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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.

Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients' group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α₂δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities. This work was supported by national grant PI14/00021 and PI17/00101 from the National Plan on I+D+I, cofinanced by ISC-III (Subdirección General de Evaluación y Fomento de la Investigación Sanitaria), the Spanish Ministry of Economy and Competitiveness (Grants IPT-2012-0561-010000, SAF2015-69762-R, MDM-2014-0370 through the “María de Maeztu” Programme for Units of Excellence in R&D to “Departament de Ciències Experimentals i de la Salut”), FEDER (Fondo Europeo de Desarrollo Regional), and the Migraine Research Foundation (New York, USA). Mercè Izquierdo-Serra holds a “Juan de la Cierva-Formación” Fellowship funded by the Spanish Ministry of Economy and Competitiveness.

[spa] La tiamina o vitamina B1 es un cofactor involucrado en el metabolismo energético y en la síntesis de ácidos nucleicos, antioxidantes, lípidos y neurotransmisores. Se han reconocido fenotipos clínicos bien definidos en los siguientes defectos del transporte y metabolismo de la tiamina: 1) SLC19A2, (transportador de tiamina-1); 2) SLC19A3 (transportador de tiamina-2); 3) TPK1 (tiamina pirofosfoquinasa) y 4) SLC25A19 (transportador mitocondrial de tiamina pirofosfato). Las deficiencias primarias y secundarias de tiamina tienen características superponibles en pediatría, incluyendo episodios agudos de encefalopatía, lesiones cerebrales particulares y un aumento de la excreción de ácidos orgánicos específicos de las enzimas mitocondriales dependientes de tiamina, principalmente lactato, alfa-cetoglutarato y cetoácidos de cadena ramificada. Las deficiencias de tiamina no diagnosticadas y no tratadas son a menudo fatales o conducen a secuelas graves. Por lo tanto, la suplementación de tiamina tiene un fuerte impacto en el pronóstico de los pacientes con deficiencia de SLC19A3, conduciendo a la estabilidad metabólica, la reducción de la discapacidad de estos niños y la supervivencia mejorada en comparación con los pacientes no tratados. La suplementación con tiamina restaura los niveles intracelulares y en LCR, probablemente a través del transporte alternativo de la vitamina. Este trabajo demuestra que la cuantificación de tiamina por el método de HPLC en muestras de sangre entera es un método útil para la evaluación de la adherencia al tratamiento de estos pacientes y más significativamente, que el déficit de tiamina-libre en LCR puede emplearse como método diagnóstico de pacientes con déficit de SLC19A3. Esta tesis describe la historia natural de 79 pacientes con defectos heredados en el transporte de la tiamina y el metabolismo, la mayor cohorte de pacientes con estos defectos genéticos publicados hasta la fecha. Se han identificado de mal factores pronóstico incluyendo niños con lesiones cerebrales difusas al debut, sobretodo si existe compromiso del tronco cerebral y los núcleos pálidos. En esta tesis, también se presentan criterios diagnósticos para defectos heredados de tiamina que ayudan a diferenciarlos de deficiencias secundarias., [eng] Thiamine or vitamin B1 is a critical cofactor involved in energy metabolism and in the synthesis of nucleic acids, antioxidants, lipids, and neurotransmitters. Well-defined clinical phenotypes have been recognized in the following thiamine defects: 1) SLC19A2 (thiamine transporter-1); 2) SLC19A3 (thiamine transporter-2); 3) TPK1 (thiamine pyrophosphokinase) and 4) SLC25A19 (mitochondrial thiamine pyrophosphate carrier). Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Therefore, thiamine supplementation has a strong impact on the prognosis of SLC19A3-deficient patients, leading to metabolic stability, reduced disability and improved survival compared to untreated patients. Thiamine supplementation restores intracellular and CSF levels, probably through alternative transport of the vitamin. This work also demonstrates that the quantification of thiamine by the HPLC method in whole blood samples is a useful method for evaluating the adherence to treatment of these patients and more significantly, that decreased free-thiamine in CSF can be used as a diagnostic method for SLC19A3-deficient patients. This thesis describes the natural history of 79 patients with inherited defects in thiamine transport and metabolism. This study indicates a better prognosis than other causes of LS, encouraging clinicians to suspect the disease and to make an early diagnosis and accurately prescribe treatment. This thesis also contributes with diagnostic criteria for inherited thiamine defects and helps differentiate them from secondary causes of thiamine deficiency.