Variants in TCF20 in neurodevelopmental disability

Inspired by a patient

Vetrini F, McKee S, Rosenfeld JA, Suri M, Lewis AM, Nugent KM, Roeder E, Littlejohn RO, Holder S, Zhu W, Alaimo JT, Graham B, Harris JM, Gibson JB, Pastore M, McBride KL, Komara M, Al-Gazali L, Al Shamsi A, Fanning EA, Wierenga KJ, Scott DA, Ben-Neriah Z, Meiner V, Cassuto H, Elpeleg O, Holder JL Jr, Burrage LC, Seaver LH, Van Maldergem L, Mahida S, Soul JS, Marlatt M, Matyakhina L, Vogt J, Gold JA, Park SM, Varghese V, Lampe AK, Kumar A, Lees M, Holder-Espinasse M, McConnell V, Bernhard B, Blair E, Harrison V; DDD study; Muzny DM, Gibbs RA, Elsea SH, Posey JE, Bi W, Lalani S, Xia F, Yang Y, Eng CM, Lupski JR, Liu P. De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome. Genome Med. 2019 Feb 28;11(1):12. doi: 10.1186/s13073-019-0623-0. Erratum in: Genome Med. 2019 Mar 25;11(1):16. doi: 10.1186/s13073-019-0630-1. PMID: 30819258; PMCID: PMC6393995.

Vetrini F, McKee S, Rosenfeld JA, Suri M, Lewis AM, Nugent KM, Roeder E, Littlejohn RO, Holder S, Zhu W, Alaimo JT, Graham B, Harris JM, Gibson JB, Pastore M, McBride KL, Komara M, Al-Gazali L, Al Shamsi A, Fanning EA, Wierenga KJ, Scott DA, Ben-Neriah Z, Meiner V, Cassuto H, Elpeleg O, Lloyd Holder J Jr, Burrage LC, Seaver LH, Van Maldergem L, Mahida S, Soul JS, Marlatt M, Matyakhina L, Vogt J, Gold JA, Park SM, Varghese V, Lampe AK, Kumar A, Lees M, Holder-Espinasse M, McConnell V, Bernhard B, Blair E, Harrison V; DDD study; Muzny DM, Gibbs RA, Elsea SH, Posey JE, Bi W, Lalani S, Xia F, Yang Y, Eng CM, Lupski JR, Liu P. Correction to: De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome. Genome Med. 2019 Mar 25;11(1):16. doi: 10.1186/s13073-019-0630-1. Erratum for: Genome Med. 2019 Feb 28;11(1):12. doi: 10.1186/s13073-019-0623-0. PMID: 30909959; PMCID: PMC6434874.

Abstract

Background: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity).

Methods: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.

Results: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.

Conclusions: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

Torti E, Keren B, Palmer EE, Zhu Z, Afenjar A, Anderson IJ, Andrews MV, Atkinson C, Au M, Berry SA, Bowling KM, Boyle J, Buratti J, Cathey SS, Charles P, Cogne B, Courtin T, Escobar LF, Finley SL, Graham JM Jr, Grange DK, Heron D, Hewson S, Hiatt SM, Hibbs KA, Jayakar P, Kalsner L, Larcher L, Lesca G, Mark PR, Miller K, Nava C, Nizon M, Pai GS, Pappas J, Parsons G, Payne K, Putoux A, Rabin R, Sabatier I, Shinawi M, Shur N, Skinner SA, Valence S, Warren H, Whalen S, Crunk A, Douglas G, Monaghan KG, Person RE, Willaert R, Solomon BD, Juusola J. Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature. Genet Med. 2019 Sep;21(9):2036-2042. doi: 10.1038/s41436-019-0454-9. Epub 2019 Feb 11. PMID: 30739909; PMCID: PMC7171701.

Abstract

Purpose: To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients.

Methods: Patients were ascertained through molecular testing laboratories performing exome sequencing (and other testing) with orthogonal confirmation; collaborating referring clinicians provided detailed clinical information.

Results: The cohort of 27 patients all had novel variants, and ranged in age from 2 to 68 years. All had developmental delay/intellectual disability. Autism spectrum disorders/autistic features were reported in 69%, attention disorders or hyperactivity in 67%, craniofacial features (no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Additional features affecting various organ systems were described in 93%. In a majority of patients, we did not observe previously reported findings of postnatal overgrowth or craniosynostosis, in comparison with earlier reports.

Conclusion: We provide valuable data regarding the prognosis and clinical manifestations of patients with variants in TCF20.

Zhou J, Hamdan H, Yalamanchili HK, Pang K, Pohodich AE, Lopez J, Shao Y, Oses-Prieto JA, Li L, Kim W, Durham MA, Bajikar SS, Palmer DJ, Ng P, Thompson ML, Bebin EM, Müller AJ, Kuechler A, Kampmeier A, Haack TB, Burlingame AL, Liu Z, Rasband MN, Zoghbi HY. Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders. Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):e2119078119. doi: 10.1073/pnas.2119078119. PMID: 35074918; PMCID: PMC8794850.

Abstract

MeCP2 is associated with Rett syndrome (RTT), MECP2 duplication syndrome, and a number of conditions with isolated features of these diseases, including autism, intellectual disability, and motor dysfunction. MeCP2 is known to broadly bind methylated DNA, but the precise molecular mechanism driving disease pathogenesis remains to be determined. Using proximity-dependent biotinylation (BioID), we identified a transcription factor 20 (TCF20) complex that interacts with MeCP2 at the chromatin interface. Importantly, RTT-causing mutations in MECP2 disrupt this interaction. TCF20 and MeCP2 are highly coexpressed in neurons and coregulate the expression of key neuronal genes. Reducing Tcf20 partially rescued the behavioral deficits caused by MECP2 overexpression, demonstrating a functional relationship between MeCP2 and TCF20 in MECP2 duplication syndrome pathogenesis. We identified a patient exhibiting RTT-like neurological features with a missense mutation in the PHF14 subunit of the TCF20 complex that abolishes the MeCP2-PHF14-TCF20 interaction. Our data demonstrate the critical role of the MeCP2-TCF20 complex for brain function.

Schäfgen J, Cremer K, Becker J, Wieland T, Zink AM, Kim S, Windheuser IC, Kreiß M, Aretz S, Strom TM, Wieczorek D, Engels H. De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth. Eur J Hum Genet. 2016 Dec;24(12):1739-1745. doi: 10.1038/ejhg.2016.90. Epub 2016 Jul 20. PMID: 27436265; PMCID: PMC5117939.

Abstract

Recently, germline variants of the transcriptional co-regulator gene TCF20 have been implicated in the aetiology of autism spectrum disorders (ASD). However, the knowledge about the associated clinical picture remains fragmentary. In this study, two individuals with de novo TCF20 sequence variants were identified in a cohort of 313 individuals with intellectual disability of unknown aetiology, which was analysed by whole exome sequencing using a child-parent trio design. Both detected variants - one nonsense and one frameshift variant - were truncating. A comprehensive clinical characterisation of the patients yielded mild intellectual disability, postnatal tall stature and macrocephaly, obesity and muscular hypotonia as common clinical signs while ASD was only present in one proband. The present report begins to establish the clinical picture of individuals with de novo nonsense and frameshift variants of TCF20 which includes features such as proportionate overgrowth and muscular hypotonia. Furthermore, intellectual disability/developmental delay seems to be fully penetrant amongst known individuals with de novo nonsense and frameshift variants of TCF20, whereas ASD is shown to be incompletely penetrant. The transcriptional co-regulator gene TCF20 is hereby added to the growing number of genes implicated in the aetiology of both ASD and intellectual disability. Furthermore, such de novo variants of TCF20 may represent a novel differential diagnosis in the overgrowth syndrome spectrum.

Allan-Herndon-Dudley syndrome 2

On July 27, 2011 the Cruz family welcomed a gorgeous baby boy, Liam, to their lives. Weighing 7lbs and 19 inches long, he was born at Greenwich Hospital in Greenwich, CT and discharged with a clean bill of health.

At the age of 6 months, the family began to notice that Liam was not reaching his developmental milestones, such as holding his head up properly, rolling over from his belly on to his back, sitting up on his own and bringing his hands to his mouth. Liam’s appetite was very poor as well. At best, they noticed that he was only finishing half of his feedings at a time. It was then that they brought their concerns to Liam’s pediatrician whom suggested that Liam be evaluated with an Early Childhood Intervention Specialist, as well as conduct a battery of tests to determine if something was off neurologically, metabolically, etc.

Liam 5Several tests were conducted to determine the cause of Liam’s developmental delays, from numerous blood tests, to sleep studies, to MRI’s of the brain. However, none provided any leads on what was causing Liam’s delays with achieving his milestones, with the exception of determining that he had tracheomalacia and hypotonia. These were both side effects from the root cause of his condition, which was yet to be identified. At this time, Liam was constantly in and out of the hospital due to croup, bronchitis or what seemed to be seizures in his sleep. To no avail, the Cruz’s still did not receive a proper diagnosis, which inhibited them from providing the appropriate care, services and medical coverage for their son.

In 2013, relentless in their pursuit to obtain a proper diagnosis for Liam, they made countless calls to Columbia Presbyterian to have him seen by Chief of Pediatric Neurology, Dr. Chiriboga. It was then that Dr. Chiriboga diagnosed Liam with cerebral palsy, with mixed spasticity, and determined that therapy and proper treatment were needed immediately. Dr. Chiriboga further explained to them that genetic blood testing should be conducted on Liam, and both his mother and father to help determine the root cause of Liam’s condition or any other conditions that could potentially surface later on. Going off of this recommendation, the blood work was taken in order to be sent out for testing. Several weeks later the family received approval from Medicaid for the tests, only to be denied a few months later, when they had received a letter explaining that the genetic blood tests would not be covered. The expense, which exceeded $10,000, would have to be paid by them out-of-pocket. At this point in time, Medicaid was their only insurance as both of Liam’s parents lost their jobs shortly after receiving Liam’s diagnosis. With no supplemental health insurance, they were at the mercy of Medicaid to cover Liam’s medical bills. Needless to say, their quest to obtain a root cause for Liam’s condition came to a screeching halt.

Over the next several months, Liam was constantly in and out of the hospital with breathing issues, as he would wake up multiple times each night gasping for air and choking. It was then when Liam was diagnosed with “respiratory disease” and “failure to thrive” which was deemed as severe and critical. Concurrent to this, Liam’s drastic weight loss concerned his gastroenterologist. He strongly suggested inserting a G-Tube through Liam’s belly to administer daily routine feedings to regain his weight, which was critical to Liam’s development. On June 6, 2014 Liam underwent surgery to have a G-Tube inserted into his belly. After the surgery, Liam’s oxygen levels dropped dramatically and the hospital staff called a “code red” to have all hands on deck to tend to Liam and get his oxygen levels back to a stable state. The following day, Liam’s G-Tube popped out and he was rushed to emergency surgery to re-insert the G-Tube. This was an extremely stressful and trying time for the entire family, and an unbearable one for Liam. Adjusting to a routine of administering daily feedings via a pump/tube also proved to be very challenging and stressful, as everything they did needed to revolve around this new feeding system. It was imperative for Liam to regain his weight and reach an adequate one before he could be taken off his G-Tube. To this day, Liam remains with his G-Tube, as he cannot swallow whole foods without choking, aspirating and/or vomiting.

In January 2015, the family decided to move to Florida as Liam’s doctors suggested that warmer weather climate areas would be better for a child with his diagnosis and condition. Because the Cruz’s were living in a 6-story building in New York with limited access to an elevator, the move would also prove to be easier on Liam’s parents. Many times they needed to carry Liam up and down five flights of stairs with his wheelchair. There were times when Liam’s school bus would leave without him because it took them several minutes to get him down the stairs. So the family was uprooted and moved to South Florida where Liam’s mother was raised. In Florida, they had to restart the process of obtaining State Medicaid for Liam, as there are no transfers from state to state. They were informed that the process takes approximately two years for approval, so Liam would be without proper care and necessary services. In addition, they had to find new physicians and specialists to assist with Liam’s development and to provide guidance on how to care for him.

The family felt fortunate to find Joe DiMaggio Children’s Hospital where they were able to obtain a gastroenterologist, a pulmonologist, physiatrist, geneticist, neurologist, orthopedic, and an endocrinologist, all which are needed to treat Liam’s condition. At this hospital, Liam’s specialists were able to obtain his medical records from Columbia Presbyterian in NY, where they had found genetic test results from the blood tests that were taken two years prior. The same tests that were not approved by Medicaid had been conducted and the Cruz family was not aware. These tests contained the diagnosis that they had long been looking for.

The physicians at Joe DiMaggio Children’s Hospital shared these results with them and explained that Liam has Allan-Herndon-Dudley syndrome (AHDS). This syndrome is a rare X-linked inherited disorder of brain development that causes moderate to severe intellectual disability and problems with movement. This condition, which occurs almost exclusively in males, disrupts development from before birth. Most children with AHDS have weak muscle tone (hypotonia) and underdevelopment of many muscles (muscle hypoplasia). As they get older, they usually develop joint deformities called contractures, which restrict the movement of certain joints. Abnormal muscle stiffness (spasticity), muscle weakness, and involuntary movements of the arms and legs also limit mobility. As a result, many people with AHDS are unable to walk independently and become wheelchair-bound by adulthood.

Crushed with the news and discovery of this rare disease/disorder, which had unrightfully eluded the Cruz’s for four long years, the family had to devise a new road map to care of their son. There are only 80 recorded cases worldwide of children with AHDS. This disorder is so rare that there is no known treatment or cure, other than constant physical, occupational, and speech therapy. It is so rare that many services, equipment needs and medical bills are denied, as insurance companies do not recognize this disorder.

Liam’s father, Will, stated, “Liam’s future is still unclear to us; however, his unwavering spirit and loving personality is what keeps us driven to find a cure or treatment.” He explained that many who have had the opportunity to meet or work with Liam love him. He greets everyone with a warm smile and offers a hug and or a kiss to let you know that you have a friend in him forever. He never complains when it’s time for physical or occupational therapy; he actually enjoys it and puts in the hard work with each session. It’s Liam’s determination to get better and stronger with each passing day that keeps the Cruz family pressing forward!

https://rarediseases.org/liam-cruz-diagnostic-journey/

Peng W, Shi S, Yang L, Liu D. Identification of a novel nonsense SLC16A2 gene mutation in an infant with severe neurologic phenotype: A case report. Medicine (Baltimore). 2024 Jul 19;103(29):e39047. doi: 10.1097/MD.0000000000039047. PMID: 39029020; PMCID: PMC

Abstract

Rationale: Allan-Herndon-Dudley syndrome (AHDS) results from a pathogenic variant in the hemizygous subunit of the SLC16A2 gene, which encodes monocarboxylate transporter 8 and follows an X-linked recessive pattern. AHDS manifests as neuropsychomotor developmental delay, intellectual disability, movement disorders, and thyroid hormone abnormalities. It is frequently misdiagnosed as cerebral palsy or hypothyroidism.

Patient concerns: A 9-month-old male infant exhibited poor head control, hypodynamia, motor retardation, hypertonic limbs, and thyroid abnormalities. Despite levothyroxine supplementation and rehabilitation therapy, no improvements were observed. Whole-exome sequencing identified a novel nonsense mutation in SLC16A2 (c.124G > T, p.E42X), which unequivocally established the diagnosis.

Diagnoses: AHDS was confirmed.

Interventions: Levothyroxine treatment commenced early in infancy, followed by 3 months of rehabilitation therapy, starting at 5 months of age. The combined administration of levothyroxine and methimazole was initiated at 1 year and 10 months of age, respectively.

Outcomes: While improvements were noted in thyroid hormone levels, neurological developmental delays persisted.

Lessons: AHDS should be considered in patients presenting with atypical neurological features and thyroid hormone abnormalities such as elevated triiodothyronine and decreased thyroxine levels. The early utilization of exome sequencing aids in prompt diagnosis. The identified SLC16A2 nonsense mutation correlates with severe neurological phenotypes and adds to the spectrum of genetic variations associated with AHDS.11398793.

Ramon-Gomez JL, Cortés-Rojas MC, Polania-Puentes MJ, Guerrero-Ruiz GDP. Movement Disorder Perspectives on Monocarboxylate 8 Deficiency: A Case Series of 3 Colombian Patients with Allan-Herndon-Dudley Syndrome. Mov Disord Clin Pract. 2024 May;11(5):567-570. doi: 10.1002/mdc3.14009. Epub 2024 Mar 7. PMID: 38454300; PMCID: PMC11078483.

Abstract

Background: Deficiencies in the thyroid hormone transporter monocarboxylate 8 (MCT8) due to pathogenic variants in the SLC16A2 gene (OMIM 300095) result in a complex phenotype with main endocrine and neurologic symptoms. This rare disorder, named Allan-Herndon-Dudley syndrome (AHDS) (OMIM 300523), is inherited in an X-linked trait. One of the prominent features of AHDS is the presence of movement disorders (MD), which are complex and carry a significant burden of the disease.

Cases: Patient 1: male with hypotonia since birth, developmental delay, dystonic posturing at 4 months and at 15 months, and startle reaction developed with sensory stimuli. Patient 2: male, at 2 months, shows hypotonia and developmental delay, paroxysmal episodes triggered by a stimulus with sudden blush, tonic asymmetric posture, and no epileptiform activity. At 10 months, generalized dystonic posturing. Patient 3: typical neurodevelopmental milestones until 6 months; at 24 months, dystonia, startle reaction, and upper motoneuron signs.

Conclusions: We aim to describe our patients diagnosed with AHDS, focusing on MD phenomenology and strengthening the phenotype-genotype correlations for this rare condition.

Keywords: Allan–Herndon–Dudley syndrome; SLC16A2 gene; dystonia; monocarboxylate 8 deficiency; movement disorders.

García-Aldea Á, Guillén-Yunta M, Valcárcel-Hernández V, Montero-Pedrazuela A, Guadaño-Ferraz A, Bárez-López S. Insights on the role of thyroid hormone transport in neurosensory organs and implication for the Allan-Herndon-Dudley syndrome. Eur Thyroid J. 2024 Mar 19;13(2):e230241. doi: 10.1530/ETJ-23-0241. PMID: 38417253; PMCID: PMC10959056.

Abstract

Thyroid hormones play an important role during the development and functioning of the different sensory systems. In order to exert their actions, thyroid hormones need to access their target cells through transmembrane transporter proteins, among which the monocarboxylate transporter 8 (MCT8) stands out for its pathophysiological relevance. Mutations in the gene encoding for MCT8 lead to the Allan-Herndon-Dudley syndrome (AHDS), a rare disease characterised by severe neuromotor and cognitive impairments. The impact of MCT8 deficiency in the neurosensory capacity of AHDS patients is less clear, with only a few patients displaying visual and auditory impairments. In this review we aim to gather data from different animal models regarding thyroid hormone transport and action in the different neurosensory systems that could aid to identify potential neurosensorial alterations in MCT8-deficient patients.

See: https://childnervoussystem.blogspot.com/2018/10/allan-herndon-dudley-syndrome.html

Do doctors actually tell their patients they "cannot have children"?

 See: https://ask.metafilter.com/251986/Do-doctors-actually-tell-their-patients-they-cannot-have-children

I never gave up hope or my faith

One day in August 2013, I was with friends as my children, Hudson, Lola, and Bella, then ages 3, 5, and 7, were having a play date. I started to not feel well and, when I went to the restroom, I noticed I had blood in my stool. I knew this wasn't normal, so I called my doctor and then headed to urgent care. I figured they would run some tests and maybe prescribe some medication and I told my husband, Scott, that I would be home shortly.

Then the lab test came back and the results showed a platelet count of 1,000. The typical number of platelets in the blood is usually 150,000 to 450,000, so my count was incredibly low. The doctor even repeated the test, assuming the equipment must have malfunctioned the first time. It had not.

Instead of going home with a prescription in hand, an ambulance took me to the hospital. I was admitted and ended up staying for about 43 days. After nearly a month and a half and countless tests, I was diagnosed with Stage II diffuse large B-cell non-Hodgkin lymphoma. I came to learn that this is a type of cancer that affects your white blood cells, or lymphocytes, and that it's particularly fast-moving and aggressive.

As you can imagine, I was scared. At 32 years old, I was a young mom with a wonderful husband and three beautiful children, with so much life left to live. A cancer diagnosis was the furthest thing from my mind. But, I came to find out that this cancer typically responds well to treatment, and my disease was caught in a relatively early stage, which would increase my chances for survival.

I began a standard protocol of chemotherapy. Halfway through treatment, a scan showed no tumors. I was ecstatic, but about seven months later, tests revealed that the cancer had returned. Next was a stem cell transplant, which was just the hardest treatment that you could ever imagine. But my body wasn't responding the way it should and the cancer was still there.

The transplant was unsuccessful. I was driving my kids in the car when I got the news from my doctor that my transplant had failed. It took everything in me to hold it together for them. When I got home, I lost it. I was completely heartbroken. I knew I was quickly running out of options.

At this point, my chances of survival were incredibly low. In fact, I was given only six months to live, but I didn't even know it. A doctor had shared that with my husband, but he didn't tell me because he wanted to protect me as best he could from the scary stuff while I focused on my treatment. He knew how important it was for me to continue to have hope. Sometimes, when you realize how dire things are, you do become hopeless, and it's so much harder to fight when you're hopeless.

When we finally met with my doctor, he told me that my only option left was a clinical trial. The challenge was that this clinical trial wasn't available in my home state of Kansas yet, and my doctor didn't know if I had enough time to even make it. You'd think that I would have been distressed by that news, but in that moment when faced with this life-or-death situation, all I felt was hope and faith instead of fear. I knew we would find a way.

This clinical trial, ZUMA-1 as it was called, was exploring an entirely new way of treating cancer in 2015 that the doctors told me was my best—and maybe only—chance for survival at that point. It was an immunotherapy called Chimeric Antigen Receptor T-cell therapy, or CAR T-cell therapy. This one-time therapy is designed to use my immune system to fight the cancer.

CAR T-cell therapy involves using your own T cells, a type of white blood cell, which were collected through a process called leukapheresis—blood withdrawal—and sent to a manufacturing facility where they add receptors to those T cells that match the protein on the cancer. These "supercharged" T cells are then infused into the body to fight the cancer.

My local hospital wasn't participating in this trial, so I had to travel to a hospital in Houston. I hopped on a plane to see if I qualified for this trial. I was a perfect fit and was quickly enrolled.

Nearly two years after my cancer journey had begun, I became just the third person in the world to take part in the clinical trial. ultimately this treatment developed by Kite Pharma became the first CAR T-cell therapy approved by the U.S. Food and Drug Administration in 2017 to treat the type of cancer that I had. By participating in the clinical trial, I helped pave the way for thousands of blood cancer patients like me who have been successfully treated since.

Within a month, scans showed that the cancer was gone. The same thing at 18 months. And now, nine years later, I'm still cancer-free. I never gave up hope or my faith, both in God and in the incredible doctors who were treating me. I'm grateful to be a survivor and for the opportunity to be a part of something as revolutionary as CAR T-cell therapy.

I truly feel that I'm here for a reason, that it wasn't my time to go. I believe that there were things that I was meant to accomplish, and I feel a responsibility to use my experience to help others.

I've been actively involved with the Leukemia and Lymphoma Society, as have my children who grew up with their mom fighting this battle. Over the years, we've helped to raise more than $200,000 for research. I never imagined that I could be passionate about something like this, but I just feel like that was part of what I was called to do in order to give back.

Today, I'm healthy and Scott and I are happier than we've ever been. Our children are now 18, 16, and 14. Bella just started college, Lola is playing on her high school golf team, and Hudson wants to be an oncologist. I think back on the years dealing with my cancer and just trying to survive, and I feel like I missed a really special time in my family's life. That makes me appreciate the time we have now even more.

I remember thinking that I could never imagine being normal and healthy again, and that I'd never be able to get back to a normal routine. I now know that my life isn't completely the same and I've changed as a person because of this experience. People often ask me about it, and I tell them I wouldn't take it back or go back in time and not have cancer, which may seem shocking. But it helped me look at life differently and I've grown—we've all grown—so much because of that and I would never want to take that away.

Emily Dumler was diagnosed with stage II diffused large B-cell non-Hodgkin lymphoma at the age of 32 in 2013 and given six months to live. With no other approved treatment options available, Emily was brave enough to try CAR T-cell therapy that was in clinical trial stages at the time. Within a month of the trial, Emily was declared cancer-free and remains so to this day. CAR T-cell therapy is now an approved treatment.

https://www.newsweek.com/i-was-given-six-months-live-wasnt-told-1948620

Diffuse intrinsic pontine glioma 5

The family of an 11-year-old with an inoperable brain tumor are preparing for their last Christmas together after he was given six months to live -- just two weeks ago.

Reece Probert seemed perfectly healthy just last month, but his mom Jenna, 31, took him to the doctors when he suddenly developed a limp and then a slur.

Scans revealed he had a rare aggressive inoperable brain tumor which sufferers usually succumb to between six and 12 months after diagnosis.

His devastated family are rallying around to give him the best Christmas ever.

"It will be our last Christmas together and we want to make sure it's nice and comfortable and cozy for Reece," Jenna Probert, of Wombourne, South Staffordshire, said. "I want to make him feel like a king. He should feel like the most important person in the world. It will be emotional because it will be his last Christmas."

"We will decorate the whole house and make it look like Santa's grotto. It will be the most memorable Christmas ever," she said. "Reece knows he has cancer but doesn't know the reality of it. I can't face telling him. I just need him to be happy. Christmas will be a family day and we will give him anything he wants. We will just cherish it together as a family."

Reece Probert seemed perfectly healthy just last month, but his mom took him to the doctors when he suddenly developed a limp and then a slur.

Just six weeks ago, Reece was fit and healthy, but after returning from a trip to see his grandparents in Northern Ireland in November, his mom noticed unusual symptoms.

He had a limp and a sore hand, so his doctor sent him to the hospital for an X-ray, and for tests on his tendons.

But Probert really began to worry when Reece began to slur his words two weeks ago.

A neighbor, who had been diagnosed a benign brain tumor, noticed Reece struggling to speak and feared the worst, having suffered similar symptoms in the past.

Probert, a personal trainer, phoned 111 and was advised to take her son to the Russell's Hall Hospital, in Dudley, where doctors initially thought he had suffered a stroke.

But on Dec. 1, doctors at Birmingham Children's Hospital performed a CT scan and found an "abnormality" of the brain.

Two days later Probert was told her son had diffuse intrinsic pontine glioma (DIPG) - an aggressive cancer typically found in children.

"I collapsed when I was told that," she said. "I felt like my heart had been ripped out. It was a horrible feeling. They put him on steroids to reduce the swelling before he had the MRI scan."

"It was bad enough being told he had a stroke," she siad. "I was just praying that they had got it all wrong. I just started screaming 'no, no, no'. I couldn't breathe. It's the worst thing any mom can be told."

"Even the oncologist has tears in her eyes whilst she was telling me," Probert said. "We were taken into the family room and told that chemotherapy won't work and radiotherapy will only shrink the tumor. But it will come back and will eventually end his life."

"Most children die between six and 12 months from diagnosis," she said.

Reece is due to start his first round of radiotherapy to reduce the size of the tumor and give him more time.

Probert is now focused on making sure Reece has the most "amazing Christmas" with her, partner Robert Perry, 27, and his sister Trinity Alcock, 6.

"I've had to put the reality of it to the back of my mind," Probert said. "I'm just focused on enjoying him whilst we still have him. We want to make memories with him and just want to make sure he is happy and comfortable."

"Reece has been fantastic. He has taken it all in his stride and has been amazing," she said. "I couldn't be more proud of him. He is known as the class clown and his friends have been to visit him. For us, the next year is all about making him feel extra special."

Friends and family have launched fundraising campaigns and arranged charity events in a bid to raise money to ensure Reece has a Christmas to remember.

https://www.foxnews.com/health/boy-given-months-to-live-after-limp-led-to-terminal-brain-tumor-diagnosis

3-methylcrotonyl-CoA carboxylase deficiency

Inspired by a patient identified on newborn screening

Terracciano R, Ruoppolo M, Barretta F, Albano L, Crisci D, Gallo G, Uomo F, Strisciuglio P, Parenti G, Frisso G, Rossi A. An asymptomatic father diagnosed with 3-methylcrotonyl-CoA carboxylase deficiency following his son newborn screening test. Mol Genet Metab Rep. 2024 Jul 4;40:101116. doi: 10.1016/j.ymgmr.2024.101116. PMID: 39055105; PMCID: PMC11269298.

Abstract

3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is a hereditary disorder of leucine catabolism caused by pathogenetic variants in the MCCC1 or MCCC2 genes. Typically diagnosed through newborn screening (NBS), 3MCCD is characterized by elevation of 3-hydroxyisovalerylcarnitine (C5OH) in blood as well as increased excretion of 3-methylcrotonylglycine (3-MCG) in urine. While most diagnosed children remain asymptomatic, data on adults are scarce. To date, only 39 molecularly confirmed adult individuals have been reported, all being mothers diagnosed subsequent to their child NBS results. Herein, we present a 36-year-old asymptomatic man who was incidentally diagnosed with 3MCCD following his son NBS recall. Molecular analysis revealed compound heterozygosity for two pathogenic variants in the MCCC1 gene. This is the first molecularly confirmed adult man with 3MCCD reported. This case highlights the need for additional longitudinal follow-up data on individuals with 3MCCD to clarify the clinical significance of this condition and guide clinical practice, including NBS strategy.

Lin W, Wang K, Chen Y, Zheng Z, Lin Y. Newborn screening and genetic diagnosis of 3-methylcrotonyl-CoA carboxylase deficiency in Quanzhou,China. Mol Genet Metab Rep. 2024 Aug 2;40:101127. doi: 10.1016/j.ymgmr.2024.101127. PMID: 39188588; PMCID: PMC11345313.

Abstract

Background and aims: 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is an autosomal recessive leucine catabolism condition caused by 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency due to MCCC1/MCCC2 variants. We investigated its incidence and features in Quanzhou, China.

Materials and methods: We screened 643,606 newborns (January 2014 to December 2022) for elevated 3-hydroxyisovalerylcarnitine (C5OH) levels using tandem mass spectrometry (MS/MS). Molecular analyses identified MCCC1/MCCC2 variants in suspected 3-MCCD cases.

Results: Seventeen neonates, two maternal patients, and one paternal patient had 3-MCCD. Its incidence in the Quanzhou study population was 1/37,859 newborns. All patients and neonates with 3-MCCD exhibited increased C5OH concentrations. Most patients [76.5%(13/17)] had increased urinary 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA) levels. Eight neonates and all adults with 3-MCCD had secondary carnitine deficiency. We identified seventeen variants, including 6 novel ones.MCCC1and MCCC2 variants were found in 47.1% and 52.9% of patients,with c.1331G > A (31.3%) and c.351_353delTGG (50.0%) being the most prevalent, respectively. Clinical symptoms were observed in 11.8% of patients.

Conclusion: We identified six new MCCC1/MCCC2 variants, enhancing our understanding of the 3-MCCD molecular profile. Secondary carnitine deficiency occurred in eight neonates and all adult patients. Although clinical symptoms were observed in 11.8% of patients, whether they were related to 3-MCCD remain unclear. Therefore, further studies are required to decide whether 3-MCCD and C5OH indicators should continue to be used.

Jagadish A, Sclater K, Lapinski T, Adkins K, Selzer L. A Unique Presentation of 3-Methylcrotonyl-CoA Carboxylase Deficiency. Cureus. 2023 May 23;15(5):e39401. doi: 10.7759/cureus.39401. PMID: 37362523; PMCID: PMC10287026.

Abstract

3-methylcrotonyl-CoA carboxylase deficiency is an autosomal recessive disorder resulting in impaired leucine metabolism. The condition is typically diagnosed with newborn screening; patients diagnosed at a later stage generally present with symptoms including metabolic disturbances, seizures, failure to thrive, or delayed development. We present the case of a child diagnosed at 12 months of age who was noted to have recurrent viral infections and nonspecific gastrointestinal symptoms of vomiting, hematochezia, and gaseous distention of the abdomen. Newborn screening did not reveal any abnormalities. Evaluation for underlying immunodeficiency was unremarkable; genetic testing revealed bi-allelic mutations in MCCC2, a known association of 3-methylcrotonyl-CoA carboxylase deficiency. It is important to consider genetic disorders when evaluating patients even if the newborn screening is unremarkable.

Wang H, Liu S, Wang B, Yang Y, Yu B, Wang L, Wang T. 3-Methylcrotonyl-CoA carboxylase deficiency newborn screening in a population of 536,008: is routine screening necessary? J Pediatr Endocrinol Metab. 2019 Dec 18;32(12):1321-1326. doi: 10.1515/jpem-2018-0536. PMID: 31730530.

Abstract

Objective To evaluate whether 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) should be routinely screened in newborns. Methods Dried blood spots (DBS) were collected and analyzed by tandem mass spectrometry (TMS). Blood samples were collected from infants with positive 3-MCCD results. Targeted sequencing was performed using the extended panel for inherited metabolic diseases to detect 306 genes. The sequencing libraries were quantified and used for massively parallel sequencing on the Illumina HiSeq 2500 platform. Results A total of 536,008 infants underwent newborn screening (NBS) and 14 cases of 3-MCCD were diagnosed. The incidence of 3-MCCD in Jiangsu province was 1:38,286. During the last 3 years of follow-up, none of the subjects with 3-MCCD exhibited obvious clinical symptoms. Only two children had mild feeding difficulties and vomiting. Eleven patients had complex variants of the MCCC1 gene, and three patients had mutations in MCCC2. In total, 17 types of MCCC1 or MCCC2 variants were found, and c.639 + 2t > a was the most common mutation. Conclusions As far as the current results are concerned, 3-MCCD may be benign in Jiangsu province. However, additional investigations and a longer follow-up period are necessary to decide whether NBS of 3-MCCD is necessary or not.

Mirdametinib in children and adults with neurofibromatosis type 1-associated symptomatic inoperable plexiform neurofibroma

Christopher L. Moertel, Angela C. Hirbe, Hans H. Shuhaiber, David Viskochil, Alpa Sidhu, Kevin J. Bielamowicz, Michael Weber, Jack Li, L. Mary Smith, Lauren Weintraub, Rene Y. McNall-Knapp, Fouad M. Hajjar, Nicholas K. Foreman, Timothy R. Gershon, Dusica Babovic-Vuksanovic.  ReNeu: A pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma. Meeting Abstract: 2024 ASCO Annual Meeting I Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology May 29, 2024

Abstract

Background: PN in patients (pts) with NF1 can cause pain, disfigurement, impaired quality of life (QoL), and can undergo malignant transformation. ReNeu (NCT03962543), a multicenter, open-label, Phase 2b study, evaluated efficacy and safety of the highly selective, oral, investigational MEK1/2 inhibitor mirdametinib in adult (≥18 y) and pediatric (2-17 y) pts with inoperable NF1 PN causing significant morbidities. Methods: Mirdametinib was administered as a capsule or dispersible tablet (2 mg/m2 BID, max 4 mg BID) without regard to food in 3 wk on/1 wk off 28-d cycles. The primary endpoint was confirmed objective response rate (ORR; percentage of pts with MRI-assessed ≥20% reduction of target PN volume by blinded independent central review [BICR] within the 24-cycle treatment phase). The minimum clinically relevant ORR (null) was defined as 23% for adults and 20% for pediatrics. Ptscould continue treatment in an optional long-term follow-up (LTFU) phase. Additional key endpoints were duration of response (DoR), time to response (TTR), change from baseline (BL) in target PN volume, pain severity (Numerical Rating Scale-11 [NRS-11]), pain interference (Pain Interference Index [PII]), health-related (HR) QoL (PedsQL), and safety. Results: All114 pts (58 adult, 56 pediatric) received mirdametinib. As of the 20 Sept 2023 data cutoff (DCO), BICR-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P<.001 vs null) in adults and 52% (95% CI, 38-65; P<.001 vs null) in pediatric pts. Two adult pts and 1 pediatric pt also had a confirmed response in the ongoing LTFU. Median (min, max) target PN volumetric best response from BL was -41% (-90, 13) and -42% (-91, 48) in adult and pediatric pts, respectively. As of the DCO, median treatment duration was 22 mo for each cohort and median DoR was not reached. Median (range) TTR was 7.8 (4-19) mo in adult pts and 7.9 (4-19) mo in pediatric pts. Adult and pediatric pts had statistically significant improvements from BL to cycle 13 in NRS-11, PII, and key PedsQL measures. Most frequent (≥35% pts) treatment-emergent adverse events (TEAEs) were dermatitis acneiform, diarrhea, nausea, and vomiting in adults and diarrhea, dermatitis acneiform, and vomiting in pediatric pts. 16% and 25% of adult and pediatric pts, respectively, had grade ≥3 treatment-related AEs, and 22% and 9%, respectively, discontinued due to TEAEs. Conclusions: In ReNeu, the largest multicenter NF1 PN trial reported to date, mirdametinib demonstrated a statistically significant ORR by BICR, with deep and durable PN volume reductions, significant improvements in pain severity, pain interference, and HRQoL, and a manageable safety profile in both adults and children. Together with a dispersible tablet formulation, these results underscore mirdametinib’s potential to become an important new treatment option for NF1 PN pts across all ages.