Radiprodil for seizures in children with GRIN-related neurodevelopmental disorders

Treatment with radiprodil (GRIN Therapeutics, New York, NY), a selective, potent negative allosteric modulator of the N-methyl-D-aspartate receptor subtype SB (NR2B or GluN2B), was well tolerated and associated with a significant reduction in seizure frequency in children with GRIN-related neurodevelopmental disorders. Following the reporting of findings from the phase 1b Honeycomb clinical study (NCT05818943), GRIN Therapeutics announced the initiation of the phase 1b/2b Astroscape clinical study (NCT06392009), which will investigate the safety and efficacy of radiprodil treatment for children with tuberous sclerosis (TSC) or focal cortical dysplasia (FCD) type II.

The multicenter phase 1b Honeycomb trial enrolled 15 patients aged ≥6 months to ≤12 years with gain-of-function (GoF) mutations in the GRIN1, GRIN2A, or GRIN1B genes. Participants were split into 2 cohorts, with Cohort 1 assessed for the frequency of countable motor seizures (CMS) within a 28-day screening period, and Cohort 2 assessed for baseline severity of nonseizure behavioral symptoms. The study included 2 periods, with participants who completed Part A being eligible for continued study treatment in Part B, consisting of an ongoing open-label extended treatment period.In Part A, participants treated with radiprodil showed an 86% reduction from baseline in seizure frequency. 71% of participants in Part A experienced a >50% reduction in CMS, 43% experienced a >90% reduction, and 1 participant was seizure free.

Radiprodil appeared generally well tolerated throughout Part A and Part B of the study to date.
Treatment emergent adverse events (TEAEs) included pyrexia, diarrhea, respiratory tract infection, abnormal behavior, agitation, cough, dystonia, fatigue, and gastroenteritis, which were associated with infections or underlying disease symptoms.

Astroscape is an open-label phase 1b/2b study that will evaluate radiprodil treatment at different doses for a targeted enrollment of 20 participants aged 6 months to 18 years with TSC or FCD type II with treatment-resistant seizures. Primary endpoints will include safety parameters, tolerability, and pharmacokinetic measures with key secondary endpoints assessing the effect of treatment on epileptic seizure frequency and severity and symptoms related to behavior, sleep, and quality of life. Participants who complete the treatment period may have the option to enroll in a long-term extension study.

"The initiation of treatment in the first patients enrolled in this landmark study is an important milestone for the TSC and FCD communities," said Dr. Manuel Toledo, MD, PhD, Head of the Epilepsy Unit at Vall d'Hebron University Hospital, Barcelona, Spain, who enrolled the first patient in the study. "We appreciate GRIN Therapeutics' commitment to making a positive difference for patients and families impacted by these serious conditions and we look forward to completing this clinical trial and reporting results as quickly as possible."

https://practicalneurology.com/news/favorable-results-for-radiprodil-tx-for-grin-disorders-leads-to-launch-of-study-to-test-treatment-in-those-with-tuberous-sclerosis-or-focal-cortical-dysplasia?

Newly presented data from the phase 1 Honeycomb study (NCT05818943) showed that treatment with investigational radiprodil (GRIN Therapeutics) was generally well tolerated, with significant impacts on seizure frequency in patients with GRIN-related neurodevelopmental disorder. Overall, the data support the continued development of radiprodil, selective and potent negative allosteric modulator of the N-methyl-D-aspartate receptor subtype 2B (NR2B or GluN2B), in this patient population.

At the July 15th cut-off date, 15 patients with GRIN-related disorder with a gain-of-function (GoF) variant in GRIN1, GRIN2A, 2GRINB, or GRIN2D were included for analysis. The study was designed as a 2-part trial, with Part A included a screening period (35 days), titration period (approximately 51 days), and maintenance period (up to 53 days). At the end of the maintenance period, there is an additional overnight stay when the participant is invited to take part in Part B or enter the tapering (15 days) and safety follow-up period (14 days).

Patients were escalated from a starting dose of 0.05 mg/kg based on tolerability, pharmacokinetics, and predicted GluN2B receptor occupancy to a dose level to be maintained through an 8-week maintenance period. During Part A, patients treated with radiprodil showed a median reduction of 86% in seizure frequency, a secondary end point, relative to baseline.

During this same period, 71% of treated patients experienced at least a 50% reduction in countable motor seizures (CMS), with 43% who saw a greater than 90% reduction. Notably, 1 patient was considered seizure free following treatment. In addition, clinician and caregiver-related scales generally assessed patients as improved clinically throughout the trial.

“GRIN-related neurodevelopmental disorder is a devastating disease for which there are no FDA-approved treatments,” Bruce Leuchter, MD, president and chief executive officer at Neurvati Neurosciences and GRIN Therapeutics, told NeurologyLive®. “Ongoing research, including the promising results from our Honeycomb clinical trial, are deepening our understanding of the disorder and how best to help patients, families and caregivers. Our team is very excited about these results and the opportunity to advance a potential first-in-class ​therapy into a pivotal Phase 3 clinical trial. We are looking forward to working with regulatory authorities and the patient and caregiver communities to advance the development of radiprodil.”

The study was divided into 2 cohorts based on the frequency of CMS experienced during the 28-day screening period (cohort 1) and baseline severity of non-seizure behavioral symptoms. While demographics and baseline disease characteristics were generally balanced between the cohorts, there was a higher level of seizure activity at baseline in cohort 1, as explained by a mean CMS of 37.0 and median CMS of 25.5 per patient (range of 4.8 to 85.9). At baseline, there were no CMS observed in cohort 2.

GRIN-related neurodevelopmental disorder is part of a larger family of genetic diseases related to ionotropic glutamate receptors and is caused by a change in one of 7 GRIN genes including GRIN1, GRIN2A, GRIN2B, and GRIN2D. These genes contain the code to create NMDA receptors, which are essential for learning and memory. To date, there have been several research studies conducted in the search for possible treatments targeting the NMDA receptors; however, there have been no FDA-approved treatments of GRIN disorders yet.

In Honeycomb, there were no deaths, and the most common treatment-emergent adverse events (TEAEs) related to radiprodil were those associated with infections or underlying disease symptoms. These included pyrexia, diarrhea, respiratory tract infection, abnormal behavior, agitation, cough, dystonia, fatigue, and gastroenteritis. Investigators observed 3 serious AEs, which were obstructive bronchitis, viral pneumonia, and adenovirus infection, each found in 1 patient. None of these were considered related to the study treatment and none met the study criteria for stopping treatment.

Part B of Honeycomb, an open-label extended treatment period for patients who completed Part A and were eligible for continued study treatment, remains ongoing. During this period, there will be 4 visits per year, 2 of which require overnight stays. At the end of the long-term treatment period, patients will enter a 15-day tapering period, and 14-day safety follow-up period.

Despite increased efforts, there are still no approved treatments for GRIN-related neurodevelopmental disorder. Memantine, an NMDAR antagonist, has been tested in various GoF variants and has been shown to reduce the frequency of seizures in some patients. L-Serine is a NMDAR agonist that has been shown to improve motor impairments, cognition, and communication in patients with a GRIN2B loss-of-function variant. In a published phase 2a study (NCT04646447), treatment with L-serine was associated with significant improvement in the median Gross Motor Function-88 total score (P = .002) and the mean Pediatric Quality of Life total score (P = .00068) regardless of disease severity.

https://www.neurologylive.com/view/radiprodil-significantly-reduces-seizure-frequency-phase-1b-honeycomb-study-grin-related-neurodevelopmental-disorderstudy-grin-related-neurodevelopmental-disorder

Bertocchi I, Cifarelli L, Oberto A, Eva CE, Sprengel R, Mirza NR, Muglia P. Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation. Br J Pharmacol. 2024 Jun;181(12):1886-1894. doi: 10.1111/bph.16361. Epub 2024 Mar 26. PMID: 38529699.

Abstract

Background and purpose: GRIN-related disorders are neurodevelopmental disorders caused by mutations in N-methyl-D-aspartate receptor (NMDAR) subunit genes. A large fraction of these mutations lead to a 'gain of function' (GoF) of the NMDAR. Patients present with a range of symptoms including epilepsy, intellectual disability, behavioural and motor. Controlling seizures is a significant unmet medical need in most patients with GRIN-related disorders. Although several hundred GRIN mutations have been identified in humans, until recently none of the mouse models carrying Grin mutations/deletions showed an epileptic phenotype. The two recent exceptions both carry mutations of GluN2A. The aim of this study was to assess the efficacy of radiprodil, a selective negative allosteric modulator of GluN2B-containing NMDARs, in counteracting audiogenic seizures (AGS) in a murine model carrying the GluN2A(N615S) homozygous mutation (Grin2aS/S mice).

Experimental approach: Grin2aS/S mice were acutely treated with radiprodil at different doses before the presentation of a high-frequency acoustic stimulus commonly used for AGS induction.

Key results: Radiprodil significantly and dose-dependently reduced the onset and severity of AGS in Grin2aS/S mice. Surprisingly, the results revealed a sex-dependent difference in AGS susceptibility and in the dose-dependent protection of radiprodil in the two genders. Specifically, radiprodil was more effective in female versus male mice.

Conclusion and implications: Overall, our data clearly show that radiprodil, a GluN2B selective negative allosteric modulator, may have the potential to control seizures in patients with GRIN2A GoF mutations. Further studies are warranted to better understand the sex-dependent effects observed in this study.

BCL11A intellectual developmental disorder

Peron A, D'Arco F, Aldinger KA, Smith-Hicks C, Zweier C, Gradek GA, Bradbury K, Accogli A, Andersen EF, Au PYB, Battini R, Beleford D, Bird LM, Bouman A, Bruel AL, Busk ØL, Campeau PM, Capra V, Carlston C, Carmichael J, Chassevent A, Clayton-Smith J, Bamshad MJ, Earl DL, Faivre L, Philippe C, Ferreira P, Graul-Neumann L, Green MJ, Haffner D, Haldipur P, Hanna S, Houge G, Jones WD, Kraus C, Kristiansen BE, Lespinasse J, Low KJ, Lynch SA, Maia S, Mao R, Kalinauskiene R, Melver C, McDonald K, Montgomery T, Morleo M, Motter C, Openshaw AS, Palumbos JC, Parikh AS, Perilla-Young Y, Powell CM, Person R, Desai M, Piard J, Pfundt R, Scala M, Serey-Gaut M, Shears D, Slavotinek A, Suri M, Turner C, Tvrdik T, Weiss K, Wentzensen IM, Zollino M, Hsieh TC; C4RCD Research Group; Telethon Undiagnosed Disease Program (TUDP); University of Washington Center for Mendelian Genomics (UW-CMG); de Vries BBA, Guillemot F, Dobyns WB, Viskochil D, Dias C. BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations. Eur J Hum Genet. 2024 Oct 24. doi: 10.1038/s41431-024-01701-z. Epub ahead of print. PMID: 39448799.

Abstract

An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11A's role in brain development.

Peron A, Bradbury K, Viskochil DH, Dias C. BCL11A-Related Intellectual Disability. 2019 Sep 26. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 31556984.

Excerpt

Clinical characteristics: BCL11A-related intellectual disability (BCL11A-ID) is characterized by developmental delay / intellectual disability of variable degree, neonatal hypotonia, microcephaly, distinctive but variable facial characteristics, behavior problems, and asymptomatic persistence of fetal hemoglobin. Growth delay, seizures, and autism spectrum disorder have also been reported in some affected individuals.

Diagnosis/testing: The diagnosis of BCL11A-ID is established in a proband with suggestive clinical and laboratory findings and a heterozygous pathogenic variant in BCL11A identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is primarily supportive and dictated by symptoms. Standard anti-seizure medication for seizure disorder; standard treatment for abnormal vision and/or strabismus, sleep disturbance, scoliosis, joint laxity, gastroesophageal reflux disease (GERD), constipation, and developmental issues.

Surveillance: Assessment of growth parameters, feeding difficulties, GERD, constipation, scoliosis, developmental progress, and behavior at each visit. Monitor seizures as clinically indicated. Assessment of vision and eye alignment as needed.

Genetic counseling: BCL11A-ID is inherited in an autosomal dominant manner; however, most affected individuals have the disorder as the result of a de novo BCL11A pathogenic variant. Once the BCL11A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Alobar holoprosencephaly

Madysen Wilcox, 29, was just six weeks pregnant when she began having complications, including bleeding and spotting that her doctors initially suspected may be a sign of miscarriage.

"However, when we got our ultrasound, they discovered I had what was called a subchorionic hematoma," Wilcox, of Utah, tells PEOPLE in an exclusive interview. According to the Cleveland Clinic, it is a condition in which "blood forms between a baby's amniotic sac and the uterine wall."

While it can be threatening to pregnancy depending on the location and size of the hematoma, doctors said Wilcox's "was small and in a spot that wasn't concerning." So they recommended pelvic rest, telling her to pause exercising and refrain from staying on her feet for long periods of time, or lifting anything heavier than 10 pounds.

"I did that for two weeks and my hematoma resolved and everything seemed fine," Wilcox says.

Once she entered her second trimester, the spotting began again.

"I was 15 weeks pregnant and my midwife wanted to do an ultrasound to figure out if the spotting was due to the hematoma or if there were issues with my placenta," she says. "So they checked again and found another subchorionic hematoma — but this time they also found that the baby's brain was not properly forming and they had a hard time locating a nasal bone."

Doctors then advised Wilcox to undergo a genetic blood test screening and a more in-depth ultrasound, suspecting that her baby might have Down syndrome. The blood test came back negative for any genetic disorder, but Wilcox's midwife still wanted a second opinion from a specialist based on her ultrasound images.

At 18 weeks pregnant, on May 29, 2024, Wilcox learned that her unborn baby — a boy she and her husband Darin had already named Charlie — had Alobar Holoprosencephaly, a rare condition in which the brain does not separate into two hemispheres.

https://people.com/woman-who-is-pregnant-with-a-baby-with-terminal-diagnosis-opens-up-exclusive-8717611

The condition, she learned, is fatal.

"The outcomes that doctors [gave] us are very grim," Wilcox says, noting that she saw four separate doctors after receiving the diagnosis. While each physician offered a somewhat different answer when asked about exact life expectancy, they all offered the same outlook: Charlie would not live long, and had a high likelihood of not even making it to birth.

However, Wilcox and Charlie defied some of the odds. "Most babies with this condition end in a miscarriage before the second trimester," she says. "Those who survive the first trimester, do not live past 24 weeks gestation."

But at 34 weeks pregnant, Charlie's heartbeat remained strong.

As she explains to PEOPLE, Wilcox was told that only one out of 10,000 pregnancies with Alobar Holoprosencephaly make it to a live birth, but she remained optimistic, sharing details of the condition, and her pregnancy, on TikTok.

She also made an effort to speak about Charlie as much as she could throughout her pregnancy, both with her husband and their two other children.

"Carrying a baby with a terminal diagnosis is an emotional roller coaster to say the least," she says. "I call it emotional chaos. It's a mixture of love, gratitude, compassion, joy, grief, fear, despair, guilt, and apathy, all at once. In the same day I can feel all of these emotions ten times over."

Though she adds, "I love this baby more than life," she admits "it’s also painful to get attached, because once I do, the grief and despair set in."

As the couple got closer to delivery day, they met with their doctors to plan how best to handle Charlie’s arrival, making "plans for every possible scenario," Wilcox says.

While Wilcox's due date was Oct. 27, doctors had planned to induce her on Oct. 4, just one day shy of a full-term pregnancy.

But on Oct. 4, the hospital was too full to accommodate her inducement — and she gave birth on Oct. 5 as she had hoped.

Ahead of his due date, Wilcox's plan was to "cherish the little time we get with our son, just getting to know him and holding him in our arms, where he is warm and knows he is loved," she shares.

In the end, they got to do just that. In a video posted to TikTok, Wilcox explained that Charlie "made his debut on the morning of October 5, 2024. We spent 41 beautiful minutes with him until he peacefully passed in our arms. Charlie's life was brief but perfect ... he only knew love and the warmth of his parents' arms."

For Wilcox, the moments she spent with Charlie were life-changing.

"It’s been the most beautiful and the most painful experience I’ve ever gone through in my life," she tells PEOPLE. "It’s hard to prepare to say goodbye to a person you’ve never met, but that you've also carried for nine months."

https://people.com/woman-who-is-pregnant-with-a-baby-with-terminal-diagnosis-opens-up-exclusive-8717611

Treatment of the leukodystrophies

Inspired by a patient

Sevin C, Mochel F. Hematopoietic stem cell transplantation in leukodystrophies. Handb Clin Neurol. 2024;204:355-366. doi: 10.1016/B978-0-323-99209-1.00017-X. PMID: 39322389.

Abstract

More than 50 leukodystrophies have been described. This group of inherited disorders affects myelin development and/or maintenance and can manifest from birth to adulthood. Neuroinflammation is a hallmark of some leukodystrophies, explaining in part the therapeutic benefit of hematopoietic stem cell transplantation (HSCT). Indeed, in addition to supplying the CNS with myelomonocyte donor cells expressing the deficient protein or enzyme, HSCT allows the restoration of normal microglia function, which may act on neuroinflammation. In this chapter, we explore the rationale, indication, and outcome of HSCT in Cerebral Adrenoleukodystrophy (CALD), Metachromatic Leukodystrophy (MLD), Krabbe Disease (KD), and Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP), which are among the most frequent leukodystrophies. For these leukodystrophies, HSCT may modify notably the natural history and improve CNS-related deficits, provided that the procedure is performed early into the disease course. In addition, we discuss the recent development of ex vivo gene therapy for CALD and MLD as a promising alternative to allograft.

Metovic J, Li Y, Gong Y, Eichler F. Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials. Neurotherapeutics. 2024 Jul;21(4):e00443. doi: 10.1016/j.neurot.2024.e00443. Epub 2024 Sep 13. PMID: 39276676; PMCID: PMC11418141.

Abstract

Leukodystrophies are progressive single gene disorders affecting the white matter of the brain. Several gene therapy trials are in progress to address the urgent unmet need for this patient population. We performed a comprehensive literature review of all gene therapy clinical trials listed in www.clinicaltrials.gov through August 2024, and the relevant preclinical studies that enabled clinical translation. Of the approximately 50 leukodystrophies described to date, only eight have existing gene therapy clinical trials: metachromatic leukodystrophy, X-linked adrenoleukodystrophy, globoid cell leukodystrophy, Canavan disease, giant axonal neuropathy, GM2 gangliosidoses, Alexander disease and Pelizaeus-Merzbacher disease. What led to the emergence of gene therapy trials for these specific disorders? What preclinical data or disease context was enabling? For each of these eight disorders, we first describe its pathophysiology and clinical presentation. We discuss the impact of gene therapy delivery route, targeted cell type, delivery modality, dosage, and timing on therapeutic efficacy. We note that use of allogeneic hematopoietic stem cell transplantation in some leukodystrophies allowed for an accelerated path to clinic even in the absence of available animal models. In other leukodystrophies, small and large animal model studies enabled clinical translation of experimental gene therapies. Human clinical trials for the leukodystrophies include ex vivo lentiviral gene delivery, in vivo AAV-mediated gene delivery, and intrathecal antisense oligonucleotide approaches. We outline adverse events associated with each modality focusing specifically on genotoxicity and immunotoxicity. We review monitoring and management of events related to insertional mutagenesis and immune responses. The data presented in this review show that gene therapy, while promising, requires systematic monitoring to account for the precarious disease biology and the adverse events associated with new technology.

Khanal P, Patil VS, Bhattacharya K, Shrivastava AK, Bhandare VV. Exploring the globoid cell leukodystrophy protein network and therapeutic interventions. Sci Rep. 2024 Aug 5;14(1):18067. doi: 10.1038/s41598-024-66437-8. PMID: 39103379; PMCID: PMC11300594.

Abstract

Globoid cell leukodystrophy is a severe rare disorder characterized by white matter degradation, resulting in a progressive loss of physical and mental abilities and has extremely limited therapeutic interventions. Therefore, this study aimed to delve into the Globoid cell leukodystrophy associated intricate network of differentially expressed genes (p < 0.05, |Fc|> 1) to identify potential druggable targets and possible therapeutic interventions using small molecules. The disease-associated neuronal protein circuit was constructed and analyzed, identifying 53 nodes (minimum edge cutoff 1), among which five (FOS, FOSB, GDNF, GFRA1, and JUN) were discerned as potential core protein nodes. Although our research enumerates the potential small molecules to target various protein nodes in the proposed disease network, we particularly underscore T-5224 to inhibit c-Jun activity as JUN was identified as one of the pivotal elements within the disease-associated neuronal protein circuit. The evaluation of T-5224 binding energy (- 11.0 kcal/mol) from docking study revealed that the compound to exhibit a notable affinity towards Jun/CRE complex. Moreover, the structural integrity of complex was affirmed through comprehensive molecular dynamics simulations, indicating a stable hydrophilic interaction between T-5224 and the Jun/CRE complex, thereby enhancing protein compactness and reducing solvent accessibility. This binding energy was further substantiated by free binding analysis, revealing a substantial thermodynamics complex state (- 448.00 ± 41.73 kJ/mol). Given that this investigation is confined to a computational framework, we additionally propose a hypothetical framework to ascertain the feasibility of inhibiting the Jun/CRE complex with T-5224 against Globoid cell leukodystrophy, employing a combination of in vitro and in vivo methodologies as a prospective avenue of this study.

Coulombe B, Chapleau A, Macintosh J, Durcan TM, Poitras C, Moursli YA, Faubert D, Pinard M, Bernard G. Towards a Treatment for Leukodystrophy Using Cell-Based Interception and Precision Medicine. Biomolecules. 2024 Jul 17;14(7):857. doi: 10.3390/biom14070857. PMID: 39062571; PMCID: PMC11274857.

Abstract

Cell-based interception and precision medicine is a novel approach aimed at improving healthcare through the early detection and treatment of diseased cells. Here, we describe our recent progress towards developing cell-based interception and precision medicine to detect, understand, and advance the development of novel therapeutic approaches through a single-cell omics and drug screening platform, as part of a multi-laboratory collaborative effort, for a group of neurodegenerative disorders named leukodystrophies. Our strategy aims at the identification of diseased cells as early as possible to intercept progression of the disease prior to severe clinical impairment and irreversible tissue damage.

Nemaline rod myopathy

Going the extra mile: Woman with muscular dystrophy completes 12 marathons to raise funds

Peri Finkelstein isn't letting her disability define her. The MBA grad and advocate has raised more than $1 million to help families with children battling deadly diseases.

Born with a rare form of muscular dystrophy, Peri Finkelstein has never let her disorder define her.

Instead, the 24-year-old New Yorker has used her challenges as a springboard to make the world a better place, completing 12 marathons to raise funds for charity.

In January 2024, Finkelstein’s nonprofit organization — the Team Peri Foundation — exceeded the $1 million fundraising milestone for its Chai Lifeline project, which offers support to families following an illness diagnosis or trauma.

Muscular dystrophy is a group of more than 30 genetic conditions that affect the functioning of the muscles, according to Cleveland Clinic.

Finkelstein's form of the condition, called nemaline rod myopathy, causes severe muscle weakness and affects her speech and mobility. 

Despite her physical limitations, she was inspired to start doing marathons in 2010 when her mother and brother began running them for charity.

"After watching everybody do the marathon and cheering from the sidelines, I knew that I wanted to make more of an impact," she said during an interview with Fox News Digital. 

For the first few years, Finkelstein’s mother pushed her in a jogging stroller with all the necessary medical equipment secured to the bottom.

Then, in 2016, Finkelstein decided it was time to stand up and walk a few steps over the finish line, with the help of her physical therapist and her parents.

"At that moment, it felt as if I could do anything that I put my mind to," she said. 

          Finkelstein's family and friends support her during a marathon in Miami. (Team Peri Foundation)

"It was a defining moment, when I realized the only person who could get in my way was myself — and that it was up to me to change my life."

In subsequent marathons, those initial steps turned into walking more than 1,000 steps, then a mile, and then a mile and a half, forwards and backwards across the finish line.

After several years of pushing that "extra mile," Finkelstein experienced medical challenges in 2022 that made her unable to compete.

"It never dawned on me that part of my life would be over," she said. 

"You have to push yourself to the limit for each mile marker, as nothing will ever come easily."

"Once I officially lost that part of myself, I realized that I couldn’t allow this setback to get to me — I knew that I had to keep moving."

Instead of competing physically, Finkelstein now funnels her energy into her foundation’s fundraising efforts.

"Since I was 8 years old, my dream was to launch a nonprofit organization of my own," she said.

"The same mindset that I used to prepare both physically and mentally for a marathon is what I carry into my daily life as an entrepreneur."

The Team Peri Foundation strives to make the world a "more connected and inclusive place for all," Finkelstein said, with the mission to "educate others on the power of inclusion and to disrupt the stereotypical views revolving around disability."

‘Not all rainbows and sunshine’

While Finkelstein strives to stay positive and focus on her goals, she acknowledges that her day-to-day life isn’t always easy.

"Not every day is all rainbows and sunshine — some days are harder than others, to the point where severe migraines, fatigue and pain keep me from doing what I have to do," she said. 

Finkelstein undergoes different forms of therapy multiple times a week, has frequent doctor’s appointments and is "always in pain," she shared.

Her social media posts highlight the highs and lows.

"My hope is that by sharing bits and pieces of my world — portraying all the different sides of me, whether it’s rather dark or filled with light — I can portray that people with disabilities can live a full life and step out of line in ways that can change the course of their future," she said. 

To other people living with a disabling condition, Finkelstein advises them, "Use your rareness to your advantage."

"My time is precious and I still have a lot more to accomplish."

"Growing up, I would give anything to blend in and become invisible, as being ‘different’ put a lot of labels on me that caused me to be bullied severely by students and teachers alike," she said.

"But as I’ve gotten older, I’ve realized it’s OK to be rare."

Life itself can be compared to the dozen marathons she has competed in, according to Finkelstein.

"You have to push yourself to the limit for each mile marker, as nothing will ever come easily," she said.

"All the pain, traumas and setbacks are what enable you to keep going and keep hustling."

"You have to power through the pain, because there is no other option."

Since hitting the $1 million milestone, Finkelstein and her foundation have launched new projects, including a scholarship fund in partnership with Adelphi University, where she earned her MBA in marketing.

She also works to boost awareness and education through speaking engagements, social media and podcasting, and hosts various fundraising events throughout the year.

Finkelstein plans to write and publish a memoir to share her life's journey with the world. 

"While I used to be an athlete, I am still just as competitive and am somewhat of an overachiever in the real world," Finkelstein said. 

The entrepreneur is also acutely aware that life is short.

"It’s always in the back of my mind that I cannot wait to live my life — because of physical disability and medical challenges, it could be cut short," she said.

"My time is precious, and I still have a lot more to accomplish."

https://www.foxnews.com/health/woman-muscular-dystrophy-completes-marathons-wheelchair-charity-wont-let-define

MOG antibody associated encephalitis

Madilynn Shaffer quickly went from being a bubbly and upbeat toddler to not being able to walk or talk.

“To see her going from an active child to laying in a hospital bed is the most hopeless feeling any parent could go through,” her father Thomas Shaffer, of Harrison County, West Virginia, told CBS affiliate WDTV.

She started to act sick in January, said Thomas, and a few days later she had a seizure and weak breathing. Doctors diagnosed her with ADEM, a widespread attack of inflammation in the brain and spinal cord, according to the National Institute of Neurological Disorders and Stroke.

The long-term prognosis is generally favorable and most will recover, according to the institute, but others have “mild to moderate lifelong impairment ranging from cognitive difficulties, weakness, loss of vision, or numbness.”

After the diagnosis, Thomas had a feeling that there was more to it.

“I started doing some research and doing Google doctor, which everyone tells you not to do. However I did it, and a lot of the symptoms she was having was this ANTI-MOG,” he told the news outlet.

The condition — which has only been diagnosed within the last five years — is an inflammatory demyelinating disease, according to the Mayo Clinic.

“It basically means Madilynn’s immune system is attacking the white matter of her brain,” her mother Stacy Wescott told Connect Bridgeport.

Along with not being able to walk or talk, she can’t sit up on her own and is often in pain. Since January she’s had kidney stones, pneumatosis and broken bones due to high doses of steroids, according to Bridgeport. Physicians think the steroids have made her bones brittle.

“She has so many different issues going on right now: fractures in her spine, broken right wrist, tibia, left foot and sternum,” Wescott added.

As Wescott stays with Madilynn as she is treated at the Children’s Hospital of Philadelphia, Thomas continues to work during the week. They’re both hopeful that their daughter will regain everything she’s lost, reports WDTV.

They’re also determined to speak out — and motivate people to get the answers they deserve.

“You’ve got to be out there and telling people to do all the tests you can do. Don’t settle for one or two. Push the medical field and make them do the testing,” he told WDTV. “For me this has been hell on Earth.”

https://people.com/human-interest/toddler-battles-rare-disease-unable-walk-or-talk/

See: https://childnervoussystem.blogspot.com/2020/12/mog-antibody-disease-differs-for.html

Denial of coverage for Zolgensma in twins with spinal muscular atrophy 1

Newborn twins with a rare — but often fatal — genetic disorder have been denied life-saving treatment by their family’s insurance company. 

Shortly after welcoming Eli and Easton Reed on March 31, 2024, the family tells KMBC that the twin boys were diagnosed with spinal muscular atrophy.

The genetic disorder can “damage and kill specialized nerve cells in the brain and spinal cord,” the National Institute for Neurological Disorders and Stroke explains.

While there is no cure, treatment includes “managing the symptoms and preventing complications.”  

And for the St. Joseph, Missouri, twins, treatment included the medication Zolgensma — which the family says their insurance company stopped covering just one day before the twins were born.

“Time is of the essence with this ... since they don’t have symptoms as of right now,” the twins’ mother, Amanda Reed, told KMBC. 

“It's best for them to receive this treatment now. because once symptoms start, it's un-reversible. So, time is of the essence, but we are still trying to explore all of our options.“

Out-of-pocket costs for the medication are “between $1 million and $2.5 million per child, a daunting amount that we are striving to secure through insurance appeals and your continued support,” a GoFundMe established to help them pay for the medication explains.

Zolgesnsma is a one-time treatment that “targets the genetic root cause of spinal muscular atrophy,” the website says, "stopping the progression" of the disease.

As the GoFundMe shared, the family’s insurance company “called an emergency meeting to review all of the information to decide whether or not they will allow their insurance to cover the gene therapy the boys need.”

But on April 26, the board denied their appeal, the GoFundMe says, leaving the family to pay for the life-saving therapy themselves.

“I’m holding my heart in my hands,” the twins’ father, Austin Reed, told KMBC.

“The fact that their life is in somebody’s else’s hands, whether they get this treatment or they don’t, you know, then that’s somebody else’s choice and that’s hard to cope with that right now.”

"Patients less than six months of age at disease onset will never sit independently and will likely to die of respiratory failure before two years of age," the National Library of Medicine says.

And as the Cleveland Clinic says, infants with type 1 SMA  — which means symptoms appear within the first 6 months of life — “usually die before their second birthday.”

https://people.com/insurance-denies-newborn-twins-fatal-disorder-treatment-8641768

Update 5/9/2024: Kecia Vant Hof, the organizer behind the GoFundMe page for Eli and Easton Reed, who were initially denied life-saving treatment for Spinal Muscular Atrophy (SMA), has announced that the twin newborns will be receiving the treatment next week.

In an update posted to the GoFundMe page, she wrote, “I want to personally thank each and every one of you for being so generous during my sister and her family’s time of need. Your love and encouragement has been such an incredible blessing.

“Due to all of you, the news media outlets who shared Eli and Easton’s story, and a powerful God, Eli and Easton WILL be receiving the gene therapy NEXT WEEK!! We are so blessed and thankful that the boys will have a fighting chance and we cannot thank you all enough.”

Vant Hof said that the GoFundMe has been closed but the $400,000 that was received so far will be used for any upcoming necessary treatments the boys may need.

Update 5/8/2024: Shortly after news broke that newborn twins Eli and Easton Reed had been denied the life-saving medication Zolgensma to combat Spinal Muscular Atrophy (SMA), the company that had denied the coverage, Mosaic Life Care, announced a new fund to help pay for the treatment. Mosaic Life Care, where the mother of Eli and Easton, Amanda Reed, works, is reported to have ended coverage of the life-saving drug that Eli and Easton need just one day after the boys were born and four days before they were diagnosed with SMA.

“Children’s Mercy, because that’s where we would be going for the treatment, tried to ask them if it could be covered since they were born a day before the cut, and they were denied,” Reed said. She added that the diagnosis and denial of coverage has “been a nightmare, an absolute nightmare.”

In a May 3 statement, Mosaic Life Care announced it established a fund to support treatment for rare genetic neuromuscular diseases such as SMA. It said it contributed $1.5 million to the fund after it received a $1.9 million anonymous donation. The money is said to be immediately available for the delivery of Zolgensma.

“We are pleased to announce the creation of a $3.4 million dollar philanthropic fund through the Mosaic Life Care Foundation for the purpose of supporting genetic treatment for rare genetic neuromuscular diseases such as Spinal Muscular Atrophy (SMA),” said Mosaic Life Care CEO Mike Poore. He added, “Using our extensive government, hospital and medical connections, we have been making exhaustive efforts behind the scenes to successfully secure substantial additional support for the treatment of SMA.”

5/3/2024: An insurance company is coming under fire for denying the coverage of life-saving treatment to a set of twins who will otherwise likely die before their second birthday.

People Magazine reported that Eli and Easton Reed were born on March 31, 2024, and shortly after they were both diagnosed via newborn screening with Spinal Muscular Atrophy (SMA), a progressive genetic disorder that kills nerve cells in the brain and spinal cord. The National Institute for Neurological Disorders and Stroke states that there are different forms, including Types I, II, III, and IV with Type I being the most severe. Without treatment, most children with Type I will die before the age of two as they progressively lose the ability to walk, swallow, and breathe.

However, new hope has come in the form of a single-dose treatment of a medication called Zolgensma, which is being called a “miracle drug.”

In 2021, Live Action News reported the story of baby Joseph Crew Delia who was diagnosed with SMA after birth and was given the one-time IV infusion of Zolgensma, which targets the genetic root cause of SMA and can prevent the deteriorating effects of the condition. The life-saving medication, however, costs $2.1 million. While Crew’s insurance covered $500,000 of it, his parents raised funds to cover the rest. Today, he’s a healthy toddler.

Eli and Easton Reed each need a dose, making the out-of-pocket price tag for their parents $4.2 million — and insurance is refusing to cover any of the cost.

“Time is of the essence with this … since they don’t have symptoms as of right now,” the twins’ mother, Amanda Reed, told KMBC. “It’s best for them to receive this treatment now. Because once symptoms start, it’s un-reversible. So, time is of the essence, but we are still trying to explore all of our options.”

A GoFundMe was created to help raise money for treatment while the boys’ parents appealed the insurance company’s decision. But on April 26, the insurance company denied the appeal.

“I’m holding my heart in my hands,” the twins’ father, Austin Reed, told KMBC.

“The fact that their life is in somebody else’s hands, whether they get this treatment or they don’t, you know, then that’s somebody else’s choice and that’s hard to cope with that right now.”

Without the treatment, the deteriorating effects of SMA could set in within six months, causing the boys to never be able to sit independently and likely die of respiratory failure by age two. SMA is progressive and Zolgensma can’t undo damage that is already done.

It stops the disease’s effects from progressing, so the sooner it is administered, the better.

https://www.liveaction.org/news/insurance-company-refuses-fund-newborns-care/

Two California parents are hoping to raise funds for the "most expensive drug in the world" to save the life of their daughter, who was recently diagnosed with a rare degenerative disease.

For parents Ceri and Rory Devine, things seemed to be going smoothly in the first months following the birth of their daughter, Rhys, in December 2019. But the couple noticed things were amiss when their baby girl noticeably fell behind in her development when she was 4 months old.

'That mother’s intuition was nagging me," Ceri, from Los Angeles, said on a website set up by the family. "She always struggled with tummy time, and wasn’t able to roll over or hold her head up for very long."

The couple took their daughter in for a check-up, and their pediatrician recommended physical therapy after examining Rhys' low muscle tone. But when she was reevaluated two months later, their doctor suspected Rhys had Spinal Muscular Atrophy. This rare genetic disease causes muscles to weaken throughout the body due to cellular defects in the brain stem and spinal cord.

What followed was "the longest two weeks" of the couple's lives, and after visiting numerous specialists, Rhys was officially diagnosed with SMA Type 1.

According to Boston Children's Hospital, SMA Type 1 (also known as Werdnig-Hoffmann disease) causes various symptoms in babies as their muscles waste away, such as being unable to sit without support and difficulty breathing, feeding and swallowing. There is no cure for the disease, and, tragically, many babies with SMA Type 1 die before the age of 2.

Despite the tragic news, Ceri and Rory were given some hope — doctors said there were two gene therapy treatments that could potentially improve Rhys' quality of life. But they wouldn't be easy to get.

One of the treatments, Spinraza, has shown improvement in children with SMA Type 1 and 2, according to SMA News Today. The drug — which is administered every four months through a spinal injection — costs $750,000 the first year and $375,000 every year after that for life, the parents say.

The other treatment, Zolgensma, was approved by the FDA in 2019 and is known as the "most expensive drug ever," NPR reported. It costs $2.1 million for a single dose, but the drug has shown improvement in young patients with SMA and "some patients are even able to walk independently," according to Ceri and Rory.

"Because SMA Type 1 is aggressive and degenerative, this is a race against time," the parents wrote on the website, Rise Up for Rhys.

"With each day that passes, motor neurons in Rhys’ sweet little body are becoming inactive," they continued. "In addition to the gene therapy, Rhys will need ongoing physical therapy and support equipment based on her needs to help her develop, improve mobility, and improve her quality of life."

The family started a GoFundMe campaign to raise funds for the therapies, and have raised over $273,000 as of Friday afternoon.

"Every child should have the best possible chance at life," the couple wrote. "Please join us to surround our happy little girl in love and support."

https://people.com/health/six-month-old-girl-with-rare-disease-in-need-of-life-saving-medicine-that-costs-2-1m/

See: https://www.facebook.com/riseupforrhys/

Rhys was treated with Zolgensma.

Elevidys therapy for Duchenne muscular dystrophy

Melanie Sanford's son Hudson was diagnosed with Duchenne, a fatal, progressive form of muscular dystrophy

She was told Hudson would only live until age 28 until she found hope in a breakthrough gene therapy

Three days before Hudson would have aged out of eligibility for the treatment, he was able to receive the therapy — and now he's thriving

Melanie Sanford was worried that her son, Hudson, wasn’t jumping around as much as other toddlers his age. But his pediatrician reassured her that kids all develop at their own pace, and “he wasn’t really concerned,” she tells PEOPLE.

Then Hudson, 4, started preschool. 

“His preschool teacher mentioned that he used his hands to get off the floor,” the Tuscon, Ariz., mom explained. “They have to push themselves up and then go up on their legs. And then she said he had trouble going up the stairs and not running as fast as all the other kids. So she's like, ’I would recommend going and seeing a neurologist.’ ”

Sanford made an appointment right away. His blood work came back showing highly elevated CK levels.

“CK stands for creatine kinase, an enzyme that leaks out of damaged muscle,” the Muscular Dystrophy Association explains. “When elevated CK levels are found in a blood sample, it usually means muscle is being disintegrated by some abnormal process, such as a muscular dystrophy or inflammation.”

In Hudson’s case, his CK levels were “really high. It was, like in the 17,000s,” Sanford tells PEOPLE. "When it's that elevated, it’s pretty much the indicator that it was Duchenne.”

“Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies,” the National Library of Medicine says. “Mutations in the dystrophin gene lead to progressive muscle fiber degeneration and weakness.”

And as Sanford tells PEOPLE, “When you Google it, it's really devastating. It's a horrible disease.”

At one of Hudson’s earliest appointments, she received dire news: “She basically said, ‘He's going to live to be 28. He's going to lose all of his ability to do everything. There's nothing you can do really, just give him steroids and go live your life.’ “

Sanford was floored. “It was terrible. I would never wish that on anybody. And this is when he was four. “ 

But she refused to give up, researching therapists and treatments to help her son live.

That’s when Sanford found out about Elevidys, a new one-time gene therapy targeting the root cause of Duchenne, rather than just managing its symptoms.

There was just one problem. At the time, Elevidys was only eligible for children up to 5 years old, and Hudson was about to turn 6. And, the treatment was out of state.

As Sanford tells PEOPLE, “We flew to Texas on the 17th of August, and he got his infusion on the 18th of August, and he turned [six] on the 21st.” 

As neurologist and neuromuscular physician Dr. Diana Castro, Founder and Director of the Neurology Rare Disease Center and Neurology and Neuromuscular Care Center, explains, “Duchenne is caused by the lack of dystrophin — a protein that is essential for muscle health and function. In healthy muscles, dystrophin acts as a shock absorber, helping to stabilize muscle cells during contraction and relaxation. Without dystrophin, muscles cannot repair themselves, becoming weaker and breaking down over time."

The way Elevidys works, Castro tells PEOPLE, "is to deliver a modified version of the dystrophin gene directly to muscle cells. This modified gene instructs the cells to make a version of dystrophin protein, which is incorporated into the muscle cell. While the treatment cannot restore muscles already lost to the disease, it aims to slow or stop further disease progression by stabilizing the muscle and preserving muscle function.”

This past summer, the Food and Drug Administration expanded approval for Elevidys, which is now available to treat all patients aged 4 years and older.

For Hudson, the results were almost immediate. 

“A week after the infusion, we noticed him running faster and being able to get up off the floor quicker and kind of going up the stairs a little bit quicker, and we thought maybe it was our minds playing a trick on us, but I have videos,” Sanford tells PEOPLE. 

Now Hudson is thriving. He plays in a bowling league, has signed up for coach pitch baseball — and is looking forward to being Gru from the Despicable Me movies for Halloween.

“Whether it lasts five years or a lifetime, I think the decision that we made is buying him time that he wouldn't have had,” Sanford said. “Before, he could not jump with two feet. Now he can. And every time he does something, he's like, 'It's my medicine. My medicine making me stronger.' "

"It's the sweetest thing,” Sanford says.

“It changes your perspective on what's important. Every day is a gift that we've been given. Yes, some days are hard. Do I cry when I go to sleep at night? Sometimes, yes, but just when I think of how far we've come and all the people that have helped us," she tells PEOPLE.

"Every day is a gift and we're not guaranteed that any of us will be here tomorrow, so we just live our life thankful for what we're given.”

https://people.com/muscular-dystrophy-duchenne-gene-therapy-exclusive-8722401

GRIN2D-related developmental and epileptic encephalopathy

Platzer K, Krey I, Lemke JR. GRIN2D-Related Developmental and Epileptic Encephalopathy. 2022 Jul 28. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 35914066.

Excerpt

Clinical characteristics: GRIN2D-related developmental and epileptic encephalopathy (GRIN2D-related DEE) is characterized by mild-to-profound developmental delay or intellectual disability, epilepsy, abnormal muscle tone (hypotonia and spasticity), movement disorders (dystonia, dyskinesia, chorea), autism spectrum disorder, and cortical visual impairment. Additional findings can include sleep disorders and feeding difficulties. To date 22 individuals with GRIN2D-related DEE have been reported.

Diagnosis/testing: The diagnosis of GRIN2D-related DEE is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) missense variant in GRIN2D identified by molecular genetic testing

Management: Treatment of manifestations: There is no cure for GRIN2D-related DEE. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatric neurology, pediatric ophthalmology, developmental pediatrics, feeding, orthopedics, physical medicine and rehabilitation, physical therapy, occupational therapy, and ethics.

Surveillance: In infancy: regular assessment of swallowing, feeding, and nutritional status to determine safety of oral vs gastrostomy feeding. For all age groups: routine monitoring of developmental progress, educational needs, and behavioral issues.

Genetic counseling: GRIN2D-related DEE is an autosomal dominant disorder typically caused by a de novo pathogenic variant. If the proband represents a simplex case (i.e., the only affected family member) and the GRIN2D pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental mosaicism. Once the GRIN2D pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

XiangWei W, Kannan V, Xu Y, Kosobucki GJ, Schulien AJ, Kusumoto H, Moufawad El Achkar C, Bhattacharya S, Lesca G, Nguyen S, Helbig KL, Cuisset JM, Fenger CD, Marjanovic D, Schuler E, Wu Y, Bao X, Zhang Y, Dirkx N, Schoonjans AS, Syrbe S, Myers SJ, Poduri A, Aizenman E, Traynelis SF, Lemke JR, Yuan H, Jiang Y. Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy. Brain. 2019 Oct 1;142(10):3009-3027. doi: 10.1093/brain/awz232. PMID: 31504254; PMCID: PMC6763743.

Abstract

N-methyl d-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.

Li D, Yuan H, Ortiz-Gonzalez XR, Marsh ED, Tian L, McCormick EM, Kosobucki GJ, Chen W, Schulien AJ, Chiavacci R, Tankovic A, Naase C, Brueckner F, von Stülpnagel-Steinbeis C, Hu C, Kusumoto H, Hedrich UB, Elsen G, Hörtnagel K, Aizenman E, Lemke JR, Hakonarson H, Traynelis SF, Falk MJ. GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers. Am J Hum Genet. 2016 Oct 6;99(4):802-816. doi: 10.1016/j.ajhg.2016.07.013. Epub 2016 Sep 8. PMID: 27616483; PMCID: PMC5065652.

Abstract

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated cation channels that mediate excitatory synaptic transmission. Genetic mutations in multiple NMDAR subunits cause various childhood epilepsy syndromes. Here, we report a de novo recurrent heterozygous missense mutation-c.1999G>A (p.Val667Ile)-in a NMDAR gene previously unrecognized to harbor disease-causing mutations, GRIN2D, identified by exome and candidate panel sequencing in two unrelated children with epileptic encephalopathy. The resulting GluN2D p.Val667Ile exchange occurs in the M3 transmembrane domain involved in channel gating. This gain-of-function mutation increases glutamate and glycine potency by 2-fold, increases channel open probability by 6-fold, and reduces receptor sensitivity to endogenous negative modulators such as extracellular protons. Moreover, this mutation prolongs the deactivation time course after glutamate removal, which controls the synaptic time course. Transfection of cultured neurons with human GRIN2D cDNA harboring c.1999G>A leads to dendritic swelling and neuronal cell death, suggestive of excitotoxicity mediated by NMDAR over-activation. Because both individuals' seizures had proven refractory to conventional antiepileptic medications, the sensitivity of mutant NMDARs to FDA-approved NMDAR antagonists was evaluated. Based on these results, oral memantine was administered to both children, with resulting mild to moderate improvement in seizure burden and development. The older proband subsequently developed refractory status epilepticus, with dramatic electroclinical improvement upon treatment with ketamine and magnesium. Overall, these results suggest that NMDAR antagonists can be useful as adjuvant epilepsy therapy in individuals with GRIN2D gain-of-function mutations. This work further demonstrates the value of functionally evaluating a mutation, enabling mechanistic understanding and therapeutic modeling to realize precision medicine for epilepsy.

Pathogenic PNPT1 variants

Inspired by a patient

Rius R, Van Bergen NJ, Compton AG, Riley LG, Kava MP, Balasubramaniam S, Amor DJ, Fanjul-Fernandez M, Cowley MJ, Fahey MC, Koenig MK, Enns GM, Sadedin S, Wilson MJ, Tan TY, Thorburn DR, Christodoulou J. Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants. J Clin Med. 2019 Nov 19;8(11):2020. doi: 10.3390/jcm8112020. PMID: 31752325; PMCID: PMC6912252.

Abstract

PNPT1 (PNPase-polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic PNPT1 variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype-phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects. Recently, it has been suggested that PNPase can lead to activation of an innate immune response. To better understand the clinical and molecular spectrum of patients with bi-allelic PNPT1 variants, we captured detailed clinical and molecular phenotypes of all 17 patients reported in the literature, plus seven new patients, including a 78-year-old male with the longest reported survival. A functional follow-up of genomic sequencing by cDNA studies confirmed a splicing defect in a novel, apparently synonymous, variant. Patient fibroblasts showed an accumulation of mitochondrial unprocessed PNPT1 transcripts, while blood showed an increased interferon response. Our findings suggest that functional analyses of the RNA processing function of PNPase are more sensitive than testing downstream defects in oxidative phosphorylation (OXPHPOS) enzyme activities. This research extends our knowledge of the clinical and functional consequences of bi-allelic pathogenic PNPT1 variants that may guide management and further efforts into understanding the pathophysiological mechanisms for therapeutic development.

Matilainen S, Carroll CJ, Richter U, Euro L, Pohjanpelto M, Paetau A, Isohanni P, Suomalainen A. Defective mitochondrial RNA processing due to PNPT1 variants causes Leigh syndrome. Hum Mol Genet. 2017 Sep 1;26(17):3352-3361. doi: 10.1093/hmg/ddx221. PMID: 28645153.

Abstract

Leigh syndrome is a severe infantile encephalopathy with an exceptionally variable genetic background. We studied the exome of a child manifesting with Leigh syndrome at one month of age and progressing to death by the age of 2.4 years, and identified novel compound heterozygous variants in PNPT1, encoding the polynucleotide phosphorylase (PNPase). Expression of the wild type PNPT1 in the subject's myoblasts functionally complemented the defects, and the pathogenicity was further supported by structural predictions and protein and RNA analyses. PNPase is a key enzyme in mitochondrial RNA metabolism, with suggested roles in mitochondrial RNA import and degradation. The variants were predicted to locate in the PNPase active site and disturb the RNA processing activity of the enzyme. The PNPase trimer formation was not affected, but specific RNA processing intermediates derived from mitochondrial transcripts of the ND6 subunit of Complex I, as well as small mRNA fragments, accumulated in the subject's myoblasts. Mitochondrial RNA processing mediated by the degradosome consisting of hSUV3 and PNPase is poorly characterized, and controversy on the role and location of PNPase within human mitochondria exists. Our evidence indicates that PNPase activity is essential for the correct maturation of the ND6 transcripts, and likely for the efficient removal of degradation intermediates. Loss of its activity will result in combined respiratory chain deficiency, and a classic respiratory chain-deficiency-associated disease, Leigh syndrome, indicating an essential role for the enzyme for normal function of the mitochondrial respiratory chain.

Bamborschke D, Kreutzer M, Koy A, Koerber F, Lucas N, Huenseler C, Herkenrath P, Lee-Kirsch MA, Cirak S. PNPT1 mutations may cause Aicardi-Goutières-Syndrome. Brain Dev. 2021 Feb;43(2):320-324. doi: 10.1016/j.braindev.2020.10.005. Epub 2020 Nov 4. PMID: 33158637.

Abstract

Background: Aicardi-Goutières syndrome (AGS) is a clinically and genetically heterogenous autoinflammatory disorder caused by constitutive activation of the type I interferon axis. It has been associated with the genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1. The clinical diagnosis of AGS is usually made in the context of early-onset encephalopathy in combination with basal ganglia calcification or white matter abnormalities on cranial MRI and laboratory prove of interferon I activation.

Case presentation: We report a patient with early-onset encephalopathy, severe neurodevelopmental regression, progressive secondary microcephaly, epilepsy, movement disorder, and white matter hyperintensities on T2 weighted MRI images. Via whole-exome sequencing, we identified a novel homozygous missense variant (c.1399C > T, p.Pro467Ser) in PNPT1 (NM_033109). Longitudinal assessment of the interferon signature showed a massively elevated interferon score and chronic type I interferon-mediated autoinflammation.

Conclusion: Bi-allelic mutations in PNPT1 have been reported in early-onset encephalopathy. Insufficient nuclear RNA import into mitochondria with consecutive disruption of the respiratory chain was proposed as the main underlying pathomechanism. Recent studies have shown that PNPT1 deficiency causes an accumulation of double-stranded mtRNAs in the cytoplasm, leading to aberrant type I interferon activation, however, longitudinal assessment has been lacking. Here, we present a case of AGS with continuously elevated type I interferon signature with a novel likely-pathogenic homozygous PNTP1 variant. We highlight the clinical value of assessing the interferon signature in children with encephalopathy of unknown origin and suggest all patients presenting with a phenotype of AGS should be screened for mutations in PNPT1.

Reigada S, Santos C, Ramos F, Carvalho S, Ribeiro J, Cancelinha C, Diogo L. Combined Oxidative Phosphorylation Deficiency Type-13 with Perinatal Presentation: A Case Report. Endocr Metab Immune Disord Drug Targets. 2023 Oct 11. doi: 10.2174/0118715303274239231005105248. Epub ahead of print. PMID: 37861028.

Abstract

Introduction: Polynucleotide phosphorylase is involved in RNA processing in mitochondria. Biallelic variants in PNPT1 cause mitochondrial RNA import protein deficiency and heterogeneous clinical manifestations.

Case report: The patiest was the first child of remote consanguineous parents, born at 35 weeks by caesarean section due to fetal growth restriction. Apgar index was 9/10/10. Birth weight, length and head circumference were at 3rd, <3rd and 10th percentiles, respectively. In the first hours of life, respiratory distress, hypoglycaemia and seizures ensued. She started invasive mechanic ventilation, phenobarbital and was transferred to ICU. Physical examination showed minor facial dysmorphisms, brief eye-opening, hypotonia and hyporeflexia. Electroencephalogram showed immature pattern and multifocal paroxysmal activity. MRI at D8 of life showed severe reduced brain volume. Normal aminoacid screen was also observed. Expanded newborn screening was negative. Mitochondrial organic aciduria was seen. WES showed a homozygotic likely pathogenic variant in the PNPT1 gene. MRI at 6-months showed brain atrophy, thin corpus callosum, reduced brainstem volume. Bilateral and symmetrical lesions in globi pallidi, compatible with Leigh síndrome were observed. Currently, at 14 months, no neurodevelopment progress, dystonia, visual deficit, sensorineural deafness, hypertrophic cardiomyopathy and microcephaly are observed.

Conclusion: The early and severe Leigh-like presentation of our patient expands the phenotype spectrum of this disease. As far as we know, this is the first reported case of PNPT1 mutation with onset in the perinatal period. Moreover, hypertrophic cardiomyopathy has not yet been described in association with mutation of the PNPT1 gene. WES was the key for early diagnosis in this patient. It should be done in all children with severe clinical presentation of unknown origin.

Genetic heterogeneity in Leigh syndrome

Lee JS, Yoo T, Lee M, Lee Y, Jeon E, Kim SY, Lim BC, Kim KJ, Choi M, Chae JH. Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes. Clin Genet. 2020 Apr;97(4):586-594. doi: 10.1111/cge.13713. Epub 2020 Feb 10. PMID: 32020600.

Abstract

Leigh syndrome (LS), the most common childhood mitochondrial disorder, has characteristic clinical and neuroradiologic features. Mutations in more than 75 genes have been identified in both the mitochondrial and nuclear genome, implicating a high degree of genetic heterogeneity in LS. To profile these genetic signatures and understand the pathophysiology of LS, we recruited 64 patients from 62 families who were clinically diagnosed with LS at Seoul National University Children's Hospital. Mitochondrial genetic analysis followed by whole-exome sequencing was performed on 61 patients. Pathogenic variants in mitochondrial DNA were identified in 18 families and nuclear DNA mutations in 22. The following 17 genes analyzed in 40 families were found to have genetic complexity: MTATP6, MTND1, MTND3, MTND5, MTND6, MTTK, NDUFS1, NDUFV1, NDUFAF6, SURF1, SLC19A3, ECHS1, PNPT1, IARS2, NARS2, VPS13D, and NAXE. Two treatable cases had biotin-thiamine responsive basal ganglia disease, and another three were identified as having defects in the newly recognized genes (VPS13D or NAXE). Variants in the nuclear genes that encoded mitochondrial aminoacyl tRNA synthetases were present in 27.3% of cases. Our findings expand the genetic and clinical spectrum of LS, showing genetic heterogeneity and highlighting treatable cases and those with novel genetic causes.

Quivering chin syndrome

Inspired by a patient

Sinha R, Singh S. Quivering Chin Syndrome. Neuropediatrics. 2023 Apr;54(2):159-160. doi: 10.1055/s-0042-1760103. Epub 2022 Dec 31. PMID: 36586402.

A 4-year-old neurotypical boy presented with unprovoked, involuntary intermittent tremulousness of the chin lasting for few minutes to hours, noted from 18 months of age with no family history. These movements were absent during sleep. The neurological examination, neuroimaging, and electroencephalography was otherwise normal. Surface electromyography of the mentalis muscle demonstrated a tremor frequency of 8 Hz. Quivering chin syndrome is a rare movement disorder. It may be sporadic or inherited in an autosomal dominant fashion with incomplete penetrance with locus on chromosome 9(9q13-q21). These involuntary, paroxysmal, rhythmic, movements of the chin and/or lower lip may last from seconds to hours. Episodes occur spontaneously or may be precipitated by stress and emotion. Usually no treatment is required. When indicated, injection of low-dose botulinum toxin into the mentalis muscle or low-dose clonazepam may be helpful. Recognition of this rare entity is important to avoid unnecessary investigations.