RESUMO
Dentinogenesis imperfecta (DI) is the main orodental manifestation of osteogenesis imperfecta (OI) caused by COL1A1 or COL1A2 heterozygous pathogenic variants. Its prevalence varies according to the studied population. Here, we report the molecular analysis of 81 patients with OI followed at reference centers in Brazil and France presenting COL1A1 or COL1A2 variants. Patients were submitted to clinical and radiographic dental examinations to diagnose the presence of DI. In addition, a systematic literature search and a descriptive statistical analysis were performed to investigate OI/DI phenotype-genotype correlation in a worldwide sample. In our cohort, 50 patients had COL1A1 pathogenic variants, and 31 patients had COL1A2 variants. A total of 25 novel variants were identified. Overall, data from a total of 906 individuals with OI were assessed. Results show that DI was more frequent in severe and moderate OI cases. DI prevalence was also more often associated with COL1A2 (67.6%) than with COL1A1 variants (45.4%) because COL1A2 variants mainly lead to qualitative defects that predispose to DI more than quantitative defects. For the first time, 4 DI hotspots were identified. In addition, we showed that 1) glycine substitution by branched and charged amino acids in the α2(I) chain and 2) substitutions occurring in major ligand binding regions-MLRB2 in α1(I) and MLBR 3 in α2(I)-could significantly predict DI (P < 0.05). The accumulated variant data analysis in this study provides a further basis for increasing our comprehension to better predict the occurrence and severity of DI and appropriate OI patient management.
Assuntos
Cadeia alfa 1 do Colágeno Tipo I , Colágeno Tipo I , Dentinogênese Imperfeita , Osteogênese Imperfeita , Humanos , Colágeno Tipo I/genética , Dentinogênese Imperfeita/genética , Estudos de Associação Genética , Mutação , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/genéticaRESUMO
A series of 117 cases of Pierre Robin Sequence are classified as isolated (48%), syndromic (35%), and with associated anomalies (17%); the latter group had a poor long-term prognosis. In isolated Pierre Robin Sequence, familial cases and a high incidence of twins were noted. Among syndromic Pierre Robin Sequence, 4 syndromes represent more than 50% of the diagnoses.
Assuntos
Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/genética , Pré-Escolar , Feminino , Aconselhamento Genético , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Linhagem , Síndrome de Pierre Robin/mortalidade , Prognóstico , Taxa de SobrevidaRESUMO
Several mitochondrial diseases are known to occasionally involve the cerebral white matter, namely Leigh syndrome, Kearns-Sayre syndrome, and MELAS syndrome, but in these cases the major finding is alteration in the basal ganglia and brainstem. Here we report on severe diffuse white matter involvement and respiratory chain enzyme deficiency or mitochondrial DNA rearrangement in 5 unrelated families. It is interesting that white matter lesions were the only abnormal neuroradiologic feature in 3 of the 5 families, and multiple small cyst-like white matter lesions were found in 2 of 5 probands. Respiratory chain deficiency should be considered in the diagnosis of severe white matter involvement in childhood.
Assuntos
Encefalomiopatias Mitocondriais/etiologia , Adolescente , Encéfalo/patologia , Criança , Deficiência de Citocromo-c Oxidase , DNA Mitocondrial/genética , Transporte de Elétrons , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/patologia , Fosforilação Oxidativa , Succinato Citocromo c Oxirredutase/deficiênciaRESUMO
Inborn errors of oxidative phosphorylation have been recognized as possible causes of hepatic failure in the neonate, and respiratory enzyme deficiencies have been described in the liver of affected individuals. On the basis of a series of 22 cases, we describe respiratory enzyme deficiency as a cause of early-onset fatal hepatic failure with frequent neurologic involvement. In addition, we have identified a delayed-onset form of hepatic failure with a milder clinical course and inconstant neurologic involvement. Thus we suggest that genetic defects of oxidative phosphorylation be considered as a cause of liver dysfunction in infancy, regardless of the severity of the disease.
Assuntos
Falência Hepática/genética , Erros Inatos do Metabolismo/genética , Complexos Multienzimáticos/deficiência , Fosforilação Oxidativa , Alanina Transaminase/metabolismo , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Falência Hepática/enzimologia , Falência Hepática/mortalidade , Erros Inatos do Metabolismo/enzimologia , Complexos Multienzimáticos/metabolismoRESUMO
We report two unrelated children with onset of chronic diarrhea and villous atrophy in the first years of life. Elevated plasma lactate concentrations and lactate/pyruvate and ketone body molar ratios suggested a genetic defect of oxidative phosphorylation. Analysis of the mitochondrial respiratory chain showed a complex III deficiency in muscle of both patients. Southern blot analysis provided evidence of heteroplasmic mitochondrial DNA rearrangements that involve deletion and deletion-duplication. Directly repeated sequences (10 and 11 base pairs, respectively) were present in the wild type of mitochondrial genome at the boundaries of the deletion. Neither parent of either patient had rearranged molecules in their circulating lymphocytes. It appears that a mitochondrial disorder can have chronic diarrhea and villous atrophy as the initial clinical feature. On the basis of these observations, we suggest that genetic defects of mitochondrial energy supply be considered in elucidating the origin of unexplained chronic diarrheas, especially when other, unrelated symptoms occur in the course of the disease.