RESUMO
A distinct subset of acute myeloid leukemia (AML) is characterized by the presence of the Philadelphia chromosome (Ph+), due to reciprocal translocation t(9;22)(q34;q11.2). This chromosomal rearrangement leads to the fusion of the breakpoint cluster region (BCR) gene on chromosome 22 with the ABL1 gene on chromosome 9, generating the BCR::ABL1 fusion gene. The Ph+ AML subtype is associated with poor prognosis and resistance to conventional chemotherapy. Beyond the well-established BCR::ABL1 fusion, recent studies have shed light on additional genetic abnormalities in Ph+ AML, including associations with rearrangements involving core binding factor beta (CBFB). We describe a case of de novo AML with concurrent BCR::ABL1 and CBFB::MYH11 rearrangements.
RESUMO
BACKGROUND AND AIMS: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations to the CF transmembrane conductance regulator (CFTR). Symptoms and severity of the disease can be quite variable suggesting modifier genes play an important role. MATERIALS AND METHODS: Exome sequencing was performed on six individuals carrying homozygous deltaF508 for CFTR genotype but present with rapidly progressing CF (RPCF). Data was analyzed using an unbiased genome-wide genetic burden test against 3076 controls. Single cell RNA sequencing data from LungMAP was utilized to evaluate unique and co-expression of candidate genes, and structural modeling to evaluate the deleterious effects of identified candidate variants. RESULTS: We have identified solute carrier family 26 member 9 (SLC26A9) as a modifier gene to be associated with RPCF. Two rare missense SLC26A9 variants were discovered in three of six individuals deemed to have RPCF: c.229G > A; p.G77S (present in two patients), and c.1885C > T; p.P629S. Co-expression of SLC26A9 and CFTR mRNA is limited across different lung cell types, with the highest level of co-expression seen in human (6.3 %) and mouse (9.0 %) alveolar type 2 (AT2) cells. Structural modeling suggests deleterious effects of these mutations as they are in critical protein domains which might affect the anion transport capability of SLC26A9. CONCLUSION: The enrichment of rare and potentially deleterious SLC26A9 mutations in patients with RPCF suggests SLC26A9 may act as an alternative anion transporter in CF and is a modifier gene associated with this lung phenotype.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Homozigoto , Mutação , Transportadores de Sulfato , Humanos , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/química , Transportadores de Sulfato/genética , Transportadores de Sulfato/química , Transportadores de Sulfato/metabolismo , Feminino , Masculino , Antiporters/genética , Antiporters/química , Animais , CamundongosRESUMO
Children with developmental and epileptic encephalopathies often present with co-occurring dyskinesias. Pathogenic variants in ARX cause a pleomorphic syndrome that includes infantile epilepsy with a variety of movement disorders ranging from focal hand dystonia to generalized dystonia with frequent status dystonicus. In this report, we present three patients with severe movement disorders as part of ARX-associated epilepsy-dyskinesia syndrome, including a patient with a novel pathogenic missense variant (p.R371G). These cases illustrate diagnostic and management challenges of ARX-related disorder and shed light on broader challenges concerning epilepsy-dyskinesia syndromes.
Assuntos
Proteínas de Homeodomínio , Transtornos dos Movimentos , Fatores de Transcrição , Humanos , Masculino , Feminino , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/etiologia , Pré-Escolar , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Lactente , Mutação de Sentido Incorreto , CriançaRESUMO
Status dystonicus is the most severe form of dystonia with life-threatening complications if not treated promptly. We present consensus recommendations for the initial management of acutely worsening dystonia (including pre-status dystonicus and status dystonicus), as well as refractory status dystonicus in children. This guideline provides a stepwise approach to assessment, triage, interdisciplinary treatment, and monitoring of status dystonicus. The clinical pathways aim to: (1) facilitate timely recognition/triage of worsening dystonia, (2) standardize supportive and dystonia-directed therapies, (3) provide structure for interdisciplinary cooperation, (4) integrate advances in genomics and neuromodulation, (5) enable multicenter quality improvement and research, and (6) improve outcomes. © 2024 International Parkinson and Movement Disorder Society.