Background GNAO1 -related disorders ( GNAO1 -RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden ...and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1 -RD. Objectives This study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies. Methods A Delphi consensus process was conducted involving international experts in GNAO1 -RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise. Results Consensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis. Conclusion This consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1 -RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1 -RD research.
Genetic studies have established a connection between FAT1 (FAT atypical cadherin 1) deletion and variants and autism spectrum disorder (ASD). Here, we describe a 7‐year‐old girl who sought a ...neurology consultation in order to be evaluated for ASD and was found to have a de novo 4q35.2 duplication containing the FAT1 gene. Similar to other reported cases of FAT1 variants or deletion, this patient exhibits non‐syndromic ASD without facial dysmorphism or brain MRI abnormalities. We suggest also considering FAT1 duplication as a potential ASD cause.
FAT1 (FAT atypical cadherin 1, OMIM*600976) is a gene that encodes a member of a small family of cadherin‐like proteins that are involved in cell–cell adhesion as well as polarity. We report a 7‐year‐old girl with autism spectrum disorder and a de novo 4q35.2 duplication that includes the FAT1 gene.
To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations.
A multi-gene panel of childhood-onset basal ganglia ...neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts.
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.
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.
The authors describe a 5-year-old girl who developed a Noonan syndrome-like disorder as a result of the CBL c.1194C>G/p.His398Gln variant, including headache, papilledema, intracranial hypertension, ...hyperproteinorrhachia, leucorrhachia, and brain inflammation and vasculitis with CD3 positive lymphocyte infiltration. The patient responded partially to corticosteroids, acetazolamide, and ventriculoperitoneal valve placement. The serum cytokine profile revealed persistently elevated levels of IL-1 RA, IL-2R alpha, IL-6, IL-18, MCP-1, and MCP-3. Cyclophosphamide was used as a bridge to allogeneic hematopoietic stem cell transplantation in this case.
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.
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).
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
B vitamins act as cofactors for strategic metabolic processes. The SLC19 gene family of solute carriers has a significant structural similarity, transporting substrates with different structure and ...ionic charge. Three proteins of this family are expressed ubiquitously and mediate the transport of two important water-soluble vitamins, folate and thiamine. SLC19A1 transports folate and SLC19A2 and SLC19A3 transports thiamine. PCFT and FOLR1 ensure intestinal absorption and transport of folate through the blood brain barrier and SLC19A25 transports thiamine into the mitochondria. Several damaging genetic defects in vitamin B transport and metabolism have been reported. The most relevant feature of thiamine and folate transport defects is that both of them are treatable disorders. In this review we discuss the biology and transport of thiamine and folate, as well as the clinical phenotype of the genetic defects.
This exploratory study evaluates rating scale usage by experts from the European Reference Network for Rare Neurological Diseases (ERN-RND) for paediatric MD, considering factors like diagnosis, ...intellectual disability, age, and transition to adult care. The aim is to propose a preliminary framework for consistent application.
A multicentre survey among 25 ERN-RND experts from 10 European countries examined rating scale usage in paediatric MD, categorizing MD into acute, non-progressive, and neurodegenerative types. Factors influencing scale choice and the transition to adult care practices were analysed. A comprehensive literature search was conducted to identify the earliest age of application of these scales in paediatric patients.
The study identifies various rating scales and establishes their usage frequencies for different MDs. Experts highlighted the need for standardized scales and proposed preliminary evaluation strategies based on clinical contexts. Challenges in applying scales to young, non-cooperative patients were acknowledged.
The study recommends developing standardized rating scales for paediatric MDs to improve evaluations and data collection. It suggests potential scales for specific clinical scenarios to better evaluate disease progression. Comprehensive, patient-centred care remains crucial during the transition to adult care, despite the identified challenges. This exploratory approach aims to enhance patient outcomes and care.
•Application of rating scales for movement disorders should be standardized in children.•Neurodevelopment, quality of life, and cognitive function should also be assessed.•Age, intellectual disability, multiple movement disorders, and genetic diagnoses influence the assessment.•Rating scales are crucial as a quality indicator of the paediatric-adult care transition.
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
...(encoding Ca
2.1 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 Ca
2.1 function due to aberrant
-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp,
-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
channelopathies show similarities. Hypoglycosylation of both Ca
2.1 subunits (α
and α
) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic
mutations linked to FHM and ataxia. Unoccupied
-glycosylation site N283 at α
contributes to a gain-of-function by lessening Ca
2.1 inactivation. Hypoglycosylation of the α₂δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the Ca
2.1 channel. Ca
2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant Ca
2.1
-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.
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