By the time Charlotte “Charli” Hilz’s family drove from Dallas to Austin, they had tried nearly everything they had been offered to control her seizures: Seven medications, dietary changes and steroids had failed. Some treatments helped briefly, while others brought difficult side effects. All the while, two-year-old Charli was losing abilities she had already developed.
Her parents knew the situation was worsening. What they did not have was a clear path forward.
“My trust began to waver,” says Charli’s father, Trevor Hilz. “But I also didn’t know where to go.”
A family connection led them to Dave Clarke, M.D., chief of the Comprehensive Pediatric Epilepsy Program within the neurology clinic at Dell Children’s, a clinical partnership with Dell Medical School that is now ranked No. 21 in the country. Within a week, they had made the trip to Austin and begun a new evaluation — one designed not simply to try another medication, but to understand why the treatments had failed and whether a more definitive option was possible.
“Our program is designed to engage closely with families and across our disciplines to get to the root of the problem,” says Clarke, professor of pediatrics and neurology at Dell Medical School at The University of Texas at Austin. “Highly trained epileptologists, neurosurgeons who are able to take on high-risk procedures if needed, neuropsychologists, social workers, advanced practice providers and nurses — we all collaborate with the child and family at the center. That’s what makes the difference here: We are both capable and willing to go the extra mile for each child.”
National recognition for Austin pediatric programs
Charli’s journey points to a larger shift in the Central Texas medical landscape. For years, families in Austin routinely traveled to Dallas, Houston and elsewhere for highly specialized pediatric care. Charli’s family came in the opposite direction, seeking capabilities that an emerging academic pediatric neuroscience program had assembled here.
Created in 2019, the program brought pediatric neurology, neurosurgery, neuropsychology, neuro-ophthalmology, rehabilitation and related specialties into a more integrated model. It earned its first national recognition from U.S. News & World Report three years later. By 2025, the program had reached No. 25 in the country for pediatric neurology and neurosurgery. Today, it is tied for No. 21, one of a handful of programs led by Dell Med faculty now climbing in national recognition.
“The power of academic medicine is that patient care, research and education continually strengthen one another,” says Claudia Lucchinetti, M.D., senior vice president for medical affairs and dean of Dell Medical School at The University of Texas at Austin. “The needs of patients shape research, new discoveries create better outcomes, and education prepares more physicians to deliver the most advanced care. At Dell Children’s, Dell Med faculty bring that model together with outstanding clinical teams and the broader capabilities of UT to take on complex cases and find a path forward when standard answers fall short.
“These rankings reflect what matters for children and families: deeper expertise, more options, and access to nationally recognized care here in Central Texas.”
Charli’s journey from uncertainty to recovery
Other leading pediatric epilepsy centers around the country have access to many of the same advanced tools. But what Charli and her family needed — and had not yet found — was a team of advanced specialists prepared to put them together around her particular case.
“When advanced specialists come together, we can look at complex cases from every angle,” says Adam Messer, president of Dell Children’s Medical Center. “This collaboration helps us understand each child’s unique needs so we can provide comprehensive care that supports the entire family.”
Charli’s epilepsy began in one area of the brain but spread so rapidly that it could resemble a different type of seizure disorder. At the same time, abnormal electrical activity was disrupting more than half of her sleep, interfering with her brain’s ability to rest, learn and develop. She was having as many as 20 seizures a day, struggling to walk and speak clearly, and losing the use of her left hand.
At Dell Children’s, the team began again with inpatient monitoring, capturing Charli’s seizures and studying the electrical activity in her brain. Advanced imaging helped narrow the suspected source. Epileptologists, neurosurgeons and neuropsychologists then used stereo-EEG, placing small electrodes in and around the target area to determine precisely where her seizures began and how closely that area bordered functions that needed to be preserved.
The evaluation located a small area of atypical cells near Charli’s sensory cortex. The target was so tightly surrounded by functional tissue that conventional surgical removal could have caused harm.
Instead, the team guided a needle-sized probe between two folds of her brain and used laser energy to deactivate the cells driving the seizures while protecting the surrounding tissue.
Today, Charli is six years old and remains seizure-free. Her overnight epileptic episodes have largely disappeared. She is using both sides of her body more fully, taking fewer medications and rapidly regaining function her family once feared had been permanently lost.
“For the first time, we felt heard,” says Charli’s mother, Mackenzie Hilz. “Dr. Clarke believed us. He looked at her and us and said, ‘I have a plan.’ We hadn’t heard that from anyone before. We took the leap, and it saved her life.”
https://news.utexas.edu/2026/09/17/academic-medicine-raises-the-bar-for-pediatric-neuroscience-care-in-austin/
Wednesday, September 30, 2026
Diazepam Intensol shortage
It seems there is a nationwide shortage of inexpensive but effective Diazepam Intensol, forcing obscenely expensive Valtoco to be prescribed in yet more obscenely expensive 5 packs.
Tuesday, September 29, 2026
Great experiments 5
Courtesy of a colleague
Hot air? BMJ. 2001 Dec 22;323(7327):1449. PMCID: PMC1121900.
“It all started with an enquiry from a nurse,” Dr Karl Kruszelnicki told listeners to his science phone-in show on the Triple J radio station in Brisbane. “She wanted to know whether she was contaminating the operating theatre she worked in by quietly farting in the sterile environment during operations, and I realised that I didn't know. But I was determined to find out.”
Dr Kruszelnicki then described the method by which he had established whether human flatus was germ-laden, or merely malodorous. “I contacted Luke Tennent, a microbiologist in Canberra, and together we devised an experiment. He asked a colleague to break wind directly onto two Petri dishes from a distance of 5 centimetres, first fully clothed, then with his trousers down. Then he observed what happened. Overnight, the second Petri dish sprouted visible lumps of two types of bacteria that are usually found only in the gut and on the skin. But the flatus which had passed through clothing caused no bacteria to sprout, which suggests that clothing acts as a filter.
“Our deduction is that the enteric zone in the second Petri dish was caused by the flatus itself, and the splatter ring around that was caused by the sheer velocity of the fart, which blew skin bacteria from the cheeks and blasted it onto the dish. It seems, therefore, that flatus can cause infection if the emitter is naked, but not if he or she is clothed. But the results of the experiment should not be considered alarming, because neither type of bacterium is harmful. In fact, they're similar to the ‘friendly’ bacteria found in yoghurt.
“Our final conclusion? Don't fart naked near food. All right, it's not rocket science. But then again, maybe it is?”
Hot air? BMJ. 2001 Dec 22;323(7327):1449. PMCID: PMC1121900.
“It all started with an enquiry from a nurse,” Dr Karl Kruszelnicki told listeners to his science phone-in show on the Triple J radio station in Brisbane. “She wanted to know whether she was contaminating the operating theatre she worked in by quietly farting in the sterile environment during operations, and I realised that I didn't know. But I was determined to find out.”
Dr Kruszelnicki then described the method by which he had established whether human flatus was germ-laden, or merely malodorous. “I contacted Luke Tennent, a microbiologist in Canberra, and together we devised an experiment. He asked a colleague to break wind directly onto two Petri dishes from a distance of 5 centimetres, first fully clothed, then with his trousers down. Then he observed what happened. Overnight, the second Petri dish sprouted visible lumps of two types of bacteria that are usually found only in the gut and on the skin. But the flatus which had passed through clothing caused no bacteria to sprout, which suggests that clothing acts as a filter.
“Our deduction is that the enteric zone in the second Petri dish was caused by the flatus itself, and the splatter ring around that was caused by the sheer velocity of the fart, which blew skin bacteria from the cheeks and blasted it onto the dish. It seems, therefore, that flatus can cause infection if the emitter is naked, but not if he or she is clothed. But the results of the experiment should not be considered alarming, because neither type of bacterium is harmful. In fact, they're similar to the ‘friendly’ bacteria found in yoghurt.
“Our final conclusion? Don't fart naked near food. All right, it's not rocket science. But then again, maybe it is?”
Levacetylleucine for treatment of Niemann-Pick disease type C 2
Davis LC, Annaert W, Braine R, Churchill GC, Factor M, Fields T, Patterson M, Platt F, Shepherd D, Strupp M, Galione A. N-acetyl-L-leucine normalizes Transcription Factor EB activity by stereospecific bidirectional modulation in a HeLa cell model of Niemann-Pick disease type C. PLoS One. 2026 Jul 17;21(7):e0353834. doi: 10.1371/journal.pone.0353834. PMID: 42467639; PMCID: PMC13378962.
Abstract
Levacetylleucine (Aqneursa™), an acetylated derivative and pro-drug of L-leucine, is the only FDA-approved monotherapy for Niemann-Pick disease type C (NPC). Its acetyl group enables transport via monocarboxylate transporters, supporting blood-brain barrier penetration and efficient cellular uptake. Inside cells, levacetylleucine is metabolised by acylases, generating elevated levels of L-leucine that enhance mitochondrial bioenergetics and is thought to ameliorate lysosomal dysfunction indirectly. Here, we describe a direct effect of levacetylleucine on lysosomal regulation through modulation of TFEB, the master transcription factor for lysosomal and autophagy genes. Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner. In wild-type HeLa cells, levacetylleucine promotes TFEB activation and nuclear localisation. However, in NPC1 disease models, where we show that TFEB is over-activated and enriched in the nucleus due to lysosomal stress, levacetylleucine reduces nuclear TFEB and restores a more normal cytoplasmic-to-nuclear balance. These effects occur at clinically relevant concentrations associated with lysosomal storage reduction. The effects of the drug are stereospecific: while the L-enantiomer is active, the D-enantiomer and racemate show no effect, revealing the antagonistic properties of the D-enantiomer. This bidirectional normalisation of TFEB activity highlights a direct mechanism through which levacetylleucine modulates lysosomal and autophagic pathways in the HeLa cell model, giving mechanistic insight into its therapeutic potential in NPC, and also across diverse neurological and neurodevelopmental disorders.
Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannová S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K. Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. PMID: 38294974.
Abstract
Background: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C.
Methods: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.
Results: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.
Conclusions: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).
Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M. N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. PMID: 37248494; PMCID: PMC10226221.
Abstract
Background: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC.
Methods: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.
Discussion: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.
Trial registrations: The trial (IB1001-301) has been registered at www.
Clinicaltrials: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.
Keywords: Cerebellar ataxia; Lysosomal storage disease; N-acetyl-L-leucine; Niemann-Pick type C (NPC); Pharmaceutical intervention; Randomized controlled trial; Symptomatic treatment.
Du K, Chen H, Pan Z, Zhao M, Cheng S, Luo Y, Zhang W, Li D. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis. Elife. 2025 Apr 4;13:RP103137. doi: 10.7554/eLife.103137. PMID: 40184172; PMCID: PMC11970905.
Abstract
Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
Abstract
Levacetylleucine (Aqneursa™), an acetylated derivative and pro-drug of L-leucine, is the only FDA-approved monotherapy for Niemann-Pick disease type C (NPC). Its acetyl group enables transport via monocarboxylate transporters, supporting blood-brain barrier penetration and efficient cellular uptake. Inside cells, levacetylleucine is metabolised by acylases, generating elevated levels of L-leucine that enhance mitochondrial bioenergetics and is thought to ameliorate lysosomal dysfunction indirectly. Here, we describe a direct effect of levacetylleucine on lysosomal regulation through modulation of TFEB, the master transcription factor for lysosomal and autophagy genes. Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner. In wild-type HeLa cells, levacetylleucine promotes TFEB activation and nuclear localisation. However, in NPC1 disease models, where we show that TFEB is over-activated and enriched in the nucleus due to lysosomal stress, levacetylleucine reduces nuclear TFEB and restores a more normal cytoplasmic-to-nuclear balance. These effects occur at clinically relevant concentrations associated with lysosomal storage reduction. The effects of the drug are stereospecific: while the L-enantiomer is active, the D-enantiomer and racemate show no effect, revealing the antagonistic properties of the D-enantiomer. This bidirectional normalisation of TFEB activity highlights a direct mechanism through which levacetylleucine modulates lysosomal and autophagic pathways in the HeLa cell model, giving mechanistic insight into its therapeutic potential in NPC, and also across diverse neurological and neurodevelopmental disorders.
Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannová S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K. Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. PMID: 38294974.
Abstract
Background: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C.
Methods: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.
Results: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.
Conclusions: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).
Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M. N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. PMID: 37248494; PMCID: PMC10226221.
Abstract
Background: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC.
Methods: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.
Discussion: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.
Trial registrations: The trial (IB1001-301) has been registered at www.
Clinicaltrials: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.
Keywords: Cerebellar ataxia; Lysosomal storage disease; N-acetyl-L-leucine; Niemann-Pick type C (NPC); Pharmaceutical intervention; Randomized controlled trial; Symptomatic treatment.
Du K, Chen H, Pan Z, Zhao M, Cheng S, Luo Y, Zhang W, Li D. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis. Elife. 2025 Apr 4;13:RP103137. doi: 10.7554/eLife.103137. PMID: 40184172; PMCID: PMC11970905.
Abstract
Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
Levacetylleucine for treatment of ataxia-telangiectasia
The U.S. Food and Drug Administration has approved Aqneursa (levacetylleucine) for oral suspension to treat ataxia in adults and pediatric patients with ataxia-telangiectasia weighing at least 15 kg (about 33 pounds). Aqneursa was previously approved in 2024 to treat the neurological manifestations of Niemann-Pick disease type C. Today’s approval makes Aqneursa the first treatment approved for ataxia in patients with ataxia-telangiectasia.
Condition
Ataxia-telangiectasia is a rare, inherited neurodegenerative disorder caused by mutations in the ATM gene. It primarily affects the nervous system, causing progressive loss of muscle control and coordination (ataxia) that typically begins in early childhood. The disease also causes small dilated blood vessels (telangiectasias), immune deficiencies, and an elevated risk of cancer. There is no cure for ataxia-telangiectasia, and treatment options for the neurological symptoms of the disease have been limited.
Data Supporting Aqneursa
The effectiveness of Aqneursa was evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT06673056) of 73 patients aged 4 years or older with a confirmed diagnosis of ataxia-telangiectasia. Patients were randomly assigned to receive Aqneursa followed by placebo, or placebo followed by Aqneursa, with each treatment period lasting 12 weeks. Of the 73 patients (26 adults and 47 pediatric patients), 38 were female and 35 were male. The median age at treatment initiation was 13 years (range: 4 to 50 years). A total of 70 patients (96%) completed the study.
Efficacy was assessed using the functional Scale for Assessment and Rating of Ataxia (fSARA), a modified clinical tool evaluating gait, sitting, stance, and speech disturbance, with scores ranging from 0 (best neurological status) to 16 (worst). When patients were taking Aqneursa, they scored better on the fSARA compared to when these patients were taking placebo and showed significant improvement in neurological function.
Safety Information
There are no contraindications for Aqneursa, although this drug may cause fetal harm based on data from animal studies. The most common adverse reactions in patients with ataxia-telangiectasia were fall, skin laceration, and urinary tract infection.
Aqneursa interacts with N-acetyl-DL-leucine and simultaneous use should be avoided. Patients receiving P-glycoprotein (P-gp) substrates should be monitored more frequently for related adverse reactions when used with Aqneursa.
Designation
Aqneursa received Orphan Drug designation and Priority Review for the ataxia-telangiectasia indication. Approval was granted to IntraBio Inc.
https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-therapy-treat-ataxia-patients-ataxia-telangiectasia-rare-genetic-disorder
Martakis K, Bremova-Ertl T, Bolton C, Foltan T, Del Mar Garcia Romero M, Gautschi M, Han V, Hahn A, Kolnikova M, Panagioti O, Perlman S, Prasad M, Schmahmann J, Skorvanek M, Thakur N, Thiel M, Hoche F. Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial. Lancet Neurol. 2026 Jul;25(7):633-644. doi: 10.1016/S1474-4422(26)00158-4. PMID: 42309084.
Abstract
Background: Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia.
Methods: In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing.
Findings: Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred.
Interpretation: Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects.
Funding: IntraBio.
Condition
Ataxia-telangiectasia is a rare, inherited neurodegenerative disorder caused by mutations in the ATM gene. It primarily affects the nervous system, causing progressive loss of muscle control and coordination (ataxia) that typically begins in early childhood. The disease also causes small dilated blood vessels (telangiectasias), immune deficiencies, and an elevated risk of cancer. There is no cure for ataxia-telangiectasia, and treatment options for the neurological symptoms of the disease have been limited.
Data Supporting Aqneursa
The effectiveness of Aqneursa was evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT06673056) of 73 patients aged 4 years or older with a confirmed diagnosis of ataxia-telangiectasia. Patients were randomly assigned to receive Aqneursa followed by placebo, or placebo followed by Aqneursa, with each treatment period lasting 12 weeks. Of the 73 patients (26 adults and 47 pediatric patients), 38 were female and 35 were male. The median age at treatment initiation was 13 years (range: 4 to 50 years). A total of 70 patients (96%) completed the study.
Efficacy was assessed using the functional Scale for Assessment and Rating of Ataxia (fSARA), a modified clinical tool evaluating gait, sitting, stance, and speech disturbance, with scores ranging from 0 (best neurological status) to 16 (worst). When patients were taking Aqneursa, they scored better on the fSARA compared to when these patients were taking placebo and showed significant improvement in neurological function.
Safety Information
There are no contraindications for Aqneursa, although this drug may cause fetal harm based on data from animal studies. The most common adverse reactions in patients with ataxia-telangiectasia were fall, skin laceration, and urinary tract infection.
Aqneursa interacts with N-acetyl-DL-leucine and simultaneous use should be avoided. Patients receiving P-glycoprotein (P-gp) substrates should be monitored more frequently for related adverse reactions when used with Aqneursa.
Designation
Aqneursa received Orphan Drug designation and Priority Review for the ataxia-telangiectasia indication. Approval was granted to IntraBio Inc.
https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-therapy-treat-ataxia-patients-ataxia-telangiectasia-rare-genetic-disorder
Martakis K, Bremova-Ertl T, Bolton C, Foltan T, Del Mar Garcia Romero M, Gautschi M, Han V, Hahn A, Kolnikova M, Panagioti O, Perlman S, Prasad M, Schmahmann J, Skorvanek M, Thakur N, Thiel M, Hoche F. Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial. Lancet Neurol. 2026 Jul;25(7):633-644. doi: 10.1016/S1474-4422(26)00158-4. PMID: 42309084.
Abstract
Background: Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia.
Methods: In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing.
Findings: Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred.
Interpretation: Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects.
Funding: IntraBio.
Sunday, September 27, 2026
Most transcription is not a consequence of background noise.
For decades, many scientists have confidently dismissed the vast majority of the human DNA as useless evolutionary garbage. Yet a recently published scientific paper in Cell, one of the world’s most prestigious biology journals, declares a “paradigm shift” against the idea that huge portions of the human genome are merely “junk DNA.”
After the Human Genome Project was completed in 2003, a startling discovery was made. Only about 2 percent of the entire human genome codes for proteins. Scientists naturally asked, what is the other 98 percent doing?
Evolutionary biology was ready with an answer. For decades, they had claimed that the vast majority of the human genome was essentially genetic garbage — “junk DNA.” This idea had deep roots in evolutionary thinking — which loves to claim humanity and other living things are poorly designed.
A 1969 paper titled “Non-Darwinian Evolution” in the journal Science proposed that “99 percent of mammalian DNA is not true genetic material.” Three years later, the great Japanese biologist Susumu Ohno coined the term “junk DNA” and predicted that “at least 90% of the mammalian genomic DNA appears to represent ‘nonsense.’”
Atheist evolutionary biologists loved the idea. Richard Dawkins wrote in his 2003 book "A Devil’s Chaplain" that “genomes are littered with nonfunctional … junk.” But even theistic evolutionists — Christians who believe God created life through evolution — found junk DNA an expedient argument to bolster their theory.
In his 2006 book "The Language of God," Francis Collins — who headed the Human Genome Project — wrote that some “45 percent of the human genome” is little better than “genetic flotsam and jetsam.”
Meanwhile, proponents of intelligent design (ID) developed a very different view of so-called "junk DNA."
In 1994, pro-ID scientist Forrest Mims wrote a letter to Science warning against assuming that “junk” DNA was “useless.” Four years later, mathematician William Dembski articulated the ID view: “Consider the term ‘junk DNA. … Design encourages scientists to look for function where evolution discourages it.”
But why does intelligent design predict function for junk DNA? It’s simple.
ID theory starts by observing what intelligent minds can do, and then searches nature to see if there’s evidence of a mind at work.
We know from our observation-based experience that intelligent agents do things for a reason. Engineers only put functional parts into cell phones. Every time an email is written, an intelligence generates informational sequences with a purposeful message. ID predicts function.
But which view is right? In 2012, a groundbreaking discovery started a paradigm shift in this debate.
A consortium of hundreds of scientists involved in the ENCODE Project published results in the top journal Nature showing that over 80 percent of the human genome is biochemically active. They showed the vast majority of the genome is converted into RNA — a process called “transcription” that is normally a telltale sign of function. One lead ENCODE researcher predicted that as more human cell types are studied, “that 80 percent will go to 100 percent.”
These discoveries had a dramatic effect on biological thinking. Even Francis Collins changed his tune. Speaking at a scientific conference in 2015, he admitted:
"In terms of junk DNA, we don’t use that term anymore because I think it was pretty much a case of hubris to imagine that we could dispense with any part of the genome as if we knew enough to say it wasn’t functional."
Collins explained that most of so-called “junk” is regulating the production of proteins, called gene expression. By 2021, one mainstream scientific paper declared that “the days of ‘junk DNA’ are over.”
These discoveries represented a spectacular fulfillment of ID’s prediction that we would discover function for junk DNA, and a colossal failure for evolution.
Unsurprisingly, evolutionary biologists weren’t going to take this sitting down. One biologist, Dan Graur at the University of Houston, worried that “If ENCODE is right, then Evolution is wrong.” He shifted the goalposts by proposing that if most of our genome is producing RNA, then that “transcription is … stochastic” — i.e., it’s just randomly produced junk RNA!
But Graur’s view has been receding as we discover more and more functions for RNA. A newly published paper in the journal Genome Biology and Evolution dealt a serious blow to “junk RNA.”
This paper, along with a 2024 paper in Nature, took sections of mammalian DNA that are transcribed into RNA and reversed them. If transcription is random and uncontrolled, then scrambling their DNA should not change the amount of RNA that’s produced. But if RNA is produced in a controlled, regulated, and functional manner, then transcription in the scrambled sequence should drop dramatically. And that’s exactly what they found. As the paper found, “most transcription is not a consequence of background noise.”
To be sure, there’s still much we don’t know about the genome. But the more we study genetics, the more function we discover. Evolution’s love affair with viewing our bodies as clumsy accidents is hindering science. In contrast, when we view DNA as intelligently designed, we can make useful predictions that bear good scientific fruit, advancing our knowledge of how cells work.
Casey Luskin
https://townhall.com/columnists/casey-luskin/2026/09/20/intelligent-design-bears-good-scientific-fruit-in-the-study-of-junk-dna-n2683215
The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012). https://doi.org/10.1038/nature11247
Abstract
The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
After the Human Genome Project was completed in 2003, a startling discovery was made. Only about 2 percent of the entire human genome codes for proteins. Scientists naturally asked, what is the other 98 percent doing?
Evolutionary biology was ready with an answer. For decades, they had claimed that the vast majority of the human genome was essentially genetic garbage — “junk DNA.” This idea had deep roots in evolutionary thinking — which loves to claim humanity and other living things are poorly designed.
A 1969 paper titled “Non-Darwinian Evolution” in the journal Science proposed that “99 percent of mammalian DNA is not true genetic material.” Three years later, the great Japanese biologist Susumu Ohno coined the term “junk DNA” and predicted that “at least 90% of the mammalian genomic DNA appears to represent ‘nonsense.’”
Atheist evolutionary biologists loved the idea. Richard Dawkins wrote in his 2003 book "A Devil’s Chaplain" that “genomes are littered with nonfunctional … junk.” But even theistic evolutionists — Christians who believe God created life through evolution — found junk DNA an expedient argument to bolster their theory.
In his 2006 book "The Language of God," Francis Collins — who headed the Human Genome Project — wrote that some “45 percent of the human genome” is little better than “genetic flotsam and jetsam.”
Meanwhile, proponents of intelligent design (ID) developed a very different view of so-called "junk DNA."
In 1994, pro-ID scientist Forrest Mims wrote a letter to Science warning against assuming that “junk” DNA was “useless.” Four years later, mathematician William Dembski articulated the ID view: “Consider the term ‘junk DNA. … Design encourages scientists to look for function where evolution discourages it.”
But why does intelligent design predict function for junk DNA? It’s simple.
ID theory starts by observing what intelligent minds can do, and then searches nature to see if there’s evidence of a mind at work.
We know from our observation-based experience that intelligent agents do things for a reason. Engineers only put functional parts into cell phones. Every time an email is written, an intelligence generates informational sequences with a purposeful message. ID predicts function.
But which view is right? In 2012, a groundbreaking discovery started a paradigm shift in this debate.
A consortium of hundreds of scientists involved in the ENCODE Project published results in the top journal Nature showing that over 80 percent of the human genome is biochemically active. They showed the vast majority of the genome is converted into RNA — a process called “transcription” that is normally a telltale sign of function. One lead ENCODE researcher predicted that as more human cell types are studied, “that 80 percent will go to 100 percent.”
These discoveries had a dramatic effect on biological thinking. Even Francis Collins changed his tune. Speaking at a scientific conference in 2015, he admitted:
"In terms of junk DNA, we don’t use that term anymore because I think it was pretty much a case of hubris to imagine that we could dispense with any part of the genome as if we knew enough to say it wasn’t functional."
Collins explained that most of so-called “junk” is regulating the production of proteins, called gene expression. By 2021, one mainstream scientific paper declared that “the days of ‘junk DNA’ are over.”
These discoveries represented a spectacular fulfillment of ID’s prediction that we would discover function for junk DNA, and a colossal failure for evolution.
Unsurprisingly, evolutionary biologists weren’t going to take this sitting down. One biologist, Dan Graur at the University of Houston, worried that “If ENCODE is right, then Evolution is wrong.” He shifted the goalposts by proposing that if most of our genome is producing RNA, then that “transcription is … stochastic” — i.e., it’s just randomly produced junk RNA!
But Graur’s view has been receding as we discover more and more functions for RNA. A newly published paper in the journal Genome Biology and Evolution dealt a serious blow to “junk RNA.”
This paper, along with a 2024 paper in Nature, took sections of mammalian DNA that are transcribed into RNA and reversed them. If transcription is random and uncontrolled, then scrambling their DNA should not change the amount of RNA that’s produced. But if RNA is produced in a controlled, regulated, and functional manner, then transcription in the scrambled sequence should drop dramatically. And that’s exactly what they found. As the paper found, “most transcription is not a consequence of background noise.”
To be sure, there’s still much we don’t know about the genome. But the more we study genetics, the more function we discover. Evolution’s love affair with viewing our bodies as clumsy accidents is hindering science. In contrast, when we view DNA as intelligently designed, we can make useful predictions that bear good scientific fruit, advancing our knowledge of how cells work.
Casey Luskin
https://townhall.com/columnists/casey-luskin/2026/09/20/intelligent-design-bears-good-scientific-fruit-in-the-study-of-junk-dna-n2683215
Ho J, Douse C, Marazzi I. Transposable element DNA and RNA: Drivers of gene expression, evolution, and disease
Cell, 189, 3513-3540
Summary
Transposable elements (TEs) comprise nearly half of mammalian genomes and have shaped genome architecture, chromatin organization, and transcriptional landscapes. Thanks to recent advances in long-read sequencing and functional (epi)genomics, the focus has shifted from TE families to individual TE loci, revealing widespread, locus-specific regulatory roles. While most TEs have lost the capacity to mobilize, they still retain a DNA form and, when transcribed, an RNA form, both of which can affect genome regulation. TEs can serve as alternative promoters, exons, splicing regulators, and 3′ end modulators. They can also act as enhancers, drive three-dimensional (3D) genome organization, and give rise to long non-coding RNAs (lncRNAs) that serve as platforms for transcriptional and chromatin regulators. Mechanistically, TE repression involves DNA methylation, histone modification, phase-separated condensates, RNA modifications, RNA degradation, and nuclear compartmentalization, yet this repression can be selectively lifted during development or stress to expand regulatory potential. TEs therefore contribute to cell-type identity, developmental transitions, and responses to environmental stimuli, while their dysregulation is linked to human disorders including neurodegeneration, cancer, and autoimmune disease. TEs also hold translational promise as biomarkers and tools for gene and cell engineering. In summary, the pervasive integration of TEs as mini-genes, structural scaffolds, and regulatory elements redefines our view of the genome: rather than a gene-centric landscape dotted with repetitive “junk,” mammalian DNA is a TE-rich ecosystem in which TEs drive gene regulatory networks and evolution.
Cell, 189, 3513-3540
Summary
Transposable elements (TEs) comprise nearly half of mammalian genomes and have shaped genome architecture, chromatin organization, and transcriptional landscapes. Thanks to recent advances in long-read sequencing and functional (epi)genomics, the focus has shifted from TE families to individual TE loci, revealing widespread, locus-specific regulatory roles. While most TEs have lost the capacity to mobilize, they still retain a DNA form and, when transcribed, an RNA form, both of which can affect genome regulation. TEs can serve as alternative promoters, exons, splicing regulators, and 3′ end modulators. They can also act as enhancers, drive three-dimensional (3D) genome organization, and give rise to long non-coding RNAs (lncRNAs) that serve as platforms for transcriptional and chromatin regulators. Mechanistically, TE repression involves DNA methylation, histone modification, phase-separated condensates, RNA modifications, RNA degradation, and nuclear compartmentalization, yet this repression can be selectively lifted during development or stress to expand regulatory potential. TEs therefore contribute to cell-type identity, developmental transitions, and responses to environmental stimuli, while their dysregulation is linked to human disorders including neurodegeneration, cancer, and autoimmune disease. TEs also hold translational promise as biomarkers and tools for gene and cell engineering. In summary, the pervasive integration of TEs as mini-genes, structural scaffolds, and regulatory elements redefines our view of the genome: rather than a gene-centric landscape dotted with repetitive “junk,” mammalian DNA is a TE-rich ecosystem in which TEs drive gene regulatory networks and evolution.
Abstract
The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
Wednesday, September 23, 2026
Child neurology training
Rogers D, Stone RT, Ream M, Pearson R, Pagano LM, Bernson-Leung ME, Troy E, Otallah SI, Kossoff EH, Kessler SK, Borrero-Mejias C, Crowder D, Xixis KI, Rametta SC, Deputy S, Arya K, Nelson A, Wilson JL, McGregor A, Mangum T, Bain JM, Shiloh-Malawsky Y, Candee MS, Gilbert DL, Wollack JB, Qaiser S, Jones R, Strelzik J, Tiongson E, Venkatesan C, Goldstein J, Thamann A, Agurs LD, Schreiner TL, Wallace A, Foster-Barber A, Gottlieb-Smith R. Essential Components of Child Neurology Training: Program Director Consensus Recommendations. Ann Child Neurol Soc. 2025 Sep 17;3(4):282-291. doi: 10.1002/cns3.70038. PMID: 42563811; PMCID: PMC13359169.
Abstract
Objective: We aimed to develop a program director-derived model of essential components of child neurology residency training.
Methods: All 79 child neurology residency programs in the United States were invited to submit a block diagram with 48 months of required rotations, the minimum clinical requirement across all approved pathways. These block diagrams were then analyzed for consensus. Program directors were anonymously surveyed regarding whether a child neurology resident could be adequately trained using the consensus curriculum if implemented in either a 4- or a 5-year training program, and whether 4 years of residency could provide adequate training.
Results: Fifty of 79 residency programs (63%) submitted a block diagram (54% in pediatrics departments, 46% in neurology departments). Greater than 75% of program directors recommended the following rotations with the average number of months recommended across all program directors in parentheses: pediatric inpatient/hospital medicine (3), pediatric non-consult intensive care (3), healthy newborn (0.5), pediatric acute/emergency care (1), genetics (1), child development (1), child neurology inpatient/consults (8), child neurology general outpatient (4), child psychiatry (1), adult neurology inpatient/consults (3), neurology specialties outpatient (4), electroencephalography (2), neuroradiology (1), and electives (7). Of the program directors (53 of 79, 67%) who completed the post-survey, 87% agreed that these requirements would be adequate, and 89% agreed that child neurologists could be adequately trained for independent practice within 4 years.
Interpretation: The program director consensus supports modification of existing child neurology training requirements, with general agreement that 4 years of clinical training would be adequate.
Cohen BH, Gilbert DL, Xixis K, Banwell BL, Singh A, Pagano LM, Brooks-Kayal A, Kirkpatrick L, Schor NF, Mar SS, Crowder D, Terrell M, Kang PB. Education Research: The Future of Child Neurology Residency Training: The Perspective of a Child Neurology Society Task Force. Neurol Educ. 2026 Jun 12;5(2):e200331. doi: 10.1212/NE9.0000000000200331. PMID: 42311783; PMCID: PMC13271257.
Abstract
Background and objectives: Postgraduate residency in the United States is complex, and each medical field faces unique educational challenges. Child neurology has had a distinct identity for decades, yet its training curriculum originated from a joint venture of 2 larger and older fields, pediatrics and neurology. The traditional five-year training sequence consists of 2 years of pediatrics, 1 year of adult neurology, and 2 years of child neurology, as well as all other educational experiences, including electives. The contents of each major component have changed, in some instances dramatically, over the years, yet the original basic structure remains.
Methods: In anticipation of upcoming reviews of the child neurology training curriculum, the Child Neurology Society (CNS) convened a task force to review key aspects of this training curriculum. The task force members were surveyed anonymously both before and after a series of discussions to consider the current and expected educational needs of child neurologists in the mid-21st century, following a modified Delphi approach.
Results: The consensus was that child neurology has matured immensely as a field, with substantial subspecialization becoming common at major academic medical centers. There was significant variability in the availability of pediatric neurologic subspecialty training in fields such as neurogenetics and neuromuscular neurology across the United States. The preponderant view of the Task Force was that the child neurology training curriculum should be reviewed and potentially modified in accordance with the evolving educational needs of child neurologists, particularly with regard to general pediatrics and adult neurology training. The spectrum of faculty expertise and curricular emphasis across programs, viewed as a strength of training options, precluded reaching consensus on details of appropriate changes.
Discussion: The findings of the task force indicate that there will be a need for ongoing evaluation and updating of the child neurology training curriculum in future years. Before the next formal review of the child neurology training curriculum by the Accreditation Council for Graduate Medical Education, we recommend a robust discussion among multiple stakeholders, including accreditation bodies, medical specialty boards, and professional societies such as the CNS that represent child neurologists in practice and in training.
Thompson-Stone R, Gottlieb-Smith R, Rogers DA, Xixis K, Pearson R, Pagano L, Ream M. A Categorical 4-Year Child Neurology Residency: It's Time. Semin Neurol. 2026 Jun;46(3):275-282. doi: 10.1055/a-2767-2331. Epub 2025 Dec 11. PMID: 41380737.
Abstract
Child neurology training has undergone minimal change over the decades, despite a rapid growth in subspecialty knowledge, patient volumes, and complexity. The current 5-year structure, which was established due to necessary historical compromises between pediatrics and neurology, is increasingly misaligned with modern clinical practice and educational priorities. Most child neurologists no longer pursue dual pediatrics certification, and few provide neurologic care to adult patients. Meanwhile, the field has expanded significantly in complexity and volume, making it a large enough specialty to sustain an independent curriculum. We propose a streamlined 4-year categorical residency model that integrates relevant components of pediatrics and adult neurology while centering training around child neurology from the start. This model, which aligns better with structures seen in comparable specialties, prioritizes flexibility and increases the opportunities for longitudinal mentorship and professional development. Thoughtful planning and collaboration will be essential to surmount challenges during the transition, including changes in board certification and alterations to institutional funding. Modernizing child neurology training is essential to better prepare future specialists, support recruitment and resident development, and meet the evolving needs of children with neurologic disorders.
Abstract
Objective: We aimed to develop a program director-derived model of essential components of child neurology residency training.
Methods: All 79 child neurology residency programs in the United States were invited to submit a block diagram with 48 months of required rotations, the minimum clinical requirement across all approved pathways. These block diagrams were then analyzed for consensus. Program directors were anonymously surveyed regarding whether a child neurology resident could be adequately trained using the consensus curriculum if implemented in either a 4- or a 5-year training program, and whether 4 years of residency could provide adequate training.
Results: Fifty of 79 residency programs (63%) submitted a block diagram (54% in pediatrics departments, 46% in neurology departments). Greater than 75% of program directors recommended the following rotations with the average number of months recommended across all program directors in parentheses: pediatric inpatient/hospital medicine (3), pediatric non-consult intensive care (3), healthy newborn (0.5), pediatric acute/emergency care (1), genetics (1), child development (1), child neurology inpatient/consults (8), child neurology general outpatient (4), child psychiatry (1), adult neurology inpatient/consults (3), neurology specialties outpatient (4), electroencephalography (2), neuroradiology (1), and electives (7). Of the program directors (53 of 79, 67%) who completed the post-survey, 87% agreed that these requirements would be adequate, and 89% agreed that child neurologists could be adequately trained for independent practice within 4 years.
Interpretation: The program director consensus supports modification of existing child neurology training requirements, with general agreement that 4 years of clinical training would be adequate.
Cohen BH, Gilbert DL, Xixis K, Banwell BL, Singh A, Pagano LM, Brooks-Kayal A, Kirkpatrick L, Schor NF, Mar SS, Crowder D, Terrell M, Kang PB. Education Research: The Future of Child Neurology Residency Training: The Perspective of a Child Neurology Society Task Force. Neurol Educ. 2026 Jun 12;5(2):e200331. doi: 10.1212/NE9.0000000000200331. PMID: 42311783; PMCID: PMC13271257.
Abstract
Background and objectives: Postgraduate residency in the United States is complex, and each medical field faces unique educational challenges. Child neurology has had a distinct identity for decades, yet its training curriculum originated from a joint venture of 2 larger and older fields, pediatrics and neurology. The traditional five-year training sequence consists of 2 years of pediatrics, 1 year of adult neurology, and 2 years of child neurology, as well as all other educational experiences, including electives. The contents of each major component have changed, in some instances dramatically, over the years, yet the original basic structure remains.
Methods: In anticipation of upcoming reviews of the child neurology training curriculum, the Child Neurology Society (CNS) convened a task force to review key aspects of this training curriculum. The task force members were surveyed anonymously both before and after a series of discussions to consider the current and expected educational needs of child neurologists in the mid-21st century, following a modified Delphi approach.
Results: The consensus was that child neurology has matured immensely as a field, with substantial subspecialization becoming common at major academic medical centers. There was significant variability in the availability of pediatric neurologic subspecialty training in fields such as neurogenetics and neuromuscular neurology across the United States. The preponderant view of the Task Force was that the child neurology training curriculum should be reviewed and potentially modified in accordance with the evolving educational needs of child neurologists, particularly with regard to general pediatrics and adult neurology training. The spectrum of faculty expertise and curricular emphasis across programs, viewed as a strength of training options, precluded reaching consensus on details of appropriate changes.
Discussion: The findings of the task force indicate that there will be a need for ongoing evaluation and updating of the child neurology training curriculum in future years. Before the next formal review of the child neurology training curriculum by the Accreditation Council for Graduate Medical Education, we recommend a robust discussion among multiple stakeholders, including accreditation bodies, medical specialty boards, and professional societies such as the CNS that represent child neurologists in practice and in training.
Abstract
Child neurology training has undergone minimal change over the decades, despite a rapid growth in subspecialty knowledge, patient volumes, and complexity. The current 5-year structure, which was established due to necessary historical compromises between pediatrics and neurology, is increasingly misaligned with modern clinical practice and educational priorities. Most child neurologists no longer pursue dual pediatrics certification, and few provide neurologic care to adult patients. Meanwhile, the field has expanded significantly in complexity and volume, making it a large enough specialty to sustain an independent curriculum. We propose a streamlined 4-year categorical residency model that integrates relevant components of pediatrics and adult neurology while centering training around child neurology from the start. This model, which aligns better with structures seen in comparable specialties, prioritizes flexibility and increases the opportunities for longitudinal mentorship and professional development. Thoughtful planning and collaboration will be essential to surmount challenges during the transition, including changes in board certification and alterations to institutional funding. Modernizing child neurology training is essential to better prepare future specialists, support recruitment and resident development, and meet the evolving needs of children with neurologic disorders.
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