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

Clinical rating scale for pantothenate kinase-associated neurodegeneration: A pilot study

Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration.info:eu-repo/semantics/publishedVersio

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival

Estudio de defectos en el transporte y el metabolismo de tiamina asociados a encefalopatías recurrentes en la infancia

[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

Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia

Anoctamin 3 (ANO3) belongs to a family of transmembrane proteins that form phospholipid scramblases and ion channels. A large number of ANO3 variants were identified as the cause of craniocervical dystonia, but the underlying pathogenic mechanisms remain obscure. It was suggested that ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin were also identified as a cause of dystonia. In this study, we conducted a comprehensive evaluation of the clinical, radiological, and molecular characteristics of four individuals from four families who carried heterozygous variants in ANO3. The median age at follow-up was 6.6 years (ranging from 3.8 to 8.7 years). Three individuals presented with hypotonia and motor developmental delay. Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia. Additionally, another patient exhibited early dyskinetic encephalopathy. One patient underwent bipallidal deep brain stimulation (DBS) and showed a mild but noteworthy response, while another patient is currently being considered for DBS treatment. Neuroimaging analysis of brain MRI studies did not reveal any specific abnormalities. The molecular spectrum included two novel ANO3 variants (V561L and S116L) and two previously reported ANO3 variants (A599D and S651N). As anoctamins are suggested to affect intracellular Ca2+ signals, we compared Ca2+ signalling and activation of ion channels in cells expressing wild type ANO3 and cells expressing ANO variants. Novel V561L and S116L variants were compared with previously reported A599D and S651N variants and with wtANO3 expressed in fibroblasts isolated from patients or when overexpressed in HEK293 cells. We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions. Impaired Ca2+ signalling and compromised activation of Ca2+ dependent K+ channels were detected in cells expressing ANO3 variants. In the brain striatal cells of affected patients, impaired activation of KCa3.1 channels due to compromised Ca2+ signals may lead to depolarized membrane voltage and neuronal hyperexcitability and may also lead to reduced cellular viability, as shown in the present study. In conclusion, our study reveals the association between ANO3 variants and paroxysmal dystonia, representing the first reported link between these variants and this specific dystonic phenotype. We demonstrate that ANO3 functions as a Ca2+-activated phospholipid scramblase and ion channel; cells expressing ANO3 variants exhibit impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels. These findings provide a mechanism for the observed clinical manifestations and highlight the importance of ANO3 for neuronal excitability and cellular viability.Sin financiación14.5 Q1 JCR 20224.437 Q1 SJR 2022No data IDR 2022UE

Clinical and molecular spectrum of autosomal recessive CA8-related cerebellar ataxia

Background: Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3).Objectives: We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients.Methods: We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis.Results: Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout.Conclusion: Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Treatment of genetic defects of thiamine transport and metabolism

<p><b>Introduction</b>: Thiamine is a key cofactor for energy metabolism in brain tissue. There are four major genetic defects (<i>SLC19A2, SLC19A3, SLC25A19</i> and <i>TPK1</i>) involved in the metabolism and transport of thiamine through cellular and mitochondrial membranes. Neurological involvement predominates in three of them (<i>SLC19A3, SCL25A19</i> and <i>TPK1</i>), whereas patients with <i>SLC19A2</i> mutations mainly present extra-neurological features (e.g. diabetes mellitus, megaloblastic anaemia and sensori-neural hearing loss). These genetic defects may be amenable to therapeutic intervention with vitamins supplementation and hence, constitutes a main area of research.</p> <p><b>Areas covered</b>: We conducted a literature review of all reported cases with these genetic defects, and focused our paper on treatment efficacy and safety, adverse effects, dosing and treatment monitoring.</p> <p><b>Expert commentary</b>: Doses of thiamine vary according to the genetic defect: for <i>SLC19A2</i>, the usual dose is 25–200 mg/day (1–4 mg/kg per day), for <i>SLC19A3</i>, 10–40 mg/kg per day, and for <i>TPK1</i>, 30 mg/kg per day. Thiamine supplementation in <i>SLC19A3</i>-mutated patients restores CSF and intracellular thiamine levels, resulting in successful clinical benefits. In conclusion, evidence collected so far suggests that the administration of thiamine improves outcome in <i>SLC19A-2, SLC19A3-</i> and <i>TPK1</i>-mutated patients, so most efforts should be aimed at early diagnosis of these disorders.</p

Coexistence of junctional epidermolysis bullosa, autosomal recessive deafness type 57, and Angelman syndrome: A case report

Key Clinical Message The presence of more than one genetic/genomic disorder is not uncommon. It is therefore essential to continuously consider new signs and symptoms over time. Administration of gene therapy could be extremely difficult in particular situations. Abstract A 9‐month‐old boy presented to our department for evaluation of developmental delay. We found that he was affected by intermediate junctional epidermolysis bullosa (COL17A1, c.3766 + 1G > A, homozygous), Angelman syndrome (5,5 Mb deletion of 15q11.2‐q13.1), and autosomal recessive deafness type 57 (PDZD7, c.883C > T, homozygous)

Expanding the phenotypic spectrum of BCS1L-related mitochondrial disease

Publisher Copyright: © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological AssociationObjective: To delineate the full phenotypic spectrum of BCS1L-related disease, provide better understanding of the genotype–phenotype correlations and identify reliable prognostic disease markers. Methods: We performed a retrospective multinational cohort study of previously unpublished patients followed in 15 centres from 10 countries. Patients with confirmed biallelic pathogenic BCS1L variants were considered eligible. Clinical, laboratory, neuroimaging and genetic data were analysed. Patients were stratified into different groups based on the age of disease onset, whether homozygous or compound heterozygous for the c.232A>G (p.Ser78Gly) variant, and those with other pathogenic BCS1L variants. Results: Thirty-three patients were included. We found that growth failure, lactic acidosis, tubulopathy, hepatopathy and early death were more frequent in those with disease onset within the first month of life. In those with onset after 1 month, neurological features including movement disorders and seizures were more frequent. Novel phenotypes, particularly involving movement disorder, were identified in this group. The presence of the c.232A>G (p.Ser78Gly) variant was associated with significantly worse survival and exclusively found in those with disease onset within the first month of life, whilst other pathogenic BCS1L variants were more frequent in those with later symptom onset. Interpretation: The phenotypic spectrum of BCS1L-related disease comprises a continuum of clinical features rather than a set of separate syndromic clinical identities. Age of onset defines BCS1L-related disease clinically and early presentation is associated with poor prognosis. Genotype correlates with phenotype in the presence of the c.232A>G (p.Ser78Gly) variant.Peer reviewe