Predominance of the T14484C mutation in French-Canadian families with Leber hereditary optic neuropathy is due to a founder effect.
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Canada↗
Biomedical subjects
C Macmillan
Publications and source records attributed to C Macmillan.
Genetics and developmental delay.
The discovery of new cytogenetic and molecular genetic techniques and principles has been explosive in recent years. A secure diagnosis based on molecular evidence has become possible for many syndromes previously only clinically defined, which has helped enormously in predicting children's developmental progress, in allowing knowledgeable surveillance for potential associated health problems, in genetic counseling, and in prenatal diagnosis. This article reviews several of the most significant recently described cytogenetic and molecular genetic principles and techniques in relation to the child who presents with developmental delay.
Child↗
SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome.
Leigh Syndrome (LS) is a severe neurological disorder characterized by bilaterally symmetrical necrotic lesions in subcortical brain regions that is commonly associated with systemic cytochrome c oxidase (COX) deficiency. COX deficiency is an autosomal recessive trait and most patients belong to a single genetic complementation group. DNA sequence analysis of the genes encoding the structural subunits of the COX complex has failed to identify a pathogenic mutation. Using microcell-mediated chromosome transfer, we mapped the gene defect in this disorder to chromosome 9q34 by complementation of the respiratory chain deficiency in patient fibroblasts. Analysis of a candidate gene (SURF1) of unknown function revealed several mutations, all of which predict a truncated protein. These data suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease.
Amino Acid Sequence↗
Pedigree analysis of French Canadian families with T14484C Leber's hereditary optic neuropathy.
We analyzed the clinical phenotype and determined the recurrence risks to relatives of patients with T14484C Leber's hereditary optic neuropathy (LHON). LHON is a maternally inherited optic neuropathy that primarily affects adolescent males. It is usually associated with one of three mtDNA mutations: G3460A, G11778A, or T14484C. Definition of recurrence risks for the T14484C mutation previously has not been possible due to the relative scarcity of families with this mutation. We obtained blood samples from index patients and their consenting family members, all of whom were of French Canadian ancestry and screened for LHON mutations in mtDNA. Referring ophthalmologists furnished clinical summaries and patients provided pedigree data. T14484C was the most common mutation in the pedigrees analyzed and was always homoplasmic. In these pedigrees, the ratio of affected males to females was 8:1. Median age at onset for males was 19 years (95th percentile, 40.8 years; range, 6 to 48 years). Some improvement of vision was observed in 58% of patients. Recurrence risks to brothers were 28%, sisters 5%, nephews 30%, nieces 3%, male matrilineal first cousins 19%, and female matrilineal first cousins 4%. Recurrence risks to brothers and nephews were not different; however, recurrence risks to brothers and male cousins and to nephews and male cousins were significantly different. There were no differences in recurrence risks to sisters and nieces or to either group compared with their female cousins. Affected females did not have more affected children than unaffected females. The clinical characteristics of French Canadian patients with T14484C LHON were strikingly similar to those in previous reports, suggesting that recurrence risks are generalizable to other T14484C LHON populations for genetic counseling of T14484C LHON families.
Adolescent↗
Histologic and histochemical changes in failed auricular cartilage grafts used for a temporomandibular joint disc replacement: a report of three cases and review of the literature.
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Adult↗
Impairment of force generation after adenovirus-mediated gene transfer to muscle is alleviated by adenoviral gene inactivation and host CD8+ T cell deficiency.
Recombinant adenovirus vectors (AdV) hold promise as a means of delivering therapeutic genes to muscle in diseases such as Duchenne muscular dystrophy (DMD). However, we have previously shown that the use of AdV is hampered by the development of reduced force-generating capacity, which occurs within 1 week and is progressive up to at least 1 month after AdV delivery in immune-competent animals. Determinations of muscle force production provide a sensitive and clinically important measure of potential adverse effects of AdV-mediated gene transfer on muscle cell function. In the present study, we investigated the role of AdV-related gene expression and host T lymphocyte responses in the genesis of muscle dysfunction following AdV injection of muscle. We report that UV-irradiation of AdV particles, which reduced AdV transcriptional activity without impairing infectivity (as confirmed by in situ polymerase chain reaction), significantly reversed early (4 days post-injection) AdV-induced contractile impairment in immune-competent mice as well as in mice lacking effective CD8+ T cell activity. The superimposed additional reduction in force-generating capacity normally found between 4 and 30 days post-AdV delivery in immune-competent mice, along with the associated loss of transgene (beta-galactosidase) expression, was largely abrogated by the absence of an intact CD8+ T lymphocyte response. Furthermore, short-term administration of a neutralizing antibody against CD4+ T cells significantly prolonged transgene expression and showed a trend toward mitigation of AdV-induced reductions in force-generating capacity. Cellular infiltration and humoral immune responses against the vector and transgene product were also blunted to varying degrees in the setting of CD8+ or CD4+ T cell deficiency. We conclude that AdV-related gene expression has an early negative (probably toxic) effect on muscle cell function that is independent of CD8+ T cell-mediated immunity. In contrast, further progression of contractile impairment and the accompanying loss of transgene expression from AdV-injected muscle are largely dependent upon the activity of CD8+ T cells. These results have implications for the design of future generation vectors and the potential need for immunosuppressive therapy after AdV-mediated gene transfer to muscle.
Adenoviridae↗
Variable distribution of mutant mitochondrial DNAs (tRNA(Leu[3243])) in tissues of symptomatic relatives with MELAS: the role of mitotic segregation.
We studied multiple different postmortem tissue samples from a woman and two of her daughters with the MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) tRNA(Leu(UUR)) mutation at nucleotide 3243 in mitochondrial DNA (mtDNA). All tissues examined were heteroplasmic for the mutation. The mean proportion of mutant mtDNAs in the mother's tissues (0.30 +/- 0.10) was significantly lower than that of each of her daughters' (0.76 +/- 0.11, p < 0.03, and 0.72 +/- 0.13, p < 0.001); there was no difference in the fraction of mutant mtDNAs between the daughters (p < 0.71). This difference in the mean proportion of mtDNA mutants between family members correlates with their clinical profiles; the mother had the latest onset of disease and lived longest, while the two daughters had a strikingly similar clinical course. In individual patients, the mean proportion of mutant mtDNAs was not different in tissues deriving from ectodermal, mesodermal, and endodermal germ layers. Variance in the mutant:wild-type mtDNA ratio was normally distributed about the mean, both when all tissues were considered together and when different regions of the CNS were considered separately. Thus, the proportion of mtDNAs carrying the tRNA(Leu(3243)) mutation was not uniform in members of this pedigree and did not undergo rapid mitotic segregation along germ-layer divisions. These findings are consistent with the hypothesis that the overall proportion of mtDNAs carrying this mutation is primarily determined by segregation during oogenesis or early embryologic development and that random replicative (mitotic) segregation, subsequent to the establishment of primary germ layers, is responsible for the variation between tissues.
Adolescent↗
Plasma corticosterone concentrations in growing chickens fed diets formulated to promote different rates of growth.
No significant differences in plasma corticosterone concentrations were noted among chicks fed diets containing 16 to 25% protein or diets containing 2,800, 3,200, or 3,600 kcal metabolizable energy per kg to 6 wk of age. The ingredients used in diet formulation did, however, affect plasma corticosterone. Higher plasma corticosterone was associated with 2,800-kcal diets containing high concentrations of cornstarch and no cereal grains compared with 2,800-kcal diets containing low concentrations of cornstarch and cereal grains. In a second experiment, chicks were fed diets containing different concentrations of lysine and methionine from hatching to 4 wk of age. Half the chicks on each dietary treatment were conditioned to handling by daily gentling. Plasma corticosterone concentrations were reduced in the conditioned chicks. Plasma corticosterone increased during a period of up to 15 min after catching when the chicks were kept in a box prior to drawing blood samples. Excess dietary lysine significantly reduced plasma corticosterone in the gentled chicks but not in the control chicks.
Animal Nutritional Physiological Phenomena↗
Nasopharyngeal suction study reveals knowledge deficit.
Nasopharyngeal suction is carried out frequently in paediatric practice. A questionnaire survey was distributed to nurses and physiotherapists at The Royal Hospital for Sick Children in Edinburgh to ascertain the extent of their knowledge in the theory and practice of suctioning. Results revealed several problem areas in use of nasopharyngeal suction at this hospital. There was significant disagreement over appropriate catheter size, suction pressure and method of suction as well as use of pre-oxygenation and knowledge of adverse effects. The results indicate that further theoretical and practical education is needed in the use of nasopharyngeal suction and that a standard method should be implemented throughout the hospital.
Child↗