooked cause. It underscores the need to look beyond coding regions, which could reveal many other genetic causes, opening new diagnostic possibilities and research opportunities."

The paper is titled "Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders."

The remaining authors of the paper are Chantal Thys (KU Leuven, Belgium); Ian R. Berry, MD (University of Bristol, UK); Joanna Jarvis, MD (Birmingham Womens' Hospital, UK); Els Ortibus, MD, PhD (KU Leuven, Belgium); Andrew D. Mumford, MD (University of Bristol, UK); and Kathleen Freson, PhD (KU Leuven, Belgium).

https://www.sciencedaily.com/releases/2024/05/240531122557.htm

Greene D, Thys C, Berry IR, Jarvis J, Ortibus E, Mumford AD, Freson K, Turro E. Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders. Nat Med. 2024 May 31. doi: 10.1038/s41591-024-03085-5. Epub ahead of print. PMID: 38821540.

Abstract

Most people with intellectual disability (ID) do not receive a molecular diagnosis following genetic testing. To identify new etiologies of ID, we performed a genetic association analysis comparing the burden of rare variants in 41,132 non-coding genes between 5,529 unrelated cases and 46,401 unrelated controls. RNU4-2, which encodes U4 snRNA, a critical component of the spliceosome, was the most strongly associated gene. We implicated de novo variants among 47 cases in two regions of RNU4-2 in the etiology of a syndrome characterized by ID, microcephaly, short stature, hypotonia, seizures and motor delay. We replicated this finding in three collections, bringing the number of cases to 73. Analysis of national genomic diagnostic data showed RNU4-2 to be a more common etiological gene for neurodevelopmental abnormality than any previously reported autosomal gene. Our findings add to growing evidence of spliceosome dysfunction in the etiologies of neurological disorders.