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Biomedical subjects

G V Raymond

Publications and source records attributed to G V Raymond.

At least 37 records · Page 2Linked to original sources
PubMed2000

Acute presentation of childhood adrenoleukodystrophy.

X-linked adrenoleukodystrophy is a neurodegenerative disorder affecting the myelin of the nervous system and the adrenal cortex. The childhood form of the disease is typically heralded by subtle neurocognitive changes which later progress. Acute presentation of childhood ALD has been reported, but the incidence is not known. We reviewed the records of 485 boys with childhood ALD, determined those with acute presentation, and classified them as adrenal crisis, seizures, or encephalopathy. Of the 485 reviewed cases, 45 (9.3%) presented acutely at an average age of 5.5 years. Twenty of 45 (44%) presented with seizures, focal seizures in 6 boys and generalized in the remainder with 4 having status epilepticus. Twenty out of 45 presented with acute adrenal crisis. Five of 45 presented with acute encephalopathy or coma. The diagnosis of ALD was rarely made in the acute period, but was often suggested by neuroimaging. The accurate, rapid diagnosis of ALD has important implications for treatment as well as for other family members and should be considered in appropriate patients.

Acute Disease↗
PubMed2000

X-Linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients.

The phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progressive childhood cerebral form to the milder adrenomyeloneuropathy (AMN) in adults. It is not possible to predict phenotype by mutation analysis or biochemical assays. This study reports on 372 patients ranging in age from less than 3 years to adulthood, who have been followed at the Kennedy Krieger Institute. With the aim of determining whether a method could be developed to predict clinical course by analysis of data available at time of first contact, the patients were subdivided into 18 subgroups on the basis of age and the extent of brain magnetic resonance (MRI) abnormality utilizing the MRI scoring system devised by Loes et al. Scores to grade degree of neurologic and neuropsychologic impairment were also developed. There was strong correlation between MRI and the neurology and neuropsychology scores at baseline. Information based exclusively on age and MRI score at time of first contact was highly predictive of future clinical course and should aid the evaluation of the effects of bone marrow transplantation and the selection of patients for this procedure, as well as the evaluation of other therapies that may be developed in the future.

Adrenoleukodystrophy↗
PubMed2000

Cryptic subtelomeric translocations in the 22q13 deletion syndrome.

Cryptic subtelomeric rearrangements are suspected to underlie a substantial portion of terminal chromosomal deletions. We have previously described two children, one with an unbalanced subtelomeric rearrangement resulting in deletion of 22q13-->qter and duplication of 1qter, and a second with an apparently simple 22q13-->qter deletion. We have examined two additional patients with deletions of 22q13-->qter. In one of the new patients presented here, clinical findings were suggestive of the 22q13 deletion syndrome and FISH for 22qter was requested. Chromosome studies suggested an abnormality involving the telomere of one 22q (46,XX,?add(22)(q13. 3)). FISH using Oncor D22S39 and Vysis ARSA probes confirmed a terminal deletion. A multi-telomere FISH assay showed a signal from 19qter on the deleted chromosome 22. Results were confirmed with 19qtel and 22qtel specific probes. The patient is therefore trisomic for 19qter and monosomic for 22qter. The patient's mother was found to have a translocation (19;22)(q13.42;q13.31). We also re-examined chromosomes from two patients previously diagnosed with 22q deletions who were not known to have a rearrangement using the multi-telomere assay. One of these patients was found to have a derivative chromosome 22 (der(22)t(6;22)(p25;q13)). No evidence of rearrangement was detected in the other patient. Thus we have found the 22q13 deletion to be associated with a translocation in three of four patients. This report illustrates the usefulness of examining patients with hypotonia, severe language delay, and mild facial dysmorphism for this syndrome and suggests that most of these deletions may be unbalanced subtelomeric rearrangements.

Abnormalities, Multiple↗
PubMed2000

X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression.

BACKGROUND AND PURPOSE: Early assignment of disease progression among patients with X-linked adrenoleukodystrophy (ALD) is critical for the appropriate selection of effective therapy. We evaluated the association between contrast enhancement on T1-weighted spin-echo MR images and disease progression. METHODS: Clinical charts of patients with X-linked ALD were reviewed for age, availability of MR images of the brain, severity of neurologic impairment, and duration and number of follow-up evaluations. Forty-three male patients with X-linked ALD had undergone multiple MR imaging examinations of the brain that consisted of at least sagittal and axial T1-weighted spin-echo, axial double-echo spin-echo, and contrast-enhanced axial T1-weighted spin-echo imaging. The MR images were reviewed for the presence of contrast enhancement. In addition, global disease burden, as shown by the double-echo spin-echo images, was assessed using a visual scoring method (Loes score). RESULTS: Enhancement was seen on the initial T1-weighted spin-echo MR images of 21 (49%) patients; 18 (86%) of the 21 patients had disease progression revealed by the follow-up evaluations based on MR imaging (Loes) and neurologic scores. No enhancement was seen on the initial T1-weighted spin-echo MR images of 22 (51%) patients; for 18 (82%) of the 22 patients, no evidence of disease progression was revealed by the follow-up evaluations. CONCLUSION: There is a very strong association between the presence of contrast enhancement on T1-weighted MR images and X-linked ALD progression based on clinical evaluation and MR imaging.

Adolescent↗
PubMed1999

Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls.

The assay of plasma very long chain fatty acids (VLCFAs), developed in our laboratory in 1981, has become the most widely used procedure for the diagnosis of X-linked adrenoleukodystrophy (X-ALD) and other peroxisomal disorders. We present here our 17 years' experience with this assay. Three VLCFA parameters, the level of hexacosanoic acid (C26:0), the ratio of C26:0 to tetracosanoic acid (C24:0), and of C26:0 to docosanoic acid (C22:0), were measured in 1,097 males (hemizygotes) with X-ALD, 1,282 women heterozygous for this disorder, including 379 obligate heterozygotes, 797 patients with other peroxisomal disorders, and 29,600 control subjects. All X-ALD hemizygotes who had not previously received Lorenzo's oil or a diet with a high erucic acid content had increased VLCFA levels, but the application of a discriminant function based on all three measurements is required to avoid the serious consequences of a false-negative result. VLCFA levels are increased at day of birth, thus providing the potential for neonatal mass screening, are identical in the childhood and adult forms, and do not change with age. Eighty-five percent of obligate heterozygotes had abnormally high VLCFA levels, but a normal result does not exclude carrier status. VLCFA levels were increased in all patients homozygous for Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, and in patients with deficiencies of peroxisomal acyl-coenzyme A oxidase, bifunctional enzyme, and 3-oxoacyl-coenzyme A thiolase. In these patients the degree of VLCFA excess correlated with clinical severity.

Adolescent↗
PubMed1999

Plasma and red blood cell fatty acids in peroxisomal disorders.

The demonstration of abnormal levels of fatty acids or plasmalogens in plasma or red blood cells is key to the diagnosis of peroxisomal disorders. We report the levels of 62 fatty acids and plasmalogens in patients with X-linked adrenoleukodystrophy (X-ALD), Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD), both at baseline and after dietary interventions. "Lorenzo's Oil" therapy in X-ALD normalizes the levels of saturated very long chain fatty acids in plasma, but leads to reduced levels of omega 6 and other omega 3 fatty acids, and requires monitoring and appropriate dietary supplements. Patients with ZS, NALD and IRD have reduced levels of docosahexaenoic acid (DHA) and arachidonic acid (AA) which can be normalized by the oral administration of microencapsulated DHA and AA.

Adolescent↗
PubMed1999

Peroxisomal disorders.

Peroxisomes, subcellular organelles found in nearly all eukaryotic cells, are involved in numerous biochemical functions within the cell. There has been an increasing understanding of the genetic mechanism of the diseases of the single peroxisomal enzyme abnormalities as well as defects of peroxisome biogenesis. Peroxisome assembly disorders including Zellweger syndrome and rhizomelic chondrodysplasia punctata are caused by genetic defects in PEX genes and the altering of their proteins, peroxins, which are necessary for the importation of targeted proteins into the peroxisomes. Therapies for peroxisomal disorders have been unsatisfactory to date, but there has been interest in docosahexaenoic acid in assembly disorders and phenylbutyrate and lovastatin in adrenoleukodystrophy (ALD). Whether any of these therapies will result in clinical improvement awaits additional study.

Animals↗
PubMed1999

Adrenoleukodystrophy associated with vitiligo and ulcerative colitis.

Adrenoleukodystrophy (ALD) is an X-linked inherited disorder of lipid metabolism usually presenting in childhood or early adolescence. It is a progressive disease with symptoms of adrenal insufficiency and central nervous system demyelination. The pathology results from the accumulation of very long-chain fatty acids and an inflammatory reaction in the brain white matter. We report a case of ALD associated with adrenal insufficiency and two autoimmune diseases: vitiligo and ulcerative colitis.

Addison Disease↗
PubMed1997

Cryptic terminal rearrangement of chromosome 22q13.32 detected by FISH in two unrelated patients.

Two unrelated patients with cryptic subtelomeric deletions of 22q13.3 were identified using FISH with the commercially available Oncor probe, D22S39. Proband 1 was found to have a derivative chromosome 22 resulting from the unbalanced segregation of a t(1;22)(q44;q13.32) in her mother. Additional FISH analysis of proband 1 and her mother placed the breakpoint on chromosome 22 in this family proximal to D22S55 and D22S39 and distal to D22S45. We have mapped D22S39 to within 170 kb of D22S21 using pulsed field gel electrophoresis. D22S21 is genetically mapped between D22S55 and D22S45. These data indicate that the deletion in proband 1 is smaller than in eight of nine reported del(22)(q13.3) patients. Probands 1 and 2 share features of hypotonia, developmental delay, and expressive language delay, also seen in previously reported del(22)(q13.3) patients, although proband 1 appears to be more mildly affected. Proband 1 is also trisomic for the region 1q44-->qter. This very small duplication has been previously reported only once and the patient had idiopathic mental retardation. This is the first report where 22q13.3 terminal deletion patients have been identified through the use of FISH, and the first report of a deletion of this region occurring because of missegregation of a parental balanced cryptic translocation. We feel that investigation of the frequency of del(22)(q13.3) in the idiopathic mentally retarded population is warranted and may be aided by the ability to use a commercially available probe (D22S39), which is already currently in use in a large number of cytogenetic laboratories.

Adult↗
PubMed1997

Testing for interaction between maternal smoking and TGFA genotype among oral cleft cases born in Maryland 1992-1996.

OBJECTIVE: Infants born in Maryland between June 1992 and June 1996 were used in a case-control study of nonsyndromic oral clefts to test for effects of maternal smoking and a polymorphic genetic marker at the transforming growth factor alpha (TGFA) locus, both of which have been reported to be risk factors for these common birth defects. DESIGN AND SETTING: Cases were infants with an oral cleft ascertained through three comprehensive treatment centers, with additional ascertainment through a registry of birth defects maintained by the Maryland Health Department. Controls were healthy infants. Medical history information on infants and mothers were collected, along with DNA samples. PATIENTS, PARTICIPANTS: Among 286 cases contacted (72% ascertainment), there were 192 nonsyndromic isolated oral clefts (106 M; 86 F) available for this case-control study. MAIN OUTCOME MEASURES: The largest group of 149 Caucasian nonsyndromic cases and 86 controls was used to test for association with maternal smoking and genotype at the Taq1 polymorphism in TGFA. RESULTS: While this modest sample had limited statistical power to detect gene-environment interaction, there was a significant marginal increase in risk of having an oral cleft if the mother smoked (odds ratio = 1.75, 95% CI = 1.01 to 3.02). We could not demonstrate statistical interaction between maternal smoking and TGFA genotype in this study, however, and the observed increase in the C2 allele among cases was not statistically significant. CONCLUSIONS: We could not confirm either the reported association between oral clefts and TGFA genotype or its interaction with maternal smoking. However, these data do show an increased risk if the mother smoked during pregnancy, and this effect was greatest among infants with a bilateral cleft and no close family history of clefts.

Alleles↗
PubMed1996

Hippocampus in autism: a Golgi analysis.

Autism is a behaviorally defined syndrome in which neuropathological abnormalities have been identified in the limbic system and cerebellum. The morphology of hippocampal neurons in two cases of infantile autism was studied and compared to age-matched controls. CA4 neurons in autistic children were smaller in perikaryon area and dendritic branching of both CA4 and CA1 neurons was less than in controls. These findings are consistent with previous studies and suggest a curtailment in maturation in the pathogenesis of autism.

Adolescent↗
PubMed1996

Improved tissue characterization in adrenoleukodystrophy using magnetization transfer imaging.

OBJECTIVE: We performed this study to evaluate the usefulness of magnetization transfer (MT) imaging techniques and magnetization transfer ratio (MTR) measurements in assessing patients with adrenoleukodystrophy (ALD). SUBJECTS AND METHODS: Twelve patients who encompassed the range of ALD phenotypes were evaluated prospectively with MR and MT imaging (including digital subtraction images). The MT images and spin-echo MR images were compared by two staff neuroradiologists and a staff neurologist for extent of disease, different zones of involvement, and the presence of enhancement. MTR measurements were obtained from affected and unaffected regions of the brain. RESULTS: Eight of the 12 patients exhibited gadolinium enhancement. In seven of these patients, the MT subtraction images showed two zones of abnormal signal within the affected white matter. Their MTR measurements were classified as zone 1 (mean MTR, 35%; SD, 6%) and zone 2 (mean MTR, 20%; SD, 6%). Three of the other patients showed a single zone of involvement corresponding to the affected white matter on the standard spin-echo MR images. Their MTR measurements were similar to that of zone 1. The remaining two patients had no demonstrable signal abnormalities on any of the images. We noted no difference in any of the 12 subjects in the extent of white matter involvement on any of the imaging techniques. The MTR measurements in the unaffected white matter (mean MTR, 46%; SD, 5%) approximated established MTRs in white matter of normal volunteers. CONCLUSION: MT imaging and MTR measurements are helpful clinical techniques that may improve the evaluation of patients with ALD, particularly in the proposed ability of these techniques to divide the affected white matter into different zones that correspond to specific pathologic areas. These techniques can help the understanding of pathogenetic mechanisms and the evaluation of therapies.

Adolescent↗
PubMed1995

Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies.

The clinical distinction between patients with a disorder of peroxisome assembly (e.g., Zellweger syndrome) and those with a defect in a peroxisomal fatty acid beta-oxidation enzyme can be difficult. We studied 29 patients suspected of belonging to the latter group. Using complementation analysis, 24 were found to be deficient in enoylcoenzyme A hydratase/3-hydroxyacylcoenzyme A dehydrogenase bifunctional enzyme and 5 were deficient in acyl-CoA oxidase. Elevated plasma very long-chain fatty acids (VLCFA), impaired fibroblast VLCFA beta-oxidation, decreased fibroblast phytanic acid oxidation, normal plasmalogen synthesis, normal plasma L-pipecolic acid level, and normal subcellular catalase distribution were characteristic findings in both disorders. The elevation in plasma VLCFA levels and impairment in fibroblast VLCFA beta-oxidation were more severe in bifunctional-deficient than in oxidase-deficient patients. The clinical course in bifunctional deficiency (profound hypotonia, neonatal seizures, dysmorphic features, age at death approximately 9 months) was more severe than in oxidase deficiency (moderate hypotonia without dysmorphic features, development of a leukodystrophy, age at death approximately 4 yr). Based on these findings, accurate early diagnosis of these deficiencies of peroxisomal beta-oxidation enzymes is possible.

Acyl-CoA Oxidase↗
PubMed1995

Teratogen update: ergot and ergotamine.

Ergotamine is a purified ergot alkaloid that has been suspected of being teratogenic. Animal data have shown effects mainly at doses toxic to the mother. Clinical reports in humans have been anecdotal, but in many the malformations are consistent with vascular injury. However, epidemiologic studies have not shown any clear increase in malformations among exposed infants. This may reflect the limited exposure and toxicity when used episodically. Ergot toxicity which can result in severe vasospasm does not spare the fetus or mother and ergotamine should not be considered without risk. Ergotamine should be avoided in pregnancy, and the counselling of the woman with an exposed fetus should focus on possible toxic exposure.

Abnormalities, Drug-Induced↗
PubMed1995

Tumor necrosis factor-alpha and X-linked adrenoleukodystrophy.

The two most common forms of X-linked adrenoleukodystrophy (X-ALD), the childhood cerebral form (CCER) and the adult form, adrenomyeloneuropathy (AMN), arise from the same mutations in the X-ALD gene at Xq28. These two forms are distinguished by the degree of cerebral inflammation. Segregation analysis suggests that an autosomal modifying gene may be a major determinant of phenotype in X-ALD. Thus, a modifying gene could be involved in initiating or promoting the inflammatory response. In this study we detected a difference in tumor necrosis factor-alpha (TNF-alpha) bioactivity, but not TNF-alpha protein levels, in serum from some advanced CCER patients. Early-stage CCER patients and AMN patients were in the normal range. Allelic differences in TNF-alpha or levels of soluble TNF receptor did not account for bioactivity differences or phenotypic heterogeneity in X-ALD.

Adolescent↗