Levacetylleucine treatment of Niemann-Pick disease type C

N-acetyl-L-leucine (Levacetylleucine) normalizes Transcription Factor EB (TFEB) activity by stereospecific bidirectional modulation
Lianne C. Davis, Rebecca Braine, Grant C. Churchill, Mallory Factor, Taylor Fields, Marc Patterson, Frances Platt, Michael Strupp, Antony Galione. bioRxiv 2025.11.30.691375; doi: https://doi.org/10.64898/2025.11.30.691375

This article is a preprint and has not been certified by peer review

Abstract

Levacetylleucine (AqneursaTM), a chemically modified amino acid, is the only US Food and Drug Administration-approved monotherapy for the treatment of Niemann-Pick disease type C (NPC) (Beninger, 2024; Mullard, 2024; van Gool et al., 2025). This acetylated derivative of L-leucine functions as a pro-drug, with the acetyl group rendering it a substrate for the monocarboxylate transporter (MCT) family of transporters to allow appreciable penetration of the blood-brain barrier and its efficient uptake into cells (Churchill et al., 2021). Inside cells, levacetylleucine undergoes metabolism catalysed by acylases, and the resultant high quantities of L-leucine enter metabolic pathways which enhance mitochondrial bioenergetics and, as previously demonstrated, indirectly ameliorate lysosomal function (Kaya et al., 2020). Here, we show a novel aspect of levacetylleucine’s mechanism of action, demonstrating a direct effect on lysosomal function through its rapid modulation of the translocation of the transcription factor TFEB, a master regulator of lysosomal biogenic and autophagic genes (Napolitano and Ballabio, 2016), from cytoplasm to nucleus. Uniquely, we have demonstrated a biphasic action whereby levacetylleucine normalizes TFEB activity, consistent with levacetylleucine’s previously shown ability to regulate cellular homeostasis: in wild-type HeLa cells, levacetylleucine enhances and activates the translocation of TFEB to the nucleus. In contrast, in cellular models of NPC type 1 disease, where TFEB is already over-expressed in the nucleus (as the cell attempts to compensate for the primary defect by activating TFEB as a natural cellular response to the lysosomal substrate accumulation and associated cellular stress), treatment with levacetylleucine down-regulates and restores the distribution of TFEB to a more normalized cytoplasmic: nuclear ratio. Importantly, both effects of levacetylleucine occur at concentrations consistent with plasma concentrations in therapeutic dosing (Churchill et al., 2020). The effects were also confirmed to be stereospecific to the L-enantiomer, as neither the D-enantiomer (N-acetyl-D-leucine) or racemate (N-acetyl-DL-leucine) had any effect, The presence of the D-enantiomer in the racemic mixture inhibited the ability of levacetylleucine to promote TFEB bidirectional translocation, consistent with previous studies, which have established antagonism of N-acetyl-L-leucine by N-acetyl-D-leucine in the racemic mixture (rendering the racemic mixture without effect). This bidirectional mechanism of action of levacetylleucine to impact lysosomal function directly and normalize, either by activating basal TFEB signalling or reducing aberrant TFEB function in NPC1 knockout cells, thereby modulating lysosomal and autophagic functions, lends itself to the treatment of a broad range of neurological and neurodevelopment disorders.

Physicians receiving payments are more likely to prescribe the company’s drugs

Sayed A, Gupta R, Ramachandran R, et al. Industry payments to US neurologists related to multiple sclerosis drugs and prescribing (2015–2019): a retrospective cohort study. BMJ Open 2025;15:e095952. doi: 10.1136/bmjopen-2024-095952

Abstract

Objectives To measure the prevalence and magnitude of industry payments to neurologists prescribing multiple sclerosis (MS) drugs and determine whether payments are associated with prescribing.

Design Retrospective observational study.

Setting Data on neurologists prescribing MS drugs from 2015 to 2019 in the Medicare Part D database linked to the Centers for Medicare & Medicaid Services Open Payments database.

Participants 7401 neurologists prescribing MS drugs from 2015 to 2019 to Medicare beneficiaries.

Main outcome measures The primary outcome was the proportion of physicians’ annual prescriptions manufactured by a given company. Generalised linear mixed models were used to evaluate associations between the presence and magnitude of payments and prescribing. The association between prescription volume and the likelihood of receiving payments as well as the value of payments was also assessed.

Results Among 7401 neurologists, 5809 (78.5%) received payments totalling US$163.6 million between 2015 and 2019. While the median amount per physician was US$779 (IQR, US$188–US$2587), US$155.7 million (95.2%) accrued to the top 10% of payment recipients. Higher prescription volumes were associated with a higher likelihood of receiving any payment type, particularly for consulting services, non-consulting services and travel/lodging (p<0.001). Among payment recipients, the amount received was positively associated with prescription volume (p<0.001). Receipt of payments was associated with greater likelihood of prescribing the company’s drugs compared with those who received no payments from that company (OR 1.13 (95% CI 1.11 to 1.15)), with the largest association for non-consulting services, such as being a speaker at an event (OR 1.53 (95% CI 1.44 to 1.62)). Larger payments were associated with a greater likelihood of prescribing (OR 1.10, 1.26, 1.29 and 1.50 for US$50, US$500, US$1000 and US$5000, respectively), as were longer durations of payments (OR 1.12 for single year to 1.78 for 5 consecutive years) and more recent payments (OR 1.03 for payments made 4 years prior to 1.34 for payments made in the same year).

Conclusions Nearly 80% of neurologists prescribing MS drugs received at least one industry payment, with higher volume prescribers being more likely to receive payments. Physicians receiving payments were more likely to prescribe the company’s drugs, with a stronger association for payments that were larger, sustained and recent.

________________________________________________________________

A ‘Humbling’ Study

Two MS neurologists without ties to the research—Elizabeth Silbermann, MD, an assistant professor of neurology at Oregon Health & Sciences University (OHSU), and Mitchell Wallin, MD, MPH, FAAN, associate professor of neurology at the University of Maryland School of Medicine and director of the VA MS Center of Excellence—said Dr. Ross and his team made a good analysis of the data available to them.

“It's a good population-based sample of the United States with high numbers,” said Dr. Wallin, who thought it was wise that the researchers stopped the analysis at the beginning of the pandemic. He added that he was impressed that the study showed a dose-response relationship between payments and prescribing. “I think that it's a humbling article.”

Dr. Silberman called it a broad study that “captured data in the best way you can in the United States.” She said the high percentage of neurologists who accepted pharma money had a “bit of shock value.”
The data problem, which the researchers acknowledged, is that the study was limited to prescribing information from Medicare Part D. MS tends to be diagnosed among much younger people, so the study may have missed those just starting medications as well as some younger people with aggressive disease.

In addition, Dr. Wallin said that many MS experts at academic medical centers are now trying to wean older, stable patients from their medications. And newer infusion drugs are paid through Medicare Part B, so Part D data does not capture them.

Dr. Ross acknowledged that the data his team used skewed toward older patients and young ones with serious disabilities. However, the MS specialists included in the study also treat younger patients, and he thinks their prescribing habits likely transcended age. It is possible that industry influence on prescribing behavior is even more pronounced among younger patients because they change drugs more frequently, he said.

Dr. Wallin pointed out that insurance companies often resist paying for newer, more expensive drugs, which may mean that doctors end up prescribing medications that were not their first or even second choice.

Earlier this year, Dr. Silbermann's colleagues at OHSU published a study on uptake of generic glatiramer acetate and industry payments that found an association between the payments and prescriptions for the branded drug. Although generics became available in 2015, more than half of prescriptions in 2021 were still for the branded formulation. Neurologists who received industry payments were more likely to prescribe the branded drug, the study found.
One confounding factor, Dr. Silbermann said, is that drug companies often provide financial assistance for patients who take the branded drug.

Why Does This Problem Persist?

Asked why doctors continue to accept payments from drug companies when multiple studies have shown that it affects prescribing behavior, Dr. Ross said he has heard from other doctors that they don't think payments can influence them. Also, it's part of medical culture. Doctors think, “Everyone's doing it, so why shouldn't I?” he said.

Dr. Wallin, who does not accept direct payments from pharma, agreed that most physicians “believe that pharmaceutical reps don't really affect their behavior,” but “people are avaricious. That's the short answer.”

Unfortunately, he said, medical groups depend on industry to support their large, educational meetings, and he and Dr. Silbermann agreed that talking to sales reps can be valuable. She occasionally attends educational events sponsored by a drug company but doesn't eat or drink, except for a cappuccino she might accept from a drug company at a big meeting. Dr. Silbermann said she understands why hungry, time-pressed convention-goers might accept some food, though.

The big issue, she said, is that doctors need information about drugs, and it's hard to get it from primary sources. Keeping up to date on more than 20 medications might require reading 50 papers a year.
“Pharma picked up on a gap in the field, which is that physicians need to receive high-quality information in order to inform their practices,” she said. “It's really hard to receive high-quality information for free these days. Conferences are incredibly expensive.”

While many payments are small, they add up over time. Dr. Ross believes companies wouldn't spend the money if they didn't think the tactic was working.

“These companies aren't making these payments for nothing,” he said.

He had hoped that federal rules requiring disclosure of payments would make physicians stop taking them. At first, doctors worried about having their names and payment amounts made public. The information has been used for research, but fears of widespread embarrassment have not materialized.
“For the most part, it's kind of out of sight, out of mind,” said Dr. Ross, adding that half measures are unlikely to make a dent in the problem. “I think companies continue to engage in these practices because physicians engage in these practices. The way you would fix it would be to declare all payments to be in violation of kickback statutes and say they're illegal.” Current government guidance, he added, is “fuzzy.”

While Dr. Wallin thinks it makes sense to limit contact between drug company representatives and doctors in clinical practice, he wouldn't want to cut off all communication between drug makers and physicians. It's helpful to discuss side effects with company employees, he said. A middle ground might be an educational nonprofit that could accept pharma money but would not tie specific talks to an individual company, Dr. Wallin said.

National conferences, along with podcasts and journal groups from the AAN, can help physicians stay informed, Dr. Silbermann noted. A good starting point for further improvements, she said, would be for neurologists to raise awareness that an educational gap needs to be filled in a way that's less likely to influence physician decision-making.

Disclosures:
Dr. Ross was an expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. that was settled September 2022. He currently receives research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938), from the Greenwall Foundation, and from Arnold Ventures. Dr. Wallin is a principal investigator on a Sanofi-sponsored randomized controlled drug trial and received travel funding as a speaker from CMSC.

https://neurologytoday.aan.com/doi/10.1097/01.wnt.0001173580.24350.4e

ANKLE2 autosomal recessive congenital microcephaly

Inspired by sibling patients

Fishburn AT, Florio CJ, Lopez NJ, Link NL, Shah PS. Molecular functions of ANKLE2 and its implications in human disease. Dis Model Mech. 2024 Apr 1;17(4):dmm050554. doi: 10.1242/dmm.050554. Epub 2024 May 1. PMID: 38691001; PMCID: PMC11103583.

Abstract

Ankyrin repeat and LEM domain-containing 2 (ANKLE2) is a scaffolding protein with established roles in cell division and development, the dysfunction of which is increasingly implicated in human disease. ANKLE2 regulates nuclear envelope disassembly at the onset of mitosis and its reassembly after chromosome segregation. ANKLE2 dysfunction is associated with abnormal nuclear morphology and cell division. It regulates the nuclear envelope by mediating protein-protein interactions with barrier to autointegration factor (BANF1; also known as BAF) and with the kinase and phosphatase that modulate the phosphorylation state of BAF. In brain development, ANKLE2 is crucial for proper asymmetric division of neural progenitor cells. In humans, pathogenic loss-of-function mutations in ANKLE2 are associated with primary congenital microcephaly, a condition in which the brain is not properly developed at birth. ANKLE2 is also linked to other disease pathologies, including congenital Zika syndrome, cancer and tauopathy. Here, we review the molecular roles of ANKLE2 and the recent literature on human diseases caused by its dysfunction.

Fishburn AT, Florio CJ, Klaessens TN, Prince B, Adia NAB, Lopez NJ, Beesabathuni NS, Becker SS, Cherkashchenko L, Haggard Arcé ST, Hoang V, Shiu TN, Richardson RB, Evans MJ, Rückert C, Shah PS. Microcephaly protein ANKLE2 promotes Zika virus replication. mBio. 2025 Feb 5;16(2):e0268324. doi: 10.1128/mbio.02683-24. Epub 2025 Jan 13. PMID: 39804047; PMCID: PMC11796389.

Abstract

Orthoflaviviruses are positive-sense single-stranded RNA viruses that hijack host proteins to promote their own replication. Zika virus (ZIKV) is infamous among orthoflaviviruses for its association with severe congenital birth defects, notably microcephaly. We previously mapped ZIKV-host protein interactions and identified the interaction between ZIKV non-structural protein 4A (NS4A) and host microcephaly protein ankyrin repeat and LEM domain-containing 2 (ANKLE2). Using a fruit fly model, we showed that NS4A induced microcephaly in an ANKLE2-dependent manner. Here, we explore the role of ANKLE2 in ZIKV replication to understand the biological significance of the interaction from a viral perspective. We observe that ANKLE2 localization is drastically shifted to sites of NS4A accumulation during infection and that knockout of ANKLE2 reduces ZIKV replication in multiple human cell lines. This decrease in virus replication is coupled with a moderate increase in innate immune activation. Using microscopy, we observe dysregulated formation of virus-induced endoplasmic reticulum rearrangements in ANKLE2 knockout cells. Knockdown of the ANKLE2 ortholog in Aedes aegypti cells also decreases virus replication, suggesting ANKLE2 is a beneficial replication factor across hosts. Finally, we show that NS4A from four other orthoflaviviruses physically interacts with ANKLE2 and is also beneficial to their replication. Thus, ANKLE2 likely promotes orthoflavivirus replication by regulating membrane rearrangements that serve to accelerate viral genome replication and protect viral dsRNA from immune detection. Taken together with our previous results, our findings indicate that ZIKV and other orthoflaviviruses hijack ANKLE2 for a conserved role in replication, and this drives unique pathogenesis for ZIKV since ANKLE2 has essential roles in developing tissues.IMPORTANCEZIKV is a major concern due to its association with birth defects, including microcephaly. We previously identified a physical interaction between ZIKV NS4A and host microcephaly protein ANKLE2. Mutations in ANKLE2 cause congenital microcephaly, and NS4A induces microcephaly in an ANKLE2-dependent manner. Here, we establish the role of ANKLE2 in ZIKV replication. Depletion of ANKLE2 from cells significantly reduces ZIKV replication and disrupts virus-induced membrane rearrangements. ANKLE2's ability to promote ZIKV replication is conserved in mosquito cells and for other related mosquito-borne orthoflaviviruses. Our data point to an overall model in which ANKLE2 regulates virus-induced membrane rearrangements to accelerate orthoflavivirus replication and avoid immune detection. However, ANKLE2's unique role in ZIKV NS4A-induced microcephaly is a consequence of ZIKV infection of important developing tissues in which ANKLE2 has essential roles.

Shaheen R, Maddirevula S, Ewida N, Alsahli S, Abdel-Salam GMH, Zaki MS, Tala SA, Alhashem A, Softah A, Al-Owain M, Alazami AM, Abadel B, Patel N, Al-Sheddi T, Alomar R, Alobeid E, Ibrahim N, Hashem M, Abdulwahab F, Hamad M, Tabarki B, Alwadei AH, Alhazzani F, Bashiri FA, Kentab A, Şahintürk S, Sherr E, Fregeau B, Sogati S, Alshahwan SAM, Alkhalifi S, Alhumaidi Z, Temtamy S, Aglan M, Otaify G, Girisha KM, Tulbah M, Seidahmed MZ, Salih MA, Abouelhoda M, Momin AA, Saffar MA, Partlow JN, Arold ST, Faqeih E, Walsh C, Alkuraya FS. Genomic and phenotypic delineation of congenital microcephaly. Genet Med. 2019 Mar;21(3):545-552. doi: 10.1038/s41436-018-0140-3. Epub 2018 Sep 14. PMID: 30214071; PMCID: PMC6986385.

Abstract

Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM.

Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis.

Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1.

Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

Naveed M, Kazmi SK, Amin M, Asif Z, Islam U, Shahid K, Tehreem S. Comprehensive review on the molecular genetics of autosomal recessive primary microcephaly (MCPH). Genet Res (Camb). 2018 Aug 8;100:e7. doi: 10.1017/S0016672318000046. PMID: 30086807; PMCID: PMC6865151.

Abstract

Primary microcephaly (MCPH) is an autosomal recessive sporadic neurodevelopmental ailment with a trivial head size characteristic that is below 3-4 standard deviations. MCPH is the smaller upshot of an architecturally normal brain; a significant decrease in size is seen in the cerebral cortex. At birth MCPH presents with non-progressive mental retardation, while secondary microcephaly (onset after birth) presents with and without other syndromic features. MCPH is a neurogenic mitotic syndrome nevertheless pretentious patients demonstrate normal neuronal migration, neuronal apoptosis and neural function. Eighteen MCPH loci (MCPH1-MCPH18) have been mapped to date from various populations around the world and contain the following genes: Microcephalin, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6, MFSD2A, ANKLE2, CIT and WDFY3, clarifying our understanding about the molecular basis of microcephaly genetic disorder. It has previously been reported that phenotype disease is caused by MCB gene mutations and the causes of this phenotype are disarrangement of positions and organization of chromosomes during the cell cycle as a result of mutated DNA, centriole duplication, neurogenesis, neuronal migration, microtubule dynamics, transcriptional control and the cell cycle checkpoint having some invisible centrosomal process that can manage the number of neurons that are produced by neuronal precursor cells. Furthermore, researchers inform us about the clinical management of families that are suffering from MCPH. Establishment of both molecular understanding and genetic advocating may help to decrease the rate of this ailment. This current review study examines newly identified genes along with previously identified genes involved in autosomal recessive MCPH.

103 year old neurologist

Howard Tucker has lived through a World War, the dawn of penicillin and the invention of the MRI—but nothing prepared him for TikTok fame at more than 100 years old. The centenarian doctor-turned-viral-sensation still lectures at Case Western Reserve University—offering both medical insights and life advice in equal doses.

Tucker turns 103 today—and he’s still not ready to fully retire.

Neurologist, Navy veteran, lawyer and part-time lecturer at the School of Medicine, Tucker holds the Guinness World Record as the world’s oldest practicing doctor. Though he stopped treating patients in 2022—he still remembers the exact date, Nov. 15—he remains an active medical educator and is always looking for new opportunities.

“It all fell into place easily,” Tucker said of his long career. “Just things I did as I went. One step at a time. As far as I’m concerned, I’ve lived a pedestrian life.”

Others would disagree. A World War II veteran, Tucker earned his medical degree in 1947 (The Ohio State University College of Medicine), served as chief neurologist for the U.S. Atlantic Fleet during the Korean War and then, after law school at Cleveland State University’s Cleveland–Marshall College of Law, passed the Ohio Bar exam at age 67. His mental acuity still sharp and witty, Tucker continues to consult on medicolegal cases and lecture students at Case Western Reserve, where his seven decades of medical knowledge still resonate.

In 2021, his grandson, Austin, and filmmaker, Taylor Taglianetti, began documenting Tucker’s life in a film called What’s Next?; the pair is currently booking screenings and seeking broader distribution. The documentary’s companion TikTok account—intended mostly to archive footage—took off, attracting more than 100,000 followers. The page has 4.8 million “likes.”

“People want to hear from someone who has truly lived,” Austin Tucker said. “He flips the idea of aging. There are a lot of older adults who want to contribute—and can.”

The project earned a Webby Award in 2025—and a few unforgettable memories, including spending time with Snoop Dogg backstage.

“Grandpa closed down the (Webby) afterparty with Questlove at 2 in the morning,” Austin Tucker said. “It’s hard to put into words how surreal this has all been.”

The digital fame may be new, but Tucker’s message isn’t: Stay curious. Stay engaged. Never stop learning.

Words of wisdom

The elder Tucker reminds his Case Western Reserve medical students not to rely too heavily on technology and to value the patient’s story above all.

“The invention of the CT scan changed everything,” he said, “but you still need to take a good history.”

Tucker credits his own longevity to a combination of genetics (his younger brother turns 100 later this year), regular exercise, curiosity, humor—and a refusal to hate.

“Hatred is devastating to the person who hates,” he said. “Pulse, heart rate, blood pressure all go up. Jealousy is also tremendously unhealthy; just accept yourself as who you are.”

Tucker used to swim a mile each day and jogged regularly; now, he uses a treadmill—the handrails offer security and balance. He occasionally snowshoes with family, including his wife, Sue, of 68 years.

Asked to share his philosophy on living healthy, he doesn’t miss a beat: “Irish playwright Bernard Shaw said the key to longevity is no liquor, no smoking, no caffeine and no red meat. Winston Churchill said he started his day with brandy, smoked between eight and 12 cigars per day and finished his day with red meat. I say—with absolute hubris—that I’m smarter than both of them. Moderation is everything.”

His advice to living a long, rewarding and productive life? “Don’t smoke. Don’t hate,” he said. “And don’t retire unless you absolutely have to; there’s still so much to learn. Why stop now?
https://case.edu/news/his-103rd-birthday-case-western-reserve-university-school-medicines-howard-tucker-has-no-plans-slow-down

EEG abnormalities correlated with developmental delay/intellectual disability in the absence of clinical seizures

Lee YJ, Jo YH, Choi SH, Yoo HW, Jo HY, Park SJ, Park KH, Kong JH, Lee YJ, Nam SO, Kim YM. Is Electroencephalography Useful in Children with Developmental Delays but without Overt Seizures?. Ann Child Neurol. 2024;32(2):105-114.

Abstract

Purpose
Electroencephalography (EEG) is useful for clarifying the association between cortical activity and cognitive processes in children. We investigated whether EEG abnormalities were correlated with developmental delay/intellectual disability (DD/ID) in the absence of clinical seizures.

Methods
We retrospectively identified 166 children with DD/ID who underwent EEG at Pusan National University Hospital between January 2011 and December 2021. We compared clinical characteristics and test results between those with normal and those with abnormal EEGs. Additionally, we analyzed EEG abnormalities in relation to neurodevelopmental disorders, specifically autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).

Results
Of the 166 patients, 39 (23.5%) displayed abnormal EEGs, while 127 (76.5%) had normal EEGs. Of the former, 25 (64.1%) patients exhibited epileptiform discharges, including 22 (56.3%) with focal and three (7.7%) with generalized discharges. Focal discharges most frequently affected the central area (35.9%). Twenty patients (51.3%) exhibited rhythmic slowing patterns. Epilepsy diagnoses were significantly more common among patients with abnormal EEGs (n=8, 20.5%) than among those with normal EEGs (n=9, 7.1%) (P<0.001). Of 22 patients with ASD, five (12.8%) had abnormal EEGs. Of 13 patients with ADHD, five (36.4%) had abnormal EEGs, all with epileptiform discharges. Two patients with ASD and two with ADHD exhibited rhythmic slowing. Abnormal EEG findings were significantly more common among those with genetic abnormalities compared to genetically normal patients (26 vs. 13, P=0.017).

Conclusion
EEG represents a potential screening tool for children with DD. Abnormal EEG findings are associated with increased epilepsy risk, informing diagnosis and treatment planning.

I remain to be convinced.

Early phenotypic features of beta-propeller protein-associated neurodegeneration

Kim YS, Kim SY, Lee YJ, Oh SH, Choi SM, Lee JH. Early Phenotypic Features of Beta-Propeller Protein-Associated Neurodegeneration: Insights from a Korean Series. J Mov Disord. 2025 Dec 10. doi: 10.14802/jmd.25281. Epub ahead of print. PMID: 41367185.

Abstract

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked disorder caused by pathogenic variants in WDR45 gene. Early diagnosis remains challenging due to nonspecific presentations in childhood. We report six pediatric patients with BPAN, identified through genetic testing performed during the evaluation of neurodevelopmental disorders. All were female and exhibited early developmental delay, severe language impairment, and varying degrees of motor dysfunction. Seizures occurred in four patients with varying severity. Two patients showed signs of central precocious puberty. Serum neuron-specific enolase was elevated in all tested patients. Brain MRI revealed corpus callosum thinning in all cases. Iron accumulation in the substantia nigra and globus pallidus was observed in only two older patients. WDR45 variants included two nonsense, two splice-site, one in-frame deletion, and one novel frameshift deletion. Our findings highlight early clinical features that may aid in recognizing BPAN prior to the emergence of distinctive MRI abnormalities or degenerative-phase manifestations.

Rabies from kidney transplant

A tragic series of events led to a fatal case of transplant-related rabies earlier this year.

Health officials announced Thursday that an organ recipient who underwent transplant surgery in Ohio died of rabies in February. Further investigation revealed that the donor had become infected with the fatal virus after saving a kitten from a skunk.

The unnamed patient, from Michigan, received the donor’s kidney in December 2024, and later developed severe symptoms that prompted hospitalization and "invasive" procedures, the Centers for Disease Control and Prevention (CDC) said.

He reportedly experienced fever, tremors, difficulty swallowing and fear of water and died 51 days after the transplant.

The CDC said the donor, whose donated tissue went to three other recipients, was infected with the silver-haired bat variant of rabies, suggesting the skunk had been infected by a bat.

Records revealed that the organ donor, from Idaho, was scratched on the shin while fending off a skunk that displayed "predatory aggression" six weeks before his death.

"In late October 2024, a skunk approached the donor as he held a kitten in an outbuilding on his rural property," the CDC said. "During an encounter that rendered the skunk unconscious, the donor sustained a shin scratch that bled, but he did not think he had been bitten. According to the family, the donor attributed the skunk’s behavior to predatory aggression toward the kitten."

In the following five weeks, the donor began experiencing hallucinations, trouble swallowing, difficulty walking and a stiff neck, the agency said.

Two days later, he was discovered unresponsive at home after a suspected heart attack, according to health officials. He was reportedly revived at a hospital but was declared brain-dead and removed from life support.

The CDC said his organs were donated after the family documented the skunk encounter in a donor risk assessment. However, health officials noted that the form did not screen for rabies, citing its "rarity in humans."

"In the United States, potential donors’ family members often provide information about a donor’s infectious disease risk factors, including animal exposures," the CDC said. "Rabies is excluded from routine donor pathogen testing because of its rarity in humans in the United States and the complexity of diagnostic testing. In this case, hospital staff members who treated the donor were initially unaware of the skunk scratch and attributed his pre-admission signs and symptoms to chronic comorbidities."

Health officials added that three other patients received corneal tissue from the same infected donor. They all underwent graft removal, received rabies treatment and remained asymptomatic, the CDC reported.

Health officials also reached out to 370 people who could have been in contact with the donor, according to the agency. Forty-six of them were recommended to undergo rabies procedures.

Health officials said the kidney recipient’s death marks the fourth documented case of rabies transmission through an organ transplant in the U.S. since 1978, emphasizing that the risk of such infections remains extremely low.

Transplant teams are now advised to consult public health officials if a potential donor has recent bites or scratches from rabies-susceptible animals, especially if the donor has had unexplained neurological symptoms.

However, "no standard guidance currently exists for addressing reported donor animal exposures by transplant teams," the CDC said.

About 1.4 million Americans receive care for possible rabies exposure annually, and fewer than 10 die from the disease due to effective prevention efforts, according to the agency.

Bonny Chu

https://www.foxnews.com/health/michigan-man-dies-rabies-after-receiving-kidney-from-infected-donor-who-saved-kitten-from-skunk-cdc

A Michigan resident has died of rabies after receiving an organ transplant.

The patient, who received the transplant at an Ohio hospital in December 2024, died of the fatal virus in January 2025, a spokesperson for the Michigan Department of Health and Human Services (MDHHS) confirmed to Fox News Digital.

"The person was a recent organ transplant recipient, and a public health investigation determined they contracted rabies through the transplanted organ," the spokesperson said.

The rabies confirmation was made by the CDC Rabies Laboratory.

The Michigan Department of Health and Human Services has worked closely with the Ohio Department of Health and the Centers for Disease Control and Prevention (CDC) on the investigation, the same source stated.

"Health officials worked together to ensure that people, including healthcare providers, who were in contact with the Michigan individual were assessed for possible exposure to rabies," the MDHHS stated. "Post-exposure preventive care, if appropriate, has been provided."

"There is no threat to the general public."

The organ donor was not a Michigan or Ohio resident, according to health officials. No additional information has been provided about the resident or the donor.

While organs are routinely screened for infectious diseases, cancers, quality and functionality prior to transplant, rabies testing is not typically performed.

"There is currently no country or institution that requires the screening of rabies among donors before organ transplantation surgery," according to information published by the National Institutes of Health.

In 2013, the CDC confirmed the death of four people in Maryland who contracted rabies after receiving organs from the same donor.

In 2004, the agency reported the rabies deaths of three people who received organs from a common infected donor.

What to know about rabies

Rabies is a deadly viral disease that is mainly transmitted to people and pets through bites or scratches from an infected animal, according to the CDC.

The virus affects the central nervous system, ultimately causing brain dysfunction. The infected person may experience anxiety, confusion, agitation and hallucinations, per the health agency.

Rabies is almost always fatal if the infected person does not receive medical attention before symptoms begin.

Around 60,000 people in the U.S. receive medical care after being exposed to rabies, the CDC stated.

Fewer than 10 deaths are reported in the country each year.

Most Americans who contract rabies are infected by bats.

Other animals that commonly carry rabies include raccoons, skunks and foxes.

Melissa Rudy

https://www.foxnews.com/health/patient-dies-rabies-organ-transplant-infected-donor