Case Report of Pediatric HPCA-Associated Dystonia: Analysis of Ca and K Channel Dynamics and Experience With Pallidal Deep Brain Stimulation.

Background: Biallelic pathogenic variants in the HPCA gene cause HPCA-associated dystonia (DYT-HPCA), a rare autosomal recessive disorder characterized by generalized dystonia and complex motor symptoms. HPCA encodes hippocalcin, a Ca sensor that modulates neuronal activity through K channel activation. Here, we describe the clinical and molecular features of two children with novel HPCA variants and assess the impact of deep brain stimulation (DBS) (globus pallidus internus [Gpi]-DBS) on their movement disorders.

Recessive Loss of PI4K2A Function Causes a Developmental and Epileptic Dyskinetic Encephalopathy with Prominent Orolingual Dyskinesia.

Background: Biallelic loss-of-function variants in PI4K2A have been associated with a neurodevelopmental disorder characterized by seizures and movement disorders, including orofacial dyskinesia. However, only 4 cases have been reported. Orolingual dyskinesia-defined as involuntary movements of the mouth and tongue-is observed in various pediatric neurodevelopmental disorders (NDD) but remains under-recognized.

Molecular and clinical spectrum of epilepsy-dyskinesia syndromes: a cross-sectional study of 609 patients.

Epilepsy-dyskinesia syndromes (EDS) are a complex group of neurogenetic disorders characterized by the co-occurrence of epilepsy and movement disorders. Despite their increasing clinical recognition, the molecular and clinical spectrum of EDS remain poorly understood. While numerous genetic etiologies have been implicated, systematic characterization across diverse populations is lacking.

Neuronal oscillatory imbalances in GNAO1-related disorders associated with disease severity.

Objective: This study investigates excitatory/inhibitory (E/I) imbalances in GNAO1-related disorders (GNAO1-RD), linking neuronal dysfunction to clinical severity using E/I-sensitive electroencephalography (EEG) analyses.

Methods: We conducted an observational study involving 12 children with GNAO1-RD caused by pathogenic variants and 36 age-matched, typically developing children (TDC). EEG was recorded during eyes-closed rest.

Caregivers' Perspectives and Decision-Making on Deep Brain Stimulation in GNAO1-Related Disorders.

Objectives: Deep brain stimulation (DBS) is an advanced treatment for individuals with GNAO1-related disorders (GNAO1-RD), which are characterized by severe movement abnormalities such as status dystonicus and dyskinetic crises. Decision-making surrounding DBS is complex and influenced by medical, emotional, and logistical factors. This study aimed to explore caregiver perspectives on the decision-making process, including influencing factors and family experiences.

Novel CYFIP2 Frameshift Variant Linked to Dyskinetic Crises: Functional Studies Show Impaired Cell Motility.

CYFIP2, essential for actin cytoskeleton regulation, is implicated in early-onset developmental and epileptic encephalopathy (DEE) with neurodevelopmental impairments and variable movement disorders, including occasional dyskinetic crises. We report a novel CYFIP2 frameshift variant (c.281_282insA/p.

Respiratory and other organ manifestations in -related disorders: a systematic review.

Background: -related disorders (-RD) encompass a spectrum of conditions arising from pathogenic deletions or variants in the gene, crucial for thyroid, lung, and brain development. Respiratory manifestations in -RD range from neonatal respiratory distress to severe lung diseases, constituting a leading cause of mortality. This study will review and synthesize NKX2-1-RD respiratory phenotypes, genetic alterations, and long-term trajectories.

Pathogenic variants in Cause a Spectrum of Neurodevelopmental and Neurodegenerative Disorders with Lysosomal Dysfunction.

encodes a subunit of the BLOC-one-related complex (BORC), which is known to mediate the kinesin-dependent anterograde movement of lysosomes. Using whole-exome sequencing, we identified 12 cases from seven families carrying bi-allelic variants, including four loss-of-function and two missense variants. Carriers of homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy.

Exploring the Impact of Dyskinetic Crises in GNAO1-Related Disorders: A Survey for Parents and Caregivers.

Background: GNAO1-related disorders (GNAO1-RD) encompass developmental delay, epilepsy and movement disorders, including dyskinetic crises.

Objectives: To explore the characteristics of dyskinetic crises in GNAO1-RD, their impact and the challenges parents face.

Methods: A cross-sectional EU survey of 26 parents of children with GNAO1-RD collected demographic, clinical, and management-related data.

MBOAT7 encephalopathy: Characterizing the neurology and epileptology.

Objective: Biallelic pathogenic MBOAT7 variants are associated with neurodevelopmental disorders, intellectual disability (ID), epilepsy, and neuropsychiatric disorders such as attention-deficit/hyperactivity disorder and autism spectrum disorders. We aimed to characterize the epilepsy phenotype in a cohort of patients affected by this syndrome.

Methods: We describe epilepsy features, electroencephalography, magnetic resonance imaging (MRI) findings, antiseizure treatment response, and neurodevelopment of 15 patients with biallelic MBOAT7 variants.

A proposal to involve people living with rare and complex conditions in the development of clinical practice guidelines.

Objective: Develop a proposal to involve people living with rare and complex conditions in the development of clinical practice guidelines (CPGs) based on a systematic review of qualitative literature.

Methods: A systematic review was conducted using medical subject heading-term and text-word search strategies to identify qualitative literature on patient living with rare diseases (PLWRD) involvement during CPG development and in research studies. Databases were searched for literature in English or Spanish, published until April 2024.

Dystonia caused by ANO3 variants is due to attenuated Ca influx by ORAI1.

Background: Dystonia is a common neurological hyperkinetic movement disorder that can be caused by mutations in anoctamin 3 (ANO3, TMEM16C), a phospholipid scramblase and ion channel. We previously reported patients that were heterozygous for the ANO3 variants S651N, V561L, A599D and S651N, which cause dystonia by unknown mechanisms.

Methods: We applied electrophysiology, Ca measurements and cell biological methods to analyze the molecular mechanisms that lead to aberrant intracellular Ca signals and defective activation of K channels in patients heterozygous for the ANO3 variants.

Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature.

Background And Objectives: Developmental and epileptic encephalopathy 56 (DEE-56) is caused by pathogenic variants in YWHAG and is characterized by early-onset epilepsy and neurodevelopmental delay. This study reports on a cohort of DEE-56 individuals, correlating antiseizure medication usage and comorbidities, to aid in understanding disease evolution.

Methods: We analyzed data from thirty-nine individuals aged 3-40 years with YWHAG variants, including 12 previously unreported individuals (2 of these with recurrent distal 7q11.

Improving paediatric movement disorders care: Insights on rating scales utilization and clinical practice.

Aim: 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.

Methods: 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.

Insights from European Reference Network for rare neurological disorders study surveys on diagnosis, treatment, and management of NKX2-1-related disorders.

Background: NKX2-1-related disorder (NKX2-1-RD) is a rare disease characterized by a triad of primary hypothyroidism, neonatal respiratory distress, and neurological features, including chorea.

Objective: This study aimed to identify discrepancies in the management of NKX2-1-RD among European Union (EU) specialists.

Methods: The ERN-RND Chorea & Huntington disease group designed a survey to conduct a cross-sectional multicenter study on the management of NKX2-1-RD.

Clinical and Molecular Profiling in GNAO1 Permits Phenotype-Genotype Correlation.

Background: Defects in GNAO1, the gene encoding the major neuronal G-protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain the different phenotypes.

Objectives: We aimed to analyze the clinical phenotype and the molecular characterization of GNAO1-related disorders.

Status epilepticus in POLG disease: a large multinational study.

We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed.