Late infantile epileptic encephalopathy

Kacker S, Phitsanuwong C, Oetomo A, Nordli DR Jr. Late infantile epileptic encephalopathy: A distinct developmental and epileptic encephalopathy syndrome. Epileptic Disord. 2024 Feb;26(1):98-108. doi: 10.1002/epd2.20185. Epub 2024 Jan 3. PMID: 38100275.

Abstract

Objective: Within the spectrum of developmental and epileptic encephalopathy (DEE), there are a group of infants with features that are distinct from the well-recognized syndromes of early infantile developmental and epileptic encephalopathy (EIDEE), infantile epileptic spasm syndrome (IESS), and Lennox-Gastaut syndrome (LGS). We refer to this condition as late infantile epileptic encephalopathy (LIEE). Our objective was to highlight the characteristics of this group by analyzing patients who exhibit prototypical features.

Methods: From July 2022 to May 2023, we searched for LIEE features in pediatric patients who underwent epilepsy follow-up at the University of Chicago Comer Children's Hospital.

Results: Out of 850 patients evaluated, thirty patients (3.5%) were identified with LIEE based on electroclinical characteristics. These patients had an average onset of epilepsy at 6.8 months and an average onset of LIEE features at 18.1 months. The epilepsy etiology was most commonly genetic and metabolic (50%), followed by congenital cortical malformations (23%), acquired structural abnormalities (20%), and unknown (7%). The predominant seizure types were myoclonic-tonic (70%), spasm-tonic (50%), epileptic spasms (47%), tonic (43%), and myoclonic (43%) seizures. All patients reported a history of either spasm-tonic or myoclonic-tonic seizures in addition to other types. All patients had EEGs showing discontinuity, electrodecrements, or both along with diffuse slowing, background voltages between 100 and 300 μV, and superimposed multifocal, diffuse epileptiform discharges. Every patient, except one, fulfilled the definition of drug-resistant epilepsy, and all reported either moderate-to-severe or severe developmental delay.

Significance: Late infantile epileptic encephalopathy (LIEE) is characterized by several unique clinical and electrographic features. Typically, LIEE manifests in patients during the second year of life and occurs before two years of age, hence late infantile onset. The condition is commonly observed in infants with symptomatic epilepsy. Myoclonic-tonic and spasm-tonic seizures are the quintessential seizure types. The inter-ictal EEG exhibits more organization and lower voltages than seen with hypsarrhythmia and lacks the defining EEG characteristics of EIDEE, IESS, or LGS. We propose that LIEE is a distinct electroclinical syndrome within the spectrum of developmental and epileptic encephalopathies.

Impact of seizures while driving prior to diagnosis in people with focal epilepsy

Bases B, Barnard S, French JA, Pellinen J; Human Epilepsy Project. Impact of Seizures While Driving Prior to Diagnosis in People With Focal Epilepsy: Motor Vehicle Accidents and Time to Diagnosis. Neurology. 2023 Sep 26;101(13):e1370-e1375. doi: 10.1212/WNL.0000000000207464. Epub 2023 Jun 7. PMID: 37286361; PMCID: PMC10558166.

Abstract

Objectives: To identify the type, frequency, and consequences of seizures while driving (SzWD) in people with epilepsy before diagnosis.

Methods: We performed a retrospective cohort study using the Human Epilepsy Project (HEP) to identify prediagnostic SzWD. Clinical descriptions from seizure diaries and medical records were used to classify seizure types and frequencies, time to diagnosis, and SzWD outcomes. Data were modeled using multiple logistic regression to assess for factors independently associated with SzWD.

Results: 32 prediagnostic SzWD were reported among 23/447 (5.1%) participants. Of them, 7 (30.4%) had more than 1. Six participants (26.1%) experienced SzWD as their first lifetime seizure. Most SzWD were focal with impaired awareness (n = 27, 84.4%). Of participants who had motor vehicle accidents (MVAs), 6 (42.9%) had no recollection. SzWD led to hospitalization in 11 people. The median time from first seizure to first SzWD was 304 days (IQR = 0-4,056 days). The median time between first SzWD and diagnosis was 64 days (IQR = 10-176.5 days). Employment was associated with a 3.95-fold increased risk of SzWD (95% CI 1.2-13.2, p = 0.03), and nonmotor seizures were associated with a 4.79-fold increased risk (95% CI 1.3-17.6, p = 0.02).

Discussion: This study identifies the consequences of seizure-related MVAs and hospitalizations people experience before epilepsy diagnosis. This highlights the need for further research aimed at improving seizure awareness and improving time to diagnosis.

Continuous immunotherapy may help patients with new onset refractory status epilepticus

New research shows that immunotherapy given up to 18 weeks after onset may help some patients who suddenly develop refractory continuous seizures, according to an abstract presented at the AAN Annual Meeting, held in Denver in April.

The researchers reviewed data on 135 patients with new onset refractory status epilepticus (NORSE) over nine years, 74 of whom had cryptogenic new onset refractory status epilepticus (C-NORSE). All patients received first-line immunotherapy, such as steroids, with 83.8 percent returning to “mental functionality" within a median duration of 30 days.

Seventy patients were followed up for one year, and 62 patients for two years. A year after the first treatment, 26 of the 70 patients (37.1 percent) achieved favorable outcomes (mRS 0, 1, and 2), increasing to 31 of the 62 patients (50 percent) after two years.

Some patients did not improve; an unfavorable prognosis was associated with hippocampal atrophy plus extra-limbic lesions observed on a three-month MRI (OR1.295, 95 percent CI 1.086 to 1.544, p=006) and prolonged unconsciousness longer than 60 days. Of the 60 patients who underwent sequential brain MRI imaging, 20 (33.3 percent) exhibited both the extra-medial temporal lobe (MTL) lesion and MTL atrophy, said Yoonhyuk Jang, MD, PhD, a neurologist at Seoul National University Hospital.

Study authors said they were drawn to the research topic because patients with C-NORSE often do not respond to treatment, and researchers were uncertain why some patients responded well to longer immunotherapy treatment and some developed hippocampal atrophy.

Investigators defined "continuous immunotherapy" as an intravenous infusion of steroid and immune globulin for five days, which counted as one session, followed by rituximab or tocilizumab for three months, six months, or a year. To account for the washout period of immunotherapy, Dr. Jang said, patients were considered to have received continuous immunotherapy if the time gap between one session of any immunotherapy and the next session was less than 90 days.

“The only thing we found was that cytokines such as IL-6, CXCL9, MIP-1alpha—those involving innate immunity—had some significant differences among the groups that had hippocampal atrophy or extra limbic lesions," said Dr. Jang.

Dr. Rani Sarkis, MD, MSc, an assistant professor of neurology at Brigham and Women's Hospital, who was not involved in the study, said that because C-NORSE is an uncommon disease, determining the best treatment has been challenging.

“The strength of this study is its prospective data, because you're trying to get outcomes at different time points and determine the longitudinal imaging changes, so those are definitely strengths," he said. “They're not commonly done for a disorder like this; you're usually doing retrospective analyses and struggling to find enough patients."

There was not a lot of information about the timing and the nature of immunotherapy, particularly how to optimize treatment to avoid the risks such as infection, Dr. Sarkis said, adding that he expected that to be provided in a separate abstract.

But Dr. Sarkis said it was helpful to have information doctors could use to counsel patients, like the three-month MRI features associated with an unfavorable prognosis.

​Michael Sperling, MD, FAAN, professor of neurology at Thomas Jefferson University and director of the Jefferson Comprehensive Epilepsy Center, said the findings were consistent with past studies, and that the research needed to clearly define “continuous immunotherapy."

“Usually, after IV therapy in the acute phase, therapy that alters the immune system is prescribed over a period of time. These agents are usually given in pulse fashion if intravenous, though some oral agents might be taken on a daily basis (but the IV drugs are usually preferred when therapy is started, though there are no good, randomized trials that have compared any two therapies)," Dr. Sperling said. He added that even the pulse IV therapies have long-lasting effect —for example, rituximab is given in two doses separated by two weeks, and it then lasts for up to six months.

​“The problem with the immune therapies is that no trials have been conducted to see if they really work in NORSE, or if the improvement is coincidental. We all would like to believe that they improve outcome, but the medical profession has a history of employing ineffective therapies because these treatments made sense, until they didn't."

https://journals.lww.com/neurotodayonline/blog/NeurologyTodayConferenceReportersAANAnnualMeeting/pages/post.aspx?PostID=200&utm_source=email_marketing&utm_medium=email&utm_campaign=health_hlrp_2024-AdSales-Daily%20Meeting%20eNewsletter-AAN-Neurology-Today-At-The-Meeting-AAN%20Annual%20Meeting-April%2025.01-SEND-ASID1809+SeedList&rid=V_0000000032999587&mkt_tok=NjgxLUZIRS00MjkAAAGStS68RkD6P1U9NGxeXG_x6XfYCX2J4mDuN_dN-cqPrm2dEJjUiFnhUom-qUpuAYcMcFwAVaN24arWdOYfqVSoyGklGMHkU0OzFyMcWVU5xtugrewlURY

Auto-brewery syndrome

A Belgian man has been acquitted of drunk-driving because he has auto-brewery syndrome (ABS), an extremely rare condition whereby the body produces alcohol, his lawyer has said.

Anse Ghesquiere said on Monday that in “another unfortunate coincidence” her client worked at a brewery, but three doctors who independently examined him had confirmed he had ABS.

Belgian media said in the verdict the judge emphasised that the defendant, who was not named in line with local judicial custom, did not experience symptoms of intoxication.

The Bruges police court, which acquitted the man, did not immediately reply to an email requesting comment.

Lisa Florin, a clinical biologist with the Belgian hospital AZ Sint-Lucas, said people with ABS produced the same type of alcohol as found in alcoholic drinks but that they generally felt less of its effects.

People are not born with ABS but can develop it when they already have another intestine-related condition. Patients can present with symptoms consistent with alcohol intoxication such as slurred speech, stumbling, loss of motor functions, dizziness and belching.

https://www.theguardian.com/world/2024/apr/22/belgian-man-whose-body-makes-its-own-alcohol-cleared-of-drunk-driving

See: https://childnervoussystem.blogspot.com/2016/01/pediatric-auto-brewery-syndrome.html

Genes play a very small role in determining left-handedness

I am left-handed

NPR's Ayesha Rascoe speaks with Clyde Francks, a geneticist in the Netherlands, about the latest research into what makes people left or right-handed.

AYESHA RASCOE, HOST:

If you're left-handed, like me, you know you are one of a rare and special breed. Just 10% of the world's population is estimated to be left-handed, but many common conceptions about left-handedness turn out to be wrong, starting with that it's definitely hereditary.

CLYDE FRANCKS: We actually think that most of the left-handedness in the population is not caused by genetic variants.

RASCOE: Clyde Francks is a geneticist and neuroscientist at the Max Planck Institute for Psycholinguistics in the Netherlands. He led a team that just published a paper about left-handedness in the journal Nature Communications.

FRANCKS: It's probably just kind of random fluctuations of chemicals in the very early developing brain in the embryo.

RASCOE: That surprised me. My mother's right-handed, but all of her children are left-handed. We thought being left-handed must have something to do with the genes we inherited. And it's even stranger because we don't all have the same father.

FRANCKS: The heritability of left-handedness is actually quite low. So in studies of twins, it's been measured at about only 25%. So in most people who are left-handed, there will not be a simple genetic explanation just running through the generations in a clear way.

RASCOE: But in the new research, Francks and his team did discover one gene that sometimes has an effect on which hand is dominant.

FRANCKS: What we knew before this study was that there were various common variants in the genome that had very, very tiny effects on the probability of being left-handed. And so what we did in the latest study was a quite different approach. We were looking for variants in the genome that are very rare in the population and are located in the specific parts of the genome that code directly for the proteins that our bodies are made of. And those kinds of genetic variants can actually have quite large effects on human traits when they're present in a small number of people.

RASCOE: The gene they analyzed is called TUBB4B. If someone has a particular variant of this gene, Francks says that person is very likely to be left-handed. But very few people, even very few left-handed people, have this variant.

FRANCKS: They're very rare in the population, so they would only be accounting for about 1 in 1,000 left-handers at most.

RASCOE: It's still very much a mystery why the vast majority of left-handed people are that way. His idea about random fluctuations of chemicals in the embryo is also unproven. But what about this question?

I've also heard that left-handed people are more creative because the left side of the body's controlled by the right side of the brain, and that's the creative side. Is that true?

FRANCKS: Yeah. I mean, I don't think that's true. No.

RASCOE: (Laughter).

FRANCKS: I know that this is - it's a popular thing. That's too simple. The differences between the hemispheres of the brain are much more subtle and complex than that, and each side is doing important things in any particular task that you're doing.

RASCOE: OK, so - but we are very special if we're left-handed. Science has confirmed that, right?

(LAUGHTER)

FRANCKS: Well, 10%, you know? You decide how special that is.

RASCOE: Oh, well, thank you. I appreciate that. I'll take that. Thank you so much. Clyde Francks, a geneticist at the Max Planck Institute for Psycholinguistics in the Netherlands. Thank you so much for joining us.

FRANCKS: Thank you.

https://www.npr.org/2024/04/21/1246163875/genes-play-a-very-small-role-in-determining-left-handedness-research-finds

Schijven D, Soheili-Nezhad S, Fisher SE, Francks C. Exome-wide analysis implicates rare protein-altering variants in human handedness. Nat Commun. 2024 Apr 2;15(1):2632. doi: 10.1038/s41467-024-46277-w. PMID: 38565598; PMCID: PMC10987538.

Abstract

Handedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in neurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or brain asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) or microtubule-associated proteins. Here we examine whether left-handedness is also influenced by rare coding variants (frequencies ≤ 1%), using exome data from 38,043 left-handed and 313,271 right-handed individuals from the UK Biobank. The beta-tubulin gene TUBB4B shows exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers than right-handers. The TUBB4B variants are mostly heterozygous missense changes, but include two frameshifts found only in left-handers. Other TUBB4B variants have been linked to sensorineural and/or ciliopathic disorders, but not the variants found here. Among genes previously implicated in autism or schizophrenia by exome screening, DSCAM and FOXP1 show evidence for rare coding variant association with left-handedness. The exome-wide heritability of left-handedness due to rare coding variants was 0.91%. This study reveals a role for rare, protein-altering variants in left-handedness, providing further evidence for the involvement of microtubules and disorder-relevant genes.

SPATA5L1(AFG2B) mutations

Inspired by a patient

Richard EM, Bakhtiari S, Marsh APL, Kaiyrzhanov R, Wagner M, Shetty S, Pagnozzi A, Nordlie SM, Guida BS, Cornejo P, Magee H, Liu J, Norton BY, Webster RI, Worgan L, Hakonarson H, Li J, Guo Y, Jain M, Blesson A, Rodan LH, Abbott MA, Comi A, Cohen JS, Alhaddad B, Meitinger T, Lenz D, Ziegler A, Kotzaeridou U, Brunet T, Chassevent A, Smith-Hicks C, Ekstein J, Weiden T, Hahn A, Zharkinbekova N, Turnpenny P, Tucci A, Yelton M, Horvath R, Gungor S, Hiz S, Oktay Y, Lochmuller H, Zollino M, Morleo M, Marangi G, Nigro V, Torella A, Pinelli M, Amenta S, Husain RA, Grossmann B, Rapp M, Steen C, Marquardt I, Grimmel M, Grasshoff U, Korenke GC, Owczarek-Lipska M, Neidhardt J, Radio FC, Mancini C, Claps Sepulveda DJ, McWalter K, Begtrup A, Crunk A, Guillen Sacoto MJ, Person R, Schnur RE, Mancardi MM, Kreuder F, Striano P, Zara F, Chung WK, Marks WA, van Eyk CL, Webber DL, Corbett MA, Harper K, Berry JG, MacLennan AH, Gecz J, Tartaglia M, Salpietro V, Christodoulou J, Kaslin J, Padilla-Lopez S, Bilguvar K, Munchau A, Ahmed ZM, Hufnagel RB, Fahey MC, Maroofian R, Houlden H, Sticht H, Mane SM, Rad A, Vona B, Jin SC, Haack TB, Makowski C, Hirsch Y, Riazuddin S, Kruer MC. Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss. Am J Hum Genet. 2021 Oct 7;108(10):2006-2016. doi: 10.1016/j.ajhg.2021.08.003. PMID: 34626583; PMCID: PMC8546233.

Abstract

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Grosch S, Kehrer M, Riess O, Bevot A, Haack TB. A further case of AFG2B-related neurodevelopmental disorder with hearing loss and microcephaly allows further clarification of pathogenicity of the variant c.1313T>C, p.(Leu438Pro). Mol Genet Genomic Med. 2024 Jan;12(1):e2310. doi: 10.1002/mgg3.2310. Epub 2023 Oct 30. PMID: 37902276; PMCID: PMC10767672.

Abstract

Background: Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing loss. We report on a 6 1/2-year-old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly.

Methods: We performed trio exome sequencing on the patient and her parents.

Results: Trio exome sequencing revealed likely pathogenic compound heterozygous missense variants in AFG2B [c.527G>T, p.(Gly176Val) and c.1313T>C, p.(Leu438Pro)] in the patient.

Conclusion: Of note, the change c.1313T>C, p.(Leu438Pro) has been observed in a previously published patient as part of a complex disease allele along with a second homozygous missense change, so the exact contribution of the two alterations to this patient's disease had initially remained unclear. Our results support the pathogenic relevance of the c.1313T>C, p.(Leu438Pro) allele while providing detailed insights into the disease manifestation of a further patient.

Keywords: AFG2B; neurodevelopmental disorder; trio exome sequencing.

Corpus callosotomy in pediatric drug-resistant epilepsy

Fine A. Any Way You Slice It: Corpus Callosotomy in Pediatric Drug-Resistant Epilepsy. Epilepsy Currents. 2024;0(0). doi:10.1177/15357597241242243

Abstract

Objectives:
Corpus callosotomy (CC) is used to reduce seizures, primarily in patients with generalized drug-resistant epilepsy (DRE). The invasive nature of the procedure contributes to underutilization despite its potential superiority to other palliative procedures. The goal of this study was to use a multi-institutional epilepsy surgery database to characterize the use of CC across participating centers.

Methods:
Data were acquired from the Pediatric Epilepsy Research Consortium (PERC) Surgery Database, a prospective observational study collecting data on children 0-18 years referred for surgical evaluation of DRE across 22 U.S. pediatric epilepsy centers. Patient, epilepsy, and surgical characteristics were collected across multiple CC modalities. Outcomes and complications were recorded and analyzed statistically.

Results:
Eighty-three patients undergoing 85 CC procedures at 14 participating epilepsy centers met inclusion criteria. Mean age at seizure onset was 2.3 years (0-9.4); mean age for Phase I evaluation and surgical intervention were 9.45 (.1-20) and 10.46 (.2-20.6) years, respectively. Generalized seizure types were the most common (59%). Complete CC was performed in 88%. The majority of CC procedures (57%) were via open craniotomy, followed by laser interstitial thermal therapy (LiTT) (20%) and mini-craniotomy/endoscopic (mc/e) (22%). Mean operative times were significantly longer for LiTT, whereas mean estimated blood loss was greater in open cases. Complications occurred in 11 cases (13%) and differed significantly between surgical techniques (p < .001). There was no statistically significant difference in length of postoperative stay across approaches. Mean follow-up was 12.8 months (range 1-39). Favorable Engel outcomes were experienced by 37 (78.7%) of the patients who underwent craniotomy, 10 (58.8%) with LiTT, and 12 (63.2%) with mc/e; these differences were not statistically significant.

Significance:
CC is an effective surgical modality for children with DRE. Regardless of surgical modality, complication rates are acceptable and seizure outcomes generally favorable. Newer, less-invasive, surgical approaches may lead to increased adoption of this efficacious therapeutic option for pediatric DRE.

Possible pulmonary benefit With Viltolarsen for Duchenne Muscular Dystrophy

Viltolarsen (Viltepso) was well tolerated by boys and men with Duchenne muscular dystrophy (DMD), with no new safety signals, according to results from the open-label, phase II Galactic53 trial.

The results also suggested a clinical benefit in pulmonary function with the exon-skipping therapy, as measured by percent predicted forced vital capacity (FVC%p) and peak cough flow (PCF), Michelle Previtera, PhD, associate director for medical affairs at NS Pharma, and colleagues reported during a late-breaking poster session at the American Academy of Neurology annual meeting.

Among ambulatory participants on viltolarsen, 90% showed an increase or stabilization in FVC%p from baseline, with a significant overall change at week 49 (least squares mean change 8.3%, P=0.02). Among nonambulatory patients, FVC%p increased for participants receiving viltolarsen, and decreased for the control group (least squares mean change 1.6% vs -3.2%, respectively).

"This is the first data on pulmonary function, so this was really encouraging to see in both the ambulatory and the nonambulatory population, because we haven't studied [it] in the nonambulatory population," Previtera told MedPage Today.

"Combined with previous motor function data, these results suggest an additional treatment benefit of viltolarsen for patients with DMD amenable to exon 53-skipping therapy," Previtera and colleagues reported in the poster.

Duchenne muscular dystrophy is incurable, occurring mostly in boys and caused by mutations in the dystrophin gene, leading to a loss of functional dystrophin and muscle damage. As patients lose muscle strength, pulmonary function is impacted, eventually resulting in assisted ventilation.

Exon-skipping therapies like viltolarsen can cause parts of the mutated gene to be skipped, yielding shortened usable dystrophin, according to Previtera and colleagues. The FDA granted viltolarsen accelerated approval status in 2020, and a confirmatory phase III trial is ongoing to assess clinical benefit for the drug in DMD patients with a confirmed dystrophin gene mutation amenable to exon 53 skipping.

The FDA granted accelerated approval to another exon 53-skipping therapy, golodirsen (Vyondys 53), in 2019. The first exon-skipping treatment granted accelerated approval in DMD was eteplirsen (Exondys 51) in 2016. Both of those products are made by Sarepta Therapeutics, which also received accelerated approval for another exon-skipping therapy, casimersen (Amondys 45), in 2021.

In the latest study, the researchers compared 20 ambulatory and nonambulatory males taking 80 mg/kg of viltolarsen intravenously once weekly to a control group of 48 males from the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS), matched for age and ambulatory and steroid status, among other baseline characteristics. Ambulatory males were about 10 years old, and non-ambulatory males were nearly 16.

Nearly all participants on viltolarsen (19 out of 20) experienced mild-to-moderate treatment-emergent adverse events (TEAEs), and four events were considered treatment-related. There were no serious adverse events, discontinuations due to TEAEs, or deaths.

Previtera and colleagues also measured an exploratory endpoint, PCF, in liters per minute (L/min). For ambulatory patients, the mean PCF change from baseline was larger in those on viltolarsen than CINRG DNHS controls. For nonambulatory patients, those on viltolarsen showed a significant mean change from baseline compared to the control group at week 49 (56.7 L/min higher, P=0.01).

In both ambulatory and nonambulatory patients receiving viltolarsen, total and midlevel elbow scores on the performance of upper limb 2.0 measurement remained stable over 49 weeks.

https://www.medpagetoday.com/meetingcoverage/aan/109696

Cenobamate associated with lower inpatient days and ER visits

Treatment of Focal Epilepsy with Cenobamate Associated with Lower Inpatient Days and ER Visits Compared with 7 Leading Anti-Seizure Medications

The addition of cenobamate to the treatment regimens of people with focal epilepsy was associated with lower rates of inpatient days and emergency room (ER) visits compared with the addition of 7 other leading anti-seizure medications (ASMs). This finding, which was presented at the American Academy of Neurology (AAN) 2024 Annual Meeting, results from a retrospective claims-based analysis study of health care utilization outcomes. Each of the 7 other ASMs were associated with higher inpatient days and HR visitation rates compared with cenobamate, and this trend was consistent across focal epilepsy subgroups.

The study included data for 58,786 individuals from the HealthVerity Marketplace Private Source 20 database with diagnosed focal epilepsy who were taking at least 1 ASM between 2017 and 2021. The study population was exposed to 84,301 lines of therapy (LOT) in total, and researchers used mixed-effect regressions to evaluate statistical associations between epilepsy-associated inpatient days and ER visits and LOT adding cenobamate or 7 other ASMs, which included:

Brivaracetam

Clobazam

Eslicarbazepine

Lacosamide

Lamotrigine

Levetiracetam

Fycompa (parempanel; Eisai, Nutley, NJ)

Participants experienced 170.6 inpatient days and 41.0 ER visits per 100 patient-years over 116,859.2 person years. Inpatient day and ER visitation rates for each of the 7 ASMs were higher than those of cenobamate (P≤.001). Per 100 patient-years, adjusted mean increases in inpatient days relative to cenobamate ranged from 1.7 for lamotrigine, to 6.4 for lacosamide. Compared with cenobamate, adjusted mean increases in ER visits ranged from 2.0 for brivaracetam, to 8.8 for levetiracetam, per 100 patient-years.

The study was conducted by investigators from the University of Pittsburgh School of Medicine, SK Life Science, and Epilogix.

https://practicalneurology.com/news/treatment-of-focal-epilepsy-with-cenobamate-associated-with-lower-inpatient-days-and-er-visits-compared-with-7-leading-anti-seizure-medications#:~:text=The%20addition%20of%20cenobamate%20to,%2Dseizure%20medications%20(ASMs).

Ecopipam for Tourette syndrome

Ecopipam reduced the number of tics and the level of daily interference they cause in children and adolescents with Tourette syndrome, according to the results of a re-analysis of the phase 2b D1AMOND study presented in April at the AAN Annual Meeting in Denver.

“If this finding is confirmed in future studies, we could tell kids and their parents that this medication cuts down on both the number of different tics and how much they interfere on a daily basis," said Donald L. Gilbert, MD, FAAN, professor of pediatrics and neurology at Cincinnati Children's Hospital Center, who presented the findings.

The findings provide more specificity on how ecopipam works in Tourette syndrome, building on previously reported results of the international, multicenter D1AMOND study in which 153 children with the condition were randomized to ecopipam or placebo. The study found that patients treated with ecopipam had a significant reduction in tic scores based on the Yale Global Tic Severity Scale at 12 weeks compared with placebo without the common side effects, such as weight gain, seen with conventional drugs used in this setting.

These conventional drugs block the dopamine D2 receptor, whereas ecopipam is the first in its class to block the dopamine D1 receptor. Dr. Gilbert said if phase 3 clinical trial results confirm the efficacy of ecopipam to treat unwanted or involuntary movements, “there may be more ways in the future to down-modulate dopamine signaling via other receptors in ways that may help our patients function better."

By providing more specificity on how ecopipam affects tics, Gilbert and colleagues hope to offer clearer communication to children and their parents on what they can expect with the drug if approved.

“When you are treating a neurologic condition for which the clinical outcome is rated on a scale, it may be helpful to think about what that scale is actually capturing," said Dr. Gilbert. “Can the improvement on the scale be re-analyzed in a way that allows for simple communication about possible “bad to good" benefits?"

Dr. Gilbert and colleagues did just that in their reanalysis. They recategorized each child's Yale Global Tic Severity Scale scores from the original number (1 to 5 for each tic characteristic subscale) into “bad" (representing a rating of 3 to 5) or “good" (rating from 0 to 2) for each tic characteristic. For each category, they then calculated how likely it was for the score on ecopipam to go from “bad" at baseline to “good" at 12 weeks and compared this with outcomes for those on placebo.

They found that ecopipam was associated with a greater probability of going from a bad to a good score for the number of tics and level of daily interference compared with placebo. When looking at motor tics only, the largest reductions statistically were in intensity scores following by number, frequency, and daily interference. For vocal tics, the largest reduction was seen in complexity scores.

Dr. Gilbert cited the fact that fewer kids who start with vocal tic subscores in the “bad" range as one challenge to doing a re-analysis of the data as “it would take a larger number of kids in a study to get an accurate estimate of “bad to good" changes for vocal tics."

Jeremiah M. Scharf, MD, PhD, a behavioral neurologist and director of the Tic Disorders Unit at Massachusetts General Hospital, said the findings were encouraging because they offer more positive information about ecopipam as a promising medication for people with Tourette syndrome.

“This is certainly the type of medication we would be interested in using if medication is required," said Dr. Scharf, who was not involved with the study. He stressed that front-line behavioral therapy is not always sufficient for children with Tourette syndrome, and a gap exists in available medical treatment, given the major side effects seen with the current dopamine D2 receptor blockers.

“This is very exciting for our field," he said, adding, however, that “ultimately, it's the phase 3 trial where the rubber meets the road."

https://practicalneurology.com/news/ecopipam-reduced-tics-in-children-and-adolescents-with-tourette-syndrome

Rare disease day

Rare and odd medical syndromes are hard for many people to understand — and are often hard to treat, according to medical experts.

Rare Disease Day is Feb. 28, 2023, a "globally-coordinated movement" concerning rare diseases that works toward "equity in social opportunity, health care and access to diagnosis and therapies for people living with a rare disease," according to Rarediseaseday.org.

Read on to learn more about three very rare and baffling disorders.

In the following three conditions, sufferers believe they are dead, suffer severe size distortions in their visual perception or speak in a foreign language and don't understand why or how it's happened.

Here's what to know about these conditions.

Cotard’s Syndrome or Walking Dead Syndrome

Cotard’s Syndrome, sometimes called Walking Dead Syndrome, is a relatively rare neuropsychiatric condition that was first described by Dr. Jules Cotard, a Parisian neurologist, in 1882.

That's according to Dr. Anne Ruminjo, a second-year psychiatry resident at Beth Israel Medical Center in New York, as well as Dr. Boris Mekinulov, a unit attending physician at Kingsbrook Jewish Medical Center in Brooklyn.

They describe the condition in a case report published in the medical journal Psychiatry MMC.

(Ruminjo A, Mekinulov B. A Case Report of Cotard's Syndrome. Psychiatry (Edgmont). 2008 Jun;5(6):28-9. PMID: 19727279; PMCID: PMC2695744.)

Cotard’s Syndrome comprises any one of "a series of delusions" stemming from a belief that a person has "lost organs, blood or body parts" or "has lost one’s soul or is dead," the physicians note in their report.

Cases have been noticed in patients with "mood disorders, psychotic disorders, and medical conditions," they said.

"Most cases of Cotard’s are more responsive to electroconvulsive treatment (ECT) than to pharmacological treatment," they share in the report.

The doctors explained a case of Cotard’s Syndrome that they were involved with as part of their work.

"Ms. L, a 53-year-old Filipino woman, was admitted to the psychiatric unit when her family called 911 because the patient was complaining that she was dead, smelled like rotting flesh and wanted to be taken to a morgue so that she could be with dead people," the doctors reported.

"The patient was complaining that she was dead, smelled like rotting flesh and wanted to be taken to a morgue so that she could be with dead people."

They said the patient was fearful that "paramedics" were trying to burn down the house where she was living with family members — and admitted to "hopelessness, low energy, decreased appetite and somnolence."

After treatment with medication during a hospital stay, the patient — during discharge, the doctors reported — "denied nihilistic or paranoid delusions and hallucinations and expressed hopefulness about her future and a desire to participate in psychiatric follow-up care."

Alice in Wonderland Syndrome

Alice in Wonderland Syndrome (AIWS) is a set of symptoms that produce an "alteration of body image," reported Dr. Anne Weissenstein, Dr. Elisabeth Luchter and Dr. Stefan Bittmann of the Pediatric Mind Institute in Gronau, Germany, in a report published in the Journal of Pediatric Neurosciences.

(Weissenstein A, Luchter E, Bittmann MA. Alice in Wonderland syndrome: A rare neurological manifestation with microscopy in a 6-year-old child. J Pediatr Neurosci. 2014 Sep-Dec;9(3):303-4. doi: 10.4103/1817-1745.147612. PMID: 25624952; PMCID: PMC4302569.)

"An alteration of visual perception is found in that way that the sizes of body parts or sizes of external objects are perceived incorrectly."

"An alteration of visual perception is found in [the] way that the sizes of body parts or sizes of external objects are perceived incorrectly," the doctors noted.

They added, "The most common perceptions [occur] at night."

While all causes of AIWS cases are "still not known exactly," the physicians shared that some causes are "typical migraine, temporal lobe epilepsy, brain tumors and psychoactive drugs and Epstein-Barr virus infections."

AIWS has no effective treatment, they noted.

Treatment plans consist of migraine prophylaxis (medication) and migraine diet, they reported.

"Chronic cases of AIWS do exist," they also pointed out.

Foreign Accent Syndrome

Foreign Accent Syndrome (FAS) is a speech disorder that causes a sudden change in spoken words, causing the sufferer to be perceived as speaking with a "foreign" accent, according to the University of Texas at the Callier Center in Dallas.

The center treats thousands of patients with a variety of hearing, language and speech disorders, according to its web page.

FAS is most often caused by brain damage due to "a stroke or traumatic brain injury," the center indicates.

"Other causes have also been reported, including multiple sclerosis and conversion disorder — and in some cases no clear cause has been identified."

Speech may be "altered in terms of timing, intonation and tongue placement," the center explains, "so that is perceived as sounding foreign."

"Remarkably, the brain damage had altered her melody of language, and she spoke with a German-like accent."

However, a sufferer’s speech remains "highly intelligible" and does not "necessarily sound disordered," the center also notes.

FAS has been documented in cases around the world, the same source indicates, including accent changes from "Japanese to Korean, British English to French, American English to British English and Spanish to Hungarian."

In perhaps the most well-known case of FAS, a 28-year-old woman was hit on the head by a bomb fragment after British bombers attacked Oslo, Norway, on Sept. 6, 1941.

The particular case is shared in a medical abstract by Dr. Erland Hem, adjunct professor in the Department of Behavioral Medicine at University of Oslo, Norway, and published by the National Institutes of Health (NIH).

(Hem E. En eiendommelig språkforstyrrelse etter bombelesjon i hjernen [A peculiar speech disorder due to bomb injury of the brain]. Tidsskr Nor Laegeforen. 2006 Dec 14;126(24):3311-3. Norwegian. PMID: 17170795.)

She was "seriously wounded" with a "large defect in the cranium frontally on the left side" — and doctors did not think she was not going to live.

"The brain damage altered her melody of language and she spoke with a German-like accent."

After being unconscious for three to four days, she then awoke — and had "right-sided hemiplegia and complete aphasia," the medical abstract indicates.

"She gradually recovered and two months later she was discharged from hospital," the same source says.

"Remarkably, the brain damage had altered her melody of language and she spoke with a German-like accent."

"This led to problems for her during the war: she was, for example, not served in shops."

The case story was published after the war by the Norwegian neurologist Georg Herman Monrad-Krohn. (MONRAD-KROHN GH. Dysprosody or altered melody of language. Brain. 1947 Dec;70(Pt 4):405-15. doi: 10.1093/brain/70.4.405. PMID: 18903253.)

It is the best-known case of Foreign Accent Syndrome, the abstract notes.

https://www.foxnews.com/lifestyle/walking-dead-syndrome-rare-conditions-baffle-doctors-researchers

See: https://childnervoussystem.blogspot.com/2023/08/foreign-accent-syndrome.html

https://childnervoussystem.blogspot.com/2019/05/foreign-accent-syndrome-3.html

https://childnervoussystem.blogspot.com/2018/02/foreign-accent-syndrome-2.html

https://childnervoussystem.blogspot.com/2016/06/foreign-accent-syndrome.html

https://childnervoussystem.blogspot.com/2017/09/alice-in-wonderland-syndrome.html

https://childnervoussystem.blogspot.com/2019/11/zika-virus-and-alice-in-wonderland.html

https://childnervoussystem.blogspot.com/2019/11/cotards-syndrome.html

Prosopometamorphopsia

Mello A, Stehr D, Bujarski K, Duchaine B. Visualising facial distortions in prosopometamorphopsia. Lancet. 2024 Mar 23;403(10432):1176. doi: 10.1016/S0140-6736(24)00136-3. PMID: 38521562 (no abstract)
_______________________________________________________________

It sounds like the stuff of horror films — but for people who are afflicted with a rare disorder, it’s a terrifying reality.

A condition called prosopometamorphopsia (PMO) causes facial features to appear distorted, according to researchers from Dartmouth College in Hanover, New Hampshire.

A study published in The Lancet revealed that a 58-year-old man reported seeing faces as distorted or "demonic" for 2½ years.

"The patient stated that the distortions — severely stretched features of the face, with deep grooves on the forehead, cheeks and chin — were present on every person's face he encountered, but he reported no distortions when looking at objects, such as houses or cars," the researchers wrote in the findings.

The patient did not see those same distortions when looking at two-dimensional faces on printed paper or digital screens.

Still, despite the distortions, the patient reported that he was able to recognize people.

After the researchers showed the man some images on a screen of a person, they then had him compare the images with that same person’s actual face.

The patient provided feedback on the differences he perceived between the two — and the researchers used computer software to edit the photograph to capture what he was seeing.

"Through the process, we were able to visualize the patient’s real-time perception of the face distortions," said Antonio Mello, a PhD student in psychological and brain sciences at Dartmouth who worked on the study, in a press release.

Dr. Jonathan Tiu, a neurologist and assistant professor of neurology at Hackensack Meridian School of medicine in New Jersey, was not involved in the study but reviewed the findings.

"Fascinatingly, the patient highlighted in the recent Lancet case report was still able to recognize everyone he was looking at," Tiu told Fox News Digital.

"This suggests that the brain's way of visually ‘displaying’ faces, and the brain's ability to recognize a person's face, might be occurring in two different parts of the brain."

What to know about PMO

The name of the disorder, prosopometamorphopsia, comes from "prosopo" (the Greek word for face, prosopon) and "metamorphopsia," which refers to perceptual distortions.

Tiu described PMO as a "very rare visual disorder" that causes a person to see visual distortions of facial features.

Experts don't fully understand how PMO occurs and who is more likely to experience it.

"This can include a twisting or stretching of someone's eyes or a visual ballooning of that person's chin, or they might even see features where they shouldn't be, like seeing that person's teeth hover over their lips," he said.

Experts don't fully understand how PMO occurs and who is more likely to experience it.

"It is thought that an injury to specific parts of facial processing networks in the brain, whether it be from a stroke or tumor, can produce the symptoms of PMO," Tiu said.

The condition has also been known to occur as an effect of migraines or seizures, but sometimes it comes on without any identifiable cause.

PMO is very rare, with fewer than 100 documented cases, according to the neurologist.

There are different types of PMO, as noted in a separate article published by senior author Brad Duchaine, a professor of psychological and brain sciences at Dartmouth.

"It’s a problem that people often don’t understand."

The two most common types are full-face prosopometamorphopsia (full-face PMO) and hemi-prosopometamorphopsia (hemi-PMO), he noted.

Most cases last only a few days or weeks.

Some patients, however, continue seeing the distortions for years.

Among the people who have had PMO, it is common for them to have been misdiagnosed at some point, the researchers stated in the study findings.

"We’ve heard from multiple people with PMO that they have been diagnosed by psychiatrists as having schizophrenia and put on anti-psychotics, when their condition is a problem with the visual system," Duchaine said in the release.

"And it’s not uncommon for people who have PMO to not tell others about their problem with face perception because they fear others will think the distortions are a sign of a psychiatric disorder," he added.

For those who have the condition, the optimal treatment should be tailored to the underlying cause of the symptom, Tiu noted.

In one study from 2021 that reviewed 81 individuals with PMO, the authors found that there was full or virtually full recovery in more than half of the reported cases, he pointed out.

"Of those who recovered, the PMO resolved quickly within days to weeks," Tiu said.

The facial processing networks that involve PMO may be in a part of the brain that has generally good potential for recovery.

"However, some patients took years to recover, and in a group of patients, the symptoms did not demonstrate any improvement."

The study authors concluded that the facial processing networks that involve PMO may be in a part of the brain that has generally good potential for recovery, Tiu added.

The Dartmouth researchers expressed hope that this latest study will help raise awareness of the rare but impactful condition.

As Duchaine added, "It’s a problem that people often don’t understand."

https://www.foxnews.com/health/rare-condition-caused-patient-see-demonic-faces-study-visual-disorder

Winton-Brown TT, Smith L, Laing J, O'Brien TJ, Neal A. Ictal face perception disturbance, tattoos, and reclaiming the self. Epilepsy Behav Rep. 2023 Mar 15;22:100595. doi: 10.1016/j.ebr.2023.100595. PMID: 37025370; PMCID: PMC10070365.

Abstract

We present a case of a young man with frightening ictal disturbance of face perception, or prosopometamorphopsia, arising from the left temporo-occipital region, leading to significant psychosocial impairment. A vivid forearm tattoo of the ictal experience conveyed its nature to the treating team and facilitated a psychotherapeutic process leading to significant psychosocial recovery. This case highlights the marked psychosocial and developmental impacts of epilepsy and the benefit of incorporating these into assessment and treatment.

Herald SB, Almeida J, Duchaine B. Face distortions in prosopometamorphopsia provide new insights into the organization of face perception. Neuropsychologia. 2023 Apr 15;182:108517. doi: 10.1016/j.neuropsychologia.2023.108517. Epub 2023 Feb 20. PMID: 36813107.

Abstract

Prosopometamorphopsia (PMO) is a striking condition of visual perception in which facial features appear distorted, for example drooping, swelling, or twisting. Although numerous cases have been reported, few of those investigations have carried out formal testing motivated by theories of face perception. However, because PMO involves conscious visual distortions to faces which participants can report, it can be used to probe fundamental questions about face representations. Here we review cases of PMO that address theoretical questions in visual neuroscience including face specificity, inverted face processing, the importance of the vertical midline, dissociable representations for each half of the face, hemispheric specialization, the relationship between face recognition and conscious face perception, and the reference frames that face representations are embedded within. Finally, we list and touch upon eighteen open questions that make clear how much is left to learn about PMO and the potential it has to provide important advances in face perception.

Blom JD, Ter Meulen BC, Dool J, Ffytche DH. A century of prosopometamorphopsia studies. Cortex. 2021 Jun;139:298-308. doi: 10.1016/j.cortex.2021.03.001. Epub 2021 Mar 12. PMID: 33865569.

Abstract

Prosopometamorphopsia is an extremely rare disorder of visual perception characterised by facial distortions. We here review 81 cases (eight new ones and 73 cases published over the past century) to shed light on the perception of face gestalts. Our analysis indicates that the brain systems underlying the perception of face gestalts have genuine network properties, in the sense that they are widely disseminated and built such that spatially normal perception of faces can be maintained even when large parts of the network are compromised. We found that bilateral facial distortions were primarily associated with right-sided and bilateral occipital lesions, and unilateral facial distortions with lesions ipsilateral to the distorted hemifield and with the splenium of the corpus callosum. We also found tentative evidence for the involvement of the left frontal regions in the fusing of vertical hemi-images of faces, and of right parietal regions in the fusing of horizontal hemi-images. Evidence supporting the remarkable adaptability of the network comes from the relatively high recovery rates that we found, from the ipsilateral hemifield predominance of hemi-prosopometamorphopsia, and from a phenomenon called cerebral asthenopia (heightened visual fatigability) which points to the dynamic nature of compensatory mechanisms maintaining normal face perception, even in chronic cases of prosopometamorphopsia. Finally, our analysis suggests that specialised networks for the representation of face gestalts in familiar-versus-unfamiliar faces and for own-versus-other face may be present, although this is in need of further study.

Moebius syndrome

Tayla Clement, 26, was born with a rare disorder that has made it impossible for her to smile — but she says she is grateful for it.

Born and raised in New Zealand, Clement has Moebius syndrome, a neurological disease that affects one child out of every 50,000 to 500,000 born, research shows.

Moebius occurs when a baby’s facial nerves are underdeveloped. The primary effects are facial paralysis and inhibited eye movement, but the condition can also cause difficulty with speech, swallowing and chewing, according to Johns Hopkins.

"The syndrome affects my sixth and seventh cranial nerve, so it's essentially like facial paralysis," Clement told Fox News Digital in an interview.

It also means Clement can’t move her eyebrows or upper lip — and can’t shift her eyes from side to side.

Dr. Juliann Paolicchi, a pediatric neurologist and the director of pediatric epilepsy at Staten Island University Hospital in New York, has treated several babies with Moebius syndrome. (She was not involved in Clement's care.)

"Infants born with the syndrome may have a lopsided face, may not be able to form a smile, and may have feeding problems early in life," she told Fox News Digital.

They can also experience orthopedic anomalies, such as abnormal development of the fingers and feet.

"Other parts of the face and eyes may be affected, such as a small jaw, cleft palate and smaller-sized eyes," Paolicchi added.

While children with Moebius syndrome do not have problems with intellectual development, social situations can be a challenge due to a decreased ability to demonstrate emotions with the face, Paolicchi said.

"They are often mistaken as being sad or overly serious, when they are simply just not able to smile," she added.

Growing up without the ability to smile brought plenty of challenges for Clement, she said.


She was born in 1997, before the advent of social media, so she wasn’t able to connect with others facing the same challenge.

"With the syndrome being super rare and also coming from a small country, it was quite isolating," she said.

"As an 11-year-old girl, I thought, if I could just smile, I would have friends and wouldn’t get bullied anymore."

Clement said she was bullied for years, "for as long as I can remember."

"It started off as verbal bullying — being told that I was ugly or worthless, or being isolated and not having any friends."

Things got worse when Clement was 11, after she had a major operation in an attempt to correct her inability to smile.

During the "invasive" nine-hour surgery, doctors took tissue from her right thigh and inserted it internally into the corners of her mouth and into her temples.

"The idea was that when I would clench down on my jaw, the tissue that was planted would pull the corners of my mouth up to mimic a normal smile," she recalled to Fox News Digital.

Paolicchi confirmed that corrective surgery is sometimes performed on babies and children with Moebius syndrome.

"This is a complicated and specialized procedure."

"The procedure, called the ‘smile’ surgery, helps not only appearance, but the ability to smile and to be able to pronounce words more clearly," she said.

"This procedure does involve transferring portions of the person's own muscle to the face and connecting it to the working nerves of the face. This is a complicated and specialized procedure and should only be performed by surgeons skilled in the procedure."

The surgery does come with risks. Clement noted that there was a "very fine line" between tightening the area too much — which would leave her with a permanent smile — and leaving it too loose and not seeing any results at all.

"As an 11-year-old girl, I thought, if I could just smile, I would have friends and wouldn’t get bullied anymore. So I jumped at the opportunity," she said.

"I just chose to believe in myself — and that I was destined for something bigger."

The surgery was unsuccessful — leaving Clement scarred and "completely broken," she said.

"It was such a horrible time for me," she said. "But looking back on it now, I couldn't be more grateful for the surgery being unsuccessful. I think it was all supposed to happen that way."

After the operation, the bullying got worse. In addition to calling Clement names, students pushed her into lockers, ripped off her backpack and threw her items on the floor, she said.

"That came with a lot of mental health challenges," she said. "For much of my childhood, I was quite depressed and anxious."

While Clement's family provided her with plenty of love and support — "they're the reason why I'm still here," she said — they didn't know how bad things really were.

"When I was younger, I never told my parents about what I was going through with the bullying," Clement said.

"There are still some things that I probably won't ever tell them about, because I don't want them to feel sad or upset," she went on. "I know they would feel like they could have done something, but there's nothing they could have done."

In 2015, during her senior year of high school, Clement began collapsing and experiencing seizures.

The next year, at 18, she was diagnosed with extreme clinical depression and anxiety, along with post-traumatic stress disorder, she said.

"Because I had been through so much stress and trauma, my brain was kind of shutting down," she said. "The seizures were like a physical form of how much I was struggling internally."

At the time, doctors and specialists told Clement that she would have seizures for the rest of her life, and that she'd always be dependent on other people.

But she was determined to prove them wrong.

Intensive therapy played a big part in her recovery, she said.

After her diagnosis, Clement underwent intensive therapy, which she said played a big part in her recovery.

She found herself at a "crossroads," she said, where she had to choose between working on her mental and physical health and putting herself into a better space, or continuing to feel "unhappy and miserable."

Clement chose the first path — although it wasn’t easy.

"There were days when I just wanted to give up. I didn't want to do life anymore because it was so hard," she said.

In her role as a sports content creator and host, Clement has leveraged her love of rugby into a "new lease on life — a real purpose," she said.

"I learned quite quickly that the only person who can truly help you is yourself."

Clement "worked tirelessly," continuing with therapy, reading many self-help books and adopting healthy daily routines.

"I just chose to believe in myself — and that I was destined for something bigger," she said.

As it turned out, the "something bigger" was a new career in sports.

Clement had always been a big sports fan — with a particular love of rugby, which is very popular in New Zealand.

In March 2023, she started creating social media content around rugby and motorsports. The Chiefs, a professional rugby union team in New Zealand, gave Clement her first opportunity.

This year, Clement interviewed players from four of the Super Rugby Pacific teams, including some of the best players in the world, such as two-time World Rugby Player of the Year Beauden Barrett.

In her role as a sports content creator and host, Clement said she's leveraged her love of rugby into a "new lease on life — a real purpose."

Since entering the rugby scene, she has worked to "bring inclusion" into the sport, with a goal of "inspiring, empowering and advocating for positive change."

Clement is also aiming, she said, to help other sports organizations incorporate more inclusion into their teams.

"I’ve known from a young age that I'm meant to help people," Clement told Fox News Digital. "Using my story and my voice to advocate for others and make the sports arena more inclusive makes me so happy. And I'm just getting started."

It has been three years since Clement experienced a collapse or seizure, she told Fox News Digital.

"I'm living a life I truly never could have dreamed of," she said. "I'm doing a job that I absolutely love, and I just did not think this level of happiness and contentment was accessible or attainable for me … It's been a long journey, and I’m very grateful for all of it."

Clement has also used her platform to connect with other people who have syndromes or disabilities. Her mission is to educate others about how to treat younger people who feel like they are "not seen or heard" — whether that’s in the sports arena or everyday life.

"I really needed someone like my present self when I was younger," she said. "It’s a full-circle moment to be there for other people now."

Despite the "dark times" she's experienced, Clement said that being born with Moebius syndrome and not being able to smile has turned out to be "the greatest gift."

"We're all born different and unique," she said. "It has given me the opportunity to use my voice and to be proud of my differences."

"Being alive is such a gift, and it’s a special thing to be born with Moebius syndrome. It doesn't make us any less worthy, beautiful or amazing."

Even though she can’t smile in the traditional sense, Clement says she has her own version.

"I think everyone's smile is different, just like everyone else is different," she said.

"I just smile in my own way."

https://ww.foxnews.com/health/girl-who-cant-smile-rare-disorder-became-woman-greatest-gift

See: Goldblatt D, Williams D. "I an sniling!": Möbius' syndrome inside and out. J Child Neurol. 1986 Jan;1(1):71-8. doi: 10.1177/088307388600100114. PMID: 3298396.

https://childnervoussystem.blogspot.com/2018/12/for-couple-with-moebius-syndrome-love.html

A new path to epilepsy treatment in children

In the past, clinical epilepsy studies performed mostly in adults suggested that patient outcome was not affected by how quickly patients were treated. Physicians generally waited to see if their patients had another seizure before starting treatment, and then paused to see if several medications failed their patients before sending them to an epileptologist.

That could mean six months or even two years of continued epilepsy. We didn’t always realize that at that point, the impact of persistent epilepsy on a developing nervous system could be catastrophic.

Since arriving at the University of Chicago Medicine Comer Children’s Hospital in 2018, one of my priorities has been to establish the New Onset Seizure Clinic so that children experiencing seizures can be rapidly seen and evaluated by a team with special expertise in pediatric epilepsy.

The concept behind the clinic is simple: every child diagnosed with epilepsy should see a specialist at least once, and preferably at the start of their illness. If they’re likely to have a stable course, they can be referred back to their community physicians, where they can be very well cared for. We call it a reverse referral concept. Since the clinic’s opening, there have been numerous success stories of patients being rapidly diagnosed, appropriately treated and who are now living seizure-free.

We have more tools at our disposal for diagnosing and treating epilepsy, so the situation has changed dramatically from when I started caring for patients in the 1980s. Between surgical, imaging and genetic advances, dietary treatments, microbiome research and autoimmune regulation, the possibility of eliminating pediatric drug-resistant epilepsy by 2030 is within our reach.

Thanks to better precision in choosing medicines, we are on the threshold of figuring out which medications are good for certain genetic conditions. Research on antisense oligonucleotides (ASO) and techniques using stereo electroencephalography, coupled with surgical advances like laser ablation – at UChicago Medicine, more than 150 such procedures have been performed – are helping us to better treat epilepsy and get to previously inaccessible parts of the brain like the insula.

Even time-tested treatments like the ketogenic diet are being used more effectively and earlier in the course of genetically determined epilepsies. In the past, many centers refused to use the ketogenic diet in infants. In 2001, our study in Pediatrics examined the remarkable effectiveness of treating infantile spasms with a ketogenic diet. More recently, the experience from a single center in Chicago (authored by colleagues who are now in South Korea, other parts of Chicago and Michigan), has shown how remarkably effective the diet can be in Foundation for Angelman Syndrome Therapeutics (FAST) went from being scoffed for their hope of finding a cure to being on the threshold of one. Their funding supported critical research that helped set in motion a series of remarkable achievements that may very soon culminate in a definitive treatment. Their sense of urgent need and laser focus propelled these advances. Citizens United for Research in Epilepsy (CURE) is another example of a remarkably efficient organization that funds more pediatric epilepsy research than any other group in the world.

We in academia need to efficiently align our academic missions with these remarkable groups that have been created and continue to be inspired by these highly dedicated parents. These parents want a cure for their children. If we clarify our professional aims, continue to place the needs of all children with epilepsy as the top priority and create effective alliances, I firmly believe we can finally achieve that goal. The next decade could be the best one ever for children with epilepsy.

https://www.uchicagomedicine.org/forefront/pediatrics-articles/2023/november/new-path-to-epilepsy-treatment

Medical terrorist

A Texas doctor who was dubbed a "medical terrorist," was found guilty of injecting heart-stopping poison into IVs at his former medical clinic in North Dallas.

FOX 4 in Dallas reported that a 12-person jury found Dr. Raynaldo Ortiz guilty on all 10 counts after nearly seven hours of deliberation.

When the verdict was read, Ortiz was reportedly wearing a mask and showed no emotion.

As a result of Ortiz’s action, several patients suffered cardiac emergencies and Dr. Melanie Kaspar died after using one of the IV bags, prosecutors said.

Federal prosecutors said the anesthesiologist committed the shocking crimes at Baylor Scott and White Surgicare North Dallas in retaliation for a medical misconduct probe. 

A criminal complaint accused Ortiz of injecting nerve blocking and bronchodilation drugs into patient IV bags.

Surveillance video showed the doctor placing an IV bag in a stainless steel warmer outside an operating room on Aug. 19, 2022. Minutes later, another staffer took the bag, and a patient soon after reportedly suffered a heart attack. 

Ortiz’s colleague, beloved anesthesiologist Melanie Kaspar, took a contaminated IV bag home on June 21 to rehydrate due to an illness. Almost immediately after inserting the IV into her vein, she suffered a serious cardiac event and died. An autopsy showed she was fatally poisoned by bupivacaine — a numbing agent that the Justice Department said "is rarely abused" but used to alleviate pain during surgery.

"There’s no closure. My best friend is gone," John Kaspar, Dr. Melanie Kaspar’s widower reportedly said shortly after the verdict. "I don’t think he ever looked me in the eye… It’s almost like you have so many emotions you can’t sift them out. You get flooded."

The station reported that the witnesses called to the stand during the trial included the anesthesiologist who discovered the bags were tainted, John Kaspar, and a teen who suffered cardiac arrest during nose surgery.

The incidents first began two days after Oritz was notified of a disciplinary inquiry against him over his handling of a medical emergency. Other doctors noted he complained the center was trying to "crucify" him.

FOX 4 reported that there were 13 patients between May and August 2022 who experienced similar cardiac emergencies, though prosecutors only charged the doctor with causing bodily injury to four of the patients in August.

A judge had ordered Ortiz be held before trial after prosecutors argued that he was a danger to the community by citing, in part, a 2015 incident in which he shot his neighbor's dog in retaliation for the woman helping his then-girlfriend obtain a restraining order against him after a domestic violence incident.

Ortiz was convicted of four counts of tampering with consumer products resulting in serious bodily injury, one count of tampering with a consumer product and five counts of intentional adulteration of a drug, prosecutors said.

Ortiz is expected to be sentenced in two to three months. He faces up to life in prison.

https://www.foxnews.com/us/texas-doctor-found-guilty-poisoning-patients-putting-dangerous-drugs-bags

Risk of autoimmune disease in research-identified cases of autism spectrum disorder

Villarreal VR, Katusic MZ, Myers SM, Weaver AL, Nocton JJ, Voigt RG. Risk of Autoimmune Disease in Research-Identified Cases of Autism Spectrum Disorder: A Longitudinal, Population-Based Birth Cohort Study. J Dev Behav Pediatr. 2024 Jan 1;45(1):e46-e53. doi: 10.1097/DBP.0000000000001232. PMID: 38364086; PMCID: PMC10878713.

Objective:

Determine the risk of autoimmune disease in research-identified cases of autism spectrum disorder (ASD) compared with referents using a longitudinal, population-based birth cohort.

Methods:

ASD incident cases were identified from a population-based birth cohort of 31,220 individuals. Inclusive ASD definition based on DSM-IV-TR autistic disorder, Asperger syndrome, and pervasive developmental disorder, not otherwise specified, was used to determine ASD cases. For each ASD case, 2 age- and sex-matched referents without ASD were identified. Diagnosis codes assigned between birth and December 2017 were electronically obtained. Individuals were classified as having an autoimmune disorder if they had at least 2 diagnosis codes more than 30 days apart. Cox proportional hazards models were fit to estimate the hazard ratio (HR) between ASD status and autoimmune disorder.

Results:

Of 1014 ASD cases, 747 (73.7%) were male. Fifty ASD cases and 59 of the 1:2 matched referents were diagnosed with first autoimmune disorder at the median age of 14 and 17.1 years, respectively. ASD cases had increased risk of autoimmune disease compared with matched referents (HR 1.74; 95% confidence interval [CI], 1.21–2.52). The increased risk was statistically significant among male patients (HR 2.01; 95% CI, 1.26–3.21) but not among the smaller number of female subjects (HR 1.38; 95% CI, 0.76–2.50).

Conclusion:

This study provides evidence from a longitudinal, population-based birth cohort for co-occurrence of ASD and autoimmune disorders. Thus, children with ASD should be monitored for symptoms of autoimmune disease and appropriate workup initiated.

Clinical effectiveness of newborn screening for spinal muscular atrophy

Schwartz O, Vill K, Pfaffenlehner M, et al. Clinical Effectiveness of Newborn Screening for Spinal Muscular Atrophy: A Nonrandomized Controlled Trial. JAMA Pediatr. Published online April 08, 2024. doi:10.1001/jamapediatrics.2024.0492

Key Points

Question Is early diagnosis through newborn screening associated with improved outcomes in infants with spinal muscular atrophy compared to those diagnosed after onset of symptoms?

Findings In this nonrandomized controlled trial within the SMARTCARE registry, patients identified by newborn screening showed better motor development with disease-modifying treatments than those who were diagnosed after onset of symptoms.

Meaning These results offer supporting evidence for the benefit of newborn screening for spinal muscular atrophy.

Abstract

Importance There is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking.

Objective To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset.

Design, Setting, and Participants This nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months.

Exposure Patients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system.

Main Outcomes The primary end point was the achievement of motor milestones.

Results A total of 234 children (123 [52.6%] female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%).

Conclusions and Relevance This nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group.
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Children with spinal muscular atrophy (SMA) identified by newborn screening showed better motor development with disease-modifying treatment than those diagnosed after symptom onset, a German cohort study showed.

Nine out of 10 (90.9%) of kids identified with SMA on newborn screening gained the ability to sit independently at a median age of 9 months, compared with 74.2% of children diagnosed after symptom onset who could sit independently at a median age of 14 months, reported Janbernd Kirschner, MD, of the University of Freiburg in Germany, and colleagues.

The ability to walk independently was gained by 63.6% of patients in the newborn screening cohort at a median age of 17 months, compared with 14.7% of patients in the symptom onset group at a median age of 23.5 months, they noted in JAMA Pediatrics.

Increasingly, countries are "introducing newborn screening for spinal muscular atrophy," Kirschner told MedPage Today in an email. In the U.S., SMA newborn screening has been adopted in all 50 states. Though "good response with early initiation of treatment is evident from clinical experience and uncontrolled studies, this is the first study to evaluate the effect of newborn screening with a parallel control group," he said.

"The situation in Germany with a regional pilot project provided a unique opportunity to compare screened and unscreened patients within the same health system," he added.

Specifically, data from the SMARTCARE registry -- a registry for patients with SMA comprising 70 healthcare facilities in Germany, Austria, and Switzerland -- were used in the study. Patients born in two federal states in Germany underwent SMA screening for a newborn screening pilot project, and all other patients were diagnosed after clinical symptom onset. All patients received standard care within the same healthcare system.

Ultimately, data from the SMARTCARE registry were used to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to three SMN2 copies, as onset is often later in children with more than three SMN2 copies. Analysis was performed in February 2023, in order for patients to have a minimum follow-up of 18 months.

"The SMARTCARE study group presents an important addition to the body of evidence supporting NBS [newborn screening] for SMA by looking at real-world effectiveness of NBS," Maryam Oskoui, MD, MSc, of Montreal Children's Hospital in Canada, and colleagues wrote in an accompanying editorial. "Effectiveness will include infants who are treated late and are already symptomatic, i.e., infants who would have otherwise been excluded from the presymptomatic clinical trials."

"When counseling families of infants identified through SMA NBS programs or when building a health economic model for these programs, it is important to consider potential outcomes based on effectiveness studies rather than efficacy in presymptomatic treatment trials," they added.

A total of 234 children were included in the analysis: 44 from the newborn screening cohort, and 190 in the clinical symptom onset cohort.

Mean CHOP-INTEND [Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders] scores -- for which higher scores indicate better motor function -- at 18 months were 59.5 in the newborn screening cohort and 47.7 in the symptom onset group. At 34 months, scores were 62.6 and 52.2, respectively.

Before treatment, 5.8% of patients in the symptom onset cohort required permanent ventilator support and 10.6% used occasional ventilation. In the same group, 2.6% of patients started permanent ventilation after treatment, and 16.8% required intermittent ventilation. In the newborn screening cohort, 6.8% of patients depended on intermittent ventilation.

Once under treatment, 4.5% of patients in the newborn screening cohort and 3.2% of patients in the symptom onset cohort could be weaned from ventilator support.

Additionally, before treatment, exclusive tube feeding was required by 7.4% of patients in the symptom onset cohort and supplemental tube feeding was required by 4.7%. In the newborn screening cohort, 2.3% of patients required supplemental tube feeding.

After the start of treatment, one patient diagnosed via newborn screening required exclusive tube feeding and 29 patients in the symptom onset group began to use tube feeding (12 exclusively and 17 supplementally). None of the patients stopped tube feeding during follow-up.

Limitations of the study included that data from the minimum follow-up to 18 months of age were not available from all patients within the SMARTCARE registry, which could introduce survival bias.

Still, the study provides evidence supporting newborn screening for SMA, and is "important for prognostication and to counsel families with regard to treatment expectations," the researchers said.

"While patients still asymptomatic at treatment initiation have a good chance of achieving independent ambulation," they wrote, "this is rather unlikely for those who already exhibited clear symptoms of SMA at treatment onset."

https://www.medpagetoday.com/pediatrics/generalpediatrics/109560

Isaiah Rider update

From Facebook Team Isaiah. Quotes from Isaiah's mother. April 10, 2024

I’ve spent over the last month in hospitals and icu’s at time fighting for my life in respiratory failure , aspirations, pain , sepsis but who I’m really concerned about is my son who is disabled , has been taken out of state a couple years ago isolated from everyone, neglected and keeps waking up alone in different hospitals unconscious having non epileptic grand mal seizures of unknown cause with profuse vomiting is in Aurora Colorado has no one looking after him or his medical needs or even his life and well being. Is now confined to a bed and it was recently revealed the abuser he is with is illegally distributing “blues” look them up they are laced with synthetic fentanyl and DO NOT show up on toxicology. There were contacts in colorado who provided that information what they don’t know was 2.5 years ago it was the same pill my brother took at my sons home and only 2 other people were present Kiara Gibbs Ring and my son. She encouraged him not to call 911 and now I know why he went into cardiac arrest and was dead immediately. The first responders said it took them 6 min to restart his heart by the time they got to him

With life saving measures. He lost oxygen to his brain for a substantial amount of time and nearly died that night . He was on a ventilator for a couple weeks then in the hospital for months he had to learn how to eat and all the things and still has services coming to his home his life is forever changed. My son is in eminent danger. I’m in a hospital still alone. Someone please help help is needed. Please. My son has major memory loss. Please I’m begging people to step up and help this young man. I’m fighting for my own life.

My son a year ago. My son a month ago . Thank you Chicago you traumatized an innocent young man and his mother for no reason he ended up with yet another abuser perhaps worse than the abuse you put him through. Job well done Kiara Karrot Ring can you explain this ? Also known as Kiara Gibbs Ring ?From Facebook Team Isaiah

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From February 5, 2016

Illinois continues to “terrorize” Missouri resident Isaiah Rider and his family, even after he turned 18 last August. The family had hoped that they would leave them alone, but that has not happened. Their story has not been in the news lately, but their medical kidnapping story is anything but over. Isaiah’s mother, Michelle Rider, thought that things would settle down after an appellate court said that Illinois DCFS should not be involved after Isaiah’s 18th birthday. They thought their nightmare with the Child Protective System was finally over. However, they have learned that the Cook County Juvenile Court, with the same judge and same players, continues to hold hearings about Isaiah. Usually he and his mother are not informed or invited to these hearings, some of which are off the record, even though it is their lives that are being decided by this entity in the state they only visited for a needed surgery for Isaiah 2 years ago, for his neurofibromatosis, a painful condition in which tumors grow on his nerves. Illinois courts and DCFS to date has not done anything to address Isaiah’s sexual assault that happened under their care while he was in a foster home in a violent Chicago neighborhood for 6 months. The crime was reported to them more than a year ago. No investigation has reportedly been done, and no arrests made, even though Isaiah was able to describe his attacker with identifying details. Missouri Teen Medically Kidnapped Was Raped and Sodomized While in Illinois Foster Care Nor has Illinois DCFS reportedly dealt with any of Isaiah’s very real medical issues. They continue to hinder his medical care, instead accusing his mother of Munchausen by proxy, and saying that Isaiah’s medical problems are in his head. Since Isaiah turned 18 the family thought the appellate court was getting Illinois DCFS out of their lives, but the Riders were unable to find any hospital or doctor locally that would help him. They were forced to go out of state for care. Once they found out of state care, doctors found that his medical issues have a very real physical basis. Isaiah truly has a rare, complicated medical condition involving neurofibromatosis, numerous tumors up and down his spine, and polycystic kidney disease. He has had several incorrect diagnoses in the past, besides the DCFS involvement, which have hindered him from getting the help he truly needs. Doctors examined his leg that had been partially amputated several years prior, and they removed 7 nerves in the leg. Some of these were completely filled with tumors. One specialist later reportedly examined the records and said that his was the largest tibial nerve he had ever seen. Because of all the tumors, it looked to him more like a bone, not a nerve. Without knowing their story, another doctor reportedly quipped: “We know that your pain is real, Isaiah, and that you’re not making this up. Your mother is not making this happen.” Then, Michelle told him their story, that this is exactly what DCFS and Lurie Children’s Hospital of Chicago accused them of. It is apparent to the doctors attending him now that his pain and his condition is very real. Isaiah still has tumors and he still has pain, but he is now receiving ongoing medical care from a highly regarded institution. However, as recently as 2 months ago, they have learned that the Cook County, Illinois, judge has threatened to bring him back to Illinois. Their own state of Missouri has washed their hands of the case and are no longer involved. The interstate compact expired on Isaiah’s 18th birthday, and the family doesn’t understand how Illinois even has any jurisdiction. Isaiah signed a document stating that, as an adult, he no longer wants to be in DCFS care. Even so, the family reports that Illinois DCFS has continued to send social workers to their homes in Missouri to check on them. Their harassment continues. Michelle has learned that the state of Illinois continues to receive federal Title IV-E money for her son. Could this be the reason why Illinois won’t let go of their case? Team Isaiah is the Facebook page set up for supporters to get involved and stay updated on their story. Recently, they posted this: Team Isaiah wants to thank all of you for your continued support! We want everyone to know that this miscarriage of justice is NOT over. Many ask ” How?” “Why?” “But Isaiah is 18, he’s an Adult now?” “How can a juvenile court in a different state and the department and family CHILDREN services in a completely different state continue to harass this family and this ADULT man ?” ” How can they try to continue to intrude in their lives?” Friends, we have those same questions. Isaiah and his mom and family have those same questions. We would like answers, we would like those in authority to answer these for us. It is so “Over the top”, most people are not able to wrap their heads around this situation. It’s truly almost unbelievable. We believe that is part of their strategy. What seems like a nightmare or unreal to to many continues to be a reality for this family. In addition to Isaiahs REAL, Ongoing health needs! This family has enough on their plate. All those involved in this made an already very complex and difficult situation and burdens this family had to deal with nearly impossible. We want to continue to bring awareness and share their story far and wide. We want to share this injustice that continues to haunt this family almost two years now! This should not be happening in the year 2016 , not here in this country or anywhere. Thank you to those who continue to advocate and support the Rider’s! Please continue to share this Fb page as well as Teamisaiah.com which contains many news articles and information! We appreciate you all! – With Gratitude, Team Isaiah Team Isaiah FB

https://medicalkidnap.com/2016/02/05/isaiah-rider-is-18-now-but-illinois-maintains-custody-of-medically-kidnapped-missouri-teen/

See: https://childnervoussystem.blogspot.com/2015/06/isaiah-rider-revisited.html

https://childnervoussystem.blogspot.com/2015/04/medical-child-abuse.html

MACF1 mutations and spectraplakinopathy

Inspired by a patient

Kang L, Liu Y, Jin Y, Li M, Song J, Zhang Y, Zhang Y, Yang Y. Mutations of MACF1, Encoding Microtubule-Actin Crosslinking-Factor 1, Cause Spectraplakinopathy. Front Neurol. 2020 Jan 15;10:1335. doi: 10.3389/fneur.2019.01335. PMID: 32010038; PMCID: PMC6974614.

Abstract

As a member of spectraplakin family of cytoskeletal crosslinking proteins, microtubule-actin crosslinking factor 1 (MACF1) controls cytoskeleton network dynamics. Knockout of Macf1 in mice resulted in the developmental retardation and embryonic lethality. Spectraplakinopathy type I, a novel neuromuscular condition characterized by periodic hypotonia, lax muscles, joint contracture, and diminished motor skill, was reported to be associated with heterozygous genomic duplication involving the MACF1 loci, with incomplete penetrance and highly variable clinical presentation in a single pedigree. In this study, parental-derived compound heterozygous novel missense mutations of MACF1, c.1517C>T (p.Thr506Ile) and c.11654T>C (p.Ile3885Thr), were found to co-segregate with disease status in two affected brothers presenting with progressive spastic tetraplegia, dystonia, joint contracture, feeding difficulty and developmental delay. We speculated that MACF1 mutations cause spectraplakinopathy inherited in an autosomal recessive manner. Our clinical findings expanded the phenotype of this neuromuscular disorder and provided new insights into the function of MACF1.

Dobyns WB, Aldinger KA, Ishak GE, Mirzaa GM, Timms AE, Grout ME, Dremmen MHG, Schot R, Vandervore L, van Slegtenhorst MA, Wilke M, Kasteleijn E, Lee AS, Barry BJ, Chao KR, Szczałuba K, Kobori J, Hanson-Kahn A, Bernstein JA, Carr L, D'Arco F, Miyana K, Okazaki T, Saito Y, Sasaki M, Das S, Wheeler MM, Bamshad MJ, Nickerson DA; University of Washington Center for Mendelian Genomics; Center for Mendelian Genomics at the Broad Institute of MIT and Harvard; Engle EC, Verheijen FW, Doherty D, Mancini GMS. MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. Am J Hum Genet. 2018 Dec 6;103(6):1009-1021. doi: 10.1016/j.ajhg.2018.10.019. Epub 2018 Nov 21. PMID: 30471716; PMCID: PMC6288423.

Abstract

To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.

Moffat JJ, Ka M, Jung EM, Smith AL, Kim WY. The role of MACF1 in nervous system development and maintenance. Semin Cell Dev Biol. 2017 Sep;69:9-17. doi: 10.1016/j.semcdb.2017.05.020. Epub 2017 Jun 1. PMID: 28579452; PMCID: PMC5583038.

Abstract

Microtubule-actin crosslinking factor 1 (MACF1), also known as actin crosslinking factor 7 (ACF7), is essential for proper modulation of actin and microtubule cytoskeletal networks. Most MACF1 isoforms are expressed broadly in the body, but some are exclusively found in the nervous system. Consequentially, MACF1 is integrally involved in multiple neural processes during development and in adulthood, including neurite outgrowth and neuronal migration. Furthermore, MACF1 participates in several signaling pathways, including the Wnt/β-catenin and GSK-3 signaling pathways, which regulate key cellular processes, such as proliferation and cell migration. Genetic mutation or dysregulation of the MACF1 gene has been associated with neurodevelopmental and neurodegenerative diseases, specifically schizophrenia and Parkinson's disease. MACF1 may also play a part in neuromuscular disorders and have a neuroprotective role in the optic nerve. In this review, the authors seek to synthesize recent findings relating to the roles of MACF1 within the nervous system and explore potential novel functions of MACF1 not yet examined.