A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.

Association of polymorphisms at the ADIPOR1 regulatory region with type 2 diabetes and body mass index in a Brazilian population with European or African ancestry

Association studies between ADIPOR1 genetic variants and predisposition to type 2 diabetes (DM2) have provided contradictory results. We determined if two single nucleotide polymorphisms (SNP c.-8503G>A and SNP c.10225C>G) in regulatory regions of ADIPOR1 in 567 Brazilian individuals of European (EA; N = 443) or African (AfA; N = 124) ancestry from rural (quilombo remnants; N = 439) and urban (N = 567) areas. We detected a significant effect of ethnicity on the distribution of the allelic frequencies of both SNPs in these populations (EA: -8503A = 0.27; AfA: -8503A = 0.16; P = 0.001 and EA: 10225G = 0.35; AfA: 10225G = 0.51; P < 0.001). Neither of the polymorphisms were associated with DM2 in the case-control study in EA (SNP c.-8503G>A: DM2 group -8503A = 0.26; control group -8503A = 0.30; P = 0.14/SNP 10225C>G: DM2 group 10225G = 0.37; control group 10225G = 0.32; P = 0.40) and AfA populations (SNP c.-8503G>A: DM2 group -8503A = 0.16; control group -8503A = 0.15; P = 0.34/SNP 10225C>G: DM2 group 10225G = 0.51; control group 10225G = 0.52; P = 0.50). Similarly, none of the polymorphisms were associated with metabolic/anthropometric risk factors for DM2 in any of the three populations, except for HDL cholesterol, which was significantly higher in AfA heterozygotes (GC = 53.75 ± 17.26 mg/dL) than in homozygotes. We conclude that ADIPOR1 polymorphisms are unlikely to be major risk factors for DM2 or for metabolic/anthropometric measurements that represent risk factors for DM2 in populations of European and African ancestries.

Effect of polymorphisms of the MTHFR and APOE genes on susceptibility to diabetes and severity of diabetic retinopathy in Brazilian patients

Diabetes mellitus (DM) is a highly prevalent complex genetic disorder. There has been a worldwide effort in the identification of susceptibility genes for DM and its complications, and the 5-10-methylenetetrahydrofolate reductase (MTHFR) and apolipoprotein-E (APOE) genes have been considered good candidate susceptibility genes to this condition. The objectives of the present study were to determine if the 677T MTHFR and epsilon2/epsilon3/epsilon4 APOE alleles are risk factors for DM and for severity of diabetic retinopathy (DR). A total of 248 individuals were studied: 107 healthy individuals and 141 diabetic patients (46 with type 1 diabetes and 95 with type 2 diabetes), who also had DR (81 with non-proliferative DR and 60 with proliferative DR). The polymorphisms were analyzed by PCR followed by digestion with restriction enzyme or the single-nucleotide primer extension method. No evidence of association between the 677TT genotype of MTHFR gene and DM [cases: TT = 10/95 (10.6 percent); controls: TT = 14/107 (13 percent)] or with severity of DR was observed [cases: TT = 5/60 (8.5 percent); controls: TT = 9/81 (11.1 percent); P > 0.05]. We also did not find evidence of an association between APOE alleles and proliferative DR (epsilon2, epsilon3 and epsilon4 in cases: 9, 76, and 15 percent, and in controls: 5, 88, and 12 percent, respectively) but the carriers of epsilon2 allele were more frequent among patients with type 2 DM and DR than in controls [cases: 15/95 (15.8 percent); controls: 7/107 (6.5 percent); P < 0.05]. Therefore, our results suggest that the epsilon2 allele/APOE might be a risk factor for diabetes in the Brazilian population.

Clinical and molecular analysis of spinal muscular atrophy in brazilian patients

As amiotrofias espinhais progressivas (SMAs) constituem as doenças degenerativas de origem genética letais mais comuns do sistema nervoso central e mais freqüentes dentre as doenças autossômicas recessivas após a mucoviscidose. A incidência estimada das SMAs e de aproximadamente 1:10.000 nativivos. Clinicamente, as SMAs säo classificadas em mais grave (doença de Werdnig-Hoffmann, tipo I), intermediária (tipo II) e tardia e benigna (doença de Kugelberg-Welander, tipo III). O gene para os três tipos de SMAs foi mapeado no cromossomo 5q11.2-13.3. Foram identificados dois genes candidatos na mesma regiäo: SMN (sobrevida do neurônio motor) e NAIP (proteína inibidora de apoptose neuronal). Estudamos ambos genes em 87 pacientes brasileiros (20 tipo I, 14 tipo II e 53 tipo III) pertencentes a 74 famílias, utilizando as técnicas de PCR e SSCP. Foi encontrada deleçäo nos exons 7 e/ou 8 do gene SMN em 69 por cento das famílias: 16/20 na tipo I, 9/12 na tipo II e 26/42 na tipo III. Dentre as 51 famílias com deleçäo, 44 tiveram deleçäo no exon 5 do gene NAIP foi encontrada em 7/20 na tipo I, 2/12 na tipo II e 1/42 na tipo III. Näo foi encontrada deleçäo nos genes SMN e NAIP nos 112 progenitores, 26 irmandades assintomáticas e 104 controles normais. Näo houve correlaçäo entre deleçäo de um ou ambos genes com a gravidade do quadro clínico.

The impact of molecular biology for the understanding and prevention of hereditary myopathies in the Brazilian population

The localization and cloning of the gene resposible for Duchenne/Becker muscular dystrophy followed by the identification of its product brought great advances to the field of muscular dystrophies. More recently, other genes responsible for other forms of muscular dystrophies have been identified such as: limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy and myotonic dystrophy. Our group has already studied over 9,000 individuals belonging to families with patients affected by different forms of hereditary myopathies. In this article we are illustrating how the introduction of molecular biology technology improved clinical and differential diagnosis, the preventionnn of new cases (through identification of carriers and prenatal diagnosis) and the comprehension of the underlying pathological mechanisms which will be fundamental for future treatments based on gene therapy.