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IntroductionFriedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2 in vitro and in vivo, and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients.MethodsThe aim of our study is to investigate if DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23.EndpointsThe primary endpoint will be a change in FXN gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level, cardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales.ConclusionsThis is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration in-vivo.

A 50-year-old man was admitted to our hospital for vomit, nausea, diplopia, and headache resistant to analgesic drugs. Symptoms started the day after his third COVID-19 mRNA vaccine (Moderna) whereas SARS-CoV-2 nasal swab was negative. Pituitary MRI showed recent bleeding in macroadenoma, consistent with pituitary apoplexy. Adverse Drug Reaction was reported to AIFA (Italian Medicines Agency).A stress dexamethasone dose was administered due to the risk of adrenal insufficiency and to reduce oedema. Biochemistry showed secondary hypogonadism; inflammatory markers were elevated as well as white blood cells count, fibrinogen and D-dimer. Pituitary tumour transsphenoidal resection was performed and pathology report was consistent with pituitary adenoma with focal haemorrhage and necrosis; we found immunohistochemical evidence for SARS-CoV-2 proteins next to pituitary capillaries, in the presence of an evident lymphocyte infiltrate.Few cases of pituitary apoplexy after COVID-19 vaccination and infection have been reported. Several hypotheses have been suggested to explain this clinical picture, including cross-reactivity between SARS-CoV-2 and pituitary proteins, COVID-19-associated coagulopathy, infection-driven acutely increased pituitary blood demand, anti-Platelet Factor 4/heparin antibodies development after vaccine administration. Ours is the first case of SARS-CoV-2 evidence in pituitary tissue, suggesting that endothelial infection of pituitary capillaries could be present before vaccination, possibly due to a previous asymptomatic SARS-CoV-2 infection. Our case underlines that SARS-CoV-2 can associate with apoplexy by penetrating the central nervous system, even in cases of negative nasal swab. Patients with pituitary tumours may develop pituitary apoplexy after exposure to SARS-CoV-2, therefore clinicians should be aware of this risk.

In the staging of cancer patients, transient and spontaneously reversible bilateral adrenal hypertrophy may mimic a secondary localization of the disease. We discuss the case of an 82-year-old male patient with suspected testicular neoplasia in which abdominal CT examination reveals the onset of a bilateral macronodular adrenal enlargement, suggesting the diagnostic hypothesis of primary testicular neoplasia with secondary adrenal localization. The subsequent 18FDG-PET/CT study showed hyper-metabolism of the testicular mass, while the adrenal glands, surprisingly, did not show increased uptake of the radiotracer. After right orchifunicolectomy, primary testicular diffuse large B-cell lymphoma was diagnosed. The subsequent staging PET/CT study with iodine contrast medium, three months after the first CT examination, showed spontaneous complete regression of the adrenal hypertrophy without any use of drug therapy. The differential diagnosis of this finding considered the lack of hypermetabolism and the densitometric characteristics of the adrenal glands, the absence of possible pharmacological interactions throughout the time of the diagnostic procedures, and the available clinical-laboratory data. By excluding the main causes of adrenal hypertrophy, the most likely diagnostic hypothesis was transient adrenal hypertrophy due to stress induced by testicular lymphoma, meaning by stress a disturbance not only emotional but also an alteration of organic homeostasis. Our case suggests that the analysis of adrenal lesions appeared in cancer patients should take into account non-metastatic conditions that must be studied with a multimodal approach and with serial investigations.