Victor Cavalcanti Pardini

Clinical and molecular aspects of Berardinelli–Seip Congenital Lipodystrophy (BSCL)

Congenital Generalized Lipodystrophy (CGL) or Berardinelli-Seip Syndrome (BSCL) is a rare autosomal recessive disease characterized by complete absence of adipose tissue and by several metabolic alterations in carbohydrate (diabetes mellitus) and lipid metabolism and involvement of heart, bone and ovaries. Mental retardation and psychiatric disturbances are present in a variable proportion of affected patients. In the present review, the major advances in clinical, molecular and genetic characterization of BSCL affected subjects are recorded and discussed.

Updated Brazilian STR allele frequency data using over 100,000 individuals: An analysis of CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, Penta D, Penta E, TH01, TPOX and vWA loci

The Brazilian population is one of the most heterogeneous populations of the world, formed mainly by an admixture of European, African and Native American populations. Brazil is the fifth largest country in the world (8,511,960 km(2)), being divided into five geographical regions. This study provides population genetic data of up to 137,161 unrelated individuals representing the entire Brazilian territory. Allelic frequencies and other population data analysis are reported for the 15 autosomal STR loci included in the PowerPlex®16 kit (Promega Corporation, Madison, WI, USA). In order to guarantee that individuals were not related, we have considered only F1 data from couples undergoing paternity testing. The number of individuals genotyped for each locus was: CSF1PO (113,526); D3S1358 (135,133); D5S818 (135,181); D7S820 (137,136); D8S1179 (134,211); D13S317 (137,161); D16S539 (136,942); D18S51 (136,739); D21S11 (130,014); FGA (135,839); Penta D (110,333); Penta E (128,055); TH01 (112,695); TPOX (123,102); vWA (127,415). Allele sizes ranged from 1 to 48.2. Statistic parameters (PD, PIC and Ho; considering values ≥0.75) suggest that markers D13S317, D16S539, D18S51, D21S11, D7S820, D8S1179, Penta D, Penta E, TH01, FGA and vWA were more informative for genetic identification purposes in the Brazilian population.

Prevalence of C282Y and H63D mutations in the HFE gene of Brazilian individuals with clinical suspicion of hereditary hemochromatosis

A hemocromatose hereditaria classica (HH) e uma doenca autossomica recessiva caracterizada por uma sobrecarga sistemica de ferro, a qual esta frequentemente relacionada as mutacoes C282Y e H63D no gene HFE. No Brasil, registros das frequencias das mutacoes no gene HFE sao raros, principalmente envolvendo uma amostra representativa da populacao. Este estudo teve como objetivo a determinacao da prevalencia das mutacoes C282Y e H63D em individuos com suspeita clinica de HH. Para isto, foram estudados 1955 pacientes para os quais as mutacoes C282Y e H63D foram pesquisadas pela tecnica de Reacao em Cadeia da Polimerase seguida de digestao enzimatica. A amostra consistiu de 76,6% homens e 23,4% de mulheres. A maioria dos individuos analisados (56,9%) estava concentrada no grupo de 41 a 60 anos. Embora nao tenham sido observadas diferencas genicas e genotipicas entre os generos, foi observado um maior numero de mulheres na faixa etaria acima dos 60 anos A mutacao C282Y estava presente em homozigose em 2,9% dos individuos e em heterozigose em 10,1%, enquanto H63D estava presente em homozigose em 4,3% e em heterozigose em 30,6% dos individuos estudados. As frequencias dos alelos mutantes C282Y e H63D foram de 0,079 e 0,196, respectivamente. Alem de mais frequente entre a populacao estudada, a mutacao H63D mostrou equilibrio genetico, ao contrario da mutacao C282Y. Este trabalho tem como importância a determinacao do perfil genetico da populacao acometida pela HH no Brasil.

Assessment of microsatellite instability in colorectal cancer patients from Brazil

The replication error status analysis of DNA, through microsatellite instability detection, has become an indispensable tool for hereditary non-polyposis colorectal cancer screening. This study investigated the microsatellite instability in Brazilian individuals presenting colorectal cancer. In this study, 66 patients were clinically analyzed according to Amsterdam II and Bethesda guidelines. Normal and tumour tissues were collected and analyzed for MSI degree according to molecular markers BAT25, BAT26, BAT40, APC–D5S346, D2S123, and D17S250. Eight patients (12.1%) fulfilled the Amsterdam II guidelines, and 15 (22.7%) met the Bethesda guidelines. BAT25 was the most sensitive marker (86.7%), while BAT26 was the least sensitive (66.7%). The specificity of both markers was 100%, but all of the markers must be used since the contribution of each marker to the sensitivity and specificity of the test is complementary. Proximal tumours were significantly predominant among RER+ patients. Conclusions: Patients with a family history of colorectal cancer with the tumour in the proximal colon must be screened to replication error status as early as possible in order to avoid the progression of the disease.

Mutações predisponentes à trombofilia em indivíduos de Minas Gerais - Brasil com suspeita clínica de trombose

A trombose e reconhecidamente uma doenca de carater multifatorial. Sua ocorrencia esta intimamente relacionada a presenca de fatores geneticos e adquiridos que concorrem isoladamente ou em associacao para o seu desencadeamento. No entanto, a frequencia dos fatores geneticos pode variar de acordo com a origem etnica e com outros aspectos epidemiologicos dos grupos de individuos e populacoes estudadas. No Brasil, dados referentes a individuos brasileiros e em especial do estado de Minas Gerais sao escassos. O objetivo do presente estudo foi investigar a frequencia das mutacoes fator V Leiden e G20210A no gene protrombina em 1.103 individuos com suspeita clinica de trombofilia, empregando a tecnica da reacao em cadeia da polimerase seguida de restricao enzimatica (PCR-RFLP). Os dados foram analisados usando-se o programa Epi Info versao 6.04. A amostra consistiu de 76,16% mulheres e 23,84% homens, com media de idade de 43,06± 14,65. A mutacao fator V Leiden foi observada em heterozigose em 7,52% dos individuos e em 0,36% em homozigose. A mutacao G20210A no gene da protrombina apresentou-se em heterozigose em 5,90% dos individuos e em homozigose em 0,18%. O presente trabalho mostra a importância dos testes geneticos conforme o perfil da populacao analisada, ressaltando informacoes epidemiologicas da populacao brasileira e beneficios clinicos.

Fetal hemoglobin levels are related to metabolic control in diabetic subjects

We have investigated the relationship between fetal hemoglobin (HbF) levels and metabolic control in subjects with insulin-dependent (N = 79) and non-insulin-dependent diabetes mellitus (N = 242). HbF and hemoglobin A1c (HbA1c) levels were increased in subjects with type 1 and type 2 diabetes as compared to levels in nondiabetic individuals (P < 0.0001), and were significantly higher in type 1 than in type 2 diabetes subjects. Lower levels of HbA1c and HbF were observed in type 2 diabetes subjects treated by diet, intermediate levels in those treated with oral hypoglycemic agents, and higher levels in those treated with insulin. HbF and HbA1c levels were correlated in type 1 diabetes (R2 = 0.57, P < 0.0001) and type 2 diabetes (R2 = 0.58, P < 0.0001) subjects. Following intense treatment, twelve diabetic patients showed significant improvement both in HbA1c and HbF values. We conclude that increased HbF levels reflect poor metabolic control in subjects with diabetes mellitus.

Specific insulin and proinsulin secretion in glucokinase-deficient individuals

Glucokinase (GCK) is an enzyme that regulates insulin secretion, keeping glucose levels within a narrow range. Mutations in the glucokinase gene cause a rare form of diabetes called maturity-onset diabetes of the young (MODY). An early onset (less than 25 years), autosomal dominant inheritance and low insulin secretion stimulated by glucose characterize MODY patients. Specific insulin and proinsulin were measured in serum by immunofluorimetric assays (IFMA) during a 75-g oral glucose tolerance test (OGTT). Two kindreds (SA and LZ) were studied and compared to non-diabetic unrelated individuals (control group 1) matched for age and body mass index (BMI). In one kindred, some of these subjects were also obese (BMI > 26 kg/m2), and other family members also presented with obesity and/or late-onset NIDDM. The MODY patients were also compared to a group of five of their first-degree relatives with obesity and/or late-onset NIDDM. The proinsulin profile was different in members of the two MODY kindreds. Fasting proinsulin and the proinsulin/insulin ratio were similar in MODY members of kindred LZ and subjects from control group 1, but were significantly lower than in MODY members of kindred SA (P < 0.02 and P < 0.01, for proinsulin and proinsulin/insulin ratio, respectively). Moreover, MODY members of family SA had higher levels of proinsulin and proinsulin/insulin ratio, although not significantly different, when compared to their first-degree relatives and to subjects from control group 2. In conclusion, we observed variable degrees of proinsulin levels and proinsulin/insulin ratio in MODY members of two different kindreds. The higher values of these parameters found in MODY and non-MODY members of kindered SA is probably related to the obesity and late-onset NIDDM background present in this family.

Cutis laxa associated to cardiac failure

OBJECTIVE: To focus attention on a rare pathology of the childhood which presents premature aging of the skin and can be lethal. METHODS: The authors present a case of cutis laxa, syndrome of premature aging, in an eight year-old child, and discuss the classification, diagnosis and prognosis of the disease. RESULTS: The child presented signs of premature aging when he was four years-old. The diagnosis of cutis laxa was confirmed by skin biopsy. The patient presented heart failure, a systemic complication different from those previously described, and died at eight years of age. CONCLUSIONS: The importance of the diagnosis of cutis laxa resides in the fact that besides characteristic dermatological findings, there are frequent systemic complications that can be the focus of preventive measures, since there is no specific treatment for this disease. Genetic counseling is another important issue in this condition.

Paraganglioma funcionante do pescoço

Paragangliomas funcionantes sao tumores raros, produtores de catecolaminas que se originam da crista neural. Apresentamos o caso de um paciente de 11 anos com quadro de hipertensao arterial grave e massa em regiao cervical direita. Apresentou aumento das catecolaminas e metabolitos urinarios: epinefrina, 97,8 mg/24hs (Valor de Referencia (VR)= 0,5 a 20); norepinefrina, 184,8 mg/24hs (VR= 15 a 80); dopamina, 513,5 mg/24hs (VR= 65 a 400); metanefrina, 0,08 mg/g de creatinina (VR< 0,31); normetanefrina, 0,64 mg/g de creatinina (VR< 0,43); acido vanilmandelico, 69,3 mmol/24hs (VR= 10 a 35). A cintilografia com meta-iodo-benzil-guanidina (MIBG) mostrou a presenca de massa hiperfixante em regiao cervical direita, a qual foi confirmada pela ressonância magnetica (RM), que mostrou tambem uma lesao contra-lateral, que entretanto, nao apresentou captacao pelo MIBG. Foi realizada a exerese da lesao cervical direita, evoluindo com normalizacao dos niveis da pressao arterial, catecolaminas e metabolitos urinarios. A imuno-histoquimica identificou grânulos de secrecao para enolase neuroespecifica, neurofilamentos, cromogranina, somatostatina e serotonina, que confirmaram o diagnostico de paraganglioma funcionante, e identificou a presenca de anti-proteina S100, que e um preditor de bom prognostico. O paciente sera acompanhado com exames clinicos e laboratoriais periodicos, devido a lesao contra-lateral e para se detectar uma eventual recidiva do tumor a direita. Apesar da presenca de fatores de bom prognostico, estes tumores sao considerados potencialmente malignos.