Res Sq [Preprint]. 2024 Oct 14:rs.3.rs-4915388. doi: 10.21203/rs.3.rs-4915388/v1.

ABSTRACT

Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547C > T, p.R183*; c.775C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181A > G, p.R61G). All patients were homozygous. All affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype-phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J-domain may predict a more severe phenotype.

PMID:39483874 | PMC:PMC11527209 | DOI:10.21203/rs.3.rs-4915388/v1

Science. 2024 Nov;386(6721):477. doi: 10.1126/science.adu2387. Epub 2024 Oct 31.

ABSTRACT

Network aims to raise awareness and bolster testing and treatment for rare genetic conditions.

PMID:39480940 | DOI:10.1126/science.adu2387

PLoS One. 2024 Oct 31;19(10):e0313139. doi: 10.1371/journal.pone.0313139. eCollection 2024.

ABSTRACT

Superoxide Dismutase 3 (SOD3) scavenges extracellular superoxide giving a hydrogen peroxide metabolite. Both Reactive Oxygen Species diffuse through aquaporins causing oxidative stress and biomolecular damage. SOD3 is differentially expressed in cancer and this research utilises Gene Expression Omnibus data series GSE2109 with 2,158 cancer samples. Genome-wide expression correlation analysis was conducted with SOD3 as the seed gene. Categorical SOD3 Pearson Correlation gene lists incrementing in correlation strength by 0.01 from ρ≥|0.34| to ρ≥|0.41| were extracted from the data. Positively and negatively SOD3 correlated genes were separated for each list and checked for significance against disease overlapping genes in the ClinVar and Orphanet databases via Enrichr. Disease causal genes were added to the relevant gene list and checked against Gene Ontology, Phenotype Ontology, and Elsevier Pathways via Enrichr before the significant ontologies containing causal and non-overlapping genes were reviewed with a literature search for possible disease and oxidative stress associations. 12 significant individually discriminated disorders were identified: Autosomal Dominant Cutis Laxa (p = 6.05x10-7), Renal Tubular Dysgenesis of Genetic Origin (p = 6.05x10-7), Lethal Arteriopathy Syndrome due to Fibulin-4 Deficiency (p = 6.54x10-9), EMILIN-1-related Connective Tissue Disease (p = 6.54x10-9), Holt-Oram Syndrome (p = 7.72x10-10), Multisystemic Smooth Muscle Dysfunction Syndrome (p = 9.95x10-15), Distal Hereditary Motor Neuropathy type 2 (p = 4.48x10-7), Congenital Glaucoma (p = 5.24x210-9), Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (p = 3.77x10-16), Classical-like Ehlers-Danlos Syndrome type 1 (p = 3.77x10-16), Retinoblastoma (p = 1.9x10-8), and Lynch Syndrome (p = 5.04x10-9). 35 novel (21 unique) genes across 12 disorders were identified: ADNP, AOC3, CDC42EP2, CHTOP, CNN1, DES, FOXF1, FXR1, HLTF, KCNMB1, MTF2, MYH11, PLN, PNPLA2, REST, SGCA, SORBS1, SYNPO2, TAGLN, WAPL, and ZMYM4. These genes are proffered as potential biomarkers or therapeutic targets for the corresponding rare diseases discussed.

PMID:39480826 | DOI:10.1371/journal.pone.0313139

Orphanet J Rare Dis. 2024 Oct 30;19(1):405. doi: 10.1186/s13023-024-03392-7.

ABSTRACT

BACKGROUND: The Brazilian Policy for Comprehensive Care for People with Rare Diseases was implemented in 2014; however, national epidemiological data on rare diseases (RDs) are scarce and mainly focused on specific disorders. To address this gap, University Hospitals, Reference Services for Neonatal Screening, and Reference Services for Rare Diseases, all of which are public health institutions, established the Brazilian Rare Diseases Network (RARAS) in 2020. The objective of this study was to perform a comprehensive nationwide epidemiological investigation of individuals with RDs in Brazil. This retrospective survey collected data from patients receiving care in 34 healthcare facilities affiliated with RARAS in 2018 and 2019.

RESULTS: The survey included 12,530 participants with a median age of 15.0 years, with women representing 50.5% of the cohort. Classification according to skin color demonstrated that 5044 (47.4%) participants were admixed. Most had a confirmed diagnosis (63.2%), with a predominance of phenylketonuria (PKU), cystic fibrosis (CF), and acromegaly. Common clinical manifestations included global developmental delay and seizures. The average duration of the diagnostic odyssey was 5.4 years (± 7.9 years). Among the confirmed diagnoses, 52.2% were etiological (biochemical: 42.5%; molecular: 30.9%), while 47.8% were clinical. Prenatal diagnoses accounted for 1.2%. Familial recurrence and consanguinity rates were 21.6% and 6.4%, respectively. Mainstay treatments included drug therapy (55.0%) and rehabilitation (15.6%). The Public Health System funded most diagnoses (84.2%) and treatments (86.7%). Hospitalizations were reported in 44.5% of cases, and the mortality rate was 1.5%, primarily due to motor neuron disease and CF.

CONCLUSION: This study marks a pioneering national-level data collection effort for rare diseases in Brazil, offering novel insights to advance the understanding, management, and resource allocation for RDs. It unveils an average diagnostic odyssey of 5.4 years and a higher prevalence of PKU and CF, possibly associated with the specialized services network, which included newborn screening services.

PMID:39478612 | DOI:10.1186/s13023-024-03392-7

Pediatr Neurol. 2024 Sep 30;161:263-267. doi: 10.1016/j.pediatrneurol.2024.09.022. Online ahead of print.

ABSTRACT

BACKGROUND: To assess the age and MECP2 variants of recently identified males and set the stage for further study of clinical features in males.

METHODS: Genetic information on the specific MECP2 variant was acquired from the coordinator (K.F.) of the Parent Group for Males. Data were collected indicating whether these variants were de novo or transmitted from the mother and whether males who appeared to meet the diagnostic criteria for Rett syndrome had mosaicism for the MECP2 variant.

RESULTS: Fifty-nine males were identified through the parent group. Their ages ranged from 2 to 28 years, with the median age being 7.0 years and the mean age being 10.8 years. Of these variants, 46 (78.0%) were de novo, nine (15.3%) were maternally inherited, and for four (6.8%) inheritance was not known. Eleven (18.6%) were mosaic, 10 with somatic mosaicism and one with Klinefelter syndrome (47XXY). Together with males reported previously from the US Natural History Study, the total group represents 85 males, of whom 27 are deceased.

CONCLUSIONS: These data on males with MECP2 variants are important to caregivers, physicians, and researchers to begin to characterize their historical and clinical features, improve diagnostic recognition and overall care, and accelerate access to therapeutic studies including gene replacement strategies. Equal access to such therapies for males is critical.

PMID:39476560 | DOI:10.1016/j.pediatrneurol.2024.09.022

Mol Psychiatry. 2024 Oct 29. doi: 10.1038/s41380-024-02806-z. Online ahead of print.

ABSTRACT

De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including GSK3B. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with GSK3B variants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that GSK3B is enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that Gsk3b knockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in GSK3B loss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay.

PMID:39472663 | DOI:10.1038/s41380-024-02806-z

Orphanet J Rare Dis. 2024 Oct 28;19(1):399. doi: 10.1186/s13023-024-03343-2.

ABSTRACT

BACKGROUND: An ongoing challenge with rare diseases is limited data and, consequently, limited knowledge about the collective prevalence and impact of these conditions on individuals, families, and the health system, particularly in rural and regional areas. Using existing datasets, this project aimed to examine the epidemiology of and hospital activity for Tasmanians with rare diseases.

METHODS: Rare diseases were defined as non-infectious diseases with a prevalence of less than 1 in 2000. An initial resource set of 1028 ICD-10-AM diagnostic codes was used to identify a cohort of Tasmanians with rare diseases in Tasmanian Health datasets (1 January 2007 until 31 December 2020). Validating the resource set using a small group with known rare diseases revealed limitations in ascertainment, and so an expanded set of 1940 ICD-10-AM diagnostic codes was developed by cross-referencing ICD-10-AM codes with Orphanet data. Cohort hospital activity and admission costs were compared to statewide data for the final year of the study, 01 January 2020 to 31 December 2020.

RESULTS: Using the resource set of 1028 ICD-10-AM diagnostic codes, the period prevalence of rare diseases in Tasmania across all age groups was estimated at 3.5%, with a point prevalence of 1.5% in December 2020. In 2020, 3384 individuals within the Tasmanian rare disease cohort, representing 0.6% of the Tasmanian population, accessed the public hospital system and accounted for 5.6% of all admissions. The mean length of stay for rare disease-related hospital admissions was 5.0 days, compared to 3.3 days for non-rare disease-related admissions. The mean cost per admission for the rare disease cohort was AUD$11,310, compared to AUD$6475 for all admissions statewide. In 2020, using the expanded resource set, the total cost of public hospital admissions in Tasmania was estimated to be AUD$979 million, with rare disease-related hospital admissions accounting for 9.1% of this cost, increasing to 19.0% when the costs for all admissions for the rare disease patients were included.

CONCLUSIONS: Patients with rare diseases had more admissions, longer length of stay, and a higher average cost per admission. Patients with rare diseases have a disproportionate impact on statewide hospital activity and costs in Tasmania.

PMID:39468681 | DOI:10.1186/s13023-024-03343-2

Acta Neuropathol Commun. 2024 Oct 28;12(1):171. doi: 10.1186/s40478-024-01878-w.

ABSTRACT

Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547 C > T, p.R183*; c.775 C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181 A > G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype.

PMID:39468638 | DOI:10.1186/s40478-024-01878-w

Hum Genet. 2024 Dec;143(12):1459-1463. doi: 10.1007/s00439-024-02711-z. Epub 2024 Oct 28.

ABSTRACT

PURPOSE: With exome sequencing now standard, diagnostic labs are in need of a, in principle, to-the-day-accurate list of genes associated with rare diseases. Manual curation efforts are slow and often disease specific, while efforts relying on single sources are too inaccurate and may result in false-positive or false-negative genes.

METHODS: We established the MorbidGenes panel based on a list of publicly available databases: OMIM, PanelApp, SysNDD, ClinVar, HGMD and GenCC. A simple logic allows inclusion of genes that are supported by at least one of these sources, providing a list of all genes with diagnostic relevance.

RESULTS: The panel is freely available at https://morbidgenes.uni-leipzig.de and currently includes 5037 genes (as of October 2024) with minimally sufficient evidence on disease causality to classify them as diagnostically relevant.

CONCLUSION: The MorbidGenes panel is an open and comprehensive overview of diagnostically relevant rare disease genes based on a diverse set of resources. The panel is updated monthly to keep up with the ever increasing number of rare disease genes.

PMID:39465390 | DOI:10.1007/s00439-024-02711-z

Eye Brain. 2024 Oct 23;16:55-63. doi: 10.2147/EB.S419663. eCollection 2024.

ABSTRACT

Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts (HDBSCC) is a rare syndrome caused by biallelic mutations in the JAM3 gene with significant intrafamilial variability in clinical presentation and brain imaging phenotypes. The clinical presentation of HDBSCC includes severe recurrent hemorrhages involving the brain parenchyma and the ventricles beginning in utero and continuing in infancy together with dense central cataracts present at birth. This comprehensive review documents reported cases on this unique condition and describes its genetic, neuroradiologic and ophthalmic features. It should be included in the differential diagnosis of children with congenital cataracts and neurodevelopmental abnormalities. Unique clinical, imaging findings and genetic testing can help the diagnosis.

PMID:39464599 | PMC:PMC11512770 | DOI:10.2147/EB.S419663

J Genet Couns. 2024 Oct 28. doi: 10.1002/jgc4.1994. Online ahead of print.

ABSTRACT

Genomic sequencing has been proposed as a strategy to expand newborn screening. Perspectives on genomic newborn screening from parents of diverse racial, ethnic, and socioeconomic backgrounds are needed to shape equitable implementation of this modality. We conducted 20 semi-structured interviews (15 English, 5 Spanish) and seven focus groups (4 English, 3 Spanish) with parents from diverse backgrounds to assess their perspectives regarding which disorders and variants might be screened, data privacy, and barriers to pursuing specialized care. Parents felt that genomic newborn screening would provide them with improved understanding of their children's health and had the potential to yield health and personal benefits. Themes that became evident included: interest in childhood and family health risks, the value of emotional preparation and personal planning, understanding of uncertain and low-risk results, concerns regarding data privacy, and concerns about support following the receipt of a positive newborn screening result. The expected benefits and concerns expressed by parents of diverse backgrounds regarding genomic newborn screening should guide future policy decisions. Their preferences should be considered prior to the implementation of large-scale genomic newborn screening programs.

PMID:39465664 | DOI:10.1002/jgc4.1994

Expert Opin Biol Ther. 2024 Nov;24(11):1279-1297. doi: 10.1080/14712598.2024.2422360. Epub 2024 Nov 11.

ABSTRACT

OBJECTIVES: Orphan medicinal products (OMPs) authorized by the European Union (EU) benefit from market exclusivity, fee waivers, and national incentives. Maintaining orphan status during a marketing authorization application requires meeting eligibility criteria, especially demonstrating significant benefit (SB), which is challenging. This study identifies key features linked to successful orphan status maintenance for biological OMPs approved in the EU between 2018 and 2023.

METHODS: Data from European public assessment reports and orphan maintenance assessment reports were analyzed.

RESULTS: Among the 50 biological OMP maintained orphan designations, 68.0% had to demonstrate SB over existing treatments, with 91.2% leveraging the clinically relevant advantage area, utilizing better clinical efficacy (83.9%) and efficacy in subpopulations (38.7%) subdomains. However, 32.0% did not need to demonstrate SB due to a lack of alternative treatments, most of which were ultra-orphan drugs. Advanced therapy medicinal products and monoclonal antibodies were the most numerous OMP categories, whereas oncology and immunomodulation were the preferred therapeutic areas.

CONCLUSION: The Orphan Regulation is essential in advancing treatments for rare diseases, fostering innovation while addressing unmet medical needs. Nonetheless, the insufficient return on investment criterion remains underused, whereas refining major contribution to patient care guidelines and incorporating real-world evidence may enhance regulatory evaluations.

PMID:39460383 | DOI:10.1080/14712598.2024.2422360

Genes (Basel). 2024 Oct 15;15(10):1328. doi: 10.3390/genes15101328.

ABSTRACT

Since the advent of DNA sequencing, genetic analyses have been increasingly incorporated into clinical practice to support the diagnosis of rare disorders [...].

PMID:39457452 | DOI:10.3390/genes15101328

Genes (Basel). 2024 Sep 25;15(10):1243. doi: 10.3390/genes15101243.

ABSTRACT

BACKGROUND: The role of microRNAs (miRNAs) in the pathogenesis of rare genetic disorders has been gradually discovered. MiRNAs, a class of small non-coding RNAs, regulate gene expression by silencing target messenger RNAs (mRNAs). Their biogenesis involves transcription into primary miRNA (pri-miRNA), processing by the DROSHA-DGCR8 (DiGeorge syndrome critical region 8) complex, exportation to the cytoplasm, and further processing by DICER to generate mature miRNAs. These mature miRNAs are incorporated into the RNA-induced silencing complex (RISC), where they modulate gene expression.

METHODS/RESULTS: The dysregulation of miRNAs is implicated in various Mendelian disorders and familial diseases, including DICER1 syndrome, neurodevelopmental disorders (NDDs), and conditions linked to mutations in miRNA-binding sites. We summarized a few mechanisms how miRNA processing and regulation abnormalities lead to rare genetic disorders. Examples of such genetic diseases include hearing loss associated with MIR96 mutations, eye disorders linked to MIR184 mutations, and skeletal dysplasia involving MIR140 mutations.

CONCLUSIONS: Understanding these molecular mechanisms is crucial, as miRNA dysregulation is a key factor in the pathogenesis of these conditions, offering significant potential for the diagnosis and potential therapeutic intervention.

PMID:39457367 | DOI:10.3390/genes15101243

Int J Mol Sci. 2024 Oct 11;25(20):10949. doi: 10.3390/ijms252010949.

ABSTRACT

Rare diseases are heterogeneous diseases characterized by various symptoms and signs. Due to the low prevalence of such conditions (less than 1 in 2000 people), medical expertise is limited, knowledge is poor and patients' care provided by medical centers is inadequate. An accurate diagnosis is frequently challenging and ongoing research is also insufficient, thus complicating the understanding of the natural progression of the rarest disorders. This review aims at presenting the multimodal approach supported by the integration of multiple analyses and disciplines as a valuable solution to clarify complex genotype-phenotype correlations and promote an in-depth examination of rare disorders. Taking into account the literature from large-scale population studies and ongoing technological advancement, this review described some examples to show how a multi-skilled team can improve the complex diagnosis of rare diseases. In this regard, Facio-Scapulo-Humeral muscular Dystrophy (FSHD) represents a valuable example where a multimodal approach is essential for a more accurate and precise diagnosis, as well as for enhancing the management of patients and their families. Given their heterogeneity and complexity, rare diseases call for a distinctive multidisciplinary approach to enable diagnosis and clinical follow-up.

PMID:39456731 | DOI:10.3390/ijms252010949

Bull Cancer. 2024 Oct 24:S0007-4551(24)00333-3. doi: 10.1016/j.bulcan.2024.07.011. Online ahead of print.

ABSTRACT

BACKGROUND: Gastrointestinal stromal tumours (GIST) are tumours of the digestive tract that mainly develop in adults. Recommendations for the management of GIST in pediatrics are limited.

MATERIAL AND METHODS: We performed an updated review of the literature serving as a basis for the development of diagnostic and therapeutic recommendations for GIST in children and young adults (YA).

RESULTS: GIST in pediatric population can have a sporadic presentation but occur more often in a syndromic and/or familial context. Currently more than 170 cases of sporadic GIST or in association with Carney-Stratakis syndrome or Carney's triad family cases of familial GIST have been described in children and YA. These syndromes are frequently associated with germline or somatic alterations in a sub-unit of Succinate Dehydrogenase (SDH). In contrast, the frequency of somatic KIT and PDGFRα oncogene mutations (±15%) is significantly lower as compared to adults with GIST. The recommendations for the management of children with GIST are generally comparable to those used for adult patients, although certain biological differences influence the therapeutic attitude.

CONCLUSIONS: International collaborations have been deployed in order to increase the clinical and biological knowledge of this orphan pathology in pediatrics.

PMID:39455327 | DOI:10.1016/j.bulcan.2024.07.011

Gynecol Oncol. 2024 Oct 24;191:233-239. doi: 10.1016/j.ygyno.2024.10.019. Online ahead of print.

ABSTRACT

BACKGROUND: Granulosa cell ovarian tumors (GCT) are orphan disease with limited treatments. Hormone therapy is a potential treatment, due to the overexpression of hormone receptors in most tumors. This study explores the activity of the antiandrogen, enzalutamide, in metastatic cases.

METHODS: We designed a phase II clinical trial under the Spanish Collaborative Group for Transversal Oncology and Rare and Orphan Tumors (GETTHI). Eligible participants were adult women with advanced GCT. Primary endpoint was objective response rate. Secondary endpoints included clinical benefit rate, progression-free survival, overall survival, and safety profile. Patients received enzalutamide 160 mg once daily.

RESULTS: From April 2018 to March 2020, eighteen patients were screened, and sixteen were included across nine institutions. Median age was 56.4 years (range 45-71), and most were Caucasian (14 cases), one Arabian and one Latin. ECOG performance status was zero in 13 cases (81 %) and one in three (19 %). Six patients (38 %) had previously received hormone therapy as adjuvant treatment or for advanced disease, and 15 (94 %) chemotherapy. Median time from metastasis to study entry was 96 months (range 4.5-198). No objective response was observed, but the clinical benefit rate reached 68.8 % (95 % CI [46 %-91.5 %]). Median progression-free survival was 3.8 months (95 % CI [1.36-6.14]). Median overall survival was not reached, with a median follow-up of 6 months (range 2.2-19). At the time of database closure, 14 patients had discontinued treatment, 13 due to disease progression and one by personal choice. Two deaths attributed to disease progression were recorded. Five grade 3 adverse events were reported, with only one (asthenia) deemed related to the therapy.

CONCLUSIONS: Although enzalutamide demonstrated modest activity in GCT, durable stabilization was observed in some cases.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03464201.

PMID:39454227 | DOI:10.1016/j.ygyno.2024.10.019

J Pers Med. 2024 Sep 26;14(10):1027. doi: 10.3390/jpm14101027.

ABSTRACT

Objectives: Thyroid eye disease (TED) treatment has been recently revolutionized with the approval of teprotumumab, a targeted insulin growth factor 1 receptor (IGF1R) inhibitor. To date, teprotumumab is the only FDA-approved drug for treating TED. In this article, we would like to temper the current enthusiasm around IGF1R inhibitors. Methods: critical review of the literature by independent academic practitioners. Results: several questions should be raised. First, "how an orphan drug has become a blockbuster with annual sales exceeding $1 billion?" Teprotumumab infusions are expensive, costing about USD 45,000 for one infusion and USD 360,000 for eight infusions in a 75 kg patient. Teprotumumab approval was based on two randomized clinical trials investigating active (clinical activity score ≥ 4) TED patients. Despite this, teprotumumab was approved by the FDA for "the treatment of TED" without distinguishing between active and inactive forms. The second question is as follows: "how can a new drug, compared only to a placebo, become the new standard without being compared to historically established gold standard medical or surgical treatments?" Teprotumumab has never been compared to other medical treatments in active TED nor to surgery in chronic TED. Up to 75% of patients may experience proptosis regression after treatment discontinuation. Finally, ototoxicity has emerged as a potentially devastating side effect requiring frequent monitoring. Investigation into the long-term side effects, especially in women of childbearing age, is also warranted. Conclusions: Teprotumumab is undoubtedly a major treatment option in TED. However, before prescribing a drug, practitioners should assess its benefit/risk ratio based on the following: (i) evidence-based medicine; (ii) their empirical experience; (iii) the cost/benefit analysis; (iv) the long-term outcomes and safety profile.

PMID:39452535 | PMC:PMC11508897 | DOI:10.3390/jpm14101027

Eur J Neurol. 2024 Dec;31(12):e16446. doi: 10.1111/ene.16446. Epub 2024 Oct 24.

ABSTRACT

BACKGROUND AND PURPOSE: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by pervasive personality and behavioural disturbances with severe impact on patients and caregivers. In current clinical practice, treatment is based on nonpharmacological and pharmacological approaches. Unfortunately, trial-based evidence supporting symptomatic pharmacological treatment for the behavioural disturbances in FTD is scarce despite the significant burden this poses on the patients and caregivers.

METHOD: The study examined drug management decisions for several behavioural disturbances in patients with FTD by 21 experts across European expert centres affiliated with the European Reference Network for Rare Neurological Diseases (ERN-RND).

RESULTS: The study revealed the highest consensus on drug treatments for physical and verbal aggression, impulsivity and obsessive delusions. Antipsychotics (primarily quetiapine) were recommended for behaviours posing safety risks to both patients and caregivers (aggression, self-injury and self-harm) and nightly unrest. Selective serotonin reuptake inhibitors were recommended for perseverative somatic complaints, rigidity of thought, hyperphagia, loss of empathy and for impulsivity. Trazodone was specifically recommended for motor unrest, mirtazapine for nightly unrest, and bupropion and methylphenidate for apathy. Additionally, bupropion was strongly advised against in 10 out of the 14 behavioural symptoms, emphasizing a clear recommendation against its use in the majority of cases.

CONCLUSIONS: The survey data can provide expert guidance that is helpful for healthcare professionals involved in the treatment of behavioural symptoms. Additionally, they offer insights that may inform prioritization and design of therapeutic studies, particularly for existing drugs targeting behavioural disturbances in FTD.

PMID:39447217 | PMC:PMC11555005 | DOI:10.1111/ene.16446

BMJ Case Rep. 2024 Oct 23;17(10):e261443. doi: 10.1136/bcr-2024-261443.

ABSTRACT

Mulibrey nanism (MN) is a extremely rare genetic condition first described in 1973, with around 150 cases reported worldwide. MN is characterised by growth delay and multiorgan manifestations, the most fatal being a combination restrictive-constrictive, perimyocardial heart disease that results in diastolic heart failure. We present a male toddler with MN who presented with recurrent episodes of hypoxia, feeding intolerance, and generalised swelling (anasarca) in the setting of subtle echocardiographic findings. A multidisciplinary and systematic diagnostic approach was used to determine the underlying aetiology. Invasive cardiac testing via right heart catheterisation revealed the final diagnosis of restrictive cardiomyopathy. Transplant decision-making was limited due to hepatic involvement. This case highlights the limitations of echocardiography in diagnosing restrictive cardiomyopathy, which has a preserved ejection fraction, as well the need for multidisciplinary involvement and a family-centred approach in treating patients with this rare condition.

PMID:39448079 | DOI:10.1136/bcr-2024-261443