HepG2 PMM2-CDG knockout model: A versatile platform for variant and therapeutic evaluation.

Phosphomannomutase 2 deficiency (PMM2-CDG), the most frequent congenital disorder of glycosylation, is an autosomal recessive disease caused by biallelic pathogenic variants in the PMM2 gene. There is no cure for this multisystemic syndrome. Some of the therapeutic approaches that are currently in development include mannose-1-phosphate replacement therapy, drug repurposing, and the use of small chemical molecules to correct folding defects. Preclinical models are needed to evaluate the efficacy of treatments to overcome the high lethality of the available animal model. In addition, the number of variants with unknown significance is increasing in clinical settings. This study presents the generation of a cellular disease model by knocking out the PMM2 gene in the hepatoma HepG2 cell line using CRISPR-Cas9 gene editing. The HepG2 knockout model accurately replicates the PMM2-CDG phenotype, exhibiting a complete absence of PMM2 protein and mRNA, a 90% decrease in PMM enzymatic activity, and altered ICAM-1, LAMP1 and A1AT glycoprotein patterns. The evaluation of PMM2 disease-causing variants validates the model's utility for studying new PMM2 clinical variants, providing insights for diagnosis and potentially for evaluating therapies. A CRISPR-Cas9-generated HepG2 knockout model accurately recapitulates the PMM2-CDG phenotype, providing a valuable tool for assessing disease-causing variants and advancing therapeutic strategies.

Neurolymphomatosis as primary presentation of extra-nodal NK/T-cell lymphoma, nasal type.

Neurolymphomatosis (NL) describes an infiltration of cranial and peripheral nerves by lymphoma cells, most frequently in non-Hodgkin B-cell lymphoma. This clinical entity is rare and poses a challenging diagnosis. We describe a case of a 64-year-old female patient with NL associated with extra-nodal NK/T-cell lymphoma (ENKTL), nasal type, presenting as a painful progressive mononeuropathy multiplex with an oral cavity lesion. ENKTL is usually associated with Epstein-Barr virus (EBV) infection and rarely affects the central and peripheral nervous system. Lumbar puncture, magnetic resonance imaging (MRI), nerve biopsy, and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) help to establish the diagnosis. Thereby, NL should be considered in the differential diagnosis of painful progressive multiple neuropathies, even in patients without previous history of cancer.

No reason to smile: giant internal carotid artery aneurysm.

Giant cerebral aneurysms account for approximately 5% of all intracranial aneurysms, affecting morecommonly women in the 5th to 7th decade. When untreated, giant intracranial aneurysms face a poor prognosis withan estimated 2-year mortality of 68%. We present the case of an 82-year-old woman admitted at the emergencydepartment due to two focal to bilateral tonic-clonic seizures with a giant aneurysm of the supraclinoid segment ofthe right internal carotid artery on the CT scan. We discuss different management approaches for giant internalcarotid artery aneurysms, including direct surgical clipping, reconstructive endovascular procedures (coiling, balloon-/stent-assisted coiling, and flow diversion), deconstructive endovascular techniques (parent artery occlusion), andconservative management.

Post-COVID-19 neurocandidiasis.

Associated with a significant morbidity and mortality, neurocandidiasis affects severely immunocompromised patients, especially if recently treated with antibiotics or corticosteroids. We present the case of a 70-year-old man admitted to an intensive care unit due to a Sars-Cov-2 pneumonia, with fever, coma, and multifocal neurological deficits reported 13 days after extubation. After isolation of Candida albicans in both urine and blood cultures and a brain MRI with multiple gadolinium-enhanced ring lesions, a diagnosis of neurocandidiasis was assumed and aggressive antifungal therapy started. During treatment, the patient developed a hospital-acquired pneumonia with fatal outcome.

[A Potentially Fatal Aphrodisiac: Cantharidin Poisoning]. / Um Afrodisíaco Potencialmente Fatal: Intoxicação por Cantaridina.

Cantharidin is a toxin extracted from coleoptera beetles, commonly known as 'Spanish fly'. Traditionally it was used as an aphrodisiac, a vesicant or as an abortifacient. Intoxication by this substance has been widely reported, generally associated with gastrointestinal complications, such as digestive hemorrhage, and genitourinary disorders, such as hematuria and acute kidney injury. The authors describe the case of a 51-year old male patient who developed severe cantharidin poisoning after ingesting a preparation ('tea formulation') containing the substance. The patient reported a burning sensation in his oral cavity, diarrhea and hematuria, having sustained acute kidney injury and atypical neurological symptoms. Due to the lack of an antidote, the available treatment options are reduced to supportive measures. This case strengthens the need for a thorough medical history to ascertain the use of 'natural' products and medicinal herbs (i.e. of unregulated origin), and the importance of educating the community to their potential toxicity.

A cantaridina é uma toxina extraída de coleópteros, comummente conhecidos como 'Spanish fly'. Historicamente utilizada como afrodisíaco, vesicante e abortivo. A intoxicação por este agente encontra-se amplamente descrita, tipicamente com envolvimento das mucosas gastrointestinal, com hemorragia digestiva, e genitourinária, com hematúria e lesão renal aguda. Os autores apresentam o caso de um doente do sexo masculino, com 51 anos que desenvolveu um quadro de intoxicação aguda por cantaridina, após ingestão de uma preparação ('chá') desta substância, com ardor na cavidade oral, diarreia, disúria, hematúria, lesão renal aguda e com um quadro neurológico atípico. A toxicidade pela cantaridina é sistémica, contudo, o envolvimento neurológico é raro. Dada ausência de um antídoto, preconiza-se a terapêutica de suporte. Este caso reforça a importância de uma anamnese detalhada, incluindo a utilização de produtos 'naturais' ou de ervanária (i.e. de origem não controlada), e da necessidade de alertar os doentes para a sua potencial toxicidade.

Myasthenia Gravis Induced by Ipilimumab in a Patient With Metastatic Melanoma.

In daily clinical practice, there is a growing number of patients receiving new biological agents used in the treatment of malignancies. Ipilimumab is a fully humanized monoclonal antibody approved for patients with melanoma. It acts as an immune checkpoint inhibitor, binding and blocking cytotoxic T-lymphocyte antigen-4 in order to increase the antitumor immune response. There are several reports of autoimmune responses after its use. A 74-year-old man developed a mild rash and pruritus a few hours after the second infusion of ipilimumab and 24 h after the third dose of ipilimumab, he presented with shortness of breath, proximal limb muscle weakness, and diplopia. Repetitive nerve stimulation was consistent with a postsynaptic neuromuscular junction disorder. He began therapy with corticosteroids and pyridostigmine and ipilimumab was discontinued. Following ipilimumab suspension, the patient started to improve gradually. Here, we describe a rare case of myasthenia gravis presumably related with ipilimumab's therapy. A better knowledge of these agents is necessary, in order to identify characteristics or biomarkers that may be associated with the development of potentially serious autoimmune responses.