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N Howell

Publications and source records attributed to N Howell.

At least 37 records · Page 2Linked to original sources
PubMed1997

The epidemiology of nontuberculous mycobacterial lymphadenitis affecting New Zealand children 1986-95.

AIMS: To study the epidemiological trends of nontuberculous mycobacterial lymphadenitis affecting New Zealand children from 1986-95. METHODS: Cases were identified from the records of the three regional reference laboratories in New Zealand. All children of less than 16 years with a positive culture of nontuberculous mycobacteria from a lymph node tissue sample were included. RESULTS: One hundred and sixty eight cases were identified, 43 in the first 5 years (no data available from Waikato) and 125 in the second 5 years of the study period. One hundred and fifty three (91%) of cases were in the 0-5 year age group and 101 (60%) were female. The head and neck was the most common site of infection accounting for 141 (84%) of all infection. In 161 (96%) of cases the causative organism was Mycobacterium avium intracellulare complex. CONCLUSION: Nontuberculous mycobacterial infections cause a subacute lymphadenitis in preschool children, usually affecting the lymph nodes of the head and neck. The annual number of microbiologically confirmed cases in New Zealand had increased substantially over recent years, most notably since 1992. The reason for the increase is unknown but possible explanations include increased awareness of mycobacterial disease, external factors causing either changes in the distribution or virulence of mycobacteria in the environment and alterations in the human immune response.

Adolescent↗
PubMed1997

Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease.

Mounting evidence suggests that defects in energy metabolism contribute to the pathogenesis of Alzheimer disease (AD). Cytochrome c oxidase (CO) is kinetically abnormal, and its activity is decreased in brain and peripheral tissue in late-onset AD. CO is encoded by both the mitochondrial and the nuclear genomes. Its catalytic centers, however, are encoded exclusively by two mitochondrial genes, CO1 and CO2 (encoding CO subunits I and II, respectively). We searched these genes, as well as other mitochondrial genes, for mutations that might alter CO activity and cosegregate with AD. In the present study, specific missense mutations in the mitochondrial CO1 and CO2 genes but not the CO3 gene were found to segregate at a higher frequency with AD compared with other neurodegenerative or metabolic diseases. These mutations appear together in the same mitochondrial DNA molecule and define a unique mutant mitochondrial genome. Asymptomatic offspring of AD mothers had higher levels of these mutations than offspring of AD fathers, suggesting that these mutations can be maternally inherited. Cell lines expressing these mutant mitochondrial DNA molecules exhibited a specific decrease in CO activity and increased production of reactive oxygen species. We suggest that specific point mutations in the CO1 and CO2 genes cause the CO defect in AD. A CO defect may represent a primary etiologic event, directly participating in a cascade of events that results in AD.

Aged↗
PubMed1997

Maternally inherited diabetes and deafness: prevalence in a hospital diabetic population.

Maternally inherited diabetes and deafness (MIDD) is a new sub-type of diabetes and results from an A to G substitution at position 3243 of the mitochondrial tRNA(leu(UUR)) gene. This mutation is also associated with a neurological syndrome (MELAS). Recent studies have screened carefully selected diabetic populations and have reported MIDD prevalence rates ranging from undetectable to 60%. The aim of this work was to determine the importance of this sub-type in clinical practice by screening a routine hospital diabetic population. A total of 1440 patients (IDDM and NIDDM) of North European extraction attending two hospital diabetes services were initially screened by questionnaire. This identified 445 patients with one or more features of MIDD and/or MELAS and these subjects were then genotyped. Two patients were identified with the mutation giving a prevalence rate of 0.13% for the whole study population, and 0.45% for the sample with phenotypic features of MIDD. In conclusion, therefore, the 3243 mutation is associated with the phenotypically distinct MIDD sub-type, but this is rare in the routine hospital diabetic population.

Adult↗
PubMed1997

Leber hereditary optic neuropathy: mitochondrial mutations and degeneration of the optic nerve.

The predominant manifestation of Leber hereditary optic neuropathy (LHON) is a sudden and usually severe bilateral loss of central vision, most often in the mid-20s, that is due to a degeneration of the ganglion cell layer and optic nerve. LHON is an inherited form of blindness in which a mutation in the mitochondrial genome (mtDNA) is the primary etiological event. More than 95% of the LHON pedigrees in peoples of Northern European descent harbor one of the three mitochondrial mutations at nucleotides 3460, 11,778 and 14,484, although there are other rare primary mutations. In addition, there may be mtDNA mutations that have a secondary etiological role. The penetrance of the optic neuropathy is incomplete in LHON families, and males are affected much more often then females. The incomplete penetrance indicates that secondary etiological factors are necessary for the development of the optic neuropathy, although they are poorly understood at the present time. Several types of studies suggest that optic nerve function in LHON patients is impaired in the presymptomatic phase, probably as a result of a mitochondrial respiratory chain abnormality, although visual acuity is not compromised. In some family members, the presence of secondary etiological factors triggers a wave of optic nerve dysfunction in which vision is lost (the acute phase). Depending upon the particular primary LHON mutation that the patient carries, a variable proportion of the dysfunctional ganglion cells and optic nerve axons die during the atrophic phase, probably through an apoptotic pathway. In 11,778 LHON patients, retinal ganglion cell degeneration occurs almost without exception, and recovery of vision is extremely rare. In contrast, activation of the cell death pathway is less frequent, or less extensive, in 14,484 LHON patients and there is often a substantial recovery of vision.

DNA, Mitochondrial↗
PubMed1997

Mammalian mitochondrial genetics: heredity, heteroplasmy and disease.

Mammalian mitochondrial DNA (mtDNA) is present at high copy number (10(3)-10(4) copies) in virtually all cells of the body. The mitochondrial genome shows strict maternal inheritance and the vast majority of copies are identical at birth (homoplasmy). Occasionally, a subpopulation of mtDNA molecules carry a pathogenic mutation. When this heteroplasmic mtDNA is present during embryogenesis, it can lead to a variety of clinical symptoms predominantly affecting muscle and nerve, but also affecting other tissues. While the importance of mitochodrial heteroplasmy in human disease is unquestioned, we remain largely ignorant of many fundamental aspects of mitochondrial genetics. How do mutations arise and can they be repaired, what influences the segregation and fixation of heteroplasmic mtDNA, do levels of heteroplasmy fluctuate during life, is it possible to modulate these levels by external intervention and, finally, can we predict the segregation and transmission of a mutant genome? The aim of this article is to summarize and discuss recent observations that have addressed several of these fundamental issues and to reiterate how much we still have to learn about mitochondrial genetics.

Animals↗
PubMed1997

Leber hereditary optic neuropathy: how do mitochondrial DNA mutations cause degeneration of the optic nerve?

Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiological event is a mutation in the mitochondrial genome. The optic neuropathy involves a loss of central vision due to degeneration of the retinal ganglion cells and optic nerve axons that subserve central vision. The primary mitochondrial mutation is necessary--but not sufficient--for development of the optic neuropathy, and secondary genetic and/or epigenetic risk factors must also be present although they are poorly defined at the present time. There is broad agreement that mutations at nucleotides 3460, 11778, and 14484 are primary LHON mutations, but there may also be other rare primary mutations. It appears that the three primary LHON mutations are associated with respiratory chain dysfunction, but the derangements may be relatively subtle. There is also debate on whether there are mitochondrial mutations that have a secondary etiological or pathogenic role in LHON. The specific pattern of the optic neuropathy may arise from a "chokepoint" in the optic nerve in the region of the nerve head and lamina cribosa, and which may be more severe in those LHON family members who become visually affected. It is hypothesized that the respiratory chain dysfunction leads to axoplasmic stasis and swelling, thereby blocking ganglion cell function and causing loss of vision. In some LHON patients, this loss of function is reversible in a substantial number of ganglion cells, but in others, a cell death pathway (probably apoptotic) is activated with subsequent extensive degeneration of the retinal ganglion cell layer and optic nerve.

DNA, Mitochondrial↗
PubMed1997

Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes.

Many patients with inherited mitochondrial encephalopathies have one of two pathogenic mutations of mitochondrial DNA (mtDNA): A3243G or A8344G. Individuals who harbour these mutations carry both mutant and wild-type alleles within each cell (heteroplasmy). Despite clear evidence of a direct relationship between the level of mutation and mitochondrial respiratory chain function in vitro, it has been more difficult to demonstrate a clear correlation between clinical phenotype and the level of mutant mtDNA in vivo. To address this issue, we identified 245 individuals who carry either the A3243G or A8344G mutations, and studied the relationship between the incidence of specific clinical features and the level of mutant mtDNA in blood (for A3243G, n = 73; for A8344G, n = 25) and/or skeletal muscle (for A3234G, n = 111; for A8344G, n = 55). Within this study group, the frequency of key clinical features was significantly different for individuals harbouring the A3243G and A8344G mutations. For both mutations, there was a correlation between the frequency of the more common clinical features and the level of mutant mtDNA in muscle. In contrast, we did not observe a correlation between the frequency of clinical features and the level of mutant mtDNA in blood. Therefore, measurement of the level of the A3243G and A8344G mutations in muscle will allow the identification of individuals who are at risk of developing specific complications, thus improving the prognostic advice that can be given to patients and family members who carry these mutations.

DNA, Mitochondrial↗
PubMed1996

Association of the mitochondrial 8344 MERRF mutation with maternally inherited spinocerebellar degeneration and Leigh disease.

We report previously undescribed or atypical clinical and biochemical manifestations of the mitochondrial DNA MERRF mutation at nucleotide 8344 in members of a multigenerational family with maternally inherited, highly variable neurodegenerative disorder. The more profound neurologic abnormalities include Leigh disease, spinocerebellar degeneration, and atypical Charcot-Marie-Tooth disease.

Adult↗
PubMed1996

Longitudinal study of a heteroplasmic 3460 Leber hereditary optic neuropathy family by multiplexed primer-extension analysis and nucleotide sequencing.

Nucleotide-sequencing and multiplexed primer-extension assays have been used to quantitate the mutant-allele frequency in 14 maternal relatives, spanning three generations, from a family that is heteroplasmic for the primary Leber hereditary optic neuropathy (LHON) mutation at nucleotide 3460 of the mitochondrial genome. There was excellent agreement between the values that were obtained with the two different methods. The longitudinal study shows that the mutant-allele frequency was constant within individual family members over a sampling period of 3.5 years. Second, although there was an overall increase in the mutant-allele frequency in successive generations, segregation in the direction of the mutant allele was not invariant, and there was one instance in which there was a significant decrease in the frequency from parent to offspring. From these two sets of results, and from previous studies of heteroplasmic LHON families, we conclude that there is no evidence for a marked selective pressure that determines the replication, segregation, or transmission of primary LHON mutations to white blood cells and platelets. Instead, the mtDNA molecules are most likely to replicate and segregate under conditions of random drift at the cellular level. Finally, the pattern of transmission in this maternal lineage is compatible with a developmental bottleneck model in which the number of mitochondrial units of segregation in the female germ line is relatively small in relation to the number of mtDNA molecules within a cell. However, this is not an invariant pattern for humans, and simple models of mitochondrial gene transmission are inappropriate at the present time.

Alleles↗
PubMed1996

How rapidly does the human mitochondrial genome evolve?

The results of an empirical nucleotide-sequencing approach indicate that the evolution of the human mitochondrial noncoding D-loop is both more rapid and more complex than is revealed by standard phylogenetic approaches. The nucleotide sequence of the D-loop region of the mitochondrial genome was determined for 45 members of a large matrilineal Leber hereditary optic neuropathy pedigree. Two germ-line mutations have arisen in members of one branch of the family, thereby leading to triplasmic descendants with three mitochondrial genotypes. Segregation toward the homoplasmic state can occur within a single generation in some of these descendants, a result that suggests rapid fixation of mitochondrial mutations as a result of developmental bottlenecking. However, slow segregation was observed in other offspring, and therefore no single or simple pattern of segregation can be generalized from the available data. Evidence for rare mtDNA recombination within the D-loop was obtained for one family member. In addition to these germ-line mutations, a somatic mutation was found in the D-loop of one family member. When this genealogical approach was applied to the nucleotide sequences of mitochondrial coding regions, the results again indicated a very rapid rate of evolution.

Child↗
PubMed1995

Neonatal Fanconi syndrome due to deficiency of complex III of the respiratory chain.

Fanconi syndrome is an important presentation of respiratory chain disease. We report three patients who presented in the neonatal period with Fanconi syndrome, lactic acidosis and intrauterine growth retardation. In all three patients the major biochemical defect was in complex III of the mitochondrial respiratory chain, a relatively uncommon defect. The diagnosis could only be made by muscle biopsy as the defect was not expressed in cultured skin fibroblasts. Treatment with vitamins C and K3 and ubiquinone did not alter the course of the disease and all patients died before the age of 4 months.

Acidosis, Lactic↗
PubMed1995

Leber hereditary optic neuropathy. Electron microscopy and molecular genetic analysis of a case.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder characterized by bilateral central visual loss typically in early adulthood. Few histopathologic studies, including ultrastructural and molecular genetic analysis, have been reported. METHODS: Ocular tissue was obtained postmortem from an 81-year-old woman with LHON from the Queensland 1 pedigree characterized by mutations at nucleotide positions 4160 and 14484. Routine histopathologic studies, electron microscopy, electron-probe analysis, and molecular genetic analysis were performed. RESULTS: Marked atrophy of the nerve fiber and retinal ganglion cell layers and optic nerves was present. Results of electron microscopic examination demonstrated 1.2 microns electron-dense, double-membrane-bound inclusions, consisting of calcium by electron-probe analysis, in retinal ganglion cells. The optic nerve was homoplasmic for mutations 4160 and 14484. CONCLUSION: Optic nerve and inner retinal atrophy in LHON may be a result of metabolic mitochondrial dysfunction leading to intramitochondrial calcification. Homoplasmy for mitochondrial mutations 4160 and 14484 in the leukocyte/platelet fraction of whole blood may correlate with homoplasmy in the optic nerve.

Aged↗
PubMed1995

Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees.

The nucleotide sequences of the mitochondrial genomes from patients with Leber hereditary optic neuropathy (LHON) were used for phylogenetic analysis to study the origin and population history of pathogenic mitochondrial mutations. Sequences of both the coding region (8300 bp) and the more rapidly evolving noncoding control region (1300 bp) were analyzed. Patients with the primary LHON mutations at nucleotides 3460, 11,778, and 14,484 were included in this study, as were LHON patients and non-LHON controls that lacked these primary mutations; some of the subjects also carried secondary LHON mutations. The phylogenetic analyses demonstrate that primary LHON mutations arose and were fixed multiple times within the population, even for the small set of LHON patients that was analyzed in these initial studies. In contrast, the secondary LHON mutations at nucleotides 4216, 4917, and 13,708 arose once: the mitochondrial genomes that carried these secondary mutations formed a well-supported phylogenetic cluster that apparently arose 60,000 to 100,000 years ago. Previous studies found secondary LHON mutations at a higher frequency among LHON patients than among control subjects. However, this finding does not prove a pathogenetic role of these mutations in LHON. Instead, the increased frequency is more likely to reflect the population genetic history of secondary mutations relative to that of primary LHON mutations.

Animals↗
PubMed1994

Tobacco amblyopia.

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Alcohol Drinking↗
PubMed1994

Comparison of quality of life in hemodialysis and peritoneal dialysis patients.

This study was designed to compare severity of illness and quality of life variables in chronic peritoneal dialysis (PD) and hemodialysis (HD) patients. The patient sample consisted of 63 PD patients (38 male, 25 female; mean age 54.5 years) and 35 HD patients (23 male, 12 female; mean age 54.9 years). Disease severity was greater in in-center HD patients than in PD patients (p < 0.008), although there were no significant differences in functional status as measured by the Karnofsky Index between HD patients (68.6 +/- 2.3) and PD patients (71.9 +/- 1.7). While both patient groups reported the same number of overall physical symptoms. HD patients reported significantly greater overall discomfort from symptoms than PD patients (p < 0.008). In terms of psychological adjustment, analyses revealed that 22 PD patients (36.7%) and 9 HD patients (25.7%) were classified as clinically depressed. PD patients reported higher anxiety scores than HD patients (p < 0.02) and lower positive mood scores (p < 0.021). HD patients were more severely ill and appeared to suffer from physical symptomatology to a greater degree than PD patients, although they were not more impaired in terms of functional status. Moreover, HD patients showed better psychological adjustment along several dimensions when compared to PD patients. One reason for this finding may be that PD patients experience greater distress, and isolation due to a lack of social support from similar others and medical staff in comparison to in-center HD patients.

Female↗