Browsing by Author "Jacinto, S"
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- Atypical Phenotype in Two Patients with LAMA2 MutationsPublication . Marques, J; Duarte, S; Costa, S; Jacinto, S; Oliveira, J; Oliveira, M; Santos, R; Bronze-da-Rocha, E; Silvestre, AR; Calado, E; Evangelista, TCongenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene, which encodes the a2-chain of laminin. We report two patients with partial laminin-a2 deficiency and atypical phenotypes, one with almost exclusive central nervous system involvement (cognitive impairment and refractory epilepsy) and the second with marked cardiac dysfunction, rigid spine syndrome and limb-girdle weakness. Patients underwent clinical, histopathological, imaging and genetic studies. Both cases have two heterozygous LAMA2 variants sharing a potentially pathogenic missense mutation c.2461A>C (p.Thr821Pro) located in exon 18. Brain MRI was instrumental for the diagnosis, since muscular examination and motor achievements were normal in the first patient and there was a severe cardiac involvement in the second. The clinical phenotype of the patients is markedly different which could in part be explained by the different combination of mutations types (two missense versus a missense and a truncating mutation).
- CAT-SCRATCH Disease: Still a ChallengePublication . Bota, S; Jacinto, S; Ferreira, C; Santos, AS; Varandas, L; Gouveia, C
- Diplopia, Convergent Strabismus, and Eye Abduction Palsy in a 12-Year-Old Boy with Autoimmune ThyroiditisPublication . Marques, P; Jacinto, S; Pinto, MC; Limbert, C; Lopes, LPseudotumor cerebri (PTC) is defined by clinical criteria of increased intracranial pressure, elevated intracranial pressure with normal cerebrospinal fluid (CSF) composition, and exclusion of other causes such tumors, vascular abnormalities, or infections. The association of PTC with levothyroxine (LT4) has been reported. A 12-year-old boy has been followed up for autoimmune thyroiditis under LT4. Family history was irrelevant for endocrine or autoimmune diseases. A TSH level of 4.43 μUI/mL (0.39-3.10) motivated a LT4 adjustment from 75 to 88 μg/day. Five weeks later, he developed horizontal diplopia, convergent strabismus with left eye abduction palsy, and papilledema. Laboratorial evaluation revealed elevated free thyroxine level (1.05 ng/dL [0.65-1.01]) and low TSH, without other alterations. Lumbar puncture was performed and CSF opening pressure was 24 cm H2O with normal composition. Blood and CSF cultures were sterile. Brain MRI was normal. LT4 was temporarily discontinued and progressive improvement was observed, with a normal fundoscopy at day 10 and reversion of diplopia one month later. LT4 was restarted at lower dose and gradually titrated. The boy is currently asymptomatic. This case discloses the potential role of LT4 in inducing PTC. Despite its rarity and unclear association, PTC must be seen as a potential complication of LT4, after excluding all other intracranial hypertension causes.
- Febrile Seizures. Association with HHV6 and CMV Infection?Publication . Milheiro Silva, T; Brito, MJ; Jacinto, S; Cordeiro Ferreira, G; Bravo, S; Loureiro, V; Gonçalves, A; Chasqueira, MJ; Marques, T; Paixão, PFebrile seizures (FS) occur between the age of 1 and 60 months, with fever, are generalized and usually lasting less than 15 minutes. The etiology of FS is not known, although infections, immunizations and genetic susceptibility, all have been linked to an increased risk of FS. Herpes virus 6 (HHV6) and Cytomegalovirus (CMV) are neurotropic virus and remain latent after a primary infections. 10 to 50% of FS cases in children are associated with HHV6 primary infection. An association between FS and CMV infection has not been established.
- LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI AppearancePublication . Dallabona, C; Abbink, TEM; Carrozzo, R; Torraco, A; Legati, A; van Berkel, CGM; Niceta, M; Langella, T; Verrigni, D; Rizza, T; Diodato, D; Piemonte, F; Lamantea, E; Fang, M; Zhang, J; Martinelli, D; Bevivino, E; Dionisi-Vici, C; Vanderver, A; Philip, SG; Kurian, MA; Verma, IC; Bijarnia-Mahay, S; Jacinto, S; Furtado, F; Accorsi, P; Ardissone, A; Moroni, I; Ferrero, I; Tartaglia, M; Goffrini, P; Ghezzi, D; van der Knaap, MS; Bertini, EThis study focused on the molecular characterization of patients with leukoencephalopathy associated with a specific biochemical defect of mitochondrial respiratory chain complex III, and explores the impact of a distinct magnetic resonance imaging pattern of leukoencephalopathy to detect biallelic mutations in LYRM7 in patients with biochemically unclassified leukoencephalopathy. 'Targeted resequencing' of a custom panel including genes coding for mitochondrial proteins was performed in patients with complex III deficiency without a molecular genetic diagnosis. Based on brain magnetic resonance imaging findings in these patients, we selected additional patients from a database of unclassified leukoencephalopathies who were scanned for mutations in LYRM7 by Sanger sequencing. Targeted sequencing revealed homozygous mutations in LYRM7, encoding mitochondrial LYR motif-containing protein 7, in four patients from three unrelated families who had a leukoencephalopathy and complex III deficiency. Two subjects harboured previously unreported variants predicted to be damaging, while two siblings carried an already reported pathogenic homozygous missense change. Sanger sequencing performed in the second cohort of patients revealed LYRM7 mutations in three additional patients, who were selected on the basis of the magnetic resonance imaging pattern. All patients had a consistent magnetic resonance imaging pattern of progressive signal abnormalities with multifocal small cavitations in the periventricular and deep cerebral white matter. Early motor development was delayed in half of the patients. All patients but one presented with subacute neurological deterioration in infancy or childhood, preceded by a febrile infection, and most patients had repeated episodes of subacute encephalopathy with motor regression, irritability and stupor or coma resulting in major handicap or death. LYRM7 protein was strongly reduced in available samples from patients; decreased complex III holocomplex was observed in fibroblasts from a patient carrying a splice site variant; functional studies in yeast confirmed the pathogenicity of two novel mutations. Mutations in LYRM7 were previously found in a single patient with a severe form of infantile onset encephalopathy. We provide new molecular, clinical, and neuroimaging data allowing us to characterize more accurately the molecular spectrum of LYRM7 mutations highlighting that a distinct and recognizable magnetic resonance imaging pattern is related to mutations in this gene. Inter- and intrafamilial variability exists and we observed one patient who was asymptomatic by the age of 6 years.
- Macrossomia, Hipersomnia e Alteração do Controlo da Temperatura: Disfunção Hipotalâmica de Causa DesconhecidaPublication . Jacinto, S; Silva, R; Lopes, P; Nunes, L; Romão, G; Calado, E
- MEGDEL Syndrome: Expanding the Phenotype and New MutationsPublication . Sequeira, S; Rodrigues, M; Jacinto, S; Wevers, RA; Wortmann, SB
- MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic ProfilePublication . Jacinto, S; Guerreiro, P; de Oliveira, RM; Cunha-Oliveira, T; Santos, MJ; Grazina, M; Rego, AC; Outeiro, TFMutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.
- MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic ProfilePublication . Jacinto, S; Guerreiro, P; Machado de Oliveira, R; Cunha-Oliveira, T; Santos, MJ; Grazina, M; Rego, AC; Outeiro, TFMutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.
- Ophthalmoplegic Migraine and Infundibular Dilatation of a Cerebral ArteryPublication . Vieira, JP; Castro, J; Gomes, LB; Jacinto, S; Dias, AIOphthalmoplegic migraine (OM) is a childhood disorder of uncertain etiology manifesting recurrent unilateral headache associated with a transitory oculomotor (usually IIIrd nerve) palsy. Recent publications emphasize the finding on MRI of contrast enhancement in the IIIrd nerve suggesting that OM may be a recurrent inflammatory neuropathy. We report the case of a 7-year-old boy with typical symptoms of this disorder. Angio MR and Angio CT revealed the presence of an infundibular dilatation of a perforating branch of the posterior cerebral artery adjacent to the symptomatic IIIrd nerve. We speculate that this and perhaps other cases of OM may have a different pathophysiology related to compression of the IIIrd nerve by an adjacent vascular structure that could activate the trigeminovascular system and produce migrainous pain.