Distrofia muscular de cinturas : análise clínica, laboratorial, eletromiográfica, histopatológica, imunohistoquímica e por Western Blot de 56 casos

Orientador : Lineu César WerneckTese(doutorado) - Universidade Federal do Paraná, Setor de Ciencias da Saúde, Curso de Pós-Graduaçao em Medicina Interna. Defesa: Curitiba, 2003Inclui bibliografiaÁrea de concentraçao: Medicina InternaResumo: A distrofia muscular de cintura (DMC) representa um grupo clinico e geneticamente heterogêneo de doenças musculares degenerativas de herança autossômica dominante e recessiva, classificadas geneticamente. Com o objetivo de melhorar a abordagem diagnostica, 56 pacientes com diagnostico sugestivo de DMC, 32 masculinos e 24 femininos, submeteram-se a avaliação clinica, laboratorial, eletromiografica, histopatologica e imuno-histoquimica. A idade de inicio dos sintomas variou entre 7 meses e 56 anos. Na apresentação dos sintomas, houve o comprometimento da musculatura dos membros inferiores em 37 casos, dos membros superiores em 12 e ambos em 7. Observou-se atrofia da cintura escapular em 37 casos e da pélvica em 30. Apenas 5 pacientes tiveram hipertrofia de panturrilhas. A fraqueza da musculatura proximal dos membros superiores e inferiores, a marcha miopatica e a manobra de Gowers foram observadas na maioria dos casos. A perda da marcha ocorreu em 5 casos. Houve elevação importante dos níveis séricos de creatinaquinase (CK) em 21 casos. A eletromiografia (EMG) e a biopsia muscular apresentaram padrão miopatico na maioria dos casos. A analise da distrofina foi normal em todas as biopsias musculares. A presença isolada do padrão neurogênico na biopsia muscular não serviu como critério de exclusão. Houve deficiência de a-sarcoglicano em 14, de 3-sarcoglicano em 10, de Y-sarcoglicano em 11, de o- sarcoglicano em 13, de disferlina em 8 e de calpaina-3 em 5 casos. A deficiência na imunoidentificação das proteínas a, p, y e o-sarcoglicano permitiu classificar os casos no grupo das sarcoglicanopatias; de y-sarcoglicano, como ysarcoglicanopatia; de disferlina, como disferlinopatia, e de calpaina-3, como calpainopatia. Os casos de sarcoglicanopatias foram mais frequentes, seguidos da disferlinopatia e da calpainopatia. A hipertrofia de panturrilhas ocorreu apenas no grupo com deficiência do complexo SG. Os casos com deficiência de calpaina-3 ocorreram mais no sexo masculino, tiveram inicio mais precoce e houve maior comprometimento da forca muscular. Os casos com deficiência de disferlina ocorreram mais no sexo feminino e tiveram inicio mais tardio em relação a calpainopatia e as sarcoglicanopatias.Abstract: The limb-girdle muscle dystrophy represents a heterogeneous group of muscular diseases with dominant and recessive inheritance, individualized by gene mutation. A heterogeneous group of 56 six patients, 32 males and 24 females, with suggestive LGMD diagnosis was clinical, laboratory, electromyography, muscle biopsy and immunohistochemical evaluated to make a diagnostic approach. The onset ranged from 7 month to 57 years. The symptoms onsets were present by lower limbs in 37 cases, 12 in the upper and 7 in both. Scapular girdle atrophy was observed in 37 cases and pelvic in 30. Only 5 patients had calf hypertrophy. The weakness of proximal upper and lowers muscles, the myopathic gait and the Gowers sing was observed in most of cases. The loss of ambulation was observed only in 5. Very high CK serum levels occurred in 21. The electromyography and muscle biopsy showed myopathic pattern in most of cases. An isolated neurogenic pattern in the muscular biopsy doesn't exclude the diagnosis. The dystrophin was normal in all muscle biopsy. Deficiency of a-sarcoglycan was observed in 14, to 3- sarcoglycan in 10, to ysarcoglycan in 11, to 5- sarcoglycan in 13, dysferlin in 8 e calpain-3 in 5 cases. The cases with deficiency of tx, 3, y and 8-sarcoglycan were classified on to sarcoglycan group, y-sarcoglycan deficiency as y-sarcoglycanopathy, dysferlin deficiency as dysferlinopathy and calpain-3 deficiency as calpainopathy. The sarcoglycan deficiency group was more frequent, followed by the dysferlin and calpain-3 groups. Only the sarcoglycan deficiency group showed calf hypertrophy. The dysferlin deficiency group was more frequent in females and the onset was later then sarcoglican and calpain-3 deficiency groups. The calpain-3 deficiency group occurred only in males and showed an earlier onset and more muscular weakness

Uncontrolled headache induced by oxcarbazepine

Headache induced by acute exposure to a specific drug constitutes an idiosyncratic side effect. Metabolic imbalance appears as the leading aetiology, among several other hypotheses. Either primary headaches show a higher susceptibility to this idiosyncratic reaction or a drug-induced primary headache evolves in intensity and duration, becoming uncontrolled until the complete discontinuation of the drug in consideration. The goal of this study is to describe three patients diagnosed with migraine and epilepsy (both under control) who evolved into status migrainosus after the introduction of oxcarbazepine (OXC), as part of a switch off from carbamazepine (CBZ). Twenty-four to seventy-two hours following the switch, all patients developed intractable headache, despite the use of different symptomatic drugs. Complete recovery of the headache symptoms occurred only after OXC was discontinued. We discuss the potential mechanisms associated to OXC and status migrainosus, drug-induced headaches and uncontrolled headaches

Guidelines for the diagnosis, treatment and clinical monitoring of patients with juvenile and adult Pompe disease

Pompe disease (PD) is a potentially lethal illness involving irreversible muscle damage resulting from glycogen storage in muscle fiber and activation of autophagic pathways. A promising therapeutic perspective for PD is enzyme replacement therapy (ERT) with the human recombinant enzyme acid alpha-glucosidase (Myozyme (R)). The need to organize a diagnostic flowchart, systematize clinical follow-up, and establish new therapeutic recommendations has become vital, as ERT ensures greater patient longevity. A task force of experienced clinicians outlined a protocol for diagnosis, monitoring, treatment, genetic counseling, and rehabilitation for PD patients. The study was conducted under the coordination of REBREPOM, the Brazilian Network for Studies of PD. The meeting of these experts took place in October 2013, at L'Hotel Port Bay in Sao Paulo, Brazil. In August 2014, the text was reassessed and updated. Given the rarity of PD and limited high-impact publications, experts submitted their views.Inst Fernandes Figueira FIOCRUZ, Dept Med Genet, Rio De Janeiro, RJ, BrazilUniv Fed Fluminense, Dept Neurol & NeuroUPC, BR-22031171 Rio De Janeiro, RJ, BrazilUniv Fed Sao Paulo, Dept Neurol, Sao Paulo, SP, BrazilUniv Fed Rio Grande do Norte, Dept Neurol, Caiaco, RN, BrazilClin Marrone, Porto Alegre, RS, BrazilUniv Cuiaba, Dept Neurol, Cuiaba, MT, BrazilUniv Sao Paulo, Dept Neurociencias, BR-14049 Ribeirao Preto, SP, BrazilHosp Base Dist Fed, Serv Neurol, Brasilia, DF, BrazilUniv Fed Parana, Serv Doencas Neuromusculares, BR-80060000 Curitiba, Parana, BrazilUniv Fed Sao Paulo, Dept Neurol, Sao Paulo, SP, BrazilWeb of Scienc

Identification and Functional Characterization of a Novel Mutation in theNKX2-1Gene: Comparison with the Data in the Literature

Background: NKX2-1 mutations have been described in several patients with primary congenital hypothyroidism, respiratory distress, and benign hereditary chorea, which are classical manifestations of the brain-thyroid-lung syndrome (BTLS). Methods: The NKX2-1 gene was sequenced in the members of a Brazilian family with clinical features of BTLS, and a novel monoallelic mutation was identified in the affected patients. We introduced the mutation in an expression vector for the functional characterization by transfection experiments using both thyroidal and lung-specific promoters. Results: The mutation is a deletion of a cytosine at position 834 (ref. sequence NM-003317) (c.493delC) that causes a frameshift with formation of an abnormal protein from amino acid 165 and a premature stop at position 196. The last amino acid of the nuclear localization signal, the whole homeodomain, and the carboxy-terminus of NKX2-1 are all missing in the mutant protein, which has a premature stop codon at position 196 (p.Arg165Glyfs*32). The p.Arg165Glyfs*32 mutant does not bind DNA, and it is unable to transactivate the thyroglobulin (Tg) and the surfactant protein-C (SP-C) promoters. Interestingly, a dose-dependent dominant negative effect of the p.Arg165Glyfs*32 was demonstrated only on the Tg promoter, but not on the SP-C promoter. This effect was also noticed when the mutation was tested in presence of PAX8 or cofactors that synergize with NKX2-1 (P300 and TAZ). The functional effect was also compared with the data present in the literature and demonstrated that, so far, it is very difficult to establish a specific correlation among NKX2-1 mutations, their functional consequence, and the clinical phenotype of affected patients, thus suggesting that the detailed mechanisms of transcriptional regulation still remain unclear. Conclusions: We describe a novel NKX2-1 mutation and demonstrate that haploinsufficiency may not be the only explanation for BTLS. Our results indicate that NKX2-1 activity is also finely regulated in a tissue-specific manner, and additional studies are required to better understand the complexities of genotype-phenotype correlations in the NKX2-1 deficiency syndrome