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1.
Genet Med ; : 101273, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39306721

RESUMO

PURPOSE: FLVCR1 encodes a solute carrier (SLC) protein implicated in heme, choline, and ethanolamine transport. While Flvcr1-/- mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa. METHODS: We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants. RESULTS: We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (Z-score -2.5 to -10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits including macrocytic anemia and skeletal malformations with Flvcr1-/- mice and DBA. FLVCR1 variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing. CONCLUSION: These data demonstrate a broad FLVCR1-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.

2.
medRxiv ; 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38405817

RESUMO

FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis.

3.
J Matern Fetal Neonatal Med ; 36(1): 2190840, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36927241

RESUMO

OBJECTIVE: Patients with suspected placenta accreta spectrum (PAS) disorder are often referred to specialized medical centers for antepartum management and definitive treatment via cesarean hysterectomy. In 2019, our institution formed the only multidisciplinary team for the management of PAS within two of the largest counties in California. The purpose of this study was to evaluate the effects of the multidisciplinary team on patient volume and surgical outcomes for patients with PAS. METHODS: This was a single center retrospective cohort study, based in the only tertiary referral center within two of the largest counties in California. Patients who underwent cesarean hysterectomy for suspected PAS from January 2014 to April 2021 were included and divided into two groups, based on management by the multidisciplinary team from January 2019 and onward or routine care prior to that time. The outcomes of interest were quantitative blood loss, total units of packed red blood cell transfusion, referral volume, and diagnostic accuracy as well as ICU admission, bladder injury, and postoperative length of stay. Furthermore, we wanted to determine if patient's distance to the hospital impacted outcomes. Normally distributed variables were compared between groups using the t-test. Categorical variables were compared between the two groups using the chi square test. RESULTS: A total of 114 patients were included in the cohort, 59 patients were from January 2014 to December 2018 and 55 patients were from January 2019 to April 2021. Since the establishment of the multidisciplinary center, there was a 2.5-fold increase in the total patient volume (0.8 case/month to 2 cases/month) and a 2.8-fold increase in the referred patient volume. Patients undergoing cesarean hysterectomy since the establishment of the multidisciplinary team had less quantitative blood loss (1500 mL vs 2000 mL, p = .005) and required less units of packed red blood cell transfusion (2 vs 4 units, p < .001). In addition, blood loss of ≥2000 mL decreased from 57.6% to 38.2% (p = .04) and diagnostic accuracy improved from 35.6% to 83.6% (p < .001). Furthermore, we found that patient distance to the hospital did not significantly impact surgical outcomes. CONCLUSIONS: Since the establishment of the multidisciplinary team, our center experienced an increase in PAS volume and was able to demonstrate a statistically significant improvement in patient outcomes.


Assuntos
Placenta Acreta , Feminino , Gravidez , Humanos , Estudos Retrospectivos , Placenta Acreta/diagnóstico , Placenta Acreta/cirurgia , Transfusão de Eritrócitos , Centros de Atenção Terciária , Equipe de Assistência ao Paciente
4.
Skinmed ; 20(6): 450-451, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36537680

RESUMO

Calciphylaxis is a rare disease that typically presents in patients with end-stage renal disease and can be a diagnostic challenge. Calcium deposition with fibrin thrombi and necrosis of the overlying epidermis may support the diagnosis; however, depending on the stage of the disease, skin biopsy can have low sensitivity and specificity, and may be contraindicated in some situations. We discuss the utility of imaging studies in supporting the diagnosis of calciphylaxis. (SKINmed. 2022;20:450-451).


Assuntos
Calcinose , Calciofilaxia , Falência Renal Crônica , Humanos , Calciofilaxia/patologia , Pele/patologia , Biópsia/métodos
5.
Head Neck ; 41(3): 666-671, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30584672

RESUMO

BACKGROUND: The purpose of this study was to evaluate our surgical experience in patients with primary hyperparathyroidism (PHPT) with nonlocalizing sestimibi and ultrasound scans. METHODS: A retrospective review of 521 patients treated from April 2005 to July 2017 at Loma Linda University Medical Center who received parathyroidectomy for PHPT. One hundred forty-seven patients (28%) had double negative localization (nonlocalizing sestamibi and ultrasound). RESULTS: Surgical cure for PHPT was 97.3% and 99.2% with nonlocalized and localized disease, respectively, and complication rates were similar between groups. Preoperative parathyroid hormone and gland weight were significantly lower with nonlocalization. The incidence of multigland disease (MGD) was greater in patients with nonlocalization on sestamibi and ultrasound. CONCLUSION: Nonlocalization of parathyroid glands was not associated with decreased cure rate or increased morbidity. The presence of MGD and requirement for more extensive surgery were greater in patients with nonlocalizing disease.


Assuntos
Hiperparatireoidismo Primário/diagnóstico por imagem , Hiperparatireoidismo Primário/cirurgia , Paratireoidectomia , Idoso , Cálcio/sangue , Feminino , Humanos , Hiperparatireoidismo Primário/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Cintilografia , Estudos Retrospectivos , Tecnécio Tc 99m Sestamibi , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ultrassonografia
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