Eculizumab to treat children with generalized myasthenia gravis

The Food and Drug Administration (FDA) has approved the expansion of the indication of Soliris (eculizumab; Alexion Pharmaceuticals, Boston, MA) to now include treatment for pediatric patients aged ≥6 years with anti-acetylcholine receptor (AChR) antibody positive generalized myasthenia gravis (gMG). Soliris, a monoclonal antibody that targets the complement cascade, was previously approved for adults with AChR positive gMG in 2017 and adults with neuromyelitis optica spectrum disorder (NMOSD) in 2019, in addition to its initial approval for paroxysmal nocturnal hemoglobinuria (PNH) and a subsequent approval for atypical hemolytic uremic syndrome (aHUS).

In an open-label, multicenter, phase 3 clinical study (NCT03759366; ECU-MG-303) 11 adolescent participants aged 12 to 17 years with AChR positive gMG received weekly treatment with Soliris. The primary endpoint was change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score.

At week 26:QMG total score showed a least-squares mean change of -5.8 (standard error [SE], 1.2; P=.0004).
Myasthenia Gravis–Activities of Daily Living (MG-ADL) total score, a key secondary endpoint, showed a least-squares mean change of -2.3 (SE, 0.6; P=.0017).
All other secondary endpoints were met with statistical significance, demonstrating the efficacy of Soliris for improving outcomes related to symptoms, muscle strength, ability to perform daily activities, and quality of life.
Pharmacokinetic, pharmacodynamic, and safety findings were consistent with results observed in adults treated with Soliris.
3 participants experienced serious adverse events, including myasthenia gravis (MG) worsening, MG crisis, or peritonsillar abscess, and pyrexia.

Soliris’s prescribing information includes a Boxed Warning for serious meningococcal infections caused by Neisseria meningitidis.

https://practicalneurology.com/news/soliris-now-approved-to-treat-children-with-generalized-myasthenia-gravis?c4src=news:feed

Divalent small interfering RNA to treat KCNT1 genetic epilepsy

Andreone BJ, Lin J, Tocci J, Rook M, Omer A, Carito LM, Yang C, Zhoba H, DeJesus C, Traore M, Haruehanroengra P, Prinzen A, Miglis G, Deninger M, Li M, Lynch T, Howat B, Rogers KA, Gallant-Behm CL, Kinberger GA, Yudowski G, Chen Q, Jackson AL, McDonough SI. Durable suppression of seizures in a preclinical model of KCNT1 genetic epilepsy with divalent small interfering RNA. Epilepsia. 2025 Jan 27. doi: 10.1111/epi.18278. Epub ahead of print. PMID: 39871703.

Abstract

Objective: Gain-of-function variants in the KCNT1 gene, which encodes a sodium-activated potassium ion channel, drive severe early onset developmental epileptic encephalopathies including epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. No therapy provides more than sporadic or incremental improvement. Here, we report suppression of seizures in a genetic mouse model of KCNT1 epilepsy by reducing Kcnt1 transcript with divalent small interfering RNA (siRNA), an emerging variant of oligonucleotide technology developed for the central nervous system.

Methods: The ATL-201 molecule is two identical synthetic double-stranded siRNAs, covalently linked, with 100% nucleotide base pair match to sequence present in both human KCNT1 and mouse Kcnt1 that does not contain any known pathogenic variant. ATL-201 activity was tested in cortical neurons cultured from wild-type mice and in mice homozygous for Kcnt1-Y777H, the mouse ortholog to the human pathogenic KCNT1-Y796H missense variant. Seizures and nest-building behavior were measured in freely behaving Kcnt1-Y777H mice. The number and duration of seizures were measured by electrocorticography in mice dosed with ATL-201 or phosphate-buffered saline in a 6-month durability study and in a 2-month dose-efficacy study.

Results: In vitro, ATL-201 reduced KCNT1 transcript from whole-cell lysate and eliminated potassium currents from KCNT1 channels in heterologous expression. ATL-201 also eliminated sodium-activated potassium currents recorded from individual cortical neurons. In vivo, ATL-201 suppressed seizures in Kcnt1-Y777H homozygous mice in a dose-dependent manner with near-complete suppression from 2 weeks to at least 4 months. Kcnt1-Y777H mice had defects in nest building, whereas in ATL-201-treated mice nest building was equivalent to wild-type mice.

Significance: Patients with KCNT1-driven epilepsy experience up to hundreds of seizures per day and have severe impairment in cognitive, motor, and language development and high mortality. The dose-dependent efficacy and long durability of ATL-201 in mice show promise for ATL-201 as a disease-modifying treatment of KCNT1 epilepsy.

Diagnosing rare diseases

Durmus H. Editorial: Diagnosis and identification of novel disorders and ultra-rare disorders in science and clinical routine. Front Genet. 2024 Nov 20;15:1522931. doi: 10.3389/fgene.2024.1522931. PMID: 39634273; PMCID: PMC11614831.

The application of rapid exome sequencing (rES) has emerged as a crucial advance in diagnostic landscape, especially for critically ill patients presenting with rare diseases. This editorial reflects findings from a comprehensive study involving 575 patients that highlighted the transformative impact of rES on clinical decision-making and patient outcomes .

In recent years, rES has become the preferred genetic testing modality for critically ill patients, including neonates and young infants, in urgent clinical situations. Its ability to provide timely diagnoses can significantly guide management decisions and improve clinical care pathways. The study, conducted over 4 years (2016–2019) provides valuable insights into the operational effectiveness and clinical utility of rES. The study reported a notable increase in rES referrals, escalating from two in the first quarter of 2016 to ten per week by late 2019. This increase reflects growing recognition of rES as a critical tool in diagnosing complex genetic disorders. The median turnaround time for results improved from 17 days to 11 days, this highlighted advances in sequencing technology and laboratory efficiencies.

The overall diagnostic yield was 30.4%, with variations observed across different clinical entities. For instance, craniofacial anomalies showed a high diagnostic yield of 58.3%, whereas conditions like severe combined immune deficiency yielded no diagnoses at all. These findings suggest that rES, although not universally effective for all conditions, is vital for many patients and offers information that can change clinical management even in the absence of a definitive diagnosis.

The importance of rES extends beyond providing definitive genetic diagnoses. Even if genetic causes remain elusive, information gleaned from rES may influence clinical decisions such as direction of treatment or the need for further investigation. This dual effect in both making diagnoses and informing clinical strategies highlights the multifaceted role of rES in patient care.

Implementation of rES should be accompanied by careful ethical considerations, particularly regarding informed consent and genetic counselling. In high-stake situations, it is very important to ensure that patients and families understand the implications of genetic tests. Clinicians must navigate the complexity of informing uncertain or negative findings while remaining sensitive to the emotional impact on families.

As rES continues to evolve, its integration into routine clinical practice for older patients should be prioritized. The potential for RES to guide treatment decisions in cancer care and other adult-onset conditions is significant and requires further investigation. Ongoing research should focus on optimizing diagnostic strategies and understanding the broader implications of genetic findings in diverse cohorts.

Lessons learned from the use of rapid exome sequencing in critically ill patients underline its fundamental role in modern medicine era. The ability to quickly identify genetic causes of rare diseases not only increases diagnostic accuracy but also improves clinical outcomes. As these technologies continue to be developed and their applications expanded, the hope is to further close the gap between genetics and clinical practice, ultimately benefiting patients across the healthcare.

Wojcik MH, Lemire G, Berger E, Zaki MS, Wissmann M, Win W, White SM, Weisburd B, Wieczorek D, Waddell LB, Verboon JM, VanNoy GE, Töpf A, Tan TY, Syrbe S, Strehlow V, Straub V, Stenton SL, Snow H, Singer-Berk M, Silver J, Shril S, Seaby EG, Schneider R, Sankaran VG, Sanchis-Juan A, Russell KA, Reinson K, Ravenscroft G, Radtke M, Popp D, Polster T, Platzer K, Pierce EA, Place EM, Pajusalu S, Pais L, Õunap K, Osei-Owusu I, Opperman H, Okur V, Oja KT, O'Leary M, O'Heir E, Morel CF, Merkenschlager A, Marchant RG, Mangilog BE, Madden JA, MacArthur D, Lovgren A, Lerner-Ellis JP, Lin J, Laing N, Hildebrandt F, Hentschel J, Groopman E, Goodrich J, Gleeson JG, Ghaoui R, Genetti CA, Gburek-Augustat J, Gazda HT, Ganesh VS, Ganapathi M, Gallacher L, Fu JM, Evangelista E, England E, Donkervoort S, DiTroia S, Cooper ST, Chung WK, Christodoulou J, Chao KR, Cato LD, Bujakowska KM, Bryen SJ, Brand H, Bönnemann CG, Beggs AH, Baxter SM, Bartolomaeus T, Agrawal PB, Talkowski M, Austin-Tse C, Abou Jamra R, Rehm HL, O'Donnell-Luria A. Genome Sequencing for Diagnosing Rare Diseases. N Engl J Med. 2024 Jun 6;390(21):1985-1997. doi: 10.1056/NEJMoa2314761. PMID: 38838312; PMCID: PMC11350637.

Abstract

Background: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined.

Methods: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center.

Results: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments.

Conclusions: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).

Ketogenic diet treatment for super-refractory status epilepticus

Ren Y, Zhang M, Fu X, Zhang Y, Liu F, Wu C, Shi H, Tian F, Liu G, Lin Y, Su Y, Chen W. Ketogenic diet treatment for super-refractory status epilepticus in the intensive care unit: feasibility, safety and effectiveness. Front Neurol. 2025 Jan 13;15:1517850. doi: 10.3389/fneur.2024.1517850. PMID: 39871989; PMCID: PMC11769800.

Abstract

Background and aims: To investigate the feasibility, safety and effectiveness of the ketogenic diet (KD) for super-refractory status epilepticus (SRSE) in the intensive care unit (ICU).

Methods: We conducted a prospective investigation on patients with SRSE treated with the KD. The primary outcome measures were ketosis development as a biomarker of feasibility and resolution of SRSE as effectiveness. KD-related side effects were also investigated.

Results: Twelve patients (9 females and 3 males) with SRSE, with a median age of 34 years [range 16-69, interquartile range (IQR) 18-52], were treated with a KD. The median duration of SRSE prior to KD treatment was 21 days (range 4-46). SRSE resolved in 75% (9/12) of patients at a median of 3 days (range 1-18) after KD initiation. Among the nine KD responders, all were successfully weaned off anesthetic agents at a median of 16 days (range 4-32) after KD initiation, and all were also successfully weaned off ventilator. Side effects varied, and included gastrointestinal intolerances, malnutrition and metabolic abnormalities, electrolyte disturbance, and acute weight loss, although most of them could be corrected. No patient died due to KD, and neurofunctions continued to improve under KD therapy.

Conclusion: The KD may be feasible and effective for the treatment of SRSE in the ICU. Moreover, it is relatively safe. However, there are numerous adverse events that can be corrected under close monitoring.

Ketogenic diet for drug-resistant epilepsy caused by structural pathology

Zhang H, Su S, Zhang H, Sun L, Liu Y, Liu G. Effectiveness and safety analysis of ketogenic diet therapy for drug-resistant epilepsy caused by structural pathology. Front Neurol. 2024 Oct 30;15:1497969. doi: 10.3389/fneur.2024.1497969. PMID: 39539663; PMCID: PMC11557543.

Abstract

Objective: To explore the effectiveness and safety of the ketogenic diet (KD) in children with drug resistant epilepsy (DRE) caused by structural etiology.

Methods: The children were categorized into acquired brain injury group and malformations of cortical development (MCD) group based on the etiology. Follow-up assessments were performed at 1, 3, and 6 months after KD treatment to observe seizure reduction, behavioral and cognitive improvements, adverse reactions events, and reasons for discontinuation withdrawal. Statistical analysis was conducted on the results.

Results: We found the seizure-free rates at 1, 3, and 6 months were 4.8% (2/42), 19% (8/42), and 21.4% (9/42), respectively. The seizure control effective rates were 42.9% (18/42), 52.4% (22/42), and 54.8% (23/42) at the corresponding time points. Compared to the acquired brain injury group, the MCD group showed a higher seizure control effective rate. Further analysis within the MCD group revealed the highest efficacy in focal cortical dysplasia (FCD). At the 3-month follow-up, cognitive and behavioral improvements were observed in 69% (29/42) of children. The main reasons for discontinuation were lack of efficacy and poor compliance.

Significance: Finally, we get that KD is a safe and effective treatment for drug resistant epilepsy caused by structural etiology, with the added benefit of improving behavioral and cognitive abilities in children. The efficacy is higher in children with MCD, particularly in cases of FCD. Early intervention with KD is recommended for this population.

Lucy Illingworth

Lucy is completely blind and has a chromosome 16 duplication, which is a rare condition affecting mental health with autism traits and affecting overall communication. Lucy is hypermobile and suffers with cyclic vomiting syndrome. She is in remission from bilateral retinoblastoma and is globally developmentally delayed.

However, Lucy has an extraordinary talent and it is by using this natural talent, Lucy is able to communicate.

World-renowned, pianist, Lang Lang and pop sensation, Mika crowned 13-year-old Lucy, the ‘unofficial’ winner of the competition with her stunning performance of Debussy’s Arabesque No1, which she performed in front of 2000 people at the Royal Festival Hall.

Lucy was invited to perform at HRH King‘s Coronation Concert at Windsor Castle, where she played a note perfect performance of Bach Prelude in C in front of 18 million people.

https://www.lucythepianist.com/ (videos at link)

Verbesselt J, Breckpot J, Zink I, Swillen A. Language Profiles of School-Age Children With 16p11.2 Copy Number Variants in a Clinically Ascertained Cohort. J Speech Lang Hear Res. 2024 Nov 7;67(11):4487-4503. doi: 10.1044/2024_JSLHR-24-00257. Epub 2024 Oct 17. PMID: 39418585; PMCID: PMC11567083.

Abstract

Purpose: Individuals with proximal 16p11.2 copy number variants (CNVs), either deletions (16p11.2DS) or duplications (16p11.2Dup), are predisposed to neurodevelopmental difficulties and disorders, such as language disorders, intellectual disability, and autism spectrum disorder. The purpose of the current study was to characterize language profiles of school-age children with proximal 16p11.2 CNVs, in relation to the normative sample and unaffected siblings of children with 16p11.2DS.

Method: Standardized language tests were conducted in 33 school-age children with BP4-BP5 16p11.2 CNVs and eight unaffected siblings of children with 16p11.2DS to evaluate language production and comprehension skills across various language domains. A standardized intelligence test was also administered, and parents completed a standardized questionnaire to assess autistic traits. Language profiles were compared across 16p11.2 CNVs and intrafamilial pairs. The influence of nonverbal intelligence and autistic traits on language outcomes was investigated.

Results: No significant differences were found between children with 16p11.2DS and those with 16p11.2Dup, although both groups exhibited significantly poorer language skills compared to the normative sample and unaffected siblings of children with 16p11.2DS. Severe language deficits were identified in 70% of individuals with 16p11.2 CNVs across all language subdomains, with significantly better receptive vocabulary skills than overall receptive language abilities. In children with 16p11.2DS, expressive language deficits were more pronounced than receptive deficits. In contrast, only in children with 16p11.2Dup did nonverbal intelligence influence their language outcomes.

Conclusions: The current study contributes to the deeper understanding of language profiles in 16p11.2 CNVs in a clinically ascertained cohort, indicating generalized deficits across multiple language domains, rather than a syndrome-specific pattern targeting specific subdomains. The findings underscore the importance of early diagnosis, targeted therapy, and monitoring of language skills in children with 16p11.2 CNVs.

Tang D, Chen A, Xu J, Huang Y, Fan J, Wang J, Zhu H, Pi G, Yang L, Xiong F, Luo Z, Li G, Zeng L, Zhu S. Genetic analysis of partial duplication of the long arm of chromosome 16. BMC Med Genomics. 2024 Dec 23;17(1):294. doi: 10.1186/s12920-024-02059-3. PMID: 39716170; PMCID: PMC11667835.

Abstract

Background: Pure partial trisomy 16q12.1q22.1 is a rare chromosome copy number variant (CNV). The primary clinical phenotypes associated with this syndrome include abnormal facial morphology, global developmental delay (GDD), short stature, and reported predisposing factors for atypical behavior, autism, the development of learning disabilities, and neuropsychiatric disorders. The dosage-sensitive genes associated with partial trisomy are not disclosed preventing to establish a genotype-phenotype correlation.

Methods: We report a case of a Chinese patient diagnosed with GDD and an abnormal facial shape, who was found to have partial trisomy 16 through karyotyping and high-throughput sequencing analysis. Karyotype and CNV tracing analyses were also conducted on the biological parents of the patient to assess for any chromosomal structural abnormalities. Additionally, we included 29 patients with pure partial trisomy 16q, reported in the DECIPHER database and the literature. We and performed a genotype-phenotype correlation analysis.

Results: The proband, a 2-year-old female, was found to have a de novo 21.96 Mb duplication located between 16q12.1q22.1, with no other deletions observed on other chromosomes, indicating a pure partial trisomy of 16q. Through genotype and phenotype analysis of 29 individuals, we found that patients with the duplicated region located at the distal region of 16q may exhibit more severe symptoms than those with duplication at the proximal region; however, no relationship was identified between phenotype and the size of the duplicated segment.

Conclusion: We report, for the first time, a patient with partial trisomy 16q validated by multiple genetic tests, including CNV-seq, whole exome sequencing (WES), and karyotyping. It is speculated that partial trisomy of 16q may be associated with continuous gene duplication. However, functional studies are necessary to identify the causative gene or critical region linked to duplication syndrome of chromosome 16q.

Hyperbaric oxygen for sleep apnea and attention-deficit/hyperactivity disorder

Boy, 5, dies after oxygen therapy chamber explodes

A curious, energetic, smart, outgoing and thoughtful little boy.

That’s how family, friends and teachers say they will remember 5-year-old Thomas Cooper who tragically died inside a hyperbaric chamber at a medical facility in Troy, Michigan, last month.

The descriptions form part of a heartfelt obituary written about Cooper ahead of a memorial visitation held on Thursday, about two weeks after he died. 

Cooper was receiving treatment inside a chamber, a pressurized container containing 100% oxygen, when it suddenly exploded at The Oxford Center at 165 Kirts Blvd.

Thomas Cooper died when the chamber he was inside exploded in Michigan

Police and fire officials said he was dead inside the chamber when they arrived on the scene, while his mother Annie, who was also inside the room, suffered injuries to her arm.

Cooper, who was in preschool, was always on the move and loved looking out for his younger brother, who was his best friend, according to the obituary.

"His favorite thing to do was play Minecraft on his Nintendo Switch, as he loved to show his Mommy and Daddy the things he could create," the tribute reads.

"His favorite activities were running, jumping, rolling and stomping … He wanted to grow up to be a chef because that meant he could ‘cook with Mommy and Daddy and stay with them forever.’"

The boy was receiving treatment for sleep apnea and attention-deficit/hyperactivity disorder at the Oxford Center, James Harrington, an attorney for the family told NBC Washington. 

The chambers are used to provide Hyperbaric oxygen therapy (HBOT) and a typical chamber can hold one person. It requires the patient to lie down in the tube-shaped device that looks like an MRI machine and breathe the oxygen. A hyperbaric chamber contains up to three times the amount of oxygen than a normal room.

Harrington said the boy’s parents were hopeful the services would improve his quality of life. 

"This wasn’t some type of lifesaving measure that was absolutely needed," Harrington told the outlet. "It was just a mother who was trying to help her son with some conditions that he had and was promised that with these conditions and this treatment, that they would be able to help."

"Annie was trying to help her child as any parent would — as good parents do."

Harrington, who is a managing partner of Fieger Law in Southfield, Michigan, said the boy had received multiple sessions of hyperbaric oxygen therapy at the center before tragedy struck.

It’s unclear what caused the chamber to explode. The family intends on filing a lawsuit to prevent a similar incident from taking place again, Harrington said, adding that the boy’s parents are "absolutely devastated."

The obituary also mentions that Cooper loved to make art and was constantly curious about the world around him and liked to know how things worked.

"At night, he liked to listen to audiobooks as he tried to go to sleep, with some of his favorites being Yoto Daily, Charlie and the Chocolate Factory, and James and the Giant Peach," the obituary reads.

As well as being used to tackle sleep apnea and attention-deficit/hyperactivity disorder, the devices are also used to treat a variety of other health problems, including carbon monoxide poisoning, diabetic foot ulcers, anemia, infection of the skin and bone and vision loss.

Such devices require FDA clearance to ensure that they are approved to be used as intended and are safe and effective.

HBOY is also well known for treating scuba and deep-sea divers affected by the rapid change in pressure around them, according to the FDA. 

In a statement to the Detroit Free Press immediately after the incident, The Oxford Center spokesperson Andrew Kistner wrote that the cause of the explosion is unknown.

"As law enforcement officials have shared, at our location in Troy, Michigan this morning, a fire started inside of a hyperbaric oxygen chamber. The child being treated in that chamber did not survive and the child’s mother was injured," the statement reads.

"The safety and wellbeing of the children we serve is our highest priority. Nothing like this has happened in our more than 15 years of providing this type of therapy. We… will participate in all of the investigations that now need to take place."

The location is temporarily closed while authorities investigate the deadly incident, NBC Washington reported. No charges have been filed, per the outlet citing police. 

In May 2009, an explosion of a pressurized oxygen chamber killed a 4-year-old and his 62-year-old grandmother. Authorities said a blast dislodged a tube attached to the hyperbaric chamber, which resulted in an explosion and flash fire, according to CBS.

https://www.foxnews.com/us/boy-killed-hyperbaric-oxygen-chamber-remembered-curious-energetic-smart-family-intends-sue

Suztrigine for the treatment of adults with moderate-to-severe acute pain

Journavx (suzetrigine; Vertex Pharmaceuticals, Boston, MA) has received approval from the Food and Drug Administration (FDA) for the treatment of adults with moderate-to-severe acute pain. Journavx is an oral, non-opioid, selective inhibitor of Nav1.8, which is a voltage-gated sodium channel that plays a role in pain signaling in the peripheral nervous system. According to a statement from the FDA, Journavx represents the first approval in a new class of non-opioid medicines for pain management.

The approval is based on positive data from 2 phase 3 studies evaluating the safety and efficacy of Journavx treatment for acute pain after bunionectomy and abdominoplasty. The primary outcome measures were time-weighted sum of the pain intensity difference from 0 to 48 hours (SPID48) and clinically meaningful reductions in pain from baseline at 48 hours, according to the Numeric Pain Rating Scale (NPRS).For participants who received bunionectomy, the least squares mean difference in SPID48 was 29.3 for Journavx vs placebo (95% CI, 14.0 to 44.6; P=.0002).
For abdominoplasty, the least squares mean difference was 48.4 for Journavx vs placebo (95% CI, 33.6 to 63.1; P<.0001).
Journavx was associated with more rapid onset to meaningful pain relief vs placebo, as defined by a ≥2-point reduction in NPRS from baseline.

“Today’s approval is an important public health milestone in acute pain management,” said Jacqueline Corrigan-Curay, JD, MD, Acting Director of the FDA's Center for Drug Evaluation and Research. “A new non-opioid analgesic therapeutic class for acute pain offers an opportunity to mitigate certain risks associated with using an opioid for pain and provides patients with another treatment option.”

In addition to pooled data from the bunionectomy and abdominoplasty studies, the safety profile for Journavx was supported by data from a single-arm phase 3 (NCT05661734) study in participants who received treatment for surgical and nonsurgical pain. The most common adverse events were itching, muscle spasms, increased levels of creatine phosphokinase in the blood, and rash. The medicine is contraindicated for concomitant use with strong CYP3A inhibitors.

https://practicalneurology.com/news/journavx-a-non-opioid-nav18-inhibitor-for-pain-management-approved-by-the-fda

The putaminal eye: A highly characteristic imaging feature of MEGDEL syndrome

Inspired by a patient. Images obtained at 19 months. T2 above and FLAIR below.

                                                                        

Bhanudeep S, Koneti BB. Pathognomonic Neuroimaging in MEGDEL Syndrome. Indian J Pediatr. 2024 Dec 20. doi: 10.1007/s12098-024-05377-7. Epub ahead of print. PMID: 39704917. (no abstract)

Altamimi R, Aldhalaan H, Tous E, Nicolas-Jilwan M. Teaching NeuroImage: The Putaminal Eye: A Highly Characteristic Imaging Feature of MEGDEL Syndrome. Neurology. 2023 Nov 7;101(19):e1943-e1944. doi: 10.1212/WNL.0000000000207823. Epub 2023 Aug 21. PMID: 37604663; PMCID: PMC10663015. (no abstract)

Monteiro-Cardoso VF, Giordano F. New roles of LPGAT1: From mitochondrial import of phosphatidylglycerol to MEGDEL disease. Cell Rep. 2023 Nov 28;42(11):113376. doi: 10.1016/j.celrep.2023.113376. Epub 2023 Nov 2. PMID: 37917588.

Abstract

Dysregulation of mitochondrial lipidome is associated with several human pathologies. Sun et al.1 show that LPGAT1 cooperates with TIMM14 to regulate phosphatidylglycerol transport from the endoplasmic reticulum to the mitochondria, and uncover the involvement of LPGAT1 deficiency in MEGDEL syndrome.

Alfaraidi AT, ALSulimani NK, Garout W. Incidental Finding of MEGDEL Syndrome at a Tertiary Care Center in Saudi Arabia. Cureus. 2024 Mar 1;16(3):e55308. doi: 10.7759/cureus.55308. PMID: 38559521; PMCID: PMC10981795.

Abstract

MEGDEL syndrome, a rare autosomal recessive disorder characterized by 3-methylglutaconic aciduria, deafness, encephalopathy, and Leigh-like syndrome, results from mutations in the SERAC1 gene. This case report explores the clinical presentation, diagnostic challenges, and genetic findings of an 11-year-old boy with MEGDEL syndrome at a tertiary care center in Saudi Arabia. The patient, born to consanguineous parents, presented with developmental delay, cerebral palsy, intellectual disability, and seizures. Diagnostic evaluation at 15 months revealed 3-methylglutaconic aciduria, and subsequent genetic testing through whole exome sequencing confirmed a rare homozygous deletion variant in the SERAC1 gene. The patient exhibited brain atrophy, tracheal stenosis, laryngomalacia, and skeletal abnormalities. The complexity of MEGDEL syndrome manifestations and the challenge of distinguishing it from other metabolic disorders are discussed, emphasizing the significance of genetic testing in confirming the diagnosis. This case underscores the occurrence of MEGDEL syndrome in a child with cerebral palsy, highlighting the importance of a multidisciplinary approach for diagnosis and the need for genetic counseling in consanguineous families. Although the management remains primarily supportive, the report calls for more comprehensive epidemiological studies to determine the prevalence and incidence of MEGDEL syndrome. The findings contribute to the growing understanding of this rare disorder, thus emphasizing the necessity for ongoing research to enhance diagnostic accuracy and management strategies.

Martins E, Durães J, Nogueira C, Gomes J, Vilarinho L, Macário C. SERAC1 Deficiency- A New Phenotype. Endocr Metab Immune Disord Drug Targets. 2023 Sep 14. doi: 10.2174/1871530323666230914114456. Epub ahead of print. PMID: 37711114.

Abstract

Introduction - SERAC1 deficiency phenotype range from MEGD(H)EL syndrome, the most severe, to juvenile complicated spastic paraplegia, to adult-onset dystonic features (in only one patient). The MEGD(H)EL syndrome is characterized by (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome). Biochemical abnormalities: elevated urinary 3 - metilglutaconic and 3-metilglutaric acids, high lactate and alanine in serum. Diagnosis is confirmed when biallelic pathogenic variants in SERAC1 gene are found. Brain MRI: basal ganglia lesions and generalized atrophy. Results/Case report - A 30-year-old patient with a moderate intellectual disability, developed, since the age of 25, a progressive loss of previous capacities (hand dexterity, oral language), and later subacute generalized dystonic features. Currently he has spastic tetraparesis, dystonia, scoliosis and autistic behavior, with bilateral basal ganglia lesions on brain MRI. Genetic study revealed biallelic pathogenic variants in SERAC1 gene, confirm MEGD(H)EL. A 73 years old patient with cognitive impairment and progressive spastic tetraparesis had multiple periventricular T2 hyperintense lesions. She has a homozygotic SERAC1 variant NM_032861: exon4:c.T139A: p.F471 (rs112780453), considered benign. Biochemical study revealed elevated plasmatic alanine and urinary3-metilglutaconic and 3-metilglutaric acid. This profile is concordant with mitochondrial dysfunction and SERAC1 Deficit. Conclusion - The first patient has the clinical symptoms associated to the MEGD(H)EL syndrome, and the biochemical and genetic confirmation of the diagnosis, without reservations. However, in the second patient, the progressive paraparesis and cognitive impairment did not appear to be caused by multiple sclerosis nor subcortical vascular leukoencephalopathy (without vascular risk factors). The abnormal biochemical profile is suggestive of SERAC1 Deficiency, even without genetic confirmation. In what should we believe?

GNB2 mutations

Inspired by a patient

Tan NB, Pagnamenta AT, Ferla MP, Gadian J, Chung BH, Chan MC, Fung JL, Cook E, Guter S, Boschann F, Heinen A, Schallner J, Mignot C, Keren B, Whalen S, Sarret C, Mittag D, Demmer L, Stapleton R, Saida K, Matsumoto N, Miyake N, Sheffer R, Mor-Shaked H, Barnett CP, Byrne AB, Scott HS, Kraus A, Cappuccio G, Brunetti-Pierri N, Iorio R, Di Dato F, Pais LS, Yeung A, Tan TY, Taylor JC, Christodoulou J, White SM. Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability. J Med Genet. 2022 May;59(5):511-516. doi: 10.1136/jmedgenet-2020-107462. Epub 2021 Jun 28. PMID: 34183358.

Abstract

Purpose: Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.

Methods: We discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.

Results: We identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.

Conclusion: Missense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

Fukuda T, Hiraide T, Yamoto K, Nakashima M, Kawai T, Yanagi K, Ogata T, Saitsu H. Exome reports A de novo GNB2 variant associated with global developmental delay, intellectual disability, and dysmorphic features. Eur J Med Genet. 2020 Apr;63(4):103804. doi: 10.1016/j.ejmg.2019.103804. Epub 2019 Nov 4. PMID: 31698099.

Abstract

Heterotrimeric G proteins are composed of α, β, and γ subunits and are involved in integrating signals between receptors and effector proteins. The 5 human Gβ proteins (encoded by GNB1, GNB2, GNB3, GNB4, and GNB5) are highly similar. Variants in GNB1 were identified as a genetic cause of developmental delay. De novo variant in GNB2 has recently been reported as a cause of sinus node dysfunction and atrioventricular block but not as a cause of developmental delay. Trio-based whole-exome sequencing was performed on an individual with global developmental delay, muscle hypotonia, multiple congenital joint contractures and dysmorphism such as brachycephalus, thick eyebrows, thin upper lip, micrognathia, prominent chin, and bilateral tapered fingers. We identified a de novo GNB2 variant c.229G>A, p.(Gly77Arg). Notably, pathogenic substitutions of the homologous Gly77 residue including an identical variant (p.Gly77Arg, p.Gly77Val, p.Gly77Ser, p.Gly77Ala) of GNB1, a paralog of GNB2, was reported in individuals with global developmental delay and hypotonia. Clinical features of our case overlap with those of GNB1 variants. Our study suggests that a GNB2 variant may be associated with syndromic global developmental delay.

Lansdon LA, Fleming EA, Viso FD, Sullivan BR, Saunders CJ. Second patient with GNB2-related neurodevelopmental disease: Further evidence for a gene-disease association. Eur J Med Genet. 2021 Jul;64(7):104243. doi: 10.1016/j.ejmg.2021.104243. Epub 2021 May 7. PMID: 33971351.

Abstract

G-proteins are ubiquitously expressed heterotrimeric proteins consisting of α, β and γ subunits and mediate G-protein coupled receptor signalling cascades. The β subunit is encoded by one of five highly similar paralogs (GNB1-GNB5, accordingly). The developmental importance of G-proteins is highlighted by the clinical relevance of variants in genes such as GNB1, which cause severe neurodevelopmental disease (NDD). Recently the candidacy of GNB2 was raised in association with NDD in an individual with a de novo variant affecting a codon conserved across paralogs and recurrently mutated in GNB1-related disease, c.229G>A p.(Gly77Arg), in association with global developmental delay, intellectual disability and dysmorphic features. Here, we report a patient with strikingly similar facial features and NDD in association with a de novo GNB2 variant affecting the same codon, c.229G>T p.(Gly77Trp). In addition, this individual has epilepsy and overgrowth. Our report is the second to implicate a de novo GNB2 variant with a severe yet variable NDD.

More on Down syndrome regression disorder 2

Santoro, J.D., Jafarpour, S., Keehan, L. et al. Diagnostic abnormalities, disease severity and immunotherapy responsiveness in individuals with Down syndrome regression disorder. Sci Rep 14, 30865 (2024). https://doi.org/10.1038/s41598-024-81819-8

Abstract

Introduction: Down Syndrome Regression Disorder (DSRD) is a neuropsychiatric condition causing insomnia, catatonia, encephalopathy, and obsessive-compulsive behavior in otherwise healthy individuals with Down syndrome (DS). Smaller cohorts have identified heterogenous diagnostic abnormalities which have predicted immunotherapy responsiveness although pattern analysis in a large cohort has never been performed. Methods: A multi-center, retrospective study of individuals with DSRD was performed. Individuals met international consensus criteria for DRSD and were aged 10–30 years. Clinical, demographic, and diagnostic data was extracted for all individuals. Serum studies were compared to a group of individuals with DS only. Results: A total of 164 individuals with DSRD were identified. Individuals with DSRD were more likely to have a positive antinuclear antibody, low complement 3, abnormal cytokines, and elevated ferritin levels. In a minority of individuals, EEG (30%), MRI (33%) and cerebrospinal fluid (CSF) (21%) were abnormal. Individuals with CSF abnormalities demonstrated greater disease severity at diagnosis on the BFCRS and NPI-Q (p = 0.02 and p < 0.001). Abnormalities in cytokines (p = 0.03), neuroimaging (p < 0.001), and CSF (p = 0.02) were predictive of immunotherapy responsiveness. When MRI and LP were both abnormal or when EEG, MRI and LP were all abnormal, the odds of immunotherapy responsiveness approached 100% (p = 0.01, 95%CI: 1.75–105.1, OR: 13.56 and p = 0.02, 95%CI: 1.37–86.87, OR: 10.91, respectively). Conclusions: In a population of individuals diagnosed with DSRD, abnormalities in serum cytokine levels, neuroimaging findings, and CSF analysis emerged as indicators of disease severity and responsiveness to immunotherapy.
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KCNMA1 channelopathy

Inspired by a patient

Miller JP, Moldenhauer HJ, Keros S, Meredith AL. An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy. Channels (Austin). 2021 Dec;15(1):447-464. doi: 10.1080/19336950.2021.1938852. PMID: 34224328; PMCID: PMC8259716.

Abstract

KCNMA1-linked channelopathy is an emerging neurological disorder characterized by heterogeneous and overlapping combinations of movement disorder, seizure, developmental delay, and intellectual disability. KCNMA1 encodes the BK K+ channel, which contributes to both excitatory and inhibitory neuronal and muscle activity. Understanding the basis of the disorder is an important area of active investigation; however, the rare prevalence has hampered the development of large patient cohorts necessary to establish genotype-phenotype correlations. In this review, we summarize 37 KCNMA1 alleles from 69 patients currently defining the channelopathy and assess key diagnostic and clinical hallmarks. At present, 3 variants are classified as gain-of-function with respect to BK channel activity, 14 loss-of-function, 15 variants of uncertain significance, and putative benign/VUS. Symptoms associated with these variants were curated from patient-provided information and prior publications to define the spectrum of clinical phenotypes. In this newly expanded cohort, seizures showed no differential distribution between patients harboring GOF and LOF variants, while movement disorders segregated by mutation type. Paroxysmal non-kinesigenic dyskinesia was predominantly observed among patients with GOF alleles of the BK channel, although not exclusively so, while additional movement disorders were observed in patients with LOF variants. Neurodevelopmental and structural brain abnormalities were prevalent in patients with LOF mutations. In contrast to mutations, disease-associated KCNMA1 single nucleotide polymorphisms were not predominantly related to neurological phenotypes but covered a wider set of peripheral physiological functions. Together, this review provides additional evidence exploring the genetic and biochemical basis for KCNMA1-linked channelopathy and summarizes the clinical repository of patient symptoms across multiple types of KCNMA1 gene variants.

My apology

Yesterday, I inadvertently deleted thousands of comments, almost entirely mine, from past posts. As readers might know, these comments could be extensive and, in some cases, more interesting and/or detailed than the post itself. It seems this error is uncorrectable.

CTNNB1 syndrome

Inspired by a patient

Inver Grove Heights parents hope to raise awareness, spark research surrounding their daughter’s rare disease

A four-year-old from Inver Grove Heights is one of just a few hundred kids in the world with a rare genetic disorder. Mae Knopik has what is known as CTNNB1 Syndrome, a genetic disorder that is associated with developmental delays and cognitive impairments.

Mae is nonverbal and needs help walking.

“I want to hear her talk. I want to watch her walk unassisted. Will that happen? I don’t know. I’m hopeful, you have to stay hopeful,” said her dad Joe Knopik.

Since CTNNB1 Syndrome is so rare, it is still somewhat of a mystery to doctors and there is no real road map for Mae’s journey.

“It’s such a new diagnosis that we don’t actually know the natural history of what this disease looks like,” said Dr. Amy Authement with Gillette Children’s Specialty Healthcare.

“What I always tell my families is that they are the experts in their child’s disease,” she said.

Which is one of the reasons the Knopiks are sharing their story. They are hoping more awareness will lead to more research, which could one day lead to a cure.

The Knopiks are hoping to take place in a genetic therapy clinical trial in Europe this summer. They will find out in early 2025 if Mae has been selected as a candidate. For more information on Mae’s journey, visit Mae’s Mission. (see below)

https://kstp.com/kstp-news/top-news/inver-grove-heights-parents-hope-to-raise-awareness-spark-research-surrounding-their-daughters-rare-disease/

Mae is a 4 year old Minnesota girl who was diagnosed with a very rare genetic disorder, CTNNB1 Syndrome when she was 1.5 years old. It is so rare that there are just over 430 known diagnosed cases in the world. The CTNNB1 gene is in charge of producing a crucial developmental protein called beta-catenin. Because CTNNB1 Syndrome lacks creating enough beta-catenin, the symptoms that these children experience are detrimental to their development. Many kids including Mae, have developmental delays, intellectual/cognitive disabilities, gross and fine motor delays, sleeping issues, behavioral issues, and struggle with talking or communicating. Since Mae’s diagnosis in December of 2021, she has been in physical therapy, speech therapy, and occupational therapy and has undergone many procedures, tests, and surgeries. With all odds stacked against her, she is one determined little girly with a big personality and contagious laugh to match!

Mae’s Mission is to raise awareness about CTNNB1 Syndrome, bring accessibility to communities, and help fundraise for ongoing research.

https://maesmissionmn.org/

Freeman M, Fakhori N, Monteil D. Progressive spasticity and developmental delay in an infant with a CTNNB1 mutation. BMJ Case Rep. 2024 Jun 13;17(6):e260856. doi: 10.1136/bcr-2024-260856. PMID: 38871641.

Abstract

We present an infant referred to Developmental Paediatrics for delays, slow growth, hypotonia, esotropia and spasticity. Over the course of 2 months, the infant's exam progressed, demonstrating worsening spasticity and tonal changes in the setting of a normal brain MRI with acquired microcephaly. Genetic testing demonstrated a pathogenic CTNNB1 nonsense mutation. Following the discovery of the underlying cause for the child's clinical picture, the child was evaluated by therapeutic services and neurology, which was initially only available via asynchronous telehealth, due to a resource limited area. Cerebral palsy is a nonprogressive neurodevelopmental disorder and, when associated with developmental delay, qualifies for further genetic investigation into the underlying aetiology. Genetic testing recommendations exist for developmental delay, but there is no current algorithm regarding testing for cerebral palsy. Education and clear guidelines on genetic testing allow for better prognostication and potential treatment in cases of cerebral palsy, especially when associated with other disorders.

Dubruc E, Putoux A, Labalme A, Rougeot C, Sanlaville D, Edery P. A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency. Am J Med Genet A. 2014 Jun;164A(6):1571-5. doi: 10.1002/ajmg.a.36484. Epub 2014 Mar 25. PMID: 24668549.

Abstract

A girl patient born to healthy nonconsanguineous parents was referred at age 3 years and 2 months to our genetics department for testing due to developmental delay and postnatal microcephaly. Initial clinical evaluation revealed an overall developmental delay, mildly dysmorphic features, thin, sparse fair hair, and fair skin. Postnatal microcephaly and progressive ataxia and spasticity appeared later. Array CGH karyotyping showed a 333 kb de novo microdeletion on 3p22 covering the entire genomic sequence of a single gene, CTNNB1, which codes for β-catenin. β-catenin is a sub-unit of a multiprotein complex, which is part of the Wnt signaling pathway. In mice, a conditional homozygous β-catenin knockout displays loss of neurons, impaired craniofacial development, and hair follicle defects, which is similar to the phenotype presented by the patient described in this clinical report. Thus, CTNNB1 haploinsufficiency causes neuronal loss, craniofacial anomalies and hair follicle defects in both humans and mice. Point mutations in CTNNB1 in human have recently been reported but this is the first observation of a new recognizable multiple congenital anomaly/mental retardation syndrome caused by CTNNB1 haploinsufficiency. This clinical report should prompt a search for point mutations in CTNNB1 in patients presenting developmental delay, mild hair, skin and facial anomalies, and neurodegeneration characterized by postnatal microcephaly, and progressive ataxia and spasticity.

Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, van den Boogaard MJ, Bramswig N, Büttner C, Cremer K, Czeschik JC, Engels H, van Gassen K, Graf E, van Haelst M, He W, Hogue JS, Kempers M, Koolen D, Monroe G, de Munnik S, Pastore M, Reis A, Reuter MS, Tegay DH, Veltman J, Visser G, van Hasselt P, Smeets EE, Vissers L, Wieland T, Wissink W, Yntema H, Zink AM, Strom TM, Lüdecke HJ, Kleefstra T, Wieczorek D. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet. 2015 Jan;134(1):97-109. doi: 10.1007/s00439-014-1498-1. Epub 2014 Oct 19. PMID: 25326669.

Abstract

Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome.

Treatment of late-onset Pompe disease

Davalos L, Kushlaf H. Advances in Disease-Modifying Therapeutics for Chronic Neuromuscular Disorders. Semin Respir Crit Care Med. 2024 Dec 21. doi: 10.1055/a-2463-3385. Epub ahead of print. PMID: 39708835.

Abstract

Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications. For myasthenia gravis (MG), efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan have been Food and Drug Administration (FDA)-approved for the treatment of acetylcholine receptor (AChR) antibody-positive generalized MG in the past 2 years. Rozanolixiumab is also approved for treating MG caused by muscle-specific tyrosine kinase (MuSK) antibodies. The new MG therapeutics target the complement system or block the neonatal fragment crystallizable (Fc) receptors (FcRn), leading to significant clinical improvement. For spinal muscular atrophy (SMA), nusinersen (intrathecal route) and risdiplam (oral route) modify the splicing of the SMN2 gene, increasing the production of normal survival motor neuron (SMN) protein. Onasemnogene abeparvovec is a gene replacement therapy that encodes a functional SMN protein. All SMA medications, particularly onasemnogene abeparvovec, have led to clinically meaningful improvement. For late-onset Pompe disease (LOPD), avalglucosidase alfa has shown a greater improvement in respiratory function, ambulation, and functional outcomes in comparison to alglucosidase alfa, and cipaglucosidase alfa combined with miglustat has shown improvement in respiratory and motor function in a cohort of enzyme replacement therapy-experienced LOPD patients. Amyotrophic lateral sclerosis (ALS) remains a challenge. The two most recent FDA-approved medications, namely sodium phenylbutyrate and tofersen, may slow down the disease by a few months in a selected population but do not stop the progression of the disease.

Dalmia S, Sharma R, Ramaswami U, Hughes D, Jahnke N, Cole D, Smith S, Remmington T. Enzyme replacement therapy for late-onset Pompe disease. Cochrane Database Syst Rev. 2023 Dec 12;12(12):CD012993. doi: 10.1002/14651858.CD012993.pub2. PMID: 38084761; PMCID: PMC10714667.

Abstract

Background: Pompe disease is caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). People with infantile-onset disease have either a complete or a near-complete enzyme deficiency; people with late-onset Pompe disease (LOPD) retain some residual enzyme activity. GAA deficiency is treated with an intravenous infusion of recombinant human acid alglucosidase alfa, an enzyme replacement therapy (ERT). Alglucosidase alfa and avalglucosidase alfa are approved treatments, but cipaglucosidase alfa with miglustat is not yet approved.

Objectives: To assess the effects of enzyme replacement therapies in people with late-onset Pompe disease.

Search methods: We searched the Cochrane Inborn Errors of Metabolism Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched MEDLINE OvidSP, clinical trial registries, and the reference lists of relevant articles and reviews. Date of last search: 21 April 2022.

Selection criteria: We included randomised controlled trials (RCTs) of ERT in people with LOPD of any age.

Data collection and analysis: Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias and the certainty of the evidence (using GRADE). We resolved disagreements through discussion and by consulting a third author.

Main results: We included six trials (358 randomised participants) lasting from 12 to 78 weeks. A single trial reported on each comparison listed below. None of the included trials assessed two of our secondary outcomes: need for respiratory support and use of a walking aid or wheelchair. Certainty of evidence was most commonly downgraded for selective reporting bias. Alglucosidase alfa versus placebo (90 participants) After 78 weeks, alglucosidase alfa probably improves the six-minute walk test (6MWT) distance compared to placebo (mean difference (MD) 30.95 metres, 95% confidence interval (CI) 7.98 to 53.92; moderate-certainty evidence) and probably improves respiratory function, measured as the change in per cent (%) predicted forced vital capacity (FVC) (MD 3.55, 95% CI 1.46 to 5.64; moderate-certainty evidence). There may be little or no difference between the groups in occurrence of infusion reactions (risk ratio (RR) 1.21, 95% CI 0.57 to 2.61; low-certainty evidence), quality of life physical component score (MD -1.36 points, 95% CI -5.59 to 2.87; low-certainty evidence), or adverse events (RR 0.94, 95% CI 0.64 to 1.39; low-certainty evidence). Alglucosidase alfa plus clenbuterol versus alglucosidase alfa plus placebo (13 participants) The evidence is very uncertain about the effect of alglucosidase alfa plus clenbuterol compared to alglucosidase alfa plus placebo on: change in 6MWT distance after 52 weeks (MD 34.55 metres, 95% CI-10.11 to 79.21; very low-certainty evidence) and change in % predicted FVC (MD -13.51%, 95% CI -32.44 to 5.41; very low-certainty evidence). This study did not measure infusion reactions, quality of life, and adverse events. Alglucosidase alfa plus albuterol versus alglucosidase alfa plus placebo (13 participants) The evidence is very uncertain about the effect of alglucosidase alfa plus albuterol compared to alglucosidase alfa plus placebo on: change in 6MWT distance after 52 weeks (MD 30.00 metres, 95% CI 0.55 to 59.45; very low-certainty evidence), change in % predicted FVC (MD -4.30%, 95% CI -14.87 to 6.27; very low-certainty evidence), and risk of adverse events (RR 0.67, 95% CI 0.38 to 1.18; very low-certainty evidence). This study did not measure infusion reactions and quality of life. VAL-1221 versus alglucosidase alfa (12 participants) Insufficient information was available about this trial to generate effect estimates measured at one year or later. Compared to alglucosidase alfa, VAL-1221 may increase or reduce infusion-associated reactions at three months, but the evidence is very uncertain (RR 2.80, 95% CI 0.18 to 42.80). This study did not measure quality of life and adverse events. Cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo (125 participants) Compared to alglucosidase alfa plus placebo, cipaglucosidase alfa plus miglustat may make little or no difference to: 6MWT distance at 52 weeks (MD 13.60 metres, 95% CI -2.26 to 29.46); infusion reactions (RR 0.94, 95% CI 0.49 to 1.80); quality of life scores for physical function (MD 1.70, 95% CI -2.13 to 5.53) and fatigue (MD -0.30, 95% CI -2.76 to 2.16); and adverse effects potentially related to treatment (RR 0.83, 95% CI 0.49 to 1.40) (all low-certainty evidence). Cipaglucosidase alfa plus miglustat probably improves % predicted FVC compared to alglucosidase alfa plus placebo (MD 3.10%, 95% CI 1.04 to 5.16; moderate-certainty evidence); however, it may make little or no change in % predicted sniff nasal inspiratory pressure (MD -0.06%, 95% CI -8.91 to 7.71; low-certainty evidence). Avalglucosidase alfa versus alglucosidase alfa (100 participants) After 49 weeks, avalglucosidase alfa probably improves 6MWT compared to alglucosidase alfa (MD 30.02 metres, 95% CI 1.84 to 58.20; moderate-certainty evidence). Avalglucosidase alfa probably makes little or no difference to % predicted FVC compared to alglucosidase alfa (MD 2.43%, 95% CI -0.08 to 4.94; moderate-certainty evidence). Avalglucosidase alfa may make little or no difference to infusion reactions (RR 0.78, 95% CI 0.42 to 1.45), quality of life (MD 0.77, 95% CI -2.09 to 3.63), or treatment-related adverse events (RR 0.92, 95% CI 0.61 to 1.40), all low-certainty evidence.

Authors' conclusions: One trial compared the effect of ERT to placebo in LOPD, showing that alglucosidase alfa probably improves 6MWT and respiratory function (both moderate-certainty evidence). Avalglucosidase alfa probably improves 6MWT compared with alglucosidase alfa (moderate-certainty evidence). Cipaglucosidase plus miglustat probably improves FVC compared to alglucosidase alfa plus placebo (moderate-certainty evidence). Other trials studied the adjunct effect of clenbuterol and albuterol along with alglucosidase alfa, with little to no evidence of benefit. No significant rise in adverse events was noted with all ERTs. The impact of ERT on some outcomes remains unclear, and longer RCTs are needed to generate relevant information due to the progressive nature of LOPD. Alternative resources, such as post-marketing registries, could capture some of this information.

Kishnani PS, Byrne BJ, Claeys KG, Díaz-Manera J, Dimachkie MM, Kushlaf H, Mozaffar T, Roberts M, Schoser B, Hummel N, Kopiec A, Holdbrook F, Shohet S, Toscano A; PROPEL Study Group. Switching treatment to cipaglucosidase alfa plus miglustat positively affects patient-reported outcome measures in patients with late-onset Pompe disease. J Patient Rep Outcomes. 2024 Nov 13;8(1):132. doi: 10.1186/s41687-024-00805-w. PMID: 39535661; PMCID: PMC11561219.

Abstract

Background: Late-onset Pompe disease (LOPD), a rare autosomal recessive multisystemic disorder, substantially impacts patients' day-to-day activities, outcomes, and health-related quality of life (HRQoL). The PROPEL trial compared cipaglucosidase alfa plus miglustat (cipa+mig) with alglucosidase alfa plus placebo (alg+pbo) in adult patients with LOPD over 52 weeks and showed improved motor and respiratory function in patients switching treatment from standard-of-care enzyme replacement therapy (ERT) to cipa+mig at baseline. This study evaluated the impact of cipa+mig on patient-reported outcomes (PROs), including HRQoL in ERT-experienced patients, using data from PROPEL.

Methods: PROs evaluated included the Subject's Global Impression of Change (SGIC), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a, PROMIS Fatigue Short Form 8a, Rasch-built Pompe-specific Activity (R-PAct), and European Quality of Life-5 Dimensions 5 Response Levels (EQ-5D-5L). The proportions of responders in the cipa+mig arm and the alg+pbo arm were compared via chi-squared or Fisher's exact test (patient-level responder analysis), and least squares (LS) mean differences were calculated for change from baseline at Week 52 of the PRO measures (group-level analysis).

Results: At Week 52, patient-level SGIC responder and group-level SGIC analyses favored cipa+mig compared with alg+pbo across all SGIC domains (e.g. 90 vs. 59% responders in the cipa+mig vs. the alg+pbo group for SGIC ability to move around; P = 0.0005; and LS mean difference 0.385; P = 0.02). Similarly, PROMIS Physical Function and Fatigue domains numerically favored cipa+mig in both analyses (e.g. 50 vs. 40% responders in the cipa+mig vs. alg+pbo arm for PROMIS Physical Function; P = 0.37; and LS mean difference 3.1; P = 0.11). R-PAct for both treatment groups was similar in the patient-level responder analysis, but numerically favored alg+pbo in the group-level analysis (35% responders in both arms; P = 0.95; and LS mean difference -0.8; P = 0.48). Self-care, usual activities, and depression/anxiety domains of EQ-5D-5L numerically favored cipa+mig in both analyses (e.g. 20 vs. 12% responders in the cipa+mig vs. alg+pbo arm for EQ-5D-5L self-care; P = 0.54; and LS mean difference -0.108; P = 0.52).

Conclusions: Overall, switching treatment from alglucosidase alfa to cipa+mig positively impacted PRO measurements during the double-blind period of PROPEL.

Mir M, Rouhani K, Rouhani K, Hassani M, Damirchi M, Yazdansetad S, Aghaei M. Significance of early diagnosis and treatment of adult late-onset Pompe disease on the effectiveness of enzyme replacement therapy in improving muscle strength and respiratory function: a case report. J Med Case Rep. 2024 Oct 8;18(1):486. doi: 10.1186/s13256-024-04837-0. PMID: 39375771; PMCID: PMC11459847.

Abstract

Background: Pompe disease, a rare autosomal recessive disorder, is caused by mutations in the acid α-glucosidase gene. Pompe disease is a congenital metabolic disorder that affects all organs, particularly the striated muscle and nerve cells. Diagnosis is typically confirmed through enzyme assays that reveal reduced acid α-glucosidase activity. Enzyme replacement therapy utilizing human α-glucosidase is an available treatment option. Timely diagnosis and treatment in the early stages of the disease significantly impact the effectiveness of enzyme replacement therapy in enhancing patient condition. Here, we present a case of a patient with Pompe disease diagnosed 20 years after the onset of clinical symptoms.

Case presentation: A 38-year-old Iranian Baloch woman referred to our rheumatology clinic with progressive muscle weakness presents with a complex medical history. On mechanical ventilation for 12 years, she has endured fatigue and limb weakness since the age of 16, exacerbated following an abortion at 19. Despite undergoing corticosteroid and azathioprine therapies, the suspected diagnosis of inflammatory myopathy did not yield improvement. Hospitalization at 23 due to respiratory failure post-pregnancy led to her continued reliance on a ventilator. A dried blood spot test indicated reduced GAA enzyme activity, confirming a diagnosis of Pompe disease through genetic testing. Treatment with myozyme for 2 years demonstrated limited efficacy, as the patient experienced improved breathing but no significant overall improvement in limb-girdle muscular weakness. This case underscores the challenges and complexities involved in diagnosing and managing rare neuromuscular disorders like Pompe disease.

Conclusion: Early intervention with enzyme replacement therapy plays a crucial role in halting further muscle loss and disease progression in Pompe disease patients. It is important to note that treatment during advanced stages of the disease may not yield substantial benefits. Nevertheless, enzyme instability and denaturation due to temperature and neutral pH levels, along with limited delivery to disease-relevant tissues, can pose challenges in treatment. However, timely diagnosis of Pompe disease is paramount for its effective management and improved outcomes.