ABSTRACT
BACKGROUND: The GCH1 gene encodes the enzyme guanosine triphosphate cyclohydrolase I (GTPCH), which catalyzes the rate-limiting step in the biosynthesis of tetrahydrobiopterin (BH4), a critical cofactor in the production of monoamine neurotransmitters. Autosomal dominant GTPCH (adGTPCH) deficiency is the most common cause of dopa-responsive dystonia (DRD), whereas the recessive form (arGTPCH) is an ultrarare and poorly characterized disorder with earlier and more complex presentation that may disrupt neurodevelopmental processes. Here, we delineated the phenotypic spectrum of ARGTPCHD and investigated the predictive value of biochemical and genetic correlates for disease outcome. OBJECTIVES: The aim was to study 4 new cases of arGTPCH deficiency and systematically review patients reported in the literature. METHODS: Clinical, biochemical, and genetic data and treatment response of 45 patients are presented. RESULTS: Three phenotypes were outlined: (1) early-infantile encephalopathic phenotype with profound disability (24 of 45 patients), (2) dystonia-parkinsonism phenotype with infantile/early-childhood onset of developmental stagnation/regression preceding the emergence of movement disorder (7 of 45), and (3) late-onset DRD phenotype (14 of 45). All 3 phenotypes were responsive to pharmacological treatment, which for the first 2 must be initiated early to prevent disabling neurodevelopmental outcomes. A gradient of BH4 defect and genetic variant severity characterizes the 3 clinical subgroups. Hyperphenylalaninemia was not observed in the second and third groups and was associated with a higher likelihood of intellectual disability. CONCLUSIONS: The clinical spectrum of arGTPCH deficiency is a continuum from early-onset encephalopathies to classical DRD. Genotype and biochemical alterations may allow early diagnosis and predict clinical severity. Early treatment remains critical, especially for the most severe patients.
ABSTRACT
Chondrosarcoma (CS) is a malignant bone tumor arising from cartilage-producing cells. The conventional subtype of CS typically develops within a dense cartilaginous matrix, creating an environment deficient in oxygen and nutrients, necessitating metabolic adaptation to ensure proliferation under stress conditions. Although ketone bodies (KBs) are oxidized by extrahepatic tissue cells such as the heart and brain, specific cancer cells, including CS cells, can undergo ketolysis. In this study, we found that KBs catabolism is activated in CS cells under nutrition-deprivation conditions. Interestingly, cytosolic ß-hydroxybutyrate dehydrogenase 2 (BDH2), rather than mitochondrial BDH1, is expressed in these cells, indicating a specific metabolic adaptation for ketolysis in this bone tumor. The addition of the KB, ß-Hydroxybutyrate (ß-HB) in serum-starved CS cells re-induced the expression of BDH2, along with the key ketolytic enzyme 3-oxoacid CoA-transferase 1 (OXCT1) and monocarboxylate transporter-1 (MCT1). Additionally, internal ß-HB production was quantified in supplied and starved cells, suggesting that CS cells are also capable of ketogenesis alongside ketolysis. These findings unveil a novel metabolic adaptation wherein nutrition-deprived CS cells utilize KBs for energy supply and proliferation.
ABSTRACT
Children with developmental and epileptic encephalopathies often present with co-occurring dyskinesias. Pathogenic variants in ARX cause a pleomorphic syndrome that includes infantile epilepsy with a variety of movement disorders ranging from focal hand dystonia to generalized dystonia with frequent status dystonicus. In this report, we present three patients with severe movement disorders as part of ARX-associated epilepsy-dyskinesia syndrome, including a patient with a novel pathogenic missense variant (p.R371G). These cases illustrate diagnostic and management challenges of ARX-related disorder and shed light on broader challenges concerning epilepsy-dyskinesia syndromes.
Subject(s)
Homeodomain Proteins , Movement Disorders , Transcription Factors , Humans , Male , Female , Movement Disorders/genetics , Movement Disorders/diagnosis , Movement Disorders/etiology , Child, Preschool , Homeodomain Proteins/genetics , Transcription Factors/genetics , Infant , Mutation, Missense , ChildABSTRACT
Status dystonicus is the most severe form of dystonia with life-threatening complications if not treated promptly. We present consensus recommendations for the initial management of acutely worsening dystonia (including pre-status dystonicus and status dystonicus), as well as refractory status dystonicus in children. This guideline provides a stepwise approach to assessment, triage, interdisciplinary treatment, and monitoring of status dystonicus. The clinical pathways aim to: (1) facilitate timely recognition/triage of worsening dystonia, (2) standardize supportive and dystonia-directed therapies, (3) provide structure for interdisciplinary cooperation, (4) integrate advances in genomics and neuromodulation, (5) enable multicenter quality improvement and research, and (6) improve outcomes. © 2024 International Parkinson and Movement Disorder Society.
ABSTRACT
PURPOSE OF REVIEW: We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or 'precision medicine' (which is disease-modifying). RECENT FINDINGS: We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound. SUMMARY: Childhood-onset movement disorders have traditionally been treated symptomatically based on phenomenology, but focus has recently shifted toward targeted molecular mechanism-based therapeutics. The development of precision therapies is driven by increasing capabilities for genetic testing and a better delineation of the underlying disease mechanisms. We highlight novel and exciting approaches to the treatment of genetic childhood-onset movement disorders while also discussing general challenges in therapy development for rare diseases. We provide a framework for molecular mechanism-based treatment approaches, a summary of specific treatments for various movement disorders, and a clinical trial readiness framework.
Subject(s)
Movement Disorders , Child , Humans , Deep Brain Stimulation , Friedreich Ataxia/therapy , Friedreich Ataxia/genetics , Genetic Therapy/methods , Movement Disorders/therapy , Precision Medicine/methods , Rett Syndrome/genetics , Rett Syndrome/therapy , Tourette Syndrome/therapy , Tourette Syndrome/geneticsABSTRACT
BACKGROUND: Clinical Ethics Committees are deliberative groups whose main functions are to assess cases with ethical-clinical conflicts, to generate institutional protocols for preventive purposes, and to train health teams. AIM: To analyze the activity of a clinical ethics committee of a general hospital in the period 2007-2020. MATERIAL AND METHODS: A retrospective analysis of all session records, annual reports, case resolution and documents generated by the Clinical Ethics Committee of Carlos van Buren Hospital in Valparaíso, Chile, between 2007 and 2020, was carried out. RESULTS: On average, 12 cases are analyzed per year. Sixty percent correspond to requests from pediatric units and in 78% of these cases there was at least one neurological disease. In 62% of cases, the main ethical dilemma was adequacy of therapeutic effort, followed by dilemmas related to the exercise of autonomy in 18.2%. In education, two courses are identified aimed to doctors, residents, and other members of the health team. Regarding normative functions, several documents were generated at the request of the Hospital management or in different clinical situations. During COVID-19 pandemia, the active role of the committee was linked to the three main functions, namely evaluating cases, participating in morbidity and mortality meetings for preventive purposes, and issuing guidelines and recommendations for action. The active participation of Pediatric Neurology residents in the Committee, for educational and administrative purposes, stands out. CONCLUSIONS: The three main functions described for the ethics committees were exerted by this Committee during the evaluated period. The impact of our recommendations remain to be objectively evaluated.
Subject(s)
COVID-19 , Ethics Committees, Clinical , Child , Ethics Committees , Hospitals, General , Humans , Retrospective StudiesABSTRACT
BACKGROUND: Clinical Ethics Committees are deliberative groups whose main functions are to assess cases with ethical-clinical conflicts, to generate institutional protocols for preventive purposes, and to train health teams. Aim: To analyze the activity of a clinical ethics committee of a general hospital in the period 2007-2020. MATERIAL AND METHODS: A retrospective analysis of all session records, annual reports, case resolution and documents generated by the Clinical Ethics Committee of Carlos van Buren Hospital in Valparaíso, Chile, between 2007 and 2020, was carried out. Results: On average, 12 cases are analyzed per year. Sixty percent correspond to requests from pediatric units and in 78% of these cases there was at least one neurological disease. In 62% of cases, the main ethical dilemma was adequacy of therapeutic effort, followed by dilemmas related to the exercise of autonomy in 18.2%. In education, two courses are identified aimed to doctors, residents, and other members of the health team. Regarding normative functions, several documents were generated at the request of the Hospital management or in different clinical situations. During COVID-19 pandemia, the active role of the committee was linked to the three main functions, namely evaluating cases, participating in morbidity and mortality meetings for preventive purposes, and issuing guidelines and recommendations for action. The active participation of Pediatric Neurology residents in the Committee, for educational and administrative purposes, stands out. CONCLUSIONS: The three main functions described for the ethics committees were exerted by this Committee during the evaluated period. The impact of our recommendations remain to be objectively evaluated.
Subject(s)
Humans , Child , Ethics Committees, Clinical , COVID-19 , Retrospective Studies , Ethics Committees , Hospitals, GeneralABSTRACT
BACKGROUND: Mullerian adenosarcoma is a rare gynecological malignancy with a low malignant potential, with biphasic growth, consisting of a benign epithelial element and a malignant mesenchymal element. It occurs in all ages predominating in postmenopausal women. Cervical localization of Mullerian adenosarcomas is rare; however, it is associated with a presentation in young women. The diagnosis is made by anatomopathological study of the lesion and immunohistochemistry. The prognosis is generally good although the recurrence rate is high. CLINICAL CASE: We present the case of a 27-year-old patient who attended a gynecological consultation with bleeding and transvaginal flow. During the gynecological examination, a polypoid lesion originating in the cervix was identified, which was removed by torsion and was diagnosed as Mullerian cervical adenosarcoma. Subsequently, a cervical cone was performed because the patient refused hysterectomy. CONCLUSIONS: Mullerian cervical adenosarcoma is a rare neoplasm with a recurrence rate that can reach up to 50% of cases, so close follow-up is necessary. A local excision can be considered in patients without poor prognosis factors and who wish to preserve their fertility.
ANTECEDENTES: El adenosarcoma mulleriano (AM) es una neoplasia ginecológica rara, de bajo potencial maligno, con crecimiento bifásico, constituida por un elemento epitelial benigno y otro mesenquimatoso maligno. Se presenta en todas las edades, pero predomina en mujeres posmenopáusicas. La localización cervical de los AM es poco frecuente; sin embargo, se asocia a una presentación en mujeres jóvenes. El diagnóstico se realiza mediante estudio anatomopatológico de la lesión e inmunohistoquímica. El pronóstico es generalmente bueno, aunque la tasa de recidiva es alta. CASO CLÍNICO: Presentamos el caso de una paciente de 27 años que acudió a consulta ginecológica con sangrado y flujo transvaginal. En la exploración ginecológica se identificó una lesión polipoide originada en el cérvix, la cual se extirpó por torsión y fue diagnosticada como AM cervical. Posteriormente se realizó conización cervical debido a que la paciente rechazó la histerectomía. CONCLUSIÓN: El AM cervical es una neoplasia poco frecuente que tiene una tasa de recidiva que puede llegar hasta al 50% de los casos, por lo que es necesario un seguimiento estrecho. La escisión local puede ser considerada en pacientes sin factores de mal pronóstico y que deseen conservar su fertilidad.
Subject(s)
Adenosarcoma/therapy , Uterine Neoplasms/therapy , Adult , Conservative Treatment , Female , HumansABSTRACT
PURPOSE: Epidemiologic studies have suggested that higher levels of circulating vitamin D may reduce breast cancer risk, but no studies have investigated this association among women in developing countries, and very few studies have further investigated this association according to menopausal status. METHODS: A population-based case-control study in Mexico with 1,000 incident breast cancer cases aged 35-69 years, enrolled shortly after diagnosis (0-6 days) and frequency-matched to 1,074 controls on age, region, and health care system, was used to assess the association between serum 25-hydroxyvitamin D [25(OH)D] levels with overall, pre- and postmenopausal breast cancer risk. 25(OH)D concentration was measured on a random sub-sample of women (573 cases and 639 matched controls) using a liquid chromatography/tandem mass spectrometry method. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated from multivariable conditional logistic regression models. RESULTS: Serum 25(OH)D concentration (per 10 ng/mL increase) showed a strong inverse association with risk of breast cancer among all (p(trend) = 0.001), pre- (p(trend) = 0.006) and postmenopausal women (p(trend) = 0.0001). Compared with a predefined lower concentration of 25(OH)D (<20 ng/mL), higher levels (>30 ng/mL) were associated with lower overall (OR = 0.53, 95 % CI: 0.28-1.00; p(trend) = 0.002), pre- (OR = 0.60, 95 % CI: 0.16-2.17; p(trend) = 0.07) and postmenopausal (OR = 0.37, 95 % CI: 0.16-0.82; p(trend) = 0.004) breast cancer risk. CONCLUSIONS: The results of this large population-based case-control study indicate an inverse association between circulating vitamin D levels and breast cancer risk among pre- and postmenopausal Mexican women.