DEBORA ROMEO BERTOLA
Projetos de Pesquisa
Unidades Organizacionais
Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina - Médico
BIO, IB
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
BIO, IB
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
29 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 29
- Mucopolysaccharidosis Type IVA: Evidence of Primary and Secondary Central Nervous System Involvement(2014) BORLOT, Felippe; ARANTES, Paula Ricci; QUAIO, Caio Robledo; FRANCO, Jose Francisco da Silva; LOURENCO, Charles Marques; GOMY, Israel; BERTOLA, Debora Romeo; KIM, Chong AeMucopolysaccharidosis type IVA is a rare lysosomal storage disease caused by a deficiency of N-acetylgalactosamine 6-sulfatase. Studies usually focus on skeletal abnormalities and their consequences. This study explores the neurological manifestations in a cohort of mucopolysaccharidosis type IVA patients, with a detailed focus on brain and spinal magnetic resonance imaging (MRI) findings. We performed a cross-sectional study involving nine patients with a biochemical confirmation of mucopolysaccharidosis type IVA. The protocol consists of a comprehensive clinical examination and brain and spinal cord MRI analysis for all subjects. The mean age was 16.4 years (+/- 5.7) and the mean onset of symptoms was 11.5 months (+/- 6.3). Overall, cognition was spared in all but one patient and motor weakness was a constant finding in all patients. Deep sensation impairment was found in six patients. The brain MRIs showed non-specific white matter changes in two patients. Other abnormalities such as clival hypoplasia, basilar invagination, and arachnoid cists appeared in seven of the nine patients. Eight patients presented spinal cord compression, and in three of them, two spinal levels were compromised. Odontoid hypoplasia and degenerative features in the neuroaxis were present in all patients. Our experience with mucopolysaccharidosis type IVA patients supports the evidence of central nervous system involvement. We emphasize the importance of regular clinical assessments with complete MRI studies, as an attempt to detect the early signs of spinal cord compression. This evaluation may be especially important before surgical interventions, as occult lesions may become symptomatic and promote postoperative unfavorable outcomes. (c) 2014 Wiley Periodicals, Inc.
- Deletion 5q12: Delineation of a Phenotype Including Mental Retardation and Ocular Defects(2011) JAILLARD, Sylvie; ANDRIEUX, Joris; PLESSIS, Ghislaine; KREPISCHI, Ana C. V.; LUCAS, Josette; DAVID, Veronique; BRUN, Marine Le; BERTOLA, Debora R.; DAVID, Albert; BELAUD-ROTUREAU, Marc-Antoine; MOSSER, Jean; LAZARO, Leila; TREGUIER, Catherine; ROSENBERG, Carla; ODENT, Sylvie; DUBOURG, ChristeleArray-CGH enables the detection of submicroscopic chromosomal deletions and duplications and leads to an accurate delineation of the imbalances, raising the possibility of correlating genotype to phenotype and mapping minimal critical regions associated with particular patterns of clinical features. We report here on four patients sharing common clinical features (psychomotor retardation, coarse facies and ocular anomalies), with proximal 5q deletions identified by oligo array-CGH. The deletions range from 5.75 to 17.26-Mb in size and occurred de novo. A common 2.63-Mb region between the deletions described here can be defined in 5q12.1 (59,390,122-62,021,754 bp bp from 5pter, hg18) and includes 12 genes. Among them, KIF2A, which encodes a kinesin superfamily protein, is a particularly interesting candidate for the phenotype, as it suppresses the growth of axonal collateral branches and is involved in normal brain development. Ocular defects, albeit unspecific, seem to be common in the 5q12.1 deletion. Identification of additional cases of deletions involving the 5q12.1 region will allow more accurate genotype-phenotype correlations. (C) 2011 Wiley-Liss, Inc.
- Six Additional Cases of SEDC Due to the Same and Recurrent R989C Mutation in the COL2A1 Gene-the Clinical and Radiological Follow-up(2015) SILVEIRA, Karina C.; BONADIA, Luciana C.; SUPERTI-FURGA, Andrea; BERTOLA, Debora R.; JORGE, Alexander A. L.; CAVALCANTI, Denise P.
- Nosology of genetic skeletal disorders: 2023 revision(2023) UNGER, Sheila; FERREIRA, Carlos R. R.; MORTIER, Geert R. R.; ALI, Houda; BERTOLA, Debora R.; CALDER, Alistair; COHN, Daniel H. H.; CORMIER-DAIRE, Valerie; GIRISHA, Katta M. M.; HALL, Christine; KRAKOW, Deborah; MAKITIE, Outi; MUNDLOS, Stefan; NISHIMURA, Gen; ROBERTSON, Stephen P. P.; SAVARIRAYAN, Ravi; SILLENCE, David; SIMON, Marleen; SUTTON, V. Reid; WARMAN, Matthew L. L.; SUPERTI-FURGA, AndreaThe ""Nosology of genetic skeletal disorders"" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next-generation sequencing results, and providing a basis for novel advances in biology and medicine.
- Recurrence of Frontometaphyseal Dysplasia in Two Sisters With a Mutation in FLNA and an Atypical Paternal Phenotype: Insights Into Genotype-Phenotype Correlation(2015) BERTOLA, Debora; PASSOS-BUENO, Maria Rita; PEREIRA, Alexandre; KIM, Chong; MORGAN, Tim; ROBERTSON, Stephen P.
- Noonan syndrome patients beyond the obvious phenotype: A potential unfavorable metabolic profile(2021) NORONHA, Renata M.; VILLARES, Sandra M. F.; TORRES, Natalia; QUEDAS, Elisangela P. S.; HOMMA, Thais Kataoka; ALBUQUERQUE, Edoarda V. A.; MORAES, Michelle B.; FUNARI, Mariana F. A.; BERTOLA, Debora R.; JORGE, Alexander A. L.; MALAQUIAS, Alexsandra C.Noonan syndrome (NS) and NS related disorders (NRD) are frequent monogenic diseases. Pathogenic variants in PTPN11 are observed in approximately 50% of these NS patients. Several pleiotropic phenotypes have previously been described in this condition. This study aimed at characterizing glucose and lipid profiles in patients with NS/NRD. We assessed fasting blood glucose, insulin, cholesterol (total and fractions), and triglyceride (TG) levels in 112 prepubertal children and 73 adults. Additionally, an oral glucose tolerance test (OGTT) was performed in 40 children and 54 adults. Data were analyzed between age groups according to the presence (+) or absence (-) of PTPN11 mutation. Prepubertal patients with NS/NRD were also compared with a control group. Despite the lean phenotype of children with NS/NRD, they presented an increased frequency of low HDL-cholesterol (63% in PTPN11+, 59% in PTPN11- and 16% in control, p < .001) and high TG levels (29% in PTPN11+, 18% in PTPN11- and 2.3% in control). PTPN11+ patients had a higher median HOMA-IR (1.0, ranged from 0.3 to 3.2) in comparison with PTPN11- (0.6; 0.2 to 4.4) and controls (0.6; 0.4 to 1.4, p = .027). Impaired glucose tolerance was observed in 19% (10:54) of lean adults with NS/NRD assessed by OGTT. Moreover, women with PTPN11 mutations had lower HDL-cholesterol levels than those without. Our results suggest that children and young adult patients with NS/NRD have an unfavorable metabolic profile characterized by low HDL, a tendency of elevated TGs, and glucose metabolism impairment despite a lean phenotype.
- KRAS gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G-domain: Report of another family with metopic craniosynostosis(2012) BRASIL, Amanda S.; MALAQUIAS, Alexsandra C.; KIM, Chong A.; KRIEGER, Jose Eduardo; JORGE, Alexander A. L.; PEREIRA, Alexandre C.; BERTOLA, Debora R.Noonan syndrome (NS) and Noonan-related disorders [cardio-facio-cutaneous (CFC), Costello, Noonan syndrome with multiple lentigines (NS-ML), and neurofibromatosis-Noonan syndromes (NFNS)] are a group of developmental disorders caused by mutations in genes of the RAS/MAPK pathway. Mutations in the KRAS gene account for only a small proportion of affected Noonan and CFC syndrome patients that present an intermediate phenotype between these two syndromes, with more frequent and severe intellectual disability in NS and less ectodermal involvement in CFC syndrome, as well as atypical clinical findings such as craniosynostosis. Recently, the first familial case with a novel KRAS mutation was described. We report on a second vertical transmission (a mother and two siblings) with a novel mutation (p.M72L), in which the proband has trigonocephaly and the affected mother and sister, prominent ectodermal involvement. Metopic suture involvement has not been described before, expanding the main different cranial sutures which can be affected in NS and KRAS gene mutations. The gene alteration found in the studied family is in close proximity to the one reported in the other familial case (close to the switch II region of the G-domain), suggesting that this specific region of the gene could have less severe effects on intellectual ability than the other KRAS gene mutations found in NS patients and be less likely to hamper reproductive fitness. (c) 2012 Wiley Periodicals, Inc.
- The recurrent homozygous translation start site variant in CCDC134 in an individual with severe osteogenesis imperfecta of non-Morrocan ancestry(2022) ALI, Taccyanna M.; LINNENKAMP, Bianca D. W.; YAMAMOTO, Guilherme L.; HONJO, Rachel S.; MENEZES FILHO, Hamilton Cabral de; KIM, Chong Ae; BERTOLA, Debora R.Osteogenesis imperfecta (OI) is a rare low-bone mass skeletal Mendelian disorder characterized by bone fragility leading to bone fractures, with deformities and stunted growth in the more severe phenotypes. Other common, nonskeletal findings include blue sclerae and dentinogenesis imperfecta. It is caused mainly by quantitative or structural defects in type I collagen, although dysregulation of different signaling pathways that play a role in bone morphogenesis has been described to be associated with a small fraction of individuals with OI. Recently, a homozygous variant in the translation start site of CCDC134, showing increased activation of the RAS/MAPK signaling pathway, has been reported in three families of Moroccan origin with a severe, deforming form of OI. We report on a 9-year-old Brazilian boy, harboring the same homozygous variant in CCDC134, also presenting severe bone involvement. This report contributes to the phenotypic delineation of this novel autosomal recessive form of OI, which presents with high prevalence of nonunion fractures considered rare events in OI in general. In addition, it expands the phenotype to include base skull anomalies, potentially leading to serious complications, as seen in severe forms of OI. A poor response to bisphosphonate therapy was observed in these individuals. As the variant in CCDC134 leads to dysregulation of the RAS/MAPK signaling pathway, drugs targeted to this pathway could be an alternative to achieve a better management of these individuals.
- Microduplication of the ICR2 Domain at Chromosome 11p15 and Familial Silver-Russell Syndrome(2011) BONALDI, Adriano; MAZZEU, Juliana F.; COSTA, Silvia S.; HONJO, Rachel S.; BERTOLA, Debora R.; ALBANO, Lilian M. J.; FURQUIM, Isabel M.; KIM, Chong A.; VIANNA-MORGANTE, Angela M.Silver-Russell syndrome (SRS) is characterized by severe intrauterine and postnatal growth retardation in association with a typical small triangular face and other variable features. Genetic and epigenetic disturbances are detected in about 50% of the patients. Most frequently, SRS is caused by altered gene expression on chromosome 11p15 due to hypomethylation of the telomeric imprinting center (ICR1) that is present in at least 40% of the patients. Maternally inherited duplications encompassing ICR1 and ICR2 domains at 11p15 were found in a few patients, and a microduplication restricted to ICR2 was described in a single SRS child. We report on a microduplication of the ICR2 domain encompassing the KCNQ1, KCNQ1OT1, and CDKN1C genes in a three-generation family: there were four instances of paternal transmissions of the microduplication from a single male uniformly resulting in normal offspring, and five maternal transmissions, via two clinically normal sisters, with all the children exhibiting SRS. This report provides confirmatory evidence that a microduplication restricted to the ICR2 domain results in SRS when maternally transmitted. (C) 2011 Wiley-Liss, Inc.
- Nutritional Aspects of Noonan Syndrome and Noonan-Related Disorders(2016) SILVA, Fernanda Marchetto da; JORGE, Alexander Augusto; MALAQUIAS, Alexandra; PEREIRA, Alexandre da Costa; YAMAMOTO, Guilherme Lopes; KIM, Chong Ae; BERTOLA, DeboraRasopathies are a group of rare disorders characterized by neurocardiofaciocutaneous involvement, and caused by mutations in several genes of the RAS/MAPK pathway. In the present study, we characterized growth parameters, body composition, and nutritional aspects of children and adults (n = 62) affected by these disorders, mainly Noonan syndrome, using an indirect method-anthropometry-and a 24-hr recall questionnaire. The growth parameters in our cohort showed short stature, especially in individuals with RAF1 and SHOC2 mutations, lower obesity rates compared to the control population, and BMI scores highest in individuals with BRAF mutations and lowest in individuals with SHOC2. Body composition showed a compromise in the upper arm muscle circumference, with a statistically significant difference in the z-score of triceps skin-fold (P = 0.0204) and upper arm fat area (P = 0.0388) between BRAF and SHOC2 groups and in the z-score of triceps skinfold between RAF1 and SHOC2 (P = 0.0218). The pattern of macro-nutrient consumption was similar to the control population. Our study is the first to address body composition in RASopathy individuals and the data indicate a compromise not only in adipose tissue, but also in muscle mass. Studies using different techniques, such as dual-energy X-ray absorptiometry or imaging studies, which give a more precise delineation of fat and non-fat mass, are required to confirm our results, ultimately causing an impact on management strategies. (C) 2016 Wiley Periodicals, Inc.
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