Mitchell syndrome ACOX1 mutation

When a patient with puzzling neurological symptoms enrolled in the Undiagnosed Diseases Network, researchers led by Dr. Hugo J. Bellen were set on solving the mystery. The patient presented with an unidentified late-onset neurodegenerative disorder. The team named this new syndrome “Mitchell Syndrome” in reference to the first patient to be diagnosed with this disorder and looked to identify its genetic basis. “On comparing the patient’s and his parents’ DNA, the team identified a mutation in the patient that resulted in a single amino acid substitution (N237S) in the ACOX1 protein. This change was seen only in the patient and was not present in either of his parents’ DNA, indicating that the patient had a de novo, or new, mutation on this gene,’ said Bellen, professor at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and also a Howard Hughes Medical Institute investigator. “With the help of the online gene-matching tool GeneMatcher, we found two more patients who had the same new mutation in the ACOX1 gene.”

All three patients, who ranged from 3 to 12 years old at the time of disease onset, had remarkably similar clinical features, including degeneration of peripheral nerves that caused a progressive loss of mobility and hearing. The three individuals had identical gene variants, a clear indication that ACOX1 dysfunction likely was the cause of the symptoms.

A medical mystery

The finding that an ACOX1 mutation was linked to Mitchell Syndrome initially baffled the researchers. The only known ACOX1-related disorder described in the medical literature at that time presented earlier in infancy with seizures, severe cognitive decline, neuro-inflammation and accumulation of very-long-chain-fatty acids in plasma and, more importantly, was caused by the lack of the ACOX1 protein – none of which was true for these three patients.

“The brain has large amounts of lipids, which are critical for the proper functioning of the nervous system. Abnormal breakdown of lipids in the brain and peripheral nervous system is associated with several neurodegenerative diseases,” Bellen said.

The gene ACOX1 is involved in lipid breakdown. It produces an enzyme called Acyl-CoA oxidase 1 that initiates a series of reactions that break down very-long-chain-fatty acids in small intracellular organelles called peroxisomes.

Fruit flies help solve the medical mystery

To resolve this conundrum, the Bellen team turned to fruit flies. The first surprising discovery made by the lead author, Hyunglok Chung, was that the ACOX1 protein is abundant and critical for the maintenance of glia, cells that support neurons. This uncovered a previously unknown role of peroxisomes in glial cells and paved the way for further experiments.

To understand how ACOX1 variants affect the function of glia, they generated two mutant fly lines, the first one lacked both the copies of ACOX1 gene and the second, carried the substitution mutation (N237S) found in one of the ACOX1 genes in the Mitchell Syndrome patients.

“Flies lacking ACOX1 mimicked the symptoms of ACOX1 deficiency in humans, including elevated levels of very-long-chain-fatty acids along with dramatic loss of glia and neurons and progressively impaired neuronal function. When we reduced the synthesis of very-long-chain-fatty acids in these flies by administering the drug bezafibrate, we observed significant improvement in lifespan, vision, motor coordination and neuronal function, implicating elevated levels of these lipids and their excessive accumulation in glia as an important contributor,” said Chung, postdoctoral fellow in the Bellen lab.

It is remarkable how well bezafibrate suppressed the symptoms of ACOX1 deficiency, suggesting a new therapeutic avenue for patients with this condition,” Bellen said.

In contrast to the loss of ACOX1, the introduction of the single amino acid substitution (N237S) in ACOX1 gene resulted in a hyperactive ACOX1 protein. Typically, breakdown of very-long-chain-fatty acids by the enzymatic action of ACOX1 produces small amounts of highly reactive oxygen species, but glial cells quickly neutralize them. However, in Mitchell’s Syndrome, hyperactive ACOX1 produces copious amounts of toxic reactive oxygen species, leading to the destruction of glia and their neighboring neurons.

The harmful effects due to hyperactive ACOX1 were potently reversed with the antioxidant N-acetyl cysteine amide (NACA). However, NACA did not suppress the lethality or toxic effects in flies that lacked ACOX1, a clear indication that the two diseases act via entirely different pathways and would need to be treated with two distinct therapeutic strategies.

“This study is a prime example of how combining UDN’s unique team science approach with power of fruit fly genetics is facilitating rapid and phenomenal progress in rare diseases research. We take on cases of patients with conditions never described before, uncover new diseases and find definitive molecular diagnosis for them. We make significant progress in unraveling the causes of these novel diseases and rapidly identify and test promising new treatment options,” Bellen said. “We have successfully identified more than 25 disease-causing genes within the past three years – a task that typically takes many years.”

The study appears in the journal Neuron.

https://www.texaschildrens.org/content/news-release/solving-puzzle-mitchell-syndrome

Chung HL, Wangler MF, Marcogliese PC, Jo J, Ravenscroft TA, Zuo Z, Duraine L, Sadeghzadeh S, Li-Kroeger D, Schmidt RE, Pestronk A, Rosenfeld JA, Burrage L, Herndon MJ, Chen S; Members of Undiagnosed Diseases Network; Shillington A, Vawter-Lee M, Hopkin R, Rodriguez-Smith J, Henrickson M, Lee B, Moser AB, Jones RO, Watkins P, Yoo T, Mar S, Choi M, Bucelli RC, Yamamoto S, Lee HK, Prada CE, Chae JH, Vogel TP, Bellen HJ. Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms. Neuron. 2020 May 20;106(4):589-606.e6. doi: 10.1016/j.neuron.2020.02.021. Epub 2020 Mar 12. PMID: 32169171; PMCID: PMC7289150.

Abstract

ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme of the very-long-chain fatty acid (VLCFA) β-oxidation pathway in peroxisomes and leads to H2O2 production. Unexpectedly, Drosophila (d) ACOX1 is mostly expressed and required in glia, and loss of ACOX1 leads to developmental delay, pupal death, reduced lifespan, impaired synaptic transmission, and glial and axonal loss. Patients who carry a previously unidentified, de novo, dominant variant in ACOX1 (p.N237S) also exhibit glial loss. However, this mutation causes increased levels of ACOX1 protein and function resulting in elevated levels of reactive oxygen species in glia in flies and murine Schwann cells. ACOX1 (p.N237S) patients exhibit a severe loss of Schwann cells and neurons. However, treatment of flies and primary Schwann cells with an antioxidant suppressed the p.N237S-induced neurodegeneration. In summary, both loss and gain of ACOX1 lead to glial and neuronal loss, but different mechanisms are at play and require different treatments.

Jafarpour S, Khoshnood M, Santoro JD. Child Neurology: Neurodegenerative Encephalomyelopathy Associated With ACOX1 Gain-of-Function Variation Partially Responsive to Immunotherapy. Neurology. 2022 Aug 23;99(8):341-346. doi: 10.1212/WNL.0000000000200935. Epub 2022 Jun 17. PMID: 35715200.

Abstract

Acyl-CoA oxidase 1 (ACOX1) is a peroxisomal enzyme involved in beta-oxidation of very-long-chain fatty acids. Although loss of function of ACOX1 had been previously described, gain-of-function variation of ACOX1 gene has been only recently identified, with a paucity of known cases. Gain-of-function variation results in overproduction of reactive oxygen species, resulting in progressive neurodegeneration with discrete relapses. We report the case of a 19-year-old woman with a 5-year history of longitudinally extensive posterior predominant myelopathy, bilateral corneal scars, and white matter lesions who presented with first-time seizure, progressive sensorineural hearing loss, ichthyosiform rash, and cauda equina syndrome. Extensive workup was unrevealing. The patient showed no response to high-dose steroids but stabilization and improvement with return to baseline over 6 months with IVIg and low-dose mycophenolate mofetil. Whole-exome sequencing performed 4 years before was nondiagnostic, but subsequent reanalysis revealed a heterozygous variation in the ACOX1 gene (NM_004035.6: c.710A>G, p.Asn237Ser), now considered to be pathogenic. This case reports a rare condition and highlights the importance of reanalysis of previously nondiagnostic genome/exome sequencing data. Furthermore, the patient's clinical stability for over 1 year on immunotherapy raises the possibility of disease modification in an otherwise universally fatal condition.

Shen M, Chen Q, Gao Y, Yan H, Feng S, Ji X, Zhang X. A de novo heterozygous variant in ACOX1 gene cause Mitchell syndrome: the first case in China and literature review. BMC Med Genomics. 2023 Jul 3;16(1):156. doi: 10.1186/s12920-023-01577-w. PMID: 37400800; PMCID: PMC10318832.

Abstract

Background

Mitchell syndrome (MITCH) is a rare autosomal dominant hereditary disorder, characterized by episodic demyelination, sensorimotor polyneuropathy and hearing loss. MITCH is caused by heterozygous mutation in the ACOX1 gene, which encodes straight-chain acyl-CoA oxidase, on chromosome 17q25.1. Only 5 unrelated patients have been reported so far, and no reports from China. Here, we describe the first MITCH case in a Chinese individual.

See: https://childnervoussystem.blogspot.com/2021/02/acox1-gain-of-function-mutation.html

Primary amoebic meningoencephalitis 7

A North Carolina teenager has died from a rare and often fatal infection caused by an amoeba found in warm freshwater, state health officials said.

In a GoFundMe set up by the teen’s mother, she shared that his first symptom was "severe headaches."

"I never imagined that something like this could be so serious," she said.

The illness is caused by Naegleria fowleri, an amoeba (one-celled living organism) that inhabits ponds, lakes and rivers.

"We extend our condolences to the family, friends and community impacted by this loss," the North Carolina Department of Health and Human Services said in a statement obtained by news outlets.

The teen’s death was reported just days after an 8-year-old girl in Louisiana succumbed to the infection.

"While these infections are very rare, this is an important reminder that this amoeba is present in our state and across the U.S.," State Epidemiologist Zack Moore, M.D., said in a prior statement. "There are steps people can take to reduce their risk of infection while swimming during the warmer months."

Naegleria fowleri — commonly referred to as a "brain-eating amoeba" — causes a life-threatening brain infection called primary amebic meningoencephalitis (PAM).

The amoeba is most active in the months that the water temperature stays elevated.

"It's typically this time of year when it's very hot outside, when there hasn't been a lot of rain … and the lakes and ponds get pretty stagnant and get very warm, and that's a great breeding ground for these type of natural inhabitants of those waters," Dr. Jeffrey Kahn, chief of pediatric infectious diseases at UT Southwestern and Children's Health in Dallas, Texas, told Fox News Digital.

The infection can occur when water containing the amoeba is forced up the nose, allowing the amoeba to travel to the brain. This can occur when someone jumps or dives into the water or participates in water sports.

"Once that happens, it's nearly a lethal disease," Kahn warned. "The mortality rate is close to 100%."

Naegleria fowleri does not cause illness via swallowing.

Warning signs to recognize

The initial symptoms of PAM usually begin about five days after exposure, but they can be noticed sooner.

Early signs usually include headache, nausea, fever and/or vomiting, the CDC’s website states.

As the infection progresses, people may experience confusion, slurred speech, stiff neck, disorientation, hallucinations, seizures and coma.

"By the time the [amoeba] enters the brain and starts to basically erode the brain tissue, it's too late."

"The initial symptoms are actually quite nonspecific — they don't point to one disease or another — but they can progress very rapidly," Kahn noted.

Diagnosis involves testing cerebrospinal fluid obtained through a spinal tap; specialized laboratory testing may be needed.

Symptoms usually begin about five days after exposure, although they can appear anywhere from one to 12 days later. Once symptoms start, the disease progresses rapidly.

Most people die within one to 18 days after symptoms begin, typically around five days, per the CDC.

Prevention of infection

To prevent potentially fatal infections, Kahn recommends either avoiding the types of waters where the amoeba is likelier to be found, or taking added precautions.

"If you are swimming in those waters, wear a nose clip, don't put your head underwater, those types of things," he said.

Drinking contaminated water does not present a risk, and the infection does not spread from one person to another.

Because the amoeba is found in soil, the CDC also recommends avoiding stirring up the sediment at the bottom of lakes, ponds and rivers.

Treatment of brain-eating amoebas

When a patient has been diagnosed with a brain-eating amoeba, treatment involves a combination of antimicrobial and anti-amoebic medications, including amphotericin B, azithromycin, rifampin and miltefosine.

"There has been a cocktail of antibiotics and antimicrobials that have been tried over the years — but with a very, very small number of cases every year, it's tough to draw any conclusions from that," Kahn said.

"In the cases we've seen, we typically throw a lot of these antibiotics as a therapeutic modality, but by the time the [amoeba] enters the brain and starts to basically erode the brain tissue, it's too late."

Those who experience sudden headache, fever, stiff neck or vomiting — especially if they have recently been swimming in warm freshwater — should seek immediate medical attention, the CDC recommends.

Melissa Rudy

https://www.foxnews.com/health/teen-dies-brain-eating-amoeba-days-after-young-girl-succumbs-same-rare-infection

Unattended children again

Virginia mom speaks out after being put on child abuse registry for letting child walk alone

A Virginia mom is appealing a criminal charge and her placement on the state’s child abuse and neglect registry after her 5-year-old son was stopped by security while walking alone through their gated community.

Karyann Parkinson said her son, Sam, had been walking along a familiar neighborhood path past a pond to collect goose feathers when a security guard encountered him and brought him home.

Police and Child Protective Services became involved, and Parkinson, who was eight months pregnant at the time, had her six-month jail sentence suspended, but the charge remains.

She was convicted of contributing to the delinquency of a minor, a first-degree misdemeanor, and was also placed on Virginia's Child Abuse and Neglect Central Registry for seven years.

Parkinson said she understands the shock people feel hearing about a child alone near a body of water, but sought to clarify what happened that day.

"I didn't send him to play at the pond," she told "Fox & Friends Weekend." "I sent him down the path that happens to go past the pond to collect goose feathers... I know that a lot of people have seen the headlines and seen '5-year-old alone at a pond.' And I think if I saw that in isolation, I'd probably be alarmed, too."

"But what this was, was a 5-year-old on a pathway that he's very familiar with in his neighborhood that he loves, the only place that he can remember ever living. And it just got turned into this whole situation where a lot of people were suddenly intervening and feeling like this was a really drastic parenting choice," she said.

The most difficult part for Parkinson is being on the Child Protective Services registry for so long, she told Fox News. That means she won't be able to volunteer in Sam's classroom until he enters sixth grade.

"We need to stop parenting from a place of fear and a place, you know, of obsessing over the unknown or some boogeyman who's going to jump out from behind a bush," Parkinson said.

She said her son was "pretty shaken up" after the incident but has since recovered.

"We had to do a lot of reassuring him and telling him, 'You didn't do anything wrong,'" Parkinson said. "He would ask me, 'Mom, am I allowed to ride my bike to swim practice? Am I allowed to ride my back to the tennis courts?'"

"Now it's just a blip on his radar. It's not really a part of his life anymore," she added.

Max Bacall

https://www.foxnews.com/media/virginia-mom-placed-child-abuse-registry-7-years-letting-5-year-old-walk-alone

See: https://childnervoussystem.blogspot.com/2015/04/unattended-children.html

https://childnervoussystem.blogspot.com/2016/02/unattended-children-2.html

https://childnervoussystem.blogspot.com/2024/11/unattended-children-redux.html

Sulforaphane and autism

McGuinness G, Kim Y. Sulforaphane treatment for autism spectrum disorder: A systematic review. EXCLI J. 2020 Jun 26;19:892-903. doi: 10.17179/excli2020-2487. PMID: 33013262; PMCID: PMC7527484.

Abstract

Autism Spectrum Disorder (ASD) is defined as a neurodevelopmental condition characterized by social communication impairment, delayed development, social function deficit, and repetitive behaviors. The Center for Disease Control reports an increase in ASD diagnosis rates every year. This systematic review evaluated the use of sulforaphane (SFN) therapy as a potential treatment option for individuals with ASD. PubMed.gov, PubMed Central, Natural Medicines, BoardVitals, Google Scholar and Medline were searched for studies measuring the effects of SFN on behavior and cognitive function. All five clinical trials included in this systematic review showed a significant positive correlation between SFN use and ASD behavior and cognitive function. The current evidence shows with minimal side effects observed, SFN appears to be a safe and effective treatment option for treating ASD.

Zhang X, He Q, Zhu YY, Lorimer GH, Bayram H, Ghiladi RA, Wang J. Emerging Promise of Sulforaphane in Autism: A Comprehensive Review of Its Therapeutic Potential and Mechanisms. ACS Chem Neurosci. 2026 Aug 5;17(15):2880-2892. doi: 10.1021/acschemneuro.6c00282. PMID: 42473985.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that emerges in early childhood and significantly impacts the quality of life for individuals and families. Currently, there are no specific medications available for ASD. Increasing attention is now focused on bioactive compounds with anti-inflammatory and antioxidant properties. Sulforaphane (SFN), a key member of the isothiocyanate family, is abundant in cruciferous vegetables. It exhibits potent antioxidant and anti-inflammatory effects with minimal side effects, while oxidative stress and inflammation are recognized triggers in ASD pathogenesis. As research deepens, SFN's physiological activities─including antioxidant, neuroprotective, and anti-inflammatory properties are gaining heightened attention. Building on prior studies, this review comprehensively summarizes seven potential pathways through which SFN protects neurodevelopment or reverses ASD-related neural damage, including Keap1/Nrf2/ARE; MAPKs; NF-κB; HSR; AhR/CYP1; Sirtuin-FOXO; and mTOR/autophagy signaling pathways, elucidating the potential mechanisms underlying its multifaceted actions. This review offers new insights for the comprehensive utilization of sulforaphane and the treatment of ASD.

Long J, Liao X, Tang Z, Han K, Chen J, Wang X, Liu J, Zhang Y, Zhang H. Investigating the clinical efficacy, safety and molecular mechanism of sulforaphane in autism spectrum disorder: an integrated study combining meta-analysis, network pharmacology, and computational biology. BMC Pharmacol Toxicol. 2025 Nov 22;26(1):217. doi: 10.1186/s40360-025-01052-5. PMID: 41275316; PMCID: PMC12751817.

Abstract

Background: Sulforaphane, a natural antioxidant rich in cruciferous vegetables, has emerged as a promising dietary supplement for autism spectrum disorder (ASD). However, its therapeutic efficacy remains controversial, and the pharmacological mechanisms are not fully elucidated.

Methods: Eligible randomized controlled trials were retrieved from PubMed, Web of Science, Embase, and Cochrane Library databases. Review Manager 5.4 was used for meta-analysis and bias risk assessment. Network pharmacology, Mendelian randomization, GEO data analyses, molecular docking, and molecular dynamics simulation were employed to explore the mechanisms of sulforaphane in ASD.

Results: Six trials involving 333 participants were included in the meta-analysis. Pooled results demonstrated that both 4-5 weeks and 8-10 weeks of sulforaphane supplementation significantly decreased the scores on the Social Responsiveness Scale compared to placebo controls. No significant difference was observed in the incidence of adverse events. Network pharmacology identified 10 core targets of sulforaphane in ASD, including AKT1, EGFR, HSP90AA1, SRC, CASP3, STAT1, MAPK1, MMP9, MAPK8, and JAK2. These targets were implicated in the PI3K-Akt signaling pathway, MAPK signaling pathway, Chemokine signaling pathway, Chemical carcinogenesis - reactive oxygen species, TNF signaling pathway, Th17 cell differentiation, mTOR signaling pathway, and IL-17 signaling pathway. Mendelian randomization further revealed an inverse association between STAT1 levels and ASD risk. GEO transcriptomic data provided independent validation for the network pharmacology predictions. The binding energies between sulforaphane and the top 10 core targets are all ≤ -4.0 kcal/mol. Molecular dynamics simulations further validated the stable interaction between MMP-9 and sulforaphane.

Conclusion: Sulforaphane may serve as an efficacious and safe adjunctive therapy for ASD, mediated by its anti-oxidant and anti-inflammatory effects along with the modulation of autophagy.

Guo J, Wang Y, He W, Lou M, Peng Y, Shi H, Lian A. Effects of sulforaphane on ABC and SRS scales in patients with autism spectrum disorder: a meta-analysis. Brain Dev. 2025 Apr;47(2):104321. doi: 10.1016/j.braindev.2025.104321. Epub 2025 Feb 14. PMID: 39951914.

Abstract

Autism spectrum disorder (ASD) has become an increasingly prominent global health issue. Sulforaphane is a phytochemical with multiple functions that target many of the same biochemical and molecular pathways (biomarkers) associated with ASD. This study aimed to conduct a meta-analysis based on sulforaphane's effect on Aberrant Behavior Checklist (ABC) and Social Responsiveness Scale (SRS) in patients with ASD. We conducted comprehensive searches in the PubMed, Medline, Cochrane, EMBASE, and Web of Science databases from their inception. The modified Cochrane risk of bias tool was used to check the risk of bias of the included studies. Review Manager 5.3 software was used to conduct this meta-analysis. The results of this meta-analysis showed that sulforaphane significantly improved irritability and hyperactivity symptoms, suggesting that sulforaphane has the potential for the combined treatment of autism. Additional studies are needed to confirm and explore the effect of sulforaphane.

Ou J, Smith RC, Tobe RH, Lin J, Arriaza J, Fahey JW, Liu R, Zeng Y, Liu Y, Huang L, Shen Y, Li Y, Cheng D, Cornblatt B, Davis JM, Zhao J, Wu R, Jin H. Efficacy of Sulforaphane in Treatment of Children with Autism Spectrum Disorder: A Randomized Double-Blind Placebo-Controlled Multi-center Trial. J Autism Dev Disord. 2024 Feb;54(2):628-641. doi: 10.1007/s10803-022-05784-9. Epub 2022 Nov 24. PMID: 36427174.

Abstract

Sulforaphane has been reported to possibly improve core symptoms associated with autism spectrum disorders from mostly small size studies. Here we present results of a larger randomized clinical trial (N = 108) in China. There were no significant changes in caregiver rated scales between sulforaphane and placebo groups. However, clinician rated scales showed a significant improvement in the sulforaphane group, and one third of participants showed at least a 30% decrease in score by 12 weeks treatment. The effects of sulforaphane were seen across the full range of intelligence and greater in participants over 10 years. Sulforaphane was safe and well-tolerated even for young children. The inconsistent results between caregiver and clinician rated scales suggest more clinical trials are needed to confirm our findings.

Ecopipam for Tourette syndrome 3

Gilbert DL, Atkinson SD, Kim DJB, Miller MM, Rice PM, Flatt JA, Karkanias GB, Munschauer FE, Bittman RM, Wanaski SP, Cunniff TM, Tomczak KK. Efficacy and Safety of Ecopipam for Tourette Syndrome: A Phase 3 Randomized Clinical Trial. JAMA Neurol. 2026 Jul 1;83(7):645-653. doi: 10.1001/jamaneurol.2026.1431. PMID: 42189524; PMCID: PMC13213590.

Abstract

Importance: Current Tourette syndrome (TS) pharmacotherapy is hindered by adverse effects and high discontinuation rates.

Objective: To evaluate the safety and maintenance of effect of ecopipam, a selective dopamine D1 receptor antagonist, for up to 24 weeks for TS.

Design, setting, and participants: This randomized clinical trial was a phase 3, double-blind, placebo-controlled, randomized withdrawal study conducted between January 31, 2023, and February 4, 2025. Participants were enrolled at 77 sites in 12 countries. Individuals 6 years and older with TS were eligible.

Intervention: In the 12-week, open-label period, ecopipam was titrated over 3 to 4 weeks (target dose, 1.8 mg/kg per day). Responders (≥25% improvement in Yale Global Tic Severity Scale Total Tic Score [YGTSS-TTS] at weeks 8 and 12) were randomized to continue ecopipam or taper to placebo for the 12-week double-blind period.

Main outcomes and measures: Time to relapse (≥50% loss of open-label period YGTSS-TTS improvement) in participants aged 6 to 18 years (primary) and adults (exploratory).

Results: The trial enrolled 216 participants (n = 167 [77.3%] pediatric; 146 [67.6%] male and 70 [32.4%] female) to the open-label ecopipam period. Of these, 43 pediatric participants (mean [SD] age, 14.3 [5.5] years) and 8 adult participants were randomized to receive ecopipam; 47 pediatric (mean [SD] age, 14.0 [5.8] years) and 6 adult participants were randomized to receive placebo. Ecopipam significantly reduced the relapse risk vs placebo in pediatric participants (hazard ratio [HR], 0.47; 95% CI, 0.26-0.84; P = .008; n = 90). In adults, the effect was directionally similar (HR, 0.51; 95% CI, 0.11-2.30; P = .37; n = 14) but not significant. The most frequently reported adverse events with ecopipam (open-label and double-blind periods) were somnolence (n = 24 [11.1%]), anxiety (n = 21 [9.7%]), headache (n = 21 [9.7%]), insomnia (n = 19 [8.8%]), tic (n = 17 [7.9%]), and fatigue (n = 14 [6.5%]). Ecopipam did not have a clinically meaningful impact on weight, metabolic parameters, or psychiatric scale measures. Drug-induced movement disorders were not observed.

Conclusions and relevance: Ecopipam maintained clinically meaningful TS symptom improvements and was well tolerated for up to 24 weeks. Adverse events primarily affected the central nervous system

Panda PK, Panda P, Dawman L, Mishra AS, Kumar V, Sharawat IK. Safety and Efficacy of Ecopipam in Patients with Tourette Syndrome: A Systematic Review and Meta-analysis. CNS Drugs. 2025 Feb;39(2):127-142. doi: 10.1007/s40263-024-01140-w. Epub 2024 Dec 27. PMID: 39730854.

Abstract

Background and objectives: Ecopipam is a selective antagonist of the dopamine D1 receptor, and its efficacy and safety have recently been explored in several clinical trials involving patients with Tourette syndrome (TS). The objectives of this systematic review were to determine the pooled estimate for efficacy [in terms of reduction in tic Yale Global Tic Severity Scale (YGTSS) scores] and safety of oral ecopipam in subjects with TS.

Methods: All clinical trials that explored the efficacy and/or safety of ecopipam in patients with TS were included to determine the pooled estimate for change in YGTSS, Clinical Global Impression (CGI)-TS, and the severity of comorbid attention-deficit hyperactive disorder (ADHD), obsessive compulsion disorder (OCD), and depressive symptoms, as well as the nature and frequency of adverse effects. Case-series, retrospective studies, and case reports were excluded. Databases, such as PUBMED, EMBASE, Cochrane Central Register of Controlled Trials, and SCOPUS were searched to identify these trials using suitable combination of MESH terms/keywords on 15 June 2024. ROB 2.0 and ROBINS-I tool were used to assess the risk of bias in included randomized-controlled trials (RCTs) and non-randomized intervention studies, respectively, and the GRADE system to determine the certainty of the collated evidence.

Results: A total of 96 records were identified in the database search and 31 records were screened after removing duplicates. After excluding 23 irrelevant records, the full-text review included 8 records. Finally, six publications from three completed clinical trials (two RCTs, with one having an open-label extension) and one ongoing clinical trial were included. A total of 251 participants were included. The pooled estimate for mean change in YGTSS-TTS from baseline to the completion of the randomization period was statistically better in the ecopipam group compared with the placebo group [mean difference: - 3.0, 95% (confidence interval (CI) - 4.2 to - 1.9, I2 = 55%, p < 0.0001]. The ecopipam group also fared statistically better in terms of YGTSS-motor tic score, phonic tic score, as well as CGI-TS-S (p < 0.0001). Changes in depressive and obsessive-compulsive symptoms were comparable in both groups, as well as the incidence of adverse effects.

Conclusions: Ecopipam is effective in reducing the severity of tics in subjects with TS and has a good safety profile. However, only a limited number of studies were included in the review, with some having small sample sizes and short duration of follow-up.

Gilbert DL, Budman CL, Singer HS, Kurlan R, Chipkin RE. A D1 receptor antagonist, ecopipam, for treatment of tics in Tourette syndrome. Clin Neuropharmacol. 2014 Jan-Feb;37(1):26-30. doi: 10.1097/WNF.0000000000000017. PMID: 24434529.

Abstract

Objectives: Dysregulation of dopaminergic signaling has been hypothesized to underlie the motor and phonic tics in Tourette syndrome (TS). The objective of this trial was to evaluate the safety and tic-reducing activity of the selective dopamine D1 receptor antagonist ecopipam in adults with TS.

Methods: This was a multicenter, nonrandomized, open-label study of 50-mg ecopipam daily (weeks 1-2) and then 100 mg daily (weeks 3-8), taken orally before bedtime. The primary efficacy end point was the change in the Yale Global Tic Severity Scale (YGTSS) total tic score. Comorbid psychiatric symptoms and premonitory urges were rated; weight, serum metabolic studies, and adverse effects were monitored.

Results: Eighteen adults (15 men; 15 white, 2 African American, 1 Asian), with a mean age of 36.2 years (range, 18-63 years), were enrolled, and 15 completed the study. Mean (SD) YGTSS Total Tic score was 30.6 (8.8) at baseline and 25.3 (9.2) at 8 weeks (2-tailed paired t17 = 4.4; P = 0.0004). Mean (SD) YGTSS impairment score was 29.7 (10.9) at baseline and 22.8 (13.7) at final visit (t17 = 2.2; P = 0.04). There was no significant change in premonitory urges or psychiatric symptoms. Mean change in weight was -0.7 kg (P = 0.07). The most commonly reported adverse events were sedation (39%), fatigue (33%), insomnia (33%), somnolence (28%), anxiety (22%), headache (22%), and muscle twitching (22%).

Conclusions: In this open-label study in adults with TS, tics were reduced after 8 weeks of treatment with ecopipam. To confirm safety and efficacy, randomized, double blind, placebo-controlled trials are warranted.

Great experiments 4

Courtesy of a colleague

Garrow JS, Gardiner GT. Maintenance of weight loss in obese patients after jaw wiring. Br Med J (Clin Res Ed). 1981 Mar 14;282(6267):858-60. doi: 10.1136/bmj.282.6267.858. PMID: 6783203; PMCID: PMC1504679.

In treatment of obesity restriction of food intake is necessary to achieve good results. Various operations have been devised to prevent patients overeating, but in this study jaw wiring was used to limit food intake. This procedure produces weight loss in obese patients but when the wires are removed the weight is usually regained. This report studied a group of patients whose weight loss was maintained after the wires were removed. A nylon cord fastened round the waist of the patient after weight reduction was found to act as a psychological barrier to weight gain. Seven patients were followed for 4-14 months after removal of jaw wires and regained a mean of only 5.6 kg of the 31.8 kg lost while their jaws were wired. This procedure compares favourably with other treatments for severe obesity.

Oligodendroglioma

Busy Philipps is “grateful to be alive” after a shocking health scare.

The 47-year-old actress revealed this week that doctors discovered a rare, slow-growing malignant tumor in her brain earlier this year, despite her having no obvious symptoms.

Philipps opened up about the ordeal in a People cover story published Wednesday, saying she underwent two surgeries as a result of her grade 2 oligodendroglioma.

The “Dawson’s Creek” alum called the past six months the “weirdest” of her life, dubbing herself “the luckiest girl in the world” after following through with a full-body MRI scan her primary physician had initially talked her out of.

She ultimately decided to schedule the scan after speaking with her cousin-in-law, Dr. Justin Donlan, an internist who told her that “knowledge is power.”

Doctors spotted the tumor during a Prenuvo scan on Feb. 12, just one day after her former co-star James Van Der Beek died of colorectal cancer at age 48. The star had actually been considering canceling her appointment when her husband suggested the health check might be “the best thing” she could do for her late friend.

So, what exactly is an oligodendroglioma — and what subtle symptoms can signal the disease? Here’s what to know.

What are oligodendrogliomas?

An oligodendroglioma is a rare type of brain tumor that can also develop in the spinal cord. It starts in oligodendrocytes, cells that help support and protect the nerve cells responsible for sending messages throughout the brain and nervous system, according to the Cleveland Clinic.

Philipps was diagnosed with a grade 2 oligodendroglioma, which is considered a “low-grade” tumor by the World Health Organization. That means it typically grows slowly and is generally easier to treat than more aggressive brain tumors.

“It is considered malignant, but it has the best prognosis of all of the malignant gliomas,” Dr. Alexandra Miller, Philipps’ neuro-oncologist at NYU Langone, told People.

“It’s sort of defined as a cancerous tumor based on the ability of the tumor to regrow over time, rather than it looking very malignant under the microscope.”

Higher-grade oligodendrogliomas are more aggressive. As they become more advanced, the tumors can grow faster, damage surrounding brain tissue and become more difficult to treat.

How common is oligodendrogliomas?

Oligodendrogliomas are relatively rare, accounting for an estimated 1.3% of all brain tumors in the US. About 1,100 Americans are diagnosed with the tumor each year, according to the American Brain Tumor Association.

They are most often diagnosed in adults between the ages of 20 and 40. The tumors are considered extremely rare in children under 15.

What are the symptoms of oligodendrogliomas?

Oligodendrogliomas can cause different symptoms depending on where the tumor is located and how big it grows. The most common warning sign is a seizure, which affects nearly 80% of patients, according to Columbia University.

When a tumor develops in the frontal lobe, it can trigger personality or behavior changes, as well as weakness or partial paralysis on one side of the body, known as hemiparesis.

Other symptoms can include headaches, partial vision loss and trouble with speech or language. Tumors in the temporal lobe, however, can be especially sneaky, sometimes causing few noticeable symptoms and going undetected for years.

Philipps said doctors caught her tumor before she developed any obvious symptoms. Still, in the years before her diagnosis, she had told her former “Dawson’s Creek” co-star and close friend Michelle Williams that she felt like her brain was “broken.”

“I’ve been saying this for the last few years,” Philipps told People. “I wasn’t consciously aware that anything was really wrong, but there was something that was misfiring. Like, I could not get a handle on it.”

How are oligodendrogliomas treated?

Oligodendrogliomas are considered one of the more treatable types of brain cancer.

Surgery is usually the first line of attack, with doctors aiming to remove as much of the tumor as possible without damaging healthy brain tissue. Depending on the results, patients may also need radiation or chemotherapy.

For Philipps, that meant a roughly five-hour surgery on March 2 to remove the 2.6-centimeter mass from her brain. Doctors identified it as an oligodendroglioma after biopsying the tumor.

Her doctors told her that waiting until she developed seizures could have allowed the tumor to grow to two or three times its size — potentially making it more difficult to remove completely.

Philipps initially made it through the operation without incident, but later developed a staphylococcus infection in her incision. She needed a second surgery to clean out the infected area and remove one of the tiny titanium tacks doctors had used to hold her skull bone in place.

Are oligodendrogliomas deadly?

Many patients have a good chance of living for years after diagnosis.

The outlook is typically better when the tumor is caught early. Between 69% and 90% of people with low-grade oligodendrogliomas are still alive five years after diagnosis, according to the Cleveland Clinic, with survival rates potentially even higher among younger adults.

For people with high-grade oligodendrogliomas, the five-year survival rate ranges from 45% to 76%.

Philipps told People she feels grateful for going through with the Prenuvo scan that caught her tumor, saying she hopes she can inspire other people to listen to their gut.

“We are frequently told by doctors that there is nothing to worry about [when] you kind of know that there’s something to worry about,” she said. “There’s nothing to be afraid of in having information. It’s only empowering.” 

McKenzie Beard

https://nypost.com/health/what-is-oligodendroglioma/