Exploring the values, preferences, and information needs of patients with NKX2-1-related disorders: A qualitative study protocol

Background: NKX2-1-related disorders have a prevalence of 1:500,000 and are therefore considered a rare condition according to the European Commission's definition. The European Reference Network of Rare Neurological Disorders is developing the first clinical practice guideline on the management of this condition, with the support of the Andalusian Health Technology Assessment Area, Endo-ERN, ERN-Lung and Imegen, within the framework of the ERNs Guidelines programme (DG SANTE/2018/B3/030). Within the scope of this programme, it becomes necessary to explore the patient perspective in order to include it in the ongoing clinical practice guideline and accompanying patient information booklet. Methods and analysis: This study will use qualitative methods to explore the values, preferences and information needs of patient with NKX2-1-related disorders and their caregivers. Participants will come from a variety of countries throughout Europe. One focus group and four semi-structured interviews will be conducted. Pairs will analyse the data using Grounded Theory. The Andalusian Regional Ministry of Health's Ethics Coordinating Committee for Biomedical Research (Sevilla, Andalucía, Spain) has approved this study protocol (29/03/2022). Discussion: This is the first study to explore the values, preferences, and information needs of patients with NKX2-1-related disorders. The proposed study's findings will contribute to the generation of useful knowledge that will provide guidance to improve the care given to patients with the studied condition. While this study will provide valuable insights into the perspectives of patients with NKX2-1-related disorders, the findings are unlikely to be generalizable to patients with other conditions.This study is supported by the European Commission within the contract SANTE/2018/B3/030-SI2.813822 under which the ERNs Guidelines programme is being developed. The funders had and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Combining Literature Review With a Ground Truth Approach for Diagnosing Huntington's Disease Phenocopy.

One percent of patients with a Huntington's disease (HD) phenotype do not have the Huntington (HTT) gene mutation. These are known as HD phenocopies. Their diagnosis is still a challenge. Our objective is to provide a diagnostic approach to HD phenocopies based on medical expertise and a review of the literature. We employed two complementary approaches sequentially: a review of the literature and two surveys analyzing the daily clinical practice of physicians who are experts in movement disorders. The review of the literature was conducted from 1993 to 2020, by extracting articles about chorea or HD-like disorders from the database Pubmed, yielding 51 articles, and analyzing 20 articles in depth to establish the surveys. Twenty-eight physicians responded to the first survey exploring the red flags suggestive of specific disease entities. Thirty-three physicians completed the second survey which asked for the classification of paraclinical tests according to their diagnostic significance. The analysis of the results of the second survey used four different clustering algorithms and the density-based clustering algorithm DBSCAN to classify the paraclinical tests into 1st, 2nd, and 3rd-line recommendations. In addition, we included suggestions from members of the European Reference Network-Rare Neurological Diseases (ERN-RND Chorea & Huntington disease group). Finally, we propose guidance that integrate the detection of clinical red flags with a classification of paraclinical testing options to improve the diagnosis of HD phenocopies

Corrigendum: Combining Literature Review With a Ground Truth Approach for Diagnosing Huntington's Disease Phenocopy.

[This corrects the article DOI: 10.3389/fneur.2022.817753.]

Los suelos y la vegetación del área de influencia de las obras de Yacyreta, provincia de Corrientes, Argentina

The main objective of the present, work was to survey and to map the soils and vegetation of the area of influence of the Yacyreta dam, under construction. A total of 840.000 hs. were surveyed at a semi detailed scale (1:50.000). Geographical coordinates are from South to North: S 28°00’ - S 27°15’ and from East to West: W 55°55* -W 53°55’.. The information provided in the original work, not published, is distributed in 6 tomes included in 12 volumes as follows:Tome I -Antecedents, climate and soils (4 volumes)Tome II -Veg'etation (2 volumes)Tome III -Soil productivity (1 volume)Tome IV -Geomorphology and hydrology of 100.000 ha (1 volume)Tome V -Aptitude for irrigation of 100.000 ha (1 volume)Tome VI -Soil charts and thematicmaps (3 volumes) In this publication the following maps and charts are presented at 1:50.000 scale: a) Basic soil maps; b) Potential aptitude for irrigation, and c) Geomorphological landforms. Other maps at 1:200.000 scale are also included as follows: d) Vegetation; e) Soil regions; f) Actual use; g) Land use capability; h) Land aptitude for annual and perennial crops; i) Taxonomical soil great groups; and j) Excitangeable aluminium. The work resulted from an agreement signed in March 1981 by the Government of the Province Corrientes and the Federal Council of Investments, to be carried out by the Natural Resources Department of the Experimental Station Corrientes of the National Institute of Agricultural Technology (INTA). The complete information may be consulted at:  1. - Experimental Station of Corrientes. INTA. (C.C. 57 -3400- Corrientes)2. - Instituto Correntino del Agua (Water Institute of Corrientes)(San Martín 2250 -3400- Corrientes)3. - Federal Council of Investments(San Martín 871 -5o piso- 1004 - Buenos Aires)4. - College of Agronomy Sciences (National University of North-East) (Sargento Cabral 2139 -3400- Corrientes)El objetivo principal de este trabajo es el inventario y evaluación de los récursos suelos y vegetación del área de influencia de la Presa de Yacyretá, a nivel de semidetalle, escala 1:50.000, en una superficie de 840.000 ha. El área recorre de sur a norte más de 30 km, cuyos puntos extremos se encuentran a los 27°15' y 28° de latitud sur.y de este a oeste 300 km (55°55' de longitud oeste del meridiano de Greenwich). Se obtuvieron Cartas de Suelos, de aptitud potencial para riego y de geomorfología, escala 1:50.000. Mapas temáticos a escala 1:200.000; de vegetación; regiones de suelos; uso actual de la tierra; capacidad de uso; aptitud de las tierras para cultivos anuales y perennes; grandes grupos de suelos y de aluminio intercambiable. La Memoria contiene los resultados relacionados a las cartas y mapas citados anteriormente, distribuidos en 6 tomos, compuestos de 12 volúmenes, a saber:Tomo I -Antecedentes, climas y suelos (4 volúmenes)Tomo II -Vegetación (2 volúmenes)Tomo III -Productividad de los suelos (1 volumen)Tomo IV -Geomorfología e hidrología de 100.000 ha (1 volumen)Tomo V -Aptitud para riego de 100.000 ha (1 volumen)Tomo VI -Cartas de suelos y mapas temáticos (3 volúmenes) El trabajo es el resultado de la firma de un convenio entre el Gobierno Provincial y el Consejo Federal de Inversiones, en el mes de marzo de 1981, encomendándose la realización del estudio a la Estación Experimental del INTA - Corrientes, a través del Dpto. de Recursos Naturales. Esta Memoria no fue publicada,por consiguiente la información detallada puede ser consultada en: Biblioteca INTA Corrientes (C.C.57-3400- Corrientes); Facultad de Ciencias Agrarias (UNNE) (Sgto.Cabral 2139 -3400- Corrientes); Instituto Correntino del Agua (Gobierno de la Provincia de Corrientes) (San Martín 2250 -3400- Corrientes) y Consejo Federal de Inversiones (San Martín 871 -5o piso- 1004 - Buenos Aires

Thiamine transporter-2 deficiency: outcome and treatment monitoring

Background: The clinical characteristics distinguishing treatable thiamine transporter-2 deficiency (ThTR2) due to SLC19A3 genetic defects from the other devastating causes of Leigh syndrome are sparse. Methods. We report the clinical follow-up after thiamine and biotin supplementation in four children with ThTR2 deficiency presenting with Leigh and biotin-thiamine-responsive basal ganglia disease phenotypes. We established whole-blood thiamine reference values in 106 non-neurological affected children and monitored thiamine levels in SLC19A3 patients after the initiation of treatment. We compared our results with those of 69 patients with ThTR2 deficiency after a review of the literature. Results: At diagnosis, the patients were aged 1 month to 17 years, and all of them showed signs of acute encephalopathy, generalized dystonia, and brain lesions affecting the dorsal striatum and medial thalami. One patient died of septicemia, while the remaining patients evidenced clinical and radiological improvements shortly after the initiation of thiamine. Upon follow-up, the patients received a combination of thiamine (10-40 mg/kg/day) and biotin (1-2 mg/kg/day) and remained stable with residual dystonia and speech difficulties. After establishing reference values for the different age groups, whole-blood thiamine quantification was a useful method for treatment monitoring. Conclusions: ThTR2 deficiency is a reversible cause of acute dystonia and Leigh encephalopathy in the pediatric years. Brain lesions affecting the dorsal striatum and medial thalami may be useful in the differential diagnosis of other causes of Leigh syndrome. Further studies are needed to validate the therapeutic doses of thiamine and how to monitor them in these patientsAntecedentes: Las características clínicas distintivas del déficit tratable del trasportador de tiamina tipo 2 (ThTR2) debido a defectos genéticos del SLC19A3 de las otras causas devastadores del síndrome de Leigh son escasas. Métodos: Presentamos el seguimiento clínico después de la administración de suplementos de tiamina y biotina a cuatro niños con deficiencia ThTR2 que presentaban fenotipos de biotin-thiamine responsive basal ganglia disease y síndrome de Leigh. Hemos establecido valores de referencia de tiamina en sangre total en 106 niños sin patología neurológica y monitorizamos los niveles de tiamina en pacientes con mutación del SLC19A3 después del inicio del tratamiento. Hemos comparado nuestros resultados con los de 69 pacientes con deficiencia ThTR2 después de una revisión de la literatura. Resultados: Al momento del diagnóstico , los pacientes tenían entre 1 mes a 17 años, y todos ellos mostraron signos medial. Un paciente murió de septicemia, mientras que el resto de pacientes evidenciaron mejoras clínicas y radiológicas poco después del inicio de la tiamina. Al seguimiento, los pacientes recibieron una combinación de tiamina (10–40 mg/kg/día) y biotina (1–2 mg/kg/día) y se mantuvieron estables, aunque con distonía y dificultades del habla residual. Después de establecer valores de referencia para los diferentes grupos de edad, la cuantificación de tiamina en sangre total demuestra ser un método útil para el seguimiento del tratamiento. Conclusiones: La deficiencia ThTR2 es una causa reversible de la distonía aguda y síndrome de Leigh en la edad pediátrica. Las lesiones cerebrales que afectan el cuerpo estriado dorsal y tálamo medial pueden ser útiles en el diagnóstico diferencial de otras causas de síndrome de Leigh. Se necesitan más estudios para validar las dosis de tiamina y la monitorización terapéutica de estos pacientesSupported by Fondo de Investigación Sanitaria Grant PI12/02010 and PI12/02078; Centre for Biomedical Research on Rare Diseases, an initiative of the Instituto de Salud Carlos III, Barcelona, Spain; Agència de Gestio’ d’Ajuts Universitaris i de Recerca-Agaur FI-DGR 2014 (JD Ortigoza-Escobar

Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood

Aim: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations. Method: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts. Results: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T>C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival. Interpretation: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6

Molecular characterization of new FBXL4 mutations in patients with mtDNA depletion syndrome

Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is a rare genetic disorder caused by defects in F-box leucine-rich repeat protein 4 (FBXL4). Although FBXL4 is essential for the bioenergetic homeostasis of the cell, the precise role of the protein remains unknown. In this study, we report two cases of unrelated patients presenting in the neonatal period with hyperlactacidemia and generalized hypotonia. Severe mtDNA depletion was detected in muscle biopsy in both patients. Genetic analysis showed one patient as having in compound heterozygosis a splice site variant c.858+5G>C and a missense variant c.1510T>C (p.Cys504Arg) in FBXL4. The second patient harbored a frameshift novel variant c.851delC (p.Pro284LeufsTer7) in homozygosis. To validate the pathogenicity of these variants, molecular and biochemical analyses were performed using skin-derived fibroblasts. We observed that the mtDNA depletion was less severe in fibroblasts than in muscle. Interestingly, the cells harboring a nonsense variant in homozygosis showed normal mtDNA copy number. Both patient fibroblasts, however, demonstrated reduced mitochondrial transcript quantity leading to diminished steady state levels of respiratory complex subunits, decreased respiratory complex IV (CIV) activity, and finally, low mitochondrial ATP levels. Both patients also revealed citrate synthase deficiency. Genetic complementation assays established that the deficient phenotype was rescued by the canonical version of FBXL4, confirming the pathological nature of the variants. Further analysis of fibroblasts allowed to establish that increased mitochondrial mass, mitochondrial fragmentation, and augmented autophagy are associated with FBXL4 deficiency in cells, but are probably secondary to a primary metabolic defect affecting oxidative phosphorylation

FREEZING OF DONKEY SEMEN (EQUUS ASINUS)

Por muchas décadas, el desarrollo y utilización de la inseminación artificial en loséquidos, especialmente con semen congelado, estuvo restringido, principalmente, porimposiciones de las asociaciones de criadores. Recientemente, las legislaciones de criadoresde équidos en varios países se han tornado más flexibles, permitiendo el registro deproductos oriundos de semen congelado. En el Brasil, frente a ese nuevo cambio, laprincipal asociación de criadores de burros (Associação Brasileira de Criadores de JumentoPêga) revisó sus conceptos y comenzó a permitir la utilización de esta biotecnología.Asimismo, en muchos países, el mayor interés en el asno o burro como semental estárelacionado a la producción de mulares, pues estos animales son deseables en el mediorural, debido a que reúnen las mejores características del burro y del caballo. Los primerostrabajos en congelamiento de semen de asnos utilizaron dilutores a base de yema dehuevo y glicerol, y ampolletas de vidrio como sistema de envase, basados en la metodologíade congelamiento de toros. Sin embargo, pese al tiempo transcurrido, pocas investigacioneshan sido dirigidas a esta especie, en especial a biotecnologías del semen. Enesta revisión de literatura se discuten las principales técnicas de congelamiento de semende équidos y se describen estudios referentes al congelamiento de semen de laespecie asnal.For decades, the development and use of the artificial insemination in the equine, especially with frozen semen, was restricted due to impositions of equine breeders associations that opposed the use of the technique. Recently, these legislations have become more flexible in several countries, allowing the registration of products originating from frozen semen. In Brazil, based on these changes, the main donkey breed association (Brazilian Breeders Association of the Pêga Donkeys) revised their concepts and started to allow the use of this biotechnology. The current interest in many countries for the donkey sire is the production of mules, because their acceptability as these animals inherits suitable characteristics of both donkeys and horses. The first reports on donkey frozen semen used extenders based on egg yolk and glycerol, packed in glass ampoules, and followed the existing methodology for freezing bull semen. However, despite of the elapsed time, few research works have been carried out on this species, especially on semen. This literature review discussed the main techniques of freezing equine semen and describes studies on freezing of sperm of asinine species

The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders

Acord transformatiu CRUE-CSICThis work was supported by an NIHR Professorship (to M.A.K.). M.A.K. has received funding from the Sir Jules Thorn Award for Biomedical Research and Wellcome Trust. B.P.-D. was supported by Instituto de Salud Carlos III, PI 18/01319 and PI21/00248, and has received funding from Beca José Castillejos (CAS14/00328). K.J.P. was supported by an MRC Clinician-Scientist Fellowship (511015) and was supported by the Dystonia Medical Research Foundation and Fight for Sight. S.S.M. has received funding from the Winston Churchill Memorial trust and Cerebral Palsy Alliance.Background and Objective: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. Methods: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria. Results: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia. Conclusions: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Neurological, Psychiatric, and Biochemical Aspects of Thiamine Deficiency in Children and Adults.

Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor for a number of enzymes, mostly with mitochondrial localization. Some thiamine-dependent enzymes are involved in energy metabolism and biosynthesis of nucleic acids whereas others are part of the antioxidant machinery. The brain is highly vulnerable to thiamine deficiency due to its heavy reliance on mitochondrial ATP production. This is more evident during rapid growth (i.e., perinatal periods and children) in which thiamine deficiency is commonly associated with either malnutrition or genetic defects. Thiamine deficiency contributes to a number of conditions spanning from mild neurological and psychiatric symptoms (confusion, reduced memory, and sleep disturbances) to severe encephalopathy, ataxia, congestive heart failure, muscle atrophy, and even death. This review discusses the current knowledge on thiamine deficiency and associated morbidity of neurological and psychiatric disorders, with special emphasis on the pediatric population, as well as the putative beneficial effect of thiamine supplementation in autism spectrum disorder (ASD) and other neurological conditions