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Biomedical subjects

M A Cleary

Publications and source records attributed to M A Cleary.

At least 19 recordsLinked to original sources
PubMed2006

Expression of ezrin in glial tubes in the adult subventricular zone and rostral migratory stream.

Ezrin is a member of the ERM (ezrin-radixin-moesin) family of membrane-cytoskeletal linking proteins. ERM proteins are involved in a wide variety of cellular functions including cell motility, signal transduction, cell-cell interaction and cell-matrix recognition. A recent in situ hybridization study showed that the mRNA encoding ezrin is expressed in neurogenic regions of the mature brain including the subventricular zone (SVZ) and rostral migratory stream (RMS); however, the specific cell types expressing ezrin and their relationship to migrating and proliferating cells in these regions have not been characterized previously. In this study, we used immunocytochemistry to perform double labeling with a variety of cell-type specific markers to characterize the expression of ezrin in the SVZ and RMS of adult mice. Ezrin was expressed at high levels in both the SVZ and RMS where ezrin-immunopositive processes formed a trabecular network surrounding the proliferating and migrating cells. Ezrin-positive cells co-labeled with the glial makers S100beta and GFAP (glial fibrillary acidic protein), but only minimally with the early neuronal markers beta III tubulin and polysialylated form of neural cell adhesion molecule 1 (PSA-NCAM), indicating that ezrin was expressed primarily in the glial tube cells. Ezrin positive cells also expressed beta-catenin, a membrane-complex protein previously implicated in the regulation of stem-cell proliferation and neuronal migration. Glial tube cells act as both precursors of, and a physical channel for, migrating neuroblasts. Bi-directional signals between glial tube cells and migrating neuroblasts have been shown to regulate the rates of both proliferation of the precursor cells and migration of the newly generated neuroblasts. Our finding that ezrin and beta-catenin are both present at the cell membrane of the glial tube cells suggests that these proteins may be involved in those signaling processes.

Animals↗
PubMed2006

Randomised controlled trial of essential fatty acid supplementation in phenylketonuria.

OBJECTIVE: The long-chain polyunsaturated fatty acids (LC-PUFA) status of children with PKU is often compromised. LC-PUFA, which are important fatty acids in the development of the CNS, can be synthesised endogenously from the parent essential fatty acids (EFA) provided dietary intakes are adequate. This study was designed to assess the biochemical effect over a 20-week period of a phe-free protein substitute that has been supplemented with a balanced blend of n-3 and n-6 EFAs on LC-PUFA status of children with PKU. DESIGN, SETTING AND SUBJECTS: Fifty three community-living children aged 1-10 years diagnosed with PKU in the newborn period were recruited from seven tertiary centres in the UK and France and randomised to a fat-free control formula or the EFA-supplemented test-treatment formula in an open, prospective study. Forty four children completed the study (20 controls, 24 test-treatments). Fatty acid status was assessed at entry and 20-weeks follow-up. Three day dietary diaries were recorded at 20 weeks' follow-up. The safety, efficacy and palatability of the test-treatment formula were also assessed. RESULTS: The test-treatment group had significantly higher intakes of fat and EFA than the control group. There was a significant between group difference (P=0.04) in increases in median docosahexaenoic acid (DHA) concentrations in erythrocyte phospholipids, which increased by 19% in the test-treatment group and by 0.5% in the control group over the study period. Growth and phe control were satisfactory in all subjects. CONCLUSIONS: Supplementing the diets of children with PKU with a balanced blend of n-6 and n-3 EFA improves DHA status without compromising AA status.

Child↗
PubMed2005

Ornithine aminotransferase deficiency: diagnostic difficulties in neonatal presentation.

We describe two unrelated cases of ornithine aminotransferase (OAT) deficiency with rare neonatal presentation of hyperammonaemia. The diagnosis in the neonatal presentation of OAT deficiency is hampered as hyperornithinaemia is absent. Enzyme and mutation studies confirmed the diagnosis. OAT deficiency should be included in differential diagnosis of neonatal hyperammonaemia.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

Developmental delay: when to suspect and how to investigate for an inborn error of metabolism.

The purpose of this review is to provide a practical guideline on the suspicion and investigation of inborn errors of metabolism (IEMs) as cause of developmental delay. Developmental delay is a common paediatric problem. Inborn errors of metabolism are a rare cause of developmental delay. However, it is important to detect IEMs for several reasons: accurate counselling may be given regarding recurrence risk; metabolic decompensation may be avoided; and specific treatments may be available. Certain clinical situations are more likely to point to an IEM as the cause of developmental delay. This review highlights the risk factors in the history, the important examination findings, and the appropriate biochemical investigation of the child with developmental delay. Following these guidelines makes "missing" an IEM unlikely.

Biomarkers↗
PubMed2005

The significance of elevated CSF lactate.

The final diagnosis of 158 patients who had a cerebrospinal fluid (CSF) lactate concentration greater than 2 mmol/l was ascertained. The conditions included seizures, inflammatory changes, and proven metabolic disorders. For the diagnosis of congenital lactic acidoses, CSF lactate should ideally be measured in a seizure free patient after any acute illness.

Acidosis, Lactic↗
PubMed2002

Diagnostic criteria for respiratory chain disorders in adults and children.

BACKGROUND: Respiratory chain (RC) disorders are clinically, biochemically, and molecularly heterogeneous. The lack of standardized diagnostic criteria poses difficulties in evaluating diagnostic methodologies. OBJECTIVE: To assess proposed adult RC diagnostic criteria that classify patients into "definite," "probable," or "possible" categories. METHODS: The authors applied the adult RC diagnostic criteria retrospectively to 146 consecutive children referred for investigation of a suspected RC disorder. Data were collected from hospital, genetics, and laboratory records, and the diagnoses predicted by the adult criteria were compared with the previously assigned assessments. RESULTS: The authors identified three major difficulties in applying the adult criteria:lack of pediatric-specific criteria; difficulty in segregating continuous data into circumscribed major and minor criteria; and lack of additivity of clinical features or enzyme tests. They therefore modified the adult criteria to allow for pediatric clinical and histologic features and for more sensitive coding of RC enzyme and functional studies. Reanalysis of the patients' data resulted in congruence between the diagnostic certainty previously assigned by the authors' center and that defined by the new general RC diagnostic criteria in 99% of patients. CONCLUSIONS: These general diagnostic criteria appear to improve the sensitivity of the adult criteria. They need further assessment in prospective clinical and epidemiologic studies.

Adult↗
PubMed2002

Cardiovascular changes in children with mucopolysaccharide disorders.

UNLABELLED: The aims of this study were to evaluate cardiac involvement, assess risk factors and mortality, and define the outcome of cardiac abnormalities with age in the different types of mucopolysaccharidoses (MPS). The echocardiograms of 99 patients with MPS, aged 1-24 y (median age 10.3 y) were reviewed between 1978 and 2000. Mitral regurgitation (MR) was detected in 29 patients (29%). MR was more frequent in types IH [n = 11 (38%)], II [n = 10 (24%)] and III [n = 4 (20%)]. Sixteen patients (16%) developed aortic regurgitation (AR), seen mostly in types II [n = 9 (56%)] and IV [n = 4 (24%)]. AR and/or MR was detected in 37 patients and 8 had both abnormalities of borderline significance (odds ratio 2.95, 95% confidence interval 1.0-8.85, p = 0.05). Of 99 patients, 47 had a normal study on their first echocardiogram, whereas only 7 had a normal study on subsequent echocardiograms. Fifty-four (54%) had a single echocardiogram. Of these, 27 (50%) were abnormal and 27 normal. Forty-five patients had more than one echocardiogram, of which 25 (56%) were abnormal and 20 normal. In 13/20 (65%) a cardiac abnormality developed on a subsequent echocardiogram which was statistically significant (p = 0.002). Overall mitral and aortic valve abnormalities showed a positive association with age. Univariate analysis of risk factors showed that increasing age, MPS I and ejection fraction were significant risk factors for death. However, left ventricular hypertrophy, mitral valve abnormalities and type II MPS were not significant risk factors for death, with borderline significance for aortic valve abnormalities. CONCLUSION: This study demonstrates the evaluation of ventricular function, which is a significant risk factor for death, along with increasing age and MPS I, and outlines the borderline significance of aortic valve abnormalities, which has not been mentioned in previous studies. It also shows that mitral valve lesions, commonly seen in MPS, were not a significant risk factor for death. The results emphasize the importance of performing serial echocardiograms in patients with MPS to assess ventricular function and the progression of cardiac abnormalities with age.

Adolescent↗
PubMed2002

Facial appearance in glycogen storage disease type III.

Amylo-1,6-glucosidase deficiency (glycogen storage disease type III) is associated with hypoglycaemia, hepatomegaly, raised transaminases and in most cases skeletal myopathy and cardiomyopathy. The disorder has not been considered to cause dysmorphism. We report consistent facial features in seven patients with GSD type III consisting of midface hypoplasia with a depressed nasal bridge and a broad upturned nasal tip, indistinct philtral pillars, and bow-shaped lips with a thin vermillon border. Younger patients had in addition deepset eyes. Several children had clinical problems such as persistent otitis media or recurrent sinusitis. The underlying aetiology of these features is unknown but the similarity in all our patient suggests that there is a facial phenotype for this disorder.

Body Height↗
PubMed2001

Disruption of an imprinted gene cluster by a targeted chromosomal translocation in mice.

Genomic imprinting is an epigenetic process in which the activity of a gene is determined by its parent of origin. Mechanisms governing genomic imprinting are just beginning to be understood. However, the tendency of imprinted genes to exist in chromosomal clusters suggests a sharing of regulatory elements. To better understand imprinted gene clustering, we disrupted a cluster of imprinted genes on mouse distal chromosome 7 using the Cre/loxP recombination system. In mice carrying a site-specific translocation separating Cdkn1c and Kcnq1, imprinting of the genes retained on chromosome 7, including Kcnq1, Kcnq1ot1, Ascl2, H19 and Igf2, is unaffected, demonstrating that these genes are not regulated by elements near or telomeric to Cdkn1c. In contrast, expression and imprinting of the translocated Cdkn1c, Slc22a1l and Tssc3 on chromosome 11 are affected, consistent with the hypothesis that elements regulating both expression and imprinting of these genes lie within or proximal to Kcnq1. These data support the proposal that chromosomal abnormalities, including translocations, within KCNQ1 that are associated with the human disease Beckwith-Wiedemann syndrome (BWS) may disrupt CDKN1C expression. These results underscore the importance of gene clustering for the proper regulation of imprinted genes.

Animals↗
PubMed2000

Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet.

OBJECTIVE: To investigate whether dietary relaxation or cessation in patients with phenylketonuria (PKU) predisposes to vitamin B12 deficiency. STUDY DESIGN: Patients with PKU aged 11 to 38 years underwent a neurologic examination and dietetic assessment and were divided according to their diet into 1 of 3 groups: Strict - those on a strict low phenylalanine (phe) diet with amino acid, mineral, and vitamin supplements; Relaxed - those on a total protein intake of approximately 1 g/kg/d with 50% of this from natural protein and 50% from amino acid, mineral, and vitamin supplements; Unrestricted - those on no formal protein restriction and not taking amino acid supplements. Assays of blood samples were taken for vitamin B12 and folate levels by standard assays. Results were analyzed with Student t test. RESULTS: Vitamin B12 levels were significantly lower in the PKU groups on relaxed or unrestricted diets compared with the normal population (P <.0001 [unrestricted] and.0034 [relaxed]). Folate levels were significantly elevated in all PKU groups (<.0001). CONCLUSION: Patients with PKU who are no longer under strict dietary control may be at risk from vitamin B12 deficiency. We recommend that all patients should remain under medical and dietetic supervision and in particular have their vitamin B12 status monitored.

Adolescent↗
PubMed1999

Oppositely imprinted genes p57(Kip2) and igf2 interact in a mouse model for Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a clinically variable disorder characterized by somatic overgrowth, macroglossia, abdominal wall defects, visceromegaly, and an increased susceptibility to childhood tumors. The disease has been linked to a large cluster of imprinted genes at human chromosome 11p15.5. A subset of BWS patients has been identified with loss-of-function mutations in p57(KIP2), a maternally expressed gene encoding a G(1) cyclin-dependent kinase inhibitor. Some patients display loss of imprinting of IGF2, a fetal-specific growth factor that is paternally expressed. To understand how the same disease can result from misregulation of two linked, but unrelated, genes, we generated a mouse model for BWS that both harbors a null mutation in p57(Kip2) and displays loss of Igf2 imprinting. These mice display many of the characteristics of BWS, including placentomegaly and dysplasia, kidney dysplasia, macroglossia, cleft palate, omphalocele, and polydactyly. Some, but not all, of the phenotypes are shown to be Igf2 dependent. In two affected tissues, the two imprinted genes appear to act in an antagonistic manner, a finding that may help explain how BWS can arise from mutations in either gene.

Animals↗
PubMed1999

Respiratory chain complex I deficiency: an underdiagnosed energy generation disorder.

OBJECTIVE: To define the spectrum of clinical and biochemical features in 51 children with isolated complex I deficiency. BACKGROUND: Mitochondrial respiratory chain defects are one of the most commonly diagnosed inborn errors of metabolism. Until recently there have been technical problems with the diagnosis of respiratory chain complex I defects, and there is a lack of information about this underreported cause of respiratory chain dysfunction. METHODS: A retrospective review of clinical features and laboratory findings was undertaken in all diagnosed patients who had samples referred over a 22-year period. RESULTS: Presentations were heterogeneous, ranging from severe multisystem disease with neonatal death to isolated myopathy. Classic indicators of respiratory chain disease were not present in 16 of 42 patients in whom blood lactate levels were normal on at least one occasion, and in 23 of 37 patients in whom muscle morphology was normal or nonspecific. Ragged red fibers were present in only five patients. Tissue specificity was observed in 19 of 41 patients in whom multiple tissues were examined, thus the diagnosis may be missed if the affected tissue is not analyzed. Nine patients had only skin fibroblasts available, the diagnosis being based on enzyme assay and functional tests. Modes of inheritance include autosomal recessive (suggested in five consanguineous families), maternal (mitochondrial DNA point mutations in eight patients), and possibly X-linked (slight male predominance of 30:21). Recurrence risk was estimated as 20 to 25%. CONCLUSION: Heterogeneous clinical features, tissue specificity, and absence of lactic acidosis or abnormal mitochondrial morphology in many patients have resulted in underdiagnosis of respiratory chain complex I deficiency.

Adolescent↗
PubMed1999

Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993.

Mitochondrial genetics is complicated by heteroplasmy, or mutant load, which may be from 1%-99%, and thus may produce a gene dosage-type effect. Limited data are available for genotype/phenotype correlations in disorders caused by mtDNA mutations; therefore, prenatal diagnosis for mtDNA mutations has been hindered by an inability to predict accurately the clinical severity expected from a mutant load measured in fetal tissue. After reviewing 44 published and 12 unpublished pedigrees, we considered the possibility of prenatal diagnosis for two common mtDNA mutations at nucleotide 8993. We related the severity of symptoms to the mutant load and predicted the clinical outcome of a given mutant load. We also used the available data to generate empirical recurrence risks for genetic counseling, which may be used in conjunction with prenatal diagnosis.

Adenosine Triphosphatases↗
PubMed1999

Generalised uridine diphosphate galactose-4-epimerase deficiency.

The generalised form of epimerase deficiency galactosaemia has been described in only two children from unrelated families. Their progress is reported and three other affected children from these families are described. The initial presentation was similar to classic galactosaemia. Despite treatment all have shown poor growth and moderate learning difficulties. Three have sensorineural deafness and four have pronounced dysmorphic features. The two older female patients have normal pubertal development.

Adolescent↗
PubMed1998

Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster.

Genomic imprinting is an epigenetic process that results in the preferential silencing of one of the two parental copies of a gene. Although the precise mechanisms by which genomic imprinting occurs are unknown, the tendency of imprinted genes to exist in chromosomal clusters suggests long-range regulation through shared regulatory elements. We characterize a 800-kb region on the distal end of mouse chromosome 7 that contains a cluster of four maternally expressed genes, H19, Mash2, Kvlqt1, and p57(Kip2), as well as two paternally expressed genes, Igf2 and Ins2, and assess the expression and imprinting of Mash2, Kvlqt1, and p57(Kip2) during development in embryonic and extraembryonic tissues. Unlike Igf2 and Ins2, which depend on H19 for their imprinting, Mash2, p57(Kip2), and Kvlqt1 are unaffected by a deletion of the H19 gene region, suggesting that these more telomeric genes are not regulated by the mechanism that controls H19, Igf2, and Ins2. Mutations in human p57(Kip2) have been implicated in Beckwith-Wiedemann syndrome, a disease that has also been associated with loss of imprinting of IGF2. We find, however, that a deletion of the gene has no effect on imprinting within the cluster. Surprisingly, the three maternally expressed genes are regulated very differently by DNA methylation; p57(Kip2) is activated, Kvlqt1 is silenced, and Mash2 is unaffected in mice lacking DNA methyltransferase. We conclude that H19 is not a global regulator of imprinting on distal chromosome 7 and that the telomeric genes are imprinted by a separate mechanism(s).

Animals↗
PubMed1997

Structural flexibility in transcription complex formation revealed by protein-DNA photocrosslinking.

The Oct-1 POU domain binds diverse DNA-sequence elements and forms a higher-order regulatory complex with the herpes simplex virus coregulator VP16. The POU domain contains two separate DNA-binding domains joined by a flexible linker. By protein-DNA photocrosslinking we show that the relative positioning of the two POU DNA-binding domains on DNA varies depending on the nature of the DNA target. On a single VP16-responsive element, the POU domain adopts multiple conformations. To determine the structure of the Oct-1 POU domain in a multiprotein complex with VP16, we allowed VP16 to interact with previously crosslinked POU-domain-DNA complexes and found that VP16 can associate with multiple POU-domain conformations. These results reveal the dynamic potential of a DNA-binding domain in directing transcriptional regulatory complex formation.

Binding Sites↗
PubMed1997

Oral health implications in children with inborn errors of intermediary metabolism: a review.

Children with inborn errors of metabolism form an important group of children at risk of oral pathology. Their management includes dietary therapies which aim to promote normal growth and development but which are often highly cariogenic. It is important for paediatricians, dietitians and paediatric dentists to liaise closely in the management of these children. This paper reviews these disorders and the limited literature that exists on the oral health implications of those conditions that rely on dietary manipulation for their management, and presents suggestions for their dental care.

Child↗