EARS2 mutations

Inspired by a patient

Danhauser K, Haack TB, Alhaddad B, Melcher M, Seibt A, Strom TM, Meitinger T, Klee D, Mayatepek E, Prokisch H, Distelmaier F. EARS2 mutations cause fatal neonatal lactic acidosis, recurrent hypoglycemia and agenesis of corpus callosum. Metab Brain Dis. 2016 Jun;31(3):717-21. doi: 10.1007/s11011-016-9793-2. Epub 2016 Jan 16. PMID: 26780086.

Abstract

Mitochondrial aminoacyl tRNA synthetases are essential for organelle protein synthesis. Genetic defects affecting the function of these enzymes may cause pediatric mitochondrial disease. Here, we report on a child with fatal neonatal lactic acidosis and recurrent hypoglycemia caused by mutations in EARS2, encoding mitochondrial glutamyl-tRNA synthetase 2. Brain ultrasound revealed agenesis of corpus callosum. Studies on patient-derived skin fibroblasts showed severely decreased EARS2 protein levels, elevated reactive oxygen species (ROS) production, and altered mitochondrial morphology. Our report further illustrates the clinical spectrum of the severe neonatal-onset form of EARS2 mutations. Moreover, in this case the live-cell parameters appeared to be more sensitive to mitochondrial dysfunction compared to standard diagnostics, which indicates the potential relevance of fibroblast studies in children with mitochondrial diseases.

Ni M, Black LF, Pan C, Vu H, Pei J, Ko B, Cai L, Solmonson A, Yang C, Nugent KM, Grishin NV, Xing C, Roeder E, DeBerardinis RJ. Metabolic impact of pathogenic variants in the mitochondrial glutamyl-tRNA synthetase EARS2. J Inherit Metab Dis. 2021 Jul;44(4):949-960. doi: 10.1002/jimd.12387. Epub 2021 Apr 27. PMID: 33855712; PMCID: PMC9219168.

Abstract

Glutamyl-tRNA synthetase 2 (encoded by EARS2) is a mitochondrial aminoacyl-tRNA synthetase required to translate the 13 subunits of the electron transport chain encoded by the mitochondrial DNA. Pathogenic EARS2 variants cause combined oxidative phosphorylation deficiency, subtype 12 (COXPD12), an autosomal recessive disorder involving lactic acidosis, intellectual disability, and other features of mitochondrial compromise. Patients with EARS2 deficiency present with variable phenotypes ranging from neonatal lethality to a mitigated disease with clinical improvement in early childhood. Here, we report a neonate homozygous for a rare pathogenic variant in EARS2 (c.949G>T; p.G317C). Metabolomics in primary fibroblasts from this patient revealed expected abnormalities in TCA cycle metabolites, as well as numerous changes in purine, pyrimidine, and fatty acid metabolism. To examine genotype-phenotype correlations in COXPD12, we compared the metabolic impact of reconstituting these fibroblasts with wild-type EARS2 versus four additional EARS2 variants from COXPD12 patients with varying clinical severity. Metabolomics identified a group of signature metabolites, mostly from the TCA cycle and amino acid metabolism, that discriminate between EARS2 variants causing relatively mild and severe COXPD12. Taken together, these findings indicate that metabolomics in patient-derived fibroblasts may help establish genotype-phenotype correlations in EARS2 deficiency and likely other mitochondrial disorders.

Barbosa-Gouveia S, González-Vioque E, Hermida Á, Suarez MU, Martínez-González MJ, Borges F, Wintjes L, Kappen A, Rodenburg R, Couce ML. Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL. Genes (Basel). 2020 Sep 2;11(9):1028. doi: 10.3390/genes11091028. PMID: 32887222; PMCID: PMC7563109.

Abstract

The EARS2 nuclear gene encodes mitochondrial glutamyl-tRNA synthetase, a member of the class I family of aminoacyl-tRNA synthetases (aaRSs) that plays a crucial role in mitochondrial protein biosynthesis by catalyzing the charging of glutamate to mitochondrial tRNA(Glu). Pathogenic EARS2 variants have been associated with a rare mitochondrial disorder known as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The targeted sequencing of 150 nuclear genes encoding respiratory chain complex subunits and proteins implicated in the oxidative phosphorylation (OXPHOS) function was performed. The oxygen consumption rate (OCR), and the extracellular acidification rate (ECAR), were measured. The enzymatic activities of Complexes I-V were analyzed spectrophotometrically. We describe a patient carrying two heterozygous EARS2 variants, c.376C>T (p.Gln126*) and c.670G>A (p.Gly224Ser), with infantile-onset disease and a severe clinical presentation. We demonstrate a clear defect in mitochondrial function in the patient's fibroblasts, suggesting the molecular mechanism underlying the pathogenicity of these EARS2 variants. Experimental validation using patient-derived fibroblasts allowed an accurate characterization of the disease-causing variants, and by comparing our patient's clinical presentation with that of previously reported cases, new clinical and radiological features of LTBL were identified, expanding the clinical spectrum of this disease.

Variants in CAMTA1

Inspired by a patient's sister

Jacobs EZ, Brown K, Byler MC, D'haenens E, Dheedene A, Henderson LB, Humberson JB, van Jaarsveld RH, Kanani F, Lebel RR, Millan F, Oegema R, Oostra A, Parker MJ, Rhodes L, Saenz M, Seaver LH, Si Y, Vanlander A, Vergult S, Callewaert B. Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants. Clin Genet. 2021 Feb;99(2):259-268. doi: 10.1111/cge.13874. Epub 2020 Nov 23. PMID: 33131045.

Abstract

The CAMTA1-associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome-based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N- and C- terminal functional domains. Clinical heterogeneity is observed, but 3'-terminal variants seem to associate with less pronounced cerebellar dysfunction.

Wijnen IGM, Veenstra-Knol HE, Vansenne F, Gerkes EH, de Koning T, Vos YJ, Tijssen MAJ, Sival D, Darin N, Vanhoutte EK, Oosterloo M, Pennings M, van de Warrenburg BP, Kamsteeg EJ. De novo variants in CAMTA1 cause a syndrome variably associated with spasticity, ataxia, and intellectual disability. Eur J Hum Genet. 2020 Jun;28(6):763-769. doi: 10.1038/s41431-020-0600-5. Epub 2020 Mar 10. PMID: 32157189; PMCID: PMC7253440.

Abstract

Previously, intragenic CAMTA1 copy number variants (CNVs) have been shown to cause non-progressive, congenital ataxia with or without intellectual disability (OMIM#614756). However, ataxia, intellectual disability, and dysmorphic features were all incompletely penetrant, even within families. Here, we describe four patients with de novo nonsense, frameshift or missense CAMTA1 variants. All four patients predominantly manifested features of ataxia and/or spasticity. Borderline intellectual disability and dysmorphic features were both present in one patient only, and other neurological and behavioural symptoms were variably present. Neurodevelopmental delay was found to be mild. Our findings indicate that also nonsense, frameshift and missense variants in CAMTA1 can cause a spastic ataxia syndrome as the main phenotype.

Thevenon J, Lopez E, Keren B, Heron D, Mignot C, Altuzarra C, Béri-Dexheimer M, Bonnet C, Magnin E, Burglen L, Minot D, Vigneron J, Morle S, Anheim M, Charles P, Brice A, Gallagher L, Amiel J, Haffen E, Mach C, Depienne C, Doummar D, Bonnet M, Duplomb L, Carmignac V, Callier P, Marle N, Mosca-Boidron AL, Roze V, Aral B, Razavi F, Jonveaux P, Faivre L, Thauvin-Robinet C. Intragenic CAMTA1 rearrangements cause non-progressive congenital ataxia with or without intellectual disability. J Med Genet. 2012 Jun;49(6):400-8. doi: 10.1136/jmedgenet-2012-100856. PMID: 22693284.

Abstract

Background: Non-progressive congenital ataxias (NPCA) with or without intellectual disability (ID) are clinically and genetically heterogeneous conditions. As a consequence, the identification of the genes responsible for these phenotypes remained limited.

Objective: Identification of a new gene responsible for NPCA and ID. Methods Following the discovery of three familial or sporadic cases with an intragenic calmodulin-binding transcription activator 1 (CAMTA1) rearrangement identified by an array-CGH and recruited from a national collaboration, the authors defined the clinical and molecular characteristics of such rearrangements, and searched for patients with point mutations by direct sequencing.

Results: Intragenic copy number variations of CAMTA1 were all located in the CG-1 domain of the gene. It segregated with autosomal dominant ID with non-progressive congenital cerebellar ataxia (NPCA) in two unrelated families, and was de novo deletion located in the same domain in a child presenting with NPCA. In the patients with ID, the deletion led to a frameshift, producing a truncated protein, while this was not the case for the patient with isolated childhood ataxia. Brain MRI of the patients revealed a pattern of progressive atrophy of cerebellum medium lobes and superior vermis, parietal lobes and hippocampi. DNA sequencing of the CG-1 domain in 197 patients with sporadic or familial non-syndromic intellectual deficiency, extended to full DNA sequencing in 50 patients with ID and 47 additional patients with childhood ataxia, identified no pathogenic mutation.

Magnin E, Blagosklonov O, Sylvestre G, Minot D, Thevenon J, Faivre L, Boulahdour H, Thauvin-Robinet C, Rumbach L. Neuropsychological and neuroimaging phenotype induced by a CAMTA1 mutation. Brain Dev. 2014 Sep;36(8):711-5. doi: 10.1016/j.braindev.2013.09.008. Epub 2013 Oct 18. PMID: 24145135.

Abstract

Background/aims: CAMTA1 mutations have recently been reported in families with intellectual disability and/or non-progressive congenital ataxias. The objective of this study was to describe the neuropsychological and neuroimaging phenotype of CAMTA1 mutation.

Methods: We performed neuropsychological examinations, MRI and FDG-PET imaging in three patients with autosomal dominant mild intellectual disabilities and ataxia induced by a CAMTA1 intragenic deletion at 1p36.31p36.23.

Results: Neuropsychological tests showed similar findings in two patients, with low information processing speed, slow memory consolidation, phonological disorders, working memory deficits, but mainly preserved executive function. Bilateral parietal and medial temporal abnormalities were found on brain MRI. Diffuse parieto-occipital and local left temporo-parietal decrease of FDG uptake was observed on PET images.

Conclusion: These results suggest that CAMTA1 mutation may induce an unusual neuropsychological profile and parieto-temporal developmental abnormalities. We recommend screening for CAMTA1 mutations in patients with autosomal dominant mild intellectual disability presenting with similar a phenotype.

Conclusion: The authors have evidence that loss-of-function of CAMTA1, a brain-specific calcium responsive transcription factor, is responsible for NPCA with or without ID. Accession numbers CAMTA1 reference sequence used was ENST00000303635. Protein sequence was ENSP00000306522.

The effect of smartphone video on lead time to diagnosis of infantile spasms

Rao CK, Nordli DR 3rd, Cousin JJ, Takacs DS, Sheth RD. The Effect of Smartphone Video on Lead Time to Diagnosis of Infantile Spasms. J Pediatr. 2023 Jul;258:113387. doi: 10.1016/j.jpeds.2023.02.035. Epub 2023 Mar 15. PMID: 36931494.

Abstract

Objective: To assess whether access to smartphone video capture of infantile spasms at initial presentation is associated with improved time to diagnosis and treatment.

Methods: We conducted a collaborative retrospective cohort study of 80 consecutive infants with confirmed infantile epileptic spasms syndrome initially presenting from 2015 to 2021 at 2 US pediatric centers. Statistical methods used included Mann-Whitney U test to assess the difference in lead times to electroencephalogram (EEG), diagnosis, and treatment between groups with and without video capture. A χ2 analysis was used to assess differences in demographics, clinical characteristics, and treatment outcomes between groups. Multivariate regression analysis was used to account for etiology types and infantile spasms capture on EEG.

Results: Patients with smartphone video infantile spasms capture initially presented a median of 9 days earlier (P = .02), had their first EEG 16 days earlier (P = .007), and were diagnosed and started treatment 17 days earlier (P = .006 and P = .008, respectively) compared with the nonvideo group. The video group had a 25% greater response to initial standard treatment (P = .02) and a 21% greater freedom from infantile spasms at long-term follow-up (P = .03), although this long-term outcome lost statistical significance after adjustment for etiology type (P = .07) and EEG capture of infantile spasms (P = .059).

Conclusion: Our findings suggest a benefit of smartphone video capture of infantile spasms in reduced time to diagnosis and initial standard treatment, which are associated with improved treatment response rates. Substantial differences in lead times and treatment response highlight the clinical importance of pediatricians recommending caregivers to obtain smartphone video of events concerning for infantile spasms.

Patient-reported autonomic symptoms do not correlate with objective dysfunction

Novak P, Systrom DM, Marciano SP, Knief A, Felsenstein D, Giannetti MP, Hamilton MJ, Nicoloro-SantaBarbara J, Saco TV, Castells M, Farhad K, Pilgrim DM, Mullally WJ. Mismatch between subjective and objective dysautonomia. Sci Rep. 2024 Jan 30;14(1):2513. doi: 10.1038/s41598-024-52368-x. PMID: 38291116; PMCID: PMC10828385.

Abstract

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective-objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

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Few centers in the U.S. can provide objective, quantitative testing for the assessment of dysautonomia. Patient-reported symptom questionnaires are often used as a surrogate, even when not validated for the suspected diagnosis.

Now, researchers have confirmed in a large cohort what previous research suggested: a lack of correlation between subjective dysautonomia and standardized objective testing. Peter Novak, MD, PhD, director of the Autonomic Laboratory at Brigham and Women’s Faulkner Hospital, William J. Mullally, MD, associate chief of Clinical Neurology at Brigham and Women’s Faulkner Hospital, and colleagues published the findings in Scientific Reports.

Methods

The retrospective study included 2,627 patients who underwent autonomic testing between 2017 and 2023 at Brigham. All completed the Survey of Autonomic Symptoms (SAS), a 12-item questionnaire (11 items for women). 564 patients also completed the Composite Autonomic Symptom Score–31 (COMPASS-31), which the clinic began using in 2022.

Autonomic test results were graded on the Composite Autonomic Severity Score (CASS) and the QASAT (quantitative scale for grading cardiovascular reflex results, sudomotor test results, and skin biopsies). QASAT allows a choice of sudomotor tests; this study used electrochemical skin conductance.

Results

Correlations were strong between subjective instruments and objective instruments:

SAS vs. COMPASS-31: r, 0.74 (P<0.001)

CASS vs. QASAT: r, 0.81 (P<0.001)

However, the more critical relationships were absent: there was no correlation between SAS and QASAT or between COMPASS-31 and CASS.

The mismatch between subjective and objective results was apparent in all conditions the researchers selected for specific investigation: peripheral autonomic neuropathy (n=463), hypermobile Ehlers–Danlos syndrome (n=213), postural tachycardia syndrome (n=211), mast cell activation syndrome (n=172), post-treatment Lyme disease syndrome (n=163), preload failure (n=120), myalgic encephalomyelitis/chronic fatigue syndrome (n=95), neurogenic orthostatic hypotension (n=86), type 2 diabetes (n=71), post-acute sequelae of COVID-19 (n=61), and hereditary alpha tryptasemia (n=45).

Guidance for Physicians

SAS was designed to detect mild dysautonomia in patients with early diabetes, but in this study it strongly correlated with COMPASS-31 when applied to patients either with or without diabetes. Because SAS is simpler and shorter than the more general COMPASS-31, it should be considered a reliable alternative.

At this time, however, subjective questionnaires cannot be recommended as a replacement for autonomic testing. The lack of correlation here between subjective and objective instruments highlights that some patients overestimated their symptoms and some underestimated their deficits.

Patients who overestimate their symptom burden may represent a population with idiosyncratic dysautonomia, an intriguing issue for further study. Still, the workup should always explore factors potentially contributing to subjective dysautonomia. Examples are hypocapnic cerebral hypoperfusion and orthostatic cerebral hypoperfusion syndrome as well as comorbidities including depression, anxiety, stress, fatigue, central sensitization and mast cell disorders.

https://www.brighamhealthonamission.org/2024/06/17/patient-reported-autonomic-symptoms-do-not-correlate-with-objective-dysfunction

Genomics research with undiagnosed children: Ethical challenges

Halley MC, Young JL, Tang C, Mintz KT, Lucas-Griffin S, Maghiro A, Ashley EA, Tabor HK; Undiagnosed Diseases Network. Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care. J Pediatr. 2023 Oct;261:113537. doi: 10.1016/j.jpeds.2023.113537. Epub 2023 Jun 2. PMID: 37271495; PMCID: PMC10527480.

Abstract

Objective: To explore the perspectives of parents of undiagnosed children enrolled in genomic diagnosis research regarding their motivations for enrolling their children, their understanding of the potential burdens and benefits, and the extent to which their experiences ultimately aligned with or diverged from their original expectations.

Study design: In-depth interviews were conducted with parents, audio-recorded and transcribed. A structured codebook was applied to each transcript, after which iterative memoing was used to identify themes.

Results: Fifty-four parents participated, including 17 (31.5%) whose child received a diagnosis through research. Themes describing parents' expectations and experiences of genomic diagnosis research included (1) the extent to which parents' motivations for participation focused on their hope that it would directly benefit their child, (2) the ways in which parents' frustrations regarding the research process confused the dual clinical and research goals of their participation, and (3) the limited clinical benefits parents ultimately experienced for their children.

Conclusions: Our results suggest that parents of undiagnosed children seeking enrollment in genomic diagnosis research are at risk of a form of therapeutic misconception-in this case, diagnostic misconception. These findings indicate the need to examine the processes and procedures associated with this research to communicate appropriately and balance the potential burdens and benefits of study participation.

FDA greenlights first treatment for Niemann-Pick Disease Type C

The Food and Drug Administration (FDA) has approved Miplyffa (arimoclomol; Zevra Therapeutics, Celebration, FL) for use in combination with miglustat for the treatment of neurologic manifestations of Niemann-Pick disease type C (NPC) for adult and pediatric patients aged ≥2 years. Miplyffa is a capsule that is administered orally 3 times daily, and it is the first FDA-approved medication for NPC. In conjunction with the approval, Zevra Therapeutics announced that it has received a rare pediatric disease priority review voucher, enabling the company to receive a priority review for an additional product.

The FDA approval is based on the totality of data from Miplyffa’s New Drug Application, including positive data from a randomized, double-blind, placebo-controlled trial with a population of 50 participants with NPC who were aged 2 to 19 years. Participants were randomly assigned 2:1 to receive either Miplyffa at a weight-assigned dose or placebo 3 times daily. Thirty-nine (78%) participants received miglustat as a background treatment during the 12-month trial, and in these individuals, efficacy of Miplyffa was measured according to restored 4-domain NPC Clinical Severity Scale (R4DNPCCSS).

The 76% of participants in the treatment group who received Miplyffa in combination with miglustat experienced a 0.2-point decrease in R4DNPCCSS score from baseline through 12 months.

The 81% of participants in the placebo group who received miglustat alone experienced a 1.9-point decrease in R4DNPCCSS score from baseline through 12 months.

The trial results demonstrate that, compared with placebo, Miplyffa is associated with the halting of disease progression. Additionally, confirmatory evidence, such as data from a 48-month open label extension (OLE) study, suggest that people who receive Miplyffa experience improved disease outcomes compared with a natural history cohort. The most common adverse reactions associated with treatment are upper respiratory tract infection, diarrhea, and decreased weight. Miplyffa’s prescribing information includes precautions for hypersensitivity reactions, embryofetal toxicity, and increased creatinine without affecting glomecular function.

NPC is a rare lysosomal storage disease with a range of clinical manifestations, often presenting in children aged <10 years. The condition is associated with progressive neurologic disease, with symptoms including developmental delays, cognitive decline, tremor, epilepsy, and cerebellar ataxia, among others, with a terminal stage characterized by severe dementia, weakness, and loss of volitional movement. Miplyffa functions by increasing activation of transcription factor EB (TFEB) and transcription factor E3 (TFE3), upregulating the coordinated lysosomal expression and regulation (CLEAR) genes.

https://practicalneurology.com/news/fda-greenlights-first-treatment-for-niemann-pick-disease-type-c

Mengel E, Patterson MC, Da Riol RM, Del Toro M, Deodato F, Gautschi M, Grunewald S, Grønborg S, Harmatz P, Héron B, Maier EM, Roubertie A, Santra S, Tylki-Szymanska A, Day S, Andreasen AK, Geist MA, Havnsøe Torp Petersen N, Ingemann L, Hansen T, Blaettler T, Kirkegaard T, Í Dali C. Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment. J Inherit Metab Dis. 2021 Nov;44(6):1463-1480. doi: 10.1002/jimd.12428. Epub 2021 Sep 7. PMID: 34418116; PMCID: PMC9293014.

Abstract

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

Sitarska D, Tylki-Szymańska A, Ługowska A. Treatment trials in Niemann-Pick type C disease. Metab Brain Dis. 2021 Dec;36(8):2215-2221. doi: 10.1007/s11011-021-00842-0. Epub 2021 Oct 1. PMID: 34596813; PMCID: PMC8580890.

Abstract

Niemann-Pick type C (NPC) disease is a genetically determined neurodegenerative metabolic disease. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. It is an autosomal recessive inherited disease that results from mutations in the NPC1 or NPC2 genes. The treatment efforts are focused on the slowing its progression. The only registered drug, devoted for NPC patients is Miglustat. Effective treatment is still under development. NPC disease mainly affects the nervous system, and the crossing of the blood-brain barrier by medicines is still a challenge, therefore the combination therapies of several compounds are increasingly being worked on. The aim of this paper is to present the possibilities in treatment of Niemann-Pick type C disease. The discussed research results relate to animal studies.

From the above article:

For the development of an effective treatment, it is essential to know the molecular and biochemical bases of the disease. The pathomechanism of NPC is not yet fully understood. In human cells the cholesterol esters (CE) reach the interior of the lysosome by means of LDL. The lysosomal acid lipase cleaves free fatty acids (FFA) from the CE. FFAs cross the lysosome membrane into the cytoplasm. Free cholesterol (CH) is captured by the NPC2 protein and transported to the NPC1 protein localized in the lysosomal membrane. The NPC1 protein receives CH from NPC2 and transports it across the lysosomal membrane into the cytoplasm, where CH can then be reintroduced into the metabolic pathway. When NPC1 or NPC2 are not produced or the produced proteins are abnormal, it leads to lipid accumulation inside the lysosomes and the development of Niemann-Pick type C disease...

In summary, the treatment efforts applied in NPC were focused on i) decreasing the quantity of intra lysosomal free cholesterol, ii) reducing the synthesis of glucosylceramide by inhibiting the activity of its synthase, iii) restriction of inflammatory processes and immune system response, iv) strengthening the efflux of free cholesterol from the lysosomal compartment into cytosol, v) influencing the expression of genes needed to induce cell differentiation by inhibiting histone deacetylases (HDAC), vi) action of pharmacological chaperones to stimulate cellular protein repair pathway by activation of molecular chaperones such as heat shock proteins, vii) the development of gene therapy.

Oops

A Florida surgeon accused of removing a man's liver instead of his spleen during a surgery, causing the patient to bleed out on the operating table, has had his medical license suspended by the state.

In a damning emergency order from the Florida Department of Health, Dr. Thomas Shaknovsky is said to have removed Alabama resident Bill Bryan's liver instead of his spleen in a "grievous medical error" that makes him an "immediate, serious danger" to the public.

The order details Shaknovsky's alleged "egregious conduct," saying he went to great lengths to cover up his mistake by fabricating medical records, lying about what happened and pressuring others to lie about what happened.

Bryan, 70, died during surgery performed by Shaknovsky at Ascension Sacred Heart Emerald Coast Hospital in Miramar Beach, Florida, on August 21.

Bryan and his wife Beverly were visiting their rental property in Destin on August 18 when Bryan began feeling pain in his side.

According to the order, Bryan arrived at the hospital and was told he was suffering from an enlarged spleen. Shaknovsky said Bryan needed his spleen removed immediately, but Bryan refused.

"We called Bill’s doctor, here at home in Northwest Alabama, and he told Bill that he would have surgeons here in North Alabama waiting when we got home," Beverly told local station WMBB. "I tried to convince Dr. Shaknovsky to let me take him home or arrange for him to be transported, but Dr. Shaknovsky said that Bill would bleed to death if he was moved."

The order says after three days in the hospital, Shaknovsky continued to pressure Bryan to have surgery – and he eventually gave in.

The order says operating room staff were concerned that Shaknovsky "did not have the skill level to safely perform" the "complicated" procedure – but the operation went forward.

The order says Shaknovsky lied and gave several different accounts of what happened during the surgery, finally admitting that at one point during the operation he fired a stapling device "blindly" into the abdomen and removed an organ he "believed to be a spleen."

He claimed the spleen was grossly enlarged and deformed and that the liver was in an unusual location, which caused him to confuse the organs.

However, the state's order said witnesses in the operating room told a very different story. At one point, Shaknovsky identified a vessel he intended to cut and said he could feel it pulsing under his finger. According to the order, he told the staff member assisting him, "that’s scary."

The order details that after the organ was removed, Bryan began to severely hemorrhage and went into cardiac arrest. Despite this, the order says, Shaknovsky continued dissecting even though there was "no visibility" and he never called for a clamp or cauterizer. Witnesses confirmed that Shaknovsky "blindly" fired the stapling device into Bryan’s abdomen.

The order says Shaknovsky removed Bryan’s liver but identified it as a spleen, despite the two organs being different sizes, colors and on totally different sides of the body.

"The staff looked at the readily-identifiable liver on the table and were shocked when Dr. Shaknovsky told them it was a spleen," the order reads. "One staff member felt sick to their stomach."

Shaknovsky claimed Bryan died from a "ruptured splenic artery aneurysm," and made several efforts to convince staff in the operating room that he was correct, even though they knew it wasn’t true.

Shaknovsky requested the organ that was removed be labeled a "spleen" and be sent to pathology. The order says the person responsible for labeling the organ knew it was not a spleen but did as they were instructed.

After the "chaos of the surgery was over," Shaknovsky even went to pathology to look at the organ again, but refused to acknowledge his mistake, the order said. Instead, he fabricated his operative order in great detail, claiming specific ligaments and structures were dissected, but they were never touched.

Fox News Digital reviewed the pathology report from Ascension Sacred Heart Emerald Coast, and it confirmed the organ removed from Bryan was, in fact, his liver.

According to the state's order, removing Bryan's liver instead of his spleen was not Shaknovsky's first medical mistake. In May of 2023, Shaknovsky removed a portion of a patient’s pancreas instead of the adrenal gland, the order said. Shaknovsky claimed the adrenal gland had "migrated" to a different part of the body when he was confronted about the mistake.

The order said the patient in that case suffered "long-term, permanent harm."

"Dr. Shaknovsky’s repeated egregious surgical errors resulted in significant patient harm coupled with his failure to take responsibility for these errors indicates that his reckless conduct is likely to continue," the order says. "Therefore, Dr. Shaknovsky’s continued practice as an osteopathic physician presents an immediate, serious danger to the health, welfare, and safety of the public."

Beverly Bryan is pursing both criminal and civil proceedings in her husband's death, according to Zarzaur Law, the Florida-based firm representing the family.

"My husband died while helpless on the operating room table by Dr. Shaknovsky. I don’t want anyone else to die due to his incompetence at a hospital that should have known or knew he had previously made drastic, life-altering surgical mistakes," Bryan's widow Beverly said in a statement provided to Fox News Digital.

Fox News Digital reached out to Ascension Sacred Heart Emerald Coast for comment on Shaknovsky’s suspension, but did not immediately receive a response.

The hospital previously told Fox News Digital it was investigating Bryan's death, but said it does not comment on specific patient cases or active litigation.

"We take allegations like this very seriously, and our leadership team is performing a thorough investigation into this event," Ascension Sacred Heart spokesperson Gary Nevolis said. "Ascension Sacred Heart Emerald Coast has a longstanding history of providing safe, quality care since the hospital opened its doors in 2003. Patient safety is and remains our number one priority. Our thoughts and prayers remain with the family."

https://www.foxnews.com/us/florida-surgeon-accused-fatally-removing-mans-liver-instead-spleen-has-license-suspended

Missense variants in DPYSL5

Inspired by a patient

Jeanne M, Demory H, Moutal A, Vuillaume ML, Blesson S, Thépault RA, Marouillat S, Halewa J, Maas SM, Motazacker MM, Mancini GMS, van Slegtenhorst MA, Andreou A, Cox H, Vogt J, Laufman J, Kostandyan N, Babikyan D, Hancarova M, Bendova S, Sedlacek Z, Aldinger KA, Sherr EH, Argilli E, England EM, Audebert-Bellanger S, Bonneau D, Colin E, Denommé-Pichon AS, Gilbert-Dussardier B, Isidor B, Küry S, Odent S, Redon R, Khanna R, Dobyns WB, Bézieau S, Honnorat J, Lohkamp B, Toutain A, Laumonnier F. Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities. Am J Hum Genet. 2021 May 6;108(5):951-961. doi: 10.1016/j.ajhg.2021.04.004. Epub 2021 Apr 23. PMID: 33894126; PMCID: PMC8206156.

Abstract

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

Dr. John H. Newman

Dr Newman through the Unidentified Disease Network established my diagnosis of SORD neuropathy.  He was a pleasure to have as a diagnostician. I was sorry to hear of his passing.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11128850/

https://childnervoussystem.blogspot.com/2022/02/sord-hereditary-neuropathy.html

C5orf42 gene mutations and Joubert syndrome

Inspired by a patient

Enokizono M, Aida N, Niwa T, Osaka H, Naruto T, Kurosawa K, Ohba C, Suzuki T, Saitsu H, Goto T, Matsumoto N. Neuroimaging findings in Joubert syndrome with C5orf42 gene mutations: A milder form of molar tooth sign and vermian hypoplasia. J Neurol Sci. 2017 May 15;376:7-12. doi: 10.1016/j.jns.2017.02.065. Epub 2017 Mar 1. PMID: 28431631.

Abstract

Purpose: Little is known regarding neuroimaging-genotype correlations in Joubert syndrome (JBTS). To elucidate one of these correlations, we investigated the neuroimaging findings of JBTS patients with C5orf42 mutations.

Materials and methods: Neuroimaging findings in five JBTS patients with C5orf42 mutations were retrospectively assessed with regard to the infratentorial and supratentorial structures on T1-magnetization prepared rapid gradient echo (MPRAGE), T2-weighted images, and color-coded fractional anisotropy (FA) maps; the findings were compared to those in four JBTS patients with mutations in other genes (including three with AHI1 and one with TMEM67 mutations).

Results: In C5orf42-mutant patients, the infratentorial magnetic resonance (MR) images showed normal or minimally thickened and minimally elongated superior cerebellar peduncles (SCP), normal or minimally deepened interpeduncular fossa (IF), and mild vermian hypoplasia (VH). However, in other patients, all had severe abnormalities in the SCP and IF, and moderate to marked VH. Supratentorial abnormalities were found in one individual in other JBTS. In JBTS with all mutations, color-coded FA maps showed the absence of decussation of the SCP (DSCP).

Conclusion: The morphological neuroimaging findings in C5orf42-mutant JBTS were distinctly mild and made diagnosis difficult. However, the absence of DSCP on color-coded FA maps may facilitate the diagnosis of JBTS.

Zhang C, Sun Z, Xu L, Che F, Liu S. Novel compound heterozygous CPLANE1 variants identified in a Chinese family with Joubert syndrome. Int J Dev Neurosci. 2021 Oct;81(6):529-538. doi: 10.1002/jdn.10135. Epub 2021 Jun 25. PMID: 34091942.

Abstract

Joubert syndrome (JS) and JS-related disorders (JSRD) are a group of neurodevelopmental diseases that share the "molar tooth sign" on axial brain magnetic resonance imaging (MRI), accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. To identify variants responsible for the clinical symptoms of a Chinese family with JS and to explore the genotype-phenotype associations, we conducted a series of clinical examinations, including blood tests, brain MRI scans, ultrasound imaging, and ophthalmologic examination. Genomic DNA was extracted from the peripheral blood of the six-person family, and the pathogenic variants were detected by whole-exome sequencing (WES) and verified by Sanger sequencing. WES revealed two novel compound heterozygous variants in CPLANE1: c.1270C>T (p.Arg424*) in exon 10 and c.8901C>A (p.Tyr2967*) in exon 48 of one child, inherited from each parent. Both variants were absent in ethnically matched Chinese control individuals and were either absent or present at very low frequencies in public databases, suggesting that these variants could be the pathogenic triggers of the JS phenotype. Notably, these CPLANE1 sequence variants were related to the pathogenesis of autosomal recessive JS in this study. The newly discovered variants expand the mutation spectrum of CPLANE1, which assists in understanding the molecular mechanism underlying JS and improving the recognition of genetic counseling, particularly for families with a history of autosomal recessive JS.

Zhu H, Chen W, Ren H, Zhang Y, Niu Y, Wu D, Jiang L. Non-classic splicing mutation in the CPLANE1 (C5orf42) gene cause Joubert syndrome in a fetus with severe craniocerebral dysplasia. Eur J Med Genet. 2021 Jun;64(6):104212. doi: 10.1016/j.ejmg.2021.104212. Epub 2021 Mar 30. PMID: 33794348.

Abstract

Backgroud: Joubert syndrome is a rare neurodevelopmental disorder characterized by clinical and genetic heterogeneity. The characteristic molar tooth sign, which resulted from cerebellar vermis hypoplasia and midbrain anomalies, is expected to be the key diagnostic feature for this disease. However, it is not easy to make a definite diagnosis in prenatal only based on the imageology due to its clinical heterogeneity.

Case report: We report on a fetus who was detected cerebellum dysplasia and encephalocele by ultrasound at 19 and 23 gestational weeks and confirmed by MRI examination. The pregnancy was terminated at 23 weeks of gestation. Postaxial polydactyly and deficiency in occipital bone and skin were identified in the induced fetus.

Results: The whole exome sequencing identified a novel compound heterozygous variation in the CPLANE1 gene related with Joubert syndrome, including a 2-bp insertion, NM_023073.3:c.1383_1384dup; p.(Gly462Glufs*3) and a non-classic splicing variation, NC_000005.10(NM_023073.3):c.7691-5_7691-4del. The pathogenicity of the non-classic splicing variation was further confirmed by cDNA level sequencing, which showed a exon 39 skipping that would introduce a premature termination. The novel compound heterozygous variation caused a complete function loss of the CPLANE1 gene.

Conclusion: The cerebellum dysplasia fetus without obvious molar tooth sign was finally diagnosed as Joubert syndrome, combined with genetic detecting and the postnatal clinical symptoms. We also highlight the clinical heterogeneity of encephalodysplasia in Joubert syndrome, which increases the clinical diagnosis difficulty, especially for prenatal diagnosis. Our findings provided a new perspective for the prenatal diagnosis of Joubert syndrome with severe craniocerebral dysplasia and expanded the variation spectrum of the CPLANE1 gene.

Liu Q, Wang H, Zhao J, Liu Z, Sun D, Yuan A, Luo G, Wei W, Hou M. Four novel compound heterozygous mutations in C5orf42 gene in patients with pure and mild Joubert syndrome. Int J Dev Neurosci. 2020 Oct;80(6):455-463. doi: 10.1002/jdn.10029. Epub 2020 Jul 31. PMID: 32233090.

Abstract

Joubert syndrome (JS) is a rare clinically and genetically heterogeneous disease. Using whole or targeted exome sequencing, we identified four novel compound heterozygous mutations in chromosome 5 open reading frame 42 gene (C5orf42), including c.2876C>T (missense mutation) and c.3921+1G>A (splicing mutation), c.2292 -2delA (splicing mutation) and c.4067C>T (missense mutation), c.6997_6998insT (frameshift mutation) and c.8710C>T (nonsense mutation), c.3981G>C (nonsense mutation) and c.230 _233del (frameshift mutation), in four Chinese JS families. They were all inherited from their heterozygosis parents in the autosomal recessive inheritance mode. Pure JS clinical manifestations and mild neuroimaging findings were found in these patients. These verified the previous findings that C5orf42 mutations generally resulted in a purely neurological Joubert phenotype, and neuroimaging findings were mild in JS with C5orf42 mutations. Our report analyzed these C5orf42 mutations-associated phenotypes and neuroimaging findings in JS and updated the genetic variation spectrum of JS caused by C5orf42.These will help clinicians and geneticists reach a more accurate diagnosis for JS.

Mardani R, Taghizadeh E, Taheri F, Raeisi M, Karimzadeh MR, Rostami D, Ferns GA, Ghayour-Mobarhan M. A novel variant in C5ORF42 gene is associated with Joubert syndrome. Mol Biol Rep. 2020 May;47(5):4099-4103. doi: 10.1007/s11033-020-05465-9. Epub 2020 May 4. PMID: 32367316.
Abstract


Joubert syndrome (JS) disease is a clinically and genetically heterogeneous disorder with mutations in more than 35 genes involved in its pathogenicity. Molecular genetic methods including next generation sequencing (NGS) and Sanger sequencing are effective techniques used for identifying rare genetic variants that have a strong effect on disease pathogenesis. In this study, we tested a large pedigree with a history of several affected members with JS. At first the proband was sequenced by NGS technique then, confirmed by sanger sequencing method. After this, all available members of the pedigree were subjected to molecular analysis by sanger sequencing technique. The results of this study showed a novel variant in the C5ORF42 gene c.3080A > T: p. D1027V leading to a substitution of a valine for aspartic acid (D1027V) and may be associated with JS. This variant was present in proband compatible with autosomal recessive pattern. Also this variant was present in all parents (both father and mother) of affected individuals in a heterozygous state. It seems that mutations in C5ORF42 gene are associated with JS. However, the substantial mechanism requires further investigation.

PUS7 deficiency in human patients causes profound neurodevelopmental phenotype

Inspired by 2 sister patients

Han ST, Kim AC, Garcia K, Schimmenti LA, Macnamara E, Network UD, Gahl WA, Malicdan MC, Tifft CJ. PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation. Mol Genet Metab. 2022 Mar;135(3):221-229. doi: 10.1016/j.ymgme.2022.01.103. Epub 2022 Feb 1. PMID: 35144859; PMCID: PMC8958514.

Abstract

Protein translation is a highly regulated process involving the interaction of numerous genes on every component of the protein translation machinery. Upregulated protein translation is a hallmark of cancer and is implicated in autism spectrum disorder, but the risks of developing each disease do not appear to be correlated with one another. In this study we identified two siblings from the NIH Undiagnosed Diseases Program with loss of function variants in PUS7, a gene previously implicated in the regulation of total protein translation. These patients exhibited a neurodevelopmental phenotype including autism spectrum disorder in the proband. Both patients also had features of Lesch-Nyhan syndrome, including hyperuricemia and self-injurious behavior, but without pathogenic variants in HPRT1. Patient fibroblasts demonstrated upregulation of protein synthesis, including elevated MYC protein, but did not exhibit increased rates of cell proliferation. Interestingly, the dysregulation of protein translation also resulted in mildly decreased levels of HPRT1 protein suggesting an association between dysregulated protein translation and the LNS-like phenotypic findings. These findings strengthen the correlation between neurodevelopmental disease, particularly autism spectrum disorders, and the rate of protein translation.

Preparing the family for death

In the early morning hours of Dec. 4, 2020, the doctor called to tell me my wife Kim had hours to live.

Diagnosed with neuroendocrine cancer in January 2017, Kim endured a complicated Whipple surgery to remove a cancerous tumor from her pancreas, 14 months of chemotherapy, a hernia operation, and two liver resections over the course of three years.

Her surgeon cautiously told us in October 2019 that he had cut the remaining cancer out of her liver and for a few months we anxiously clung to the hope that she had beaten cancer.

But the cancer returned the following spring, this time blocking her bile duct. More grueling and painful treatment followed but without success.

On that December morning when I thought we were going to lose Kim, I took our sons outside and had a tear-filled conversation. I told them their mother had fought as hard as she could, but we were not going to beat the cancer. We went to the hospital to say our final goodbyes.

But by the time we reached the hospital, Kim had made a miraculous recovery.

Father Will told Kim and me that God wanted us to have more time.

And for cancer patients, there is nothing more precious than time.

Even though she was in hospice care, Kim devoted her remaining three months on this earth to our children as faithfully as she had since they were born. She ordered their holiday and birthday presents and ensured there was more than enough candy for their baskets when they celebrated Easter with family friends after Kim passed away.

When we visited and during regular facetime chats, Kim told our sons how much she loved them as she discussed their hopes and dreams for the future.

We turned her hospice room into party central, with cake and candles for the last birthday she would celebrate with our younger son.

She told our children she would be their guardian angel, watching over them.

I’m sad and devastated over losing Kim and angry at the ghastly cancer for taking her from us before her 42nd birthday.

But my overriding emotion is one of gratitude. I’m deeply grateful we met in the most unlikely of circumstances at CIA, when I was preparing for an overseas assignment, and she was randomly chosen as the disguise technician who would find crafty ways to cloak my true appearance.

Selfless and empathic, Kim always asked me how I was doing before she answered the same question that I had posed to her.

Whenever I’m asked about the best thing I ever did at CIA, my answer is most certainly not some cloak-and-dagger espionage or counterterrorism mission. It was falling for Kim in the most consequential "chance encounter."

Kim fought to beat cancer during the first three years after being diagnosed with the disease but during the last year, most especially in her final months, she fought for time to squeeze out every moment we had together as a family. Her bravery and toughness gave us time to process, adapt and prepare for a future without her.

Selfless and empathic, Kim always asked me how I was doing before she answered the same question that I had posed to her. One of her greatest gifts was the ability to see the world through the eyes of her friends and loved ones. It made her a close and trusted confidant, on whom we all comfortably relied.

We were transparent with our children about Kim’s arduous struggle but as time went on and they grew up, we were able to explain to them more fully about Kim’s prognosis. We settled into grieving together as a family while committing ourselves to living our lives to the fullest. That meant vacations to the beach and Disney, outings with our friends and family, and cherishing what we might have once considered a mundane home routine.

I’m eternally grateful to Kim for our two beautiful children, who so poignantly remind me of her. And I’m grateful for all the precious moments we spent together in health and in sickness.

With the greatest love and dedication, Kim shared her acumen, experience and deep understanding of our family so that under her tutelage I learned how to be a single parent and our sons – now immersed in competitive swimming, music study and, to their great joy, in-person school – internalized the most sacred life lesson about striving to reach their potential as human beings even while carrying their grief over their mother’s passing.

When I visited her the weekend before she passed away, no longer able to talk, Kim squeezed my hand in recognition when I told her it was OK to go when she was ready, that she had raised our sons and prepared me to carry on.

https://www.foxnews.com/opinion/thankful-kim-wife-prepared-family-death-daniel-hoffman

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.