FERNANDO KOK
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Neurologia, Faculdade de Medicina - Docente
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
9 resultados
Resultados de Busca
Agora exibindo 1 - 9 de 9
- Defects in iron-sulphur cluster assembly proteins ISCU and FDX2 cause characteristic mitochondrial myopathy(2019) THOMSEN, C.; GURGEL-GIANNETTI, J.; SUNNERHAGEN, Y.; GIANNETTI, A.; KOK, F.; VAINZOF, M.; OLDFORS, A.
- Motor impairment in a rare form of spastic paraplegia (Spoan syndrome): a 10-year follow-up(2019) GALVAO, Claudia R. C.; CAVALCANTE, Priscilla M. A.; OLINDA, Ricardo; GRACIANI, Zodja; ZATZ, Mayana; KOK, Fernando; SANTOS, Silvana; LANCMAN, SelmaBackground: Spastic paraplegia, optic atrophy and neuropathy (Spoan syndrome) is an autosomal recessive disease with approximately 70 cases recorded in Brazil and Egypt. Methods: This is a prospective longitudinal study performed with 47 patients affected with Spoan syndrome of seven communities of Rio Grande do Norte (Brazil) to investigate changes in motor function based on comparative data obtained from a 10-year follow-up. Results: The mean age of the participants was 47.21 +/- 12.42 years old, and the mean age at loss of ambulation and hand function were 10.78 +/- 5.55 and 33.58 +/- 17.47 years old, respectively. Spearman's correlation analysis between the score on the Modified Barthel Index and the investigated variables evidenced statistical significance for age (p < 0.001) and right- and left-hand grip strength (p = 0.042 and p = 0.021, respectively). Statistical significance was not evidenced for the remainder of the variables, including age at onset of symptoms (p = 0.634), age at loss of ambulation (p = 0.664) and age at loss of hand function (p = 0.118). Conclusions: Our analysis allows asserting that the participants exhibited slight dependence until age 35. The greatest losses occurred from ages 35 to 41, and starting at 50, practically all patients become completely dependent. These findings are relevant for determining the prognosis as well as suitable treatment, rehabilitation and assistive technology for these individuals.
- Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP(2019) DIJCK, Anke Van; SILFHOUT, Anneke T. Vulto-van; CAPPUYNS, Elisa; WERF, Ilse M. van der; MANCINI, Grazia M.; TZSCHACH, Andreas; BERNIER, Raphael; GOZES, Illana; EICHLER, Evan E.; ROMANO, Corrado; LINDSTRAND, Anna; NORDGREN, Ann; KVARNUNG, Malin; KLEEFSTRA, Tjitske; VRIES, Bert B. A. de; KURY, Sebastien; ROSENFELD, Jill A.; MEUWISSEN, Marije E.; VANDEWEYER, Geert; KOOY, R. Frank; BAKSHI, Madhura; WILSON, Meredith; BERMAN, Yemina; DICKSON, Rebecca; FRANSEN, Erik; HELSMOORTEL, Celine; ENDE, Jenneke Van den; AA, Nathalie Van der; WIJDEVEN, Marina J. van de; ROSENBLUM, Jessica; MONTEIRO, Fabiola; KOK, Fernando; QUERCIA, Nada; BOWDIN, Sarah; DYMENT, David; CHITAYAT, David; ALKHUNAIZI, Ebba; BOONEN, Susanne E.; KEREN, Boris; JACQUETTE, Aurelia; FAIVRE, Laurence; BEZIEAU, Stephane; ISIDOR, Bertrand; RIESS, Angelika; MOOG, Ute; LYNCH, Sally Ann; MCVEIGH, Terri; ELPELEG, Orly; SMELAND, Marie Falkenberg; FANNEMEL, Madeleine; HAERINGEN, Arie van; MAAS, Saskia M.; VEENSTRA-KNOL, H. E.; SCHOUTEN, Meyke; WILLEMSEN, Marjolein H.; MARCELIS, Carlo L.; OCKELOEN, Charlotte; BURGT, Ineke van der; FEENSTRA, Ilse; SMAGT, Jasper van der; JEZELA-STANEK, Aleksandra; KRAJEWSKA-WALASEK, Malgorzata; GONZALEZ-LAMUNO, Domingo; ANDERLID, Britt-Marie; MALMGREN, Helena; NORDENSKJOLD, Magnus; CLEMENT, Emma; HURST, Jane; METCALFE, Kay; MANSOUR, Sahar; LACHLAN, Katherine; CLAYTON-SMITH, Jill; HENDON, Laura G.; ABDULRAHMAN, Omar A.; MORROW, Eric; MCMILLAN, Clare; GERDTS, Jennifer; PEEDEN, Joseph; VERGANO, Samantha A. Schrier; VALENTINO, Caitlin; CHUNG, Wendy K.; OZMORE, Jillian R.; BEDROSIAN-SERMONE, Sandra; DENNIS, Anna; TREAT, Kayla; HUGHES, Susan Starling; SAFINA, Nicole; PICHON, Jean-Baptiste Le; MCGUIRE, Marianne; INFANTE, Elena; MADAN-KHETARPAL, Suneeta; DESAI, Sonal; BENKE, Paul; KROKOSKY, Alyson; CRISTIAN, Ingrid; BAKER, Laura; GRIPP, Karen; STESSMAN, Holly A.; EICHENBERGER, Jacob; JAYAKAR, Parul; PIZZINO, Amy; MANNING, Melanie Ann; SLATTERY, LeahBACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. METHODS: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. RESULTS: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. CONCLUSIONS: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.
- AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders(2019) SALPIETRO, Vincenzo; DIXON, Christine L.; GUO, Hui; BELLO, Oscar D.; VANDROVCOVA, Jana; EFTHYMIOU, Stephanie; MAROOFIAN, Reza; HEIMER, Gali; BURGLEN, Lydie; VALENCE, Stephanie; TORTI, Erin; HACKE, Moritz; RANKIN, Julia; TARIQ, Huma; COLIN, Estelle; PROCACCIO, Vincent; STRIANO, Pasquale; MANKAD, Kshitij; LIEB, Andreas; CHEN, Sharon; PISANI, Laura; BETTENCOURT, Conceicao; MANNIKKO, Roope; MANOLE, Andreea; BRUSCO, Alfredo; GROSSO, Enrico; FERRERO, Giovanni Battista; ARMSTRONG-MORON, Judith; GUEDEN, Sophie; BAR-YOSEF, Omer; TZADOK, Michal; MONAGHAN, Kristin G.; SANTIAGO-SIM, Teresa; PERSON, Richard E.; CHO, Megan T.; WILLAERT, Rebecca; YOO, Yongjin; CHAE, Jong-Hee; QUAN, Yingting; WU, Huidan; WANG, Tianyun; BERNIER, Raphael A.; XIA, Kun; BLESSON, Alyssa; JAIN, Mahim; MOTAZACKER, Mohammad M.; JAEGER, Bregje; SCHNEIDER, Amy L.; BOYSEN, Katja; MUIR, Alison M.; MYERS, Candace T.; GAVRILOVA, Ralitza H.; GUNDERSON, Lauren; SCHULTZ-ROGERS, Laura; KLEE, Eric W.; DYMENT, David; OSMOND, Matthew; PARELLADA, Mara; LLORENTE, Cloe; GONZALEZ-PENAS, Javier; CARRACEDO, Angel; HAERINGEN, Arie Van; RUIVENKAMP, Claudia; NAVA, Caroline; HERON, Delphine; NARDELLO, Rosaria; IACOMINO, Michele; MINETTI, Carlo; SKABAR, Aldo; FABRETTO, Antonella; CHEZ, Michael; TSAI, Anne; FASSI, Emily; SHINAWI, Marwan; CONSTANTINO, John N.; ZORZI, Rita De; FORTUNA, Sara; KOK, Fernando; KEREN, Boris; BONNEAU, Dominique; CHOI, Murim; BENZEEV, Bruria; ZARA, Federico; MEFFORD, Heather C.; SCHEFFER, Ingrid E.; CLAYTON-SMITH, Jill; MACAYA, Alfons; ROTHMAN, James E.; EICHLER, Evan E.; KULLMANN, Dimitri M.; HOULDEN, Henry; RASPALL-CHAURE, Miquel; HANNA, Michael G.; BUGIARDINI, Enrico; HOSTETTLER, Isabel; O'CALLAGHAN, Benjamin; KHAN, Alaa; CORTESE, Andrea; O'CONNOR, Emer; YAU, Wai Y.; BOURINARIS, Thomas; KAIYRZHANOV, Rauan; CHELBAN, Viorica; MADEJ, Monika; DIANA, Maria C.; VARI, Maria S.; PEDEMONTE, Marina; BRUNO, Claudio; BALAGURA, Ganna; SCALA, Marcello; FIORILLO, Chiara; NOBILI, Lino; MALINTAN, Nancy T.; ZANETTI, Maria N.; KRISHNAKUMAR, Shyam S.; LIGNANI, Gabriele; JEPSON, James E. C.; BRODA, Paolo; BALDASSARI, Simona; ROSSI, Pia; FRUSCIONE, Floriana; MADIA, Francesca; TRAVERSO, Monica; DE-MARCO, Patrizia; PEREZ-DUENAS, Belen; MUNELL, Francina; KRIOUILE, Yamna; EL-KHORASSANI, Mohamed; KARASHOVA, Blagovesta; AVDJIEVA, Daniela; KATHOM, Hadil; TINCHEVA, Radka; VAN-MALDERGEM, Lionel; NACHBAUER, Wolfgang; BOESCH, Sylvia; GAGLIANO, Antonella; AMADORI, Elisabetta; GORAYA, Jatinder S.; SULTAN, Tipu; KIRMANI, Salman; IBRAHIM, Shahnaz; JAN, Farida; MINE, Jun; BANU, Selina; VEGGIOTTI, Pierangelo; V, Gian Zuccotti; FERRARI, Michel D.; MAAGDENBERG, Arn M. J. Van Den; VERROTTI, Alberto; MARSEGLIA, Gian L.; SAVASTA, Salvatore; SOLER, Miguel A.; SCUDERI, Carmela; BORGIONE, Eugenia; CHIMENZ, Roberto; GITTO, Eloisa; DIPASQUALE, Valeria; SALLEMI, Alessia; FUSCO, Monica; CUPPARI, Caterina; CUTRUPI, Maria C.; RUGGIERI, Martino; CAMA, Armando; CAPRA, Valeria; MENCACCI, Niccolo E.; BOLES, Richard; GUPTA, Neerja; KABRA, Madhulika; PAPACOSTAS, Savvas; ZAMBA-PAPANICOLAOU, Eleni; DARDIOTIS, Efthymios; MAQBOOL, Shazia; RANA, Nuzhat; ATAWNEH, Osama; LIM, Shen Y.; SHAIKH, Farooq; KOUTSIS, George; BREZA, Marianthi; COVIELLO, Domenico A.; DAUVILLIERS, Yves A.; ALKHAWAJA, Issam; ALKHAWAJA, Mariam; AL-MUTAIRI, Fuad; STOJKOVIC, Tanya; FERRUCCI, Veronica; ZOLLO, Massimo; ALKURAYA, Fowzan S.; KINALI, Maria; SHERIFA, Hamed; BENRHOUMA, Hanene; TURKI, Ilhem B. Y.; TAZIR, Meriem; OBEID, Makram; BAKHTADZE, Sophia; SAADI, Nebal W.; ZAKI, Maha S.; TRIKI, Chahnez C.; BENFENATI, Fabio; GUSTINCICH, Stefano; KARA, Majdi; BELCASTRO, Vincenzo; SPECCHIO, Nicola; CAPOVILLA, Giuseppe; KARIMIANI, Ehsan G.; SALIH, Ahmed M.; OKUBADEJO, Njideka U.; OJO, Oluwadamilola O.; OSHINAIKE, Olajumoke O.; OGUNTUNDE, Olapeju; WAHAB, Kolawole; BELLO, Abiodun H.; ABUBAKAR, Sanni; OBIABO, Yahaya; NWAZOR, Ernest; EKENZE, Oluchi; WILLIAMS, Uduak; IYAGBA, Alagoma; TAIWO, Lolade; KOMOLAFE, Morenikeji; SENKEVICH, Konstantin; SHASHKIN, Chingiz; ZHARKYNBEKOVA, Nazira; KONEYEV, Kairgali; MANIZHA, Ganieva; ISROFILOV, Maksud; GULIYEVA, Ulviyya; SALAYEV, Kamran; KHACHATRYAN, Samson; ROSSI, Salvatore; SILVESTRI, Gabriella; HARIDY, Nourelhoda; RAMENGHI, Luca A.; XIROMERISIOU, Georgia; DAVID, Emanuele; AGUENNOUZ, Mhammed; FIDANI, Liana; SPANAKI, Cleanthe; TUCCI, AriannaAMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.
- Heterozygous loss of function of NR4A2 is associated with intellectual deficiency, rolandic epilepsy, and language impairment(2019) RAMOS, Luiza L. P.; MONTEIRO, Fabiola P.; SAMPAIO, Leticia P. B.; COSTA, Larissa A.; RIBEIRO, Mara D. O.; FREITAS, Erika L.; KITAJIMA, Joao P.; KOK, FernandoRecognition of a de novo mutation in NR4A2 associated with a neurodevelopmental phenotype reinforces its role in 2q23q24 microdeletion syndrome. Using the proband WES data and the probability of loss-of-function intolerance index (pLi) set at 1.0 (highest intolerance constraint), we could target NR4A2 as the candidate gene in this patient.
- Adult Leukodystrophies: A Step-by-Step Diagnostic Approach(2019) RESENDE, Lucas Lopes; PAIVA, Anderson Rodrigues Brandao de; KOK, Fernando; LEITE, Claudia da Costa; LUCATO, Leandro TavaresLeukodystrophies usually affect children, but in the last several decades, many instances of adult leukodystrophies have been reported in the medical literature. Because the clinical manifestation of these diseases can be nonspecific, MRI can help with establishing a diagnosis. A step-by-step approach to assist in the diagnosis of adult leukodystrophies is proposed in this article. The first step is to identify symmetric white matter involvement, which is more commonly observed in these patients. The next step is to fit the symmetric white matter involvement into one of the proposed patterns. However, a patient may present with more than one pattern of white matter involvement. Thus, the third step is to evaluate for five distinct characteristics-including enhancement, lesions with signal intensity similar to that of cerebrospinal fluid, susceptibility-weighted MRI signal intensity abnormalities, abnormal peaks at MR spectroscopy, and spinal cord involvement-to further narrow the differential diagnosis. (C) RSNA, 2019
- Paralog Studies Augment Gene Discovery: DDX and DHX Genes(2019) PAINE, Ingrid; POSEY, Jennifer E.; GROCHOWSKI, Christopher M.; JHANGIANI, Shalini N.; ROSENHECK, Sarah; KLEYNER, Robert; MARMORALE, Taylor; YOON, Margaret; WANG, Kai; ROBISON, Reid; CAPPUCCIO, Gerarda; PINELLI, Michele; MAGLI, Adriano; AKDEMIR, Zeynep Coban; HUI, Joannie; YEUNG, Wai Lan; WONG, Bibiana K. Y.; ORTEGA, Lucia; BEKHEIRNIA, Mir Reza; BIERHALS, Tatjana; HEMPEL, Maja; JOHANNSEN, Jessika; SANTER, Rene; AKTAS, Dilek; ALIKASIFOGLU, Mehmet; BOZDOGAN, Sevcan; AYDIN, Hatip; KARACA, Ender; BAYRAM, Yavuz; ITYEL, Hadas; DORSCHNER, Michael; WHITE, Janson J.; WILICHOWSKI, Ekkehard; WORTMANN, Saskia B.; CASELLA, Erasmo B.; KITAJIMA, Joao Paulo; KOK, Fernando; MONTEIRO, Fabiola; MUZNY, Donna M.; BAMSHAD, Michael; GIBBS, Richard A.; SUTTON, V. Reid; ESCH, Hilde Van; BRUNETTI-PIERRI, Nicola; HILDEBRANDT, Friedhelm; BRAUTBAR, Ariel; VEYVER, Ignatia B. Van den; GLASS, Ian; LESSEL, Davor; LYON, Gholson J.; LUPSKI, James R.Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.
- Clinical, ophthalmological, imaging and genetic features in Brazilian patients with ARSACS(2019) REZENDE FILHO, Flavio Moura; PARKINSON, Michael H.; PEDROSO, Jose Luiz; POH, Roy; FABER, Ingrid; LOURENCO, Charles Marques; MARQUES JUNIOR, Wilson; FRANCA JUNIOR, Marcondes Cavalcante; KOK, Fernando; SALLUM, Juliana M. Ferraz; GIUNTI, Paola; BARSOTTINI, Orlando Graziani PovoasBackground: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an important form of inherited ataxia with a varied clinical spectrum. Detailed studies of phenotype and genotype are necessary to improve diagnosis and elucidate this disorder pathogenesis. OBJECTIVE AND METHODS: To investigate the clinical phenotype, retinal architecture, neuroimaging features and genetic profile of Brazilian patients with ARSACS, we performed neurological and ophthalmological evaluation in thirteen Brazilian patients with molecularly confirmed ARSACS, and examined their mutation profiles. Optical coherence tomography protocol (OCT) consisted in peripapillary retinal nerve fiber layer (RNFL) measurement and qualitative analysis of perifoveal scans. Neuroimaging protocol accessed the frequency of atrophy in cerebellum, corpus callosum and parietal lobe, brainstem signal abnormalities, and posterior fossa arachnoid cysts. We reviewed the literature to delineate the ARSACS phenotype in the largest series worldwide. RESULTS: All patients had ataxia and spasticity, and 11/13 had peripheral neuropathy. Macular microcysts were present in two patients. Peripapillary striations, dentate appearance of inner retina and papillomacular fold were found in eleven cases. All individuals exhibited thickening of RNFL in OCT. The most frequent radiological signs were cerebellar atrophy (13/13), biparietal atrophy (12/13), and linear pontine hypointensities (13/13). Genetic analysis revealed 14 different SACS variants, of which two are novel. CONCLUSION: Macular microcysts, inner retina dentate appearance and papillomacular fold are novel retinal imaging signs of ARSACS. Ophthalmological and neuroimaging changes are common findings in Brazilian patients. The core clinical features of ARSACS are ataxia, spasticity and peripheral neuropathy with onset predominantly in the first decade of life.
- PUS3 mutations are associated with intellectual disability, leukoencephalopathy, and nephropathy(2019) PAIVA, Anderson Rodrigues Brandao de; LYNCH, David S.; MELO, Uira Souto; LUCATO, Leandro Tavares; FREUA, Fernando; ASSIS, Bruno Della Ripa de; BARCELOS, Isabella; LISTIK, Clarice; SANTOS, Diego de Castro dos; MACEDO-SOUZA, Lucia Ines; HOULDEN, Henry; KOK, FernandoMutations in PUS3, which encodes a highly conserved enzyme responsible for posttranscriptional modification of tRNA, have been shown in a single family to be a cause of nonsyndromic intellectual disability (ID).(1) In this study, we used whole-exome sequencing (WES) to identify biallelic mutations in PUS3 associated with syndromic ID with dysmorphic features, white matter disease (WMD), and renal abnormalities in a nonconsanguineous family from Brazil.