Neuro-ophthalmological and electrophysiological characterization of mitochondrial diseases.

Aims and methods: 1) characterization of patients with Dominant Optic Atrophy (DOA) associated with mutations in AFG3L2 and ACO2 genes in comparison with classical OPA1-DOA; 2) characterization of patients with mtDNA mutations causing MELAS and MERRF syndromes and correlation with heteroplasmy; 3) longitudinal evaluation of subacute m.11778G>A/MTND4 Leber’s Hereditary Optic Neuropathy (LHON) patients co-treated with rAAV2/2-ND4 gene therapy and idebenone. We performed a comprehensive neuro-ophthalmological assessment coupled with electrophysiological examination. Results: 1) We described and compared 23 ACO2 and 13 AFG3L2 patients with 72 OPA1 patients. All patients presented temporally predominant optic atrophy, with ACO2 showing higher RNFL and GCL thicknesses at OCT, while AFG3L2 was virtually-indistinguishable from OPA1. 2) Retinopathy was the most common manifestation in 17/33 MELAS patients, conversely, optic atrophy was the most common finding in 7/8 MERRF patients. Correlation of heteroplasmy with neuro-ophthalmological parameters failed to disclose any significance in MELAS, while it negatively correlated with OCT parameters in MERRF. 3) We compared modifications in visual acuity, OCT and electrophysiological parameters at 3 timepoints in 9 LHON patients. We observed significant decrease of RNFL thickness and reduction of PhNR amplitude. Visual acuity improved of about -0.37 LogMAR, correlating significantly with time from onset and from injection, but not with idebenone therapy duration. Discussion: 1) ACO2 seems associated to better preservation of retinal ganglion cells, depending on a different pathogenic mechanism involving mtDNA maintenance, as opposed to AFG3L2 which is involved in OPA1 processing. 2) MELAS and MERRF patients presented with a clearly distinct ocular phenotype, possibly reflecting a selective susceptibility of different retinal cell types to global energy defect or oxidative stress. 3) Follow up of LHON patients treated with gene therapy confirmed the deterioration in OCT and electrophysiological parameters, while the amount of visual improvement was similar to the one observed in recent clinical trials.

MR in vivo tractography for the reconstruction of cranial nerves course

Aim The aim of my Ph.D. was to implement a diffusion tensor tractography (DTT) pipeline to reconstruct cranial nerve I (olfactory) to study COVID-19 patients, and anterior optic pathway (AOP, including optic nerve, chiasm, and optic tract) to study patients with sellar/parasellar tumors, and with Leber’s Hereditary Optic Neuropathy (LHON). Methods We recruited 23 patients with olfactory dysfunction after COVID-19 infection (mean age 37±14 years, 12 females); 27 patients with sellar/parasellar tumors displacing the optic chiasm eligible for endonasal endoscopic surgery (mean age 53. ±16.4 years, 13 female) and 6 LHON patients (mutation 11778/MT-ND4, mean age 24.9±15.7 years). Sex- and age-matched healthy control were also recruited. In LHON patients, optical coherence tomography (OCT) was performed. Acquisitions were performed on a clinical high field 3-T MRI scanner, using a multi-shell HARDI (High Angular Resolution Diffusion Imaging) sequence (b-values 0-300-1000-2000 s/mm2, 64 maximum gradient directions, 2mm3 isotropic voxel). DTT was performed with a multi-tissue spherical deconvolution approach and mean diffusivity (MD) DTT metrics were compared with healthy controls using an unpaired t-test. Correlations of DTT metrics with clinical data were sought by regression analysis. Results In all 23 hypo/anosmic patients with previous COVID-19 infection the CN I was successfully reconstructed with no DTT metrics alterations, thus suggesting the pathogenetic role of central olfactory cortical system dysfunction. In all 27 patients with sellar/parasellar tumors the AOP was reconstructed, and in 11/13 (84.7%) undergoing endonasal endoscopic surgery the anatomical fidelity of the reconstruction was confirmed; a significant decrease in MD within the chiasma (p<0.0001) was also found. In LHON patients a reduction of MD in the AOP was significantly associated with OCT parameters (p=0.036). Conclusions Multi-shell HARDI diffusion-weighted MRI followed by multi-tissue spherical deconvolution for the DTT reconstruction of the CN I and AOP has been implemented, and its utility demonstrated in clinical practice.

Characterization and natural history of different phenotypes in hereditary transthyretin amyloidosis: 40-year experience at a single Italian referral center

- Aims: Hereditary Transthyretin Amyloidosis (ATTRv) is one of the leading etiologies of systemic amyloidosis with more than 135 mutations described and a broad spectrum of clinical manifestations. We aimed to provide a systematic description of a population of individuals carrying pathogenic mutations of transthyretin (TTR) gene and to investigate the major clinical events during follow up. - Methods: Observational, retrospective, cohort study including consecutive patients with mutations of TTR gene, admitted to a tertiary referral center in Bologna, Italy, between 1984 and 2022. - Results: Three hundred twenty-five patients were included: 106 asymptomatic carriers, 49 cardiac phenotype, 49 neurological phenotype and 121 mixed phenotype. Twenty-three different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most common. After a median follow-up of 51 months data from 290 subjects were analyzed; among them 111 (38.3%) died and 123 (42.4%) had a major clinical event (death or hospitalization for heart failure). Nine (11.5%) of the 78 asymptomatic carriers showed signs and symptoms of the disease. Carriers had a prognosis comparable to healthy population, while no significant differences were seen among the three phenotypes adjusted by age. Age at diagnosis, NYHA functional class, left ventricular ejection fraction, mPND score and disease-modifying therapy were independently associated with survival. - Conclusions: This study offers a wide and comprehensive overview of ATTRv from the point of view of a tertiary referral center in Italy. Three main phenotypes can be identified (cardiac, neurological and mixed) with specific clinical and instrumental features. Family screening programs are essential to identify paucisymptomatic affected patients or unaffected carriers of the mutation, to be followed through the years. Lastly, disease-modifying therapy represents an evolving cornerstone of the management of ATTRv, with a great impact on mortality.

Newborn Hearing Screening And Early Diagnostic In The Nicu.

The aim was to describe the outcome of neonatal hearing screening (NHS) and audiological diagnosis in neonates in the NICU. The sample was divided into Group I: neonates who underwent NHS in one step and Group II: neonates who underwent a test and retest NHS. NHS procedure was automated auditory brainstem response. NHS was performed in 82.1% of surviving neonates. For GI, referral rate was 18.6% and false-positive was 62.2% (normal hearing in the diagnostic stage). In GII, with retest, referral rate dropped to 4.1% and false-positive to 12.5%. Sensorineural hearing loss was found in 13.2% of infants and conductive in 26.4% of cases. There was one case of auditory neuropathy spectrum (1.9%). Dropout rate in whole process was 21.7% for GI and 24.03% for GII. We concluded that it was not possible to perform universal NHS in the studied sample or, in many cases, to apply it within the first month of life. Retest reduced failure and false-positive rate and did not increase evasion, indicating that it is a recommendable step in NHS programs in the NICU. The incidence of hearing loss was 2.9%, considering sensorineural hearing loss (0.91%), conductive (1.83%) and auditory neuropathy spectrum (0.19%).

Diagnosis, Treatment, And Follow-up Of Medullary Thyroid Carcinoma: Recommendations By The Thyroid Department Of The Brazilian Society Of Endocrinology And Metabolism.

Medullary thyroid carcinoma (MTC) originates in the thyroid parafollicular cells and represents 3-4% of the malignant neoplasms that affect this gland. Approximately 25% of these cases are hereditary due to activating mutations in the REarranged during Transfection (RET) proto-oncogene. The course of MTC is indolent, and survival rates depend on the tumor stage at diagnosis. The present article describes clinical evidence-based guidelines for the diagnosis, treatment, and follow-up of MTC. The aim of the consensus described herein, which was elaborated by Brazilian experts and sponsored by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism, was to discuss the diagnosis, treatment, and follow-up of individuals with MTC in accordance with the latest evidence reported in the literature. After clinical questions were elaborated, the available literature was initially surveyed for evidence in the MedLine-PubMed database, followed by the Embase and Scientific Electronic Library Online/Latin American and Caribbean Health Science Literature (SciELO/Lilacs) databases. The strength of evidence was assessed according to the Oxford classification of evidence levels, which is based on study design, and the best evidence available for each question was selected. Eleven questions corresponded to MTC diagnosis, 8 corresponded to its surgical treatment, and 13 corresponded to follow-up, for a total of 32 recommendations. The present article discusses the clinical and molecular diagnosis, initial surgical treatment, and postoperative management of MTC, as well as the therapeutic options for metastatic disease. MTC should be suspected in individuals who present with thyroid nodules and family histories of MTC, associations with pheochromocytoma and hyperparathyroidism, and/or typical phenotypic characteristics such as ganglioneuromatosis and Marfanoid habitus. Fine-needle nodule aspiration, serum calcitonin measurements, and anatomical-pathological examinations are useful for diagnostic confirmation. Surgery represents the only curative therapeutic strategy. The therapeutic options for metastatic disease remain limited and are restricted to disease control. Judicious postoperative assessments that focus on the identification of residual or recurrent disease are of paramount importance when defining the follow-up and later therapeutic management strategies.

Multimodal Mri-based Study In Patients With Spg4 Mutations.

Mutations in the SPG4 gene (SPG4-HSP) are the most frequent cause of hereditary spastic paraplegia, but the extent of the neurodegeneration related to the disease is not yet known. Therefore, our objective is to identify regions of the central nervous system damaged in patients with SPG4-HSP using a multi-modal neuroimaging approach. In addition, we aimed to identify possible clinical correlates of such damage. Eleven patients (mean age 46.0 ± 15.0 years, 8 men) with molecular confirmation of hereditary spastic paraplegia, and 23 matched healthy controls (mean age 51.4 ± 14.1years, 17 men) underwent MRI scans in a 3T scanner. We used 3D T1 images to perform volumetric measurements of the brain and spinal cord. We then performed tract-based spatial statistics and tractography analyses of diffusion tensor images to assess microstructural integrity of white matter tracts. Disease severity was quantified with the Spastic Paraplegia Rating Scale. Correlations were then carried out between MRI metrics and clinical data. Volumetric analyses did not identify macroscopic abnormalities in the brain of hereditary spastic paraplegia patients. In contrast, we found extensive fractional anisotropy reduction in the corticospinal tracts, cingulate gyri and splenium of the corpus callosum. Spinal cord morphometry identified atrophy without flattening in the group of patients with hereditary spastic paraplegia. Fractional anisotropy of the corpus callosum and pyramidal tracts did correlate with disease severity. Hereditary spastic paraplegia is characterized by relative sparing of the cortical mantle and remarkable damage to the distal portions of the corticospinal tracts, extending into the spinal cord.

Aesthetic And Functional Rehabilitation Of The Primary Dentition Affected By Amelogenesis Imperfecta.

The objective of this case report was to describe the oral rehabilitation of a five-year-old boy patient diagnosed with amelogenesis imperfecta (AI) in the primary dentition. AI is a group of hereditary disorders that affects the enamel structure. The patient was brought to the dental clinic complaining of tooth hypersensitivity during meals. The medical history and clinical examination were used to arrive at the diagnosis of AI. The treatment was oral rehabilitation of the primary molars with stainless steel crowns and resin-filled celluloid forms. The main objectives of the selected treatment were to enhance the esthetics, restore masticatory function, and eliminate the teeth sensitivity. The child was monitored in the pediatric dentistry clinic at four-month intervals until the mixed dentition stage. Treatment not only restored function and esthetic, but also showed a positive psychological impact and thereby improved perceived quality of life. The preventive, psychological, and curative measures of a young child with AI were successful. This result can encourage the clinicians to seek a cost-effective technique such as stainless steel crowns, and resin-filled celluloid forms to reestablish the oral functions and improve the child's psychosocial development.

Are Human Peripheral Nerves Sensitive To X-ray Imaging?

Diagnostic imaging techniques play an important role in assessing the exact location, cause, and extent of a nerve lesion, thus allowing clinicians to diagnose and manage more effectively a variety of pathological conditions, such as entrapment syndromes, traumatic injuries, and space-occupying lesions. Ultrasound and nuclear magnetic resonance imaging are becoming useful methods for this purpose, but they still lack spatial resolution. In this regard, recent phase contrast x-ray imaging experiments of peripheral nerve allowed the visualization of each nerve fiber surrounded by its myelin sheath as clearly as optical microscopy. In the present study, we attempted to produce high-resolution x-ray phase contrast images of a human sciatic nerve by using synchrotron radiation propagation-based imaging. The images showed high contrast and high spatial resolution, allowing clear identification of each fascicle structure and surrounding connective tissue. The outstanding result is the detection of such structures by phase contrast x-ray tomography of a thick human sciatic nerve section. This may further enable the identification of diverse pathological patterns, such as Wallerian degeneration, hypertrophic neuropathy, inflammatory infiltration, leprosy neuropathy and amyloid deposits. To the best of our knowledge, this is the first successful phase contrast x-ray imaging experiment of a human peripheral nerve sample. Our long-term goal is to develop peripheral nerve imaging methods that could supersede biopsy procedures.

Long-term follow-up of an 8-year-old boy with insulinoma as the first manifestation of a familial form of multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary cancer syndrome characterized mostly by parathyroid, enteropancreatic, and anterior pituitary tumors. We present a case of an 8-year-old boy referred because of hypoglycemic attacks. His diagnosis was pancreatic insulinoma. Paternal grandmother died due to repeated gastroduodenal ulcerations and a paternal aunt presented similar manifestations. At a first evaluation, the father presented only gastric ulceration but subsequently developed hyperparathyroidism and lung carcinoid tumor. During almost 15 years of follow-up, three brothers and the index case presented hyperparathyroidism and hyperprolactinemia. Molecular study showed a G to A substitution in intron 4, at nine nucleotides upstream of the splicing acceptor site, causing a splicing mutation. All affected members of the family have the same mutation. Paternal grandmother and aunt were not studied and the mother does not carry any mutation. MEN1 is a rare condition that requires permanent medical assistance. Early clinical and genetic identification of affected individuals is essential for their own surveillance and also for genetic counseling.

Exostose múltipla hereditária com compressão medular

A case of hereditary multiple exostoses successfully operated is reported. The patient, a 15 year-old white brazilian boy, was admitted with tetraplegia and Babinski's sign. Early diagnosis followed by prompt surgery may prevent permanent spinal cord damage.

Relações entre marcadores digito-palamres e aptidão fisica em atletas de judo de elite

Universidade Estadual de Campinas . Faculdade de Educação Física

Crescimento fisico e performance motora : um estudo em descendentes de holandeses-Holambra

Universidade Estadual de Campinas. Faculdade de Educação Física

Clinical management for epidermolysis bullosa dystrophica

Epidermolysis bullosa (EB) consists of a group of genetic hereditary disorders in which patients frequently present fragile skin and mucosa that form blisters following minor trauma. More than 20 subtypes of EB have been recognized in the literature. Specific genetic mutations are well characterized for most the different EB subtypes and variants. The most common oral manifestations of EB are painful blisters affecting all the oral surfaces. Dental treatment for patients with EB consists of palliative therapy for its oral manifestations along with typical restorative and periodontal procedures. The aim of this article is to describe two dental clinical treatments of recessive dystrophic EB cases and their specific clinical manifestations. The psychological intervention required during the dental treatment of these patients is also presented.

Psychological stress and recurrent aphthous stomatitis

INTRODUCTION AND OBJECTIVES: Recurrent aphthous stomatitis (RAS) is the most common type of ulcerative disease of the oral mucosa. Despite its worldwide occurrence and the extensive amount of research that has been devoted to the subject, the etiology of RAS remains unclear. Nevertheless, several hereditary, nutritional, infectious and psychological factors have been associated with RAS. The aim of this case-control study was to assess the influence of psychological stress on the manifestation of RAS. METHOD: Fifty patients were enrolled in the trial. Twenty-five RAS patients constituted the study group and another 25 non-RAS patients who were similarly matched for sex, age and socioeconomic status constituted the control group. Each patient was evaluated in terms of the four domains of stress (emotional, physical, social and cognitive) using an internationally validated questionnaire, which was comprised of 59 items and measured the frequency and intensity of stress symptoms. The RAS group was interviewed during an active RAS episode. Completed questionnaires were submitted to proper analytical software and interpreted by an expert psychologist. RESULTS: There was a higher level of psychological stress among RAS group patients when compared to the control group (P < 0.05). CONCLUSION: Psychological stress may play a role in the manifestation of RAS; it may serve as a trigger or a modifying factor rather than being a cause of the disease.

Inbreeding levels in Northeast Brazil: strategies for the prospecting of new genetic disorders

A new autosomal recessive genetic condition, the SPOAN syndrome (an acronym for spastic paraplegia, optic atrophy and neuropathy syndrome), was recently discovered in an isolated region of the State of Rio Grande do Norte in Northeast Brazil, in a population that was identified by the IBGE (Brazilian Institute of Geography and Statistics) as belonging to the Brazilian communities with the highest rates of "deficiencies" (Neri, 2003), a term used to describe diseases, malformations, and handicaps in general. This prompted us to conduct a study of consanguinity levels in five of its municipal districts by directly interviewing their inhabitants. Information on 7,639 couples (corresponding to about 40% of the whole population of the studied districts) was obtained. The research disclosed the existence of very high frequencies of consanguineous marriages, which varied from about 9% to 32%, suggesting the presence of a direct association between genetic diseases such as the SPOAN syndrome, genetic drift and inbreeding levels. This fact calls for the introduction of educational programs for the local populations, as well as for further studies aiming to identify and characterize other genetic conditions. Epidemiological strategies developed to collect inbreeding data, with the collaboration of health systems available in the region, might be very successful in the prospecting of genetic disorders.