Biomedical subjects

David F Moore

Publications and source records attributed to David F Moore.

12 recordsLinked to original sources

PubMed2006

Quantitative dysmorphology assessment in Fabry disease.

PURPOSE: 1) To identify morphometric characteristics in hemizygous patients with Fabry disease a treatable lysosomal storage disorder caused by the deficiency of alpha-galactosidase A where morphological abnormalities have occasionally been mentioned, but have never been investigated systematically. 2) To devise a quantitative method to evaluate dysmorphic abnormalities in Fabry disease. METHOD: Cross-sectional, single center, independent dysmorphology assessment by a panel of three clinical geneticists, based on standardized medical photography. POPULATION: consecutive hemizygous patients with Fabry disease (N = 38) unselected for the features assessed, mean age 38 +/- 10.8 years (range: 10-60), recruited for neuropathic pain into enzyme replacement therapy trials. RESULTS: The following dysmorphic features were identified (in order of descending frequency): periorbital fullness, prominent lobules of the ears, bushy eyebrows, recessed forehead, pronounced nasal angle, generous nose/bulbous nasal tip, prominent supraorbital ridges, shallow midface, full lips, prominent nasal bridge, broad alar base, coarse features, posteriorly rotated ears, and prognathism. Extremity features included broad fingertips, short fingers, prominent superficial vessels of hands, 5 digit brachydactyly, and 5 digit clinodactyly. Narrow anterior-posterior chest diameter was noted. Ten core features were statistically defined. Cronbach's alpha measuring internal consistency was 0.62. Light's kappa for global inter-rater variability was 0.26 while Cohen's kappa allowing pair-wise rater comparison varied between 0.08-0.48. CONCLUSIONS: Patients with Fabry disease share common morphological characteristics of the face, trunk, and extremities. Some of these features are subtle as documented by the inter-rater variability. Awareness of these features may facilitate the diagnosis of patients with Fabry disease, and identification of affected family members.

Adolescent↗

PubMed2006

Fabry disease and vascular risk factors: future strategies for patient-based studies and the knockout murine model.

UNLABELLED: Fabry disease is secondary to deficiency of the lysosomal enzyme alpha-galactosidase A, leading to altered glycosphingolipid metabolism and accumulation that is often associated with endothelial dysfunction. Current evidence suggests that there is impairment of the vascular nitric oxide pathway, with abnormalities evident in the cerebral circulation and in the dermal vasculature of patients with Fabry disease. Some of these findings have been confirmed in a mouse model of Fabry disease. The murine model, however, allows investigation of Fabry disease at a non-clinical level and a near complete investigation of biological processes within an affected tissue. This is of particular utility in allowing gene expression analysis of clinically inaccessible tissues such as the aorta. CONCLUSION: Future developments in array technology for proteins and DNA single nucleotide polymorphism analysis, together with gene expression microarray analysis, may open a new chapter in our understanding of the biology of lysosomal storage disorders.

Animals↗

PubMed2005

Effect of genetic modifiers on cerebral lesions in Fabry disease.

Fabry disease is associated with increased risk of premature stroke and presumptive ischemic cerebral lesions. In 57 consecutive patients, 35% of whom had lesions on brain MRI, the authors found that genotypes of polymorphisms G-174C of interleukin-6, G894T of endothelial nitric oxide synthase, factor V G1691A mutation, and the A-13G and G79A of protein Z were all significantly associated with cerebral lesions. These findings suggest that these proteins modulate Fabry cerebral vasculopathy.

Adolescent↗

PubMed2005

Pediatric Fabry disease.

BACKGROUND: Fabry disease is an underdiagnosed, treatable, X-linked, multisystem disorder. OBJECTIVES: To test the hypothesis that quality of life and sweating are decreased among pediatric patients with Fabry disease, compared with control subjects, and to provide quantitative natural history data and novel clinical end points for therapeutic trials. DESIGN: Prospective, cross-sectional, observational study. SETTING: Referral to the National Institutes of Health. PARTICIPANTS: Twenty-five male children with Fabry disease (mean age: 12.3 +/- 3.5 years) and 21 age-matched control subjects. MAIN OUTCOME MEASURES: Quality of life (measured with the Child Health Questionnaire) and sweating (assessed with the quantitative sudomotor axon reflex test). RESULTS: Quality of life scores for pediatric patients <10 years of age with Fabry disease, compared with published normative values, were 55 +/- 17 vs 83 +/- 19 for bodily pain and 62 +/- 19 vs 80 +/- 13 for mental health. Bodily pain scores for patients > or =10 years of age were 54 +/- 22 vs 74 +/- 23. Sweat volume in the Fabry disease group was 0.41 +/- 0.46 microL/mm2, compared with 0.65 +/- 0.44 microL/mm2 in the control group. Renal function, urinary protein excretion, and cardiac function and structure were normal for the majority of patients. The 3 patients with residual alpha-galactosidase A activity > or =1.5% of normal values were free of cornea verticillata and had normal serum and urinary globotriaosylceramide levels. All other children had glycolipid levels comparable to those of adult patients with Fabry disease. Acroparesthesia and cardiac abnormalities were generally present before anhidrosis and proteinuria. Mapping of the missense mutations on the crystallographic structure of alpha-galactosidase A revealed that the mutations were partially surface-exposed and distal to the active site among individuals with residual enzyme activity. Mutations associated with left ventricular hypertrophy (defined as left ventricular mass index of >51 g/m2.7) were localized near the catalytic site of the enzyme. CONCLUSIONS: Despite the absence of major organ dysfunction, Fabry disease demonstrates significant morbidity already in childhood. We have identified important, potentially correctable or preventable, outcome measures for future therapeutic trials. Prevention of complications involving major organs should be the goal for long-term specific therapy.

Adolescent↗

PubMed2005

Using peripheral blood mononuclear cells to determine a gene expression profile of acute ischemic stroke: a pilot investigation.

BACKGROUND: Direct brain biopsy is rarely indicated during acute stroke. This study uses peripheral blood mononuclear cells (PBMCs) to determine whether a systemic gene expression profile could be demonstrated in patients with acute ischemic stroke. METHODS AND RESULTS: Using oligonucleotide microarrays, we compared the gene expression profile of an index cohort of 20 patients with confirmed ischemic stroke on neuroimaging studies with that of 20 referent subjects. Validation studies used quantitative real-time polymerase chain reaction to measure the levels of 9 upregulated genes in the index cohort, and an independent cohort of 9 patients and 10 referent subjects was prospectively studied to determine the accuracy of the Prediction Analysis for Microarrays list to classify stroke. After correction for multiple comparisons with the Bonferroni technique, 190 genes were significantly different between the stroke and referent groups. Broad classes of genes included white blood cell activation and differentiation (approximately 60%), genes associated with hypoxia and vascular repair, and genes potentially associated with an altered cerebral microenvironment. Real-time polymerase chain reaction confirmed increased mRNA expression in 9 of 9 upregulated stroke-associated genes in the index cohort. A panel of 22 genes derived from the Prediction Analysis for Microarrays algorithm in the index cohort classified stroke in the validation cohort with a sensitivity of 78% and a specificity of 80%. Control for the Framingham stroke risk score revealed only a partial dependence of the stroke gene expression profile in PBMCs on vascular risk. CONCLUSIONS: This study demonstrated an altered gene expression profile in PBMCs during acute ischemic stroke. Some genes with altered expression were consistent with an adaptive response to central nervous system ischemia.

Acute Disease↗

PubMed2004

Ascorbate decreases Fabry cerebral hyperperfusion suggesting a reactive oxygen species abnormality: an arterial spin tagging study.

PURPOSE: To test the hypothesis that reactive oxygen species contribute to the cerebral hyperperfusion in Fabry disease. MATERIAL AND METHODS: We examined the effect of intravenous injection of ascorbate on cerebral blood flow (CBF) using magnetic resonance arterial spin tagging. Nineteen patients with Fabry disease and 15 control subjects were studied as part of a randomized double-blind placebo-controlled trial of enzyme replacement therapy (ERT). RESULTS: Vertebro-basilar hyperperfusion was observed in patients with Fabry disease. A decrease in systemic ascorbate levels relative to healthy controls was found in the patients. CBF decreased after ascorbate infusion in both control subjects and patients treated with ERT. The placebo group had a significantly delayed decrease in the CBF response after ascorbate infusion. Myeloperoxidase levels were elevated in Fabry patients, consistent with ongoing inflammatory processes in these patients. CONCLUSION: Increased CBF in Fabry disease may be related to increased production of reactive oxygen species, while low plasma ascorbate levels suggests a global redox imbalance. These abnormalities were improved by ERT. These observations have implications regarding oxidative processes contributing to accelerated atherosclerosis in Fabry disease.

Adult↗

PubMed2003

White matter lesions in Fabry disease occur in 'prior' selectively hypometabolic and hyperperfused brain regions.

Fabry disease is an X-linked disorder associated with early onset stroke. We previously found a significantly elevated cerebral blood flow (CBF) in patients with Fabry disease. We set to determine whether elevated resting CBF in Fabry disease is primarily a cerebrovascular abnormality or is secondary to enhanced neuronal metabolism. The relationship of cerebral metabolism and blood flow to Fabry leukoencephalopathy was also investigated. We measured the global and regional cerebral metabolic rate of glucose using 18-fluoro-deoxyglucose (FDG) and PET in 16 patients with Fabry disease (7 patients with leukoaraiotic lesions and 9 without) and in 7 control subjects. MRI fluid attenuated inversion recovery (FLAIR) studies were also performed in the patient and control groups. All control subjects had normal MRI FLAIR studies with no high-signal deep white matter lesions (WML). Patients were partitioned into FLAIR lesion and non-FLAIR lesion groups. We found no evidence of cerebral glucose hypermetabolism in Fabry disease. On the contrary, significantly decreased regional cerebral glucose metabolism (rCMRGlu) was found particularly in the deep white matter in the Fabry non-lesion group and exacerbated in the lesion group. Lesion-susceptible regions were relatively hyperperfused in non-lesion patients compared to the control group. We conclude that the elevated rCBF and decreased white matter rCMRGlu indicates a dissociation between metabolism and blood flow suggesting chronic deep white matter metabolic insufficiency.

Adult↗

PubMed2003

Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease.

Fabry disease is an X-linked disorder caused by a deficiency of lysosomal alpha-galactosidase A resulting in accumulation of alpha-D-galatosyl conjugated glycosphingolipids. Clinical manifestations include a small-fiber neuropathy associated with debilitating pain and hypohidrosis. We report the effect of a 3-year open-label extension of a previously reported 6-month placebo-controlled enzyme replacement therapy (ERT) trial in which 26 hemizygous patients with Fabry disease received 0.2 mg/kg of alpha-galactosidase A every 2 weeks. The effect of ERT on neuropathic pain scores while off pain medications, quantitative sensory testing, quantitative sudomotor axon reflex test (QSART), and thermoregulatory sweat test (TST) is reported. In the patients who crossed-over from placebo to ERT (n = 10), mean pain-at-its-worst scores on a 0-10 scale decreased (from 6.9 to 4.5). There was a significant reduction in the threshold for cold and warm sensation in the foot. At the 3-year time-point, pre-ERT sweat excretion in 17 Fabry patients was 0.24 +/- 0.33 microl/mm(2) vs. 1.05 +/- 0.81 in concurrent controls (n = 38). Sweat function improved 24-72 h post-enzyme infusion (0.57 +/- 0.71 microl/mm(2)) and normalized in four anhidrotic patients. TST confirmed the QSART results. We conclude that prolonged ERT in Fabry disease leads to a modest but significant improvement in the clinical manifestations of the small-fiber neuropathy associated with this disorder. QSART may be useful to further optimize the dose and frequency of ERT.

Adult↗

PubMed2002

Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease.

BACKGROUND: Fabry disease is a lysosomal X-linked enzyme deficiency of alpha-galactosidase A associated with an increased mortality and morbidity due to renal failure, cardiac disease and early onset stroke. METHODS: We examined the functional blood flow response of the brain after visual stimulation (reversing checkerboard pattern), and cerebral vasoreactivity following acetazolamide (15 mg/kg) with [15O]H2O and positron emission tomography (PET) in Fabry disease. Twenty-six hemizygous patients (age range 19-47 years) were enrolled in a randomized double-blind placebo-controlled 6-month trial of enzyme replacement therapy administered by intravenous infusion every two weeks. Regional cerebral blood flow (rCBF) was measured with PET at the beginning and end of the trial. RESULTS: Fabry patients had a significantly greater increase in rCBF following visual stimulation and acetazolamide challenge compared to controls. Visual reactivity was normal. The time for recovery of the cerebral vasculature following acetazolamide was prolonged in Fabry patients compared to controls. The abnormal rCBF response induced by visual stimulation and acetazolamide decreased significantly following enzyme replacement therapy, as did the prolonged recovery of the cerebral vasculature. CONCLUSIONS: Enzyme replacement therapy reverses the exaggerated cerebrovascular response in Fabry disease.

Acetazolamide↗

PubMed2002

Arterial wall properties and Womersley flow in Fabry disease.

BACKGROUND: Fabry disease is an X-linked recessive lysosomal storage disease resulting in the cellular accumulation of globotriaosylceramide particularly globotriaosylceramide. The disease is characterized by a dilated vasculopathy with arterial ectasia in muscular arteries and arterioles. Previous venous plethysomographic studies suggest enhanced endothelium-dependent vasodilation in Fabry disease indicating a functional abnormality of resistance vessels. METHODS: We examined the mechanical properties of the radial artery in Fabry disease, a typical fibro-muscular artery. Eight control subjects and seven patients with Fabry disease had a right brachial arterial line placed allowing real time recording of intra-arterial blood pressure. Real time B-mode ultrasound recordings of the right radial artery were obtained simultaneously allowing calculation of the vessel wall internal and external diameter, the incremental Young's modulus and arterial wall thickness. By simultaneously measurement of the distal index finger-pulse oximetry the pulse wave speed was calculated. From the wave speed and the internal radial artery diameter the volume flow was calculated by Womersley analysis following truncation of the late diastolic phase. RESULTS: No significant difference was found between Fabry patients and controls for internal or external arterial diameters, the incremental Young's modulus, the arterial wall thickness, the pulse wave speed and the basal radial artery blood flow. Further, no significant difference was found for the radial artery blood flow in response to intra-arterial acetylcholine or sodium nitroprusside. Both drugs however, elevated the mean arterial flow. CONCLUSIONS: The current study suggests that no structural or mechanical abnormality exists in the vessel wall of fibro-muscular arteries in Fabry disease. This may indicate that a functional abnormality downstream to the conductance vessels is the dominant feature in development Fabry vasculopathy.

Adult↗

PubMed2002

Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement.

BACKGROUND AND PURPOSE: Fabry disease is an X-linked inherited disorder resulting from a deficiency of alpha-galactosidase A. Cerebrovascular disease in Fabry disease includes small-vessel disease and larger-vessel ectasia in a predominantly posterior distribution. We assessed transcranial Doppler (TCD) blood flow velocities in naive and enzyme-treated Fabry patients. METHODS: TCD was used to noninvasively examine patients with Fabry disease for abnormal cerebral blood flow velocities. TCD measurements were also made during CO2 retention by breathholding to examine cerebrovascular vessel reactivity. Twenty-six patients were enrolled in a 6-month, double-blind, placebo-controlled trial of enzyme replacement therapy consisting of biweekly intravenous alpha-galactosidase A infusions, with a subsequent 18-month follow-up in an open-label trial. Statistical analysis consisted of applying a mixed-effects ANOVA model for correlated outcomes. RESULTS: Peak velocity, mean velocity, pulsatility index, and resistance index were found to be significantly higher in patients compared with control subjects. When the individual vessels were considered, elevated flow velocities were found in the middle cerebral M1 branch and the posterior cerebral artery. Enzyme replacement therapy significantly decreased peak, mean, and end-diastolic velocities and flow acceleration at the 18-month follow-up time point. CONCLUSIONS: Patients with Fabry disease have elevated cerebral blood flow velocities. These velocities significantly improved with enzyme replacement therapy.

Adult↗

PubMedDate not supplied

Increased signal intensity in the pulvinar on T1-weighted images: a pathognomonic MR imaging sign of Fabry disease.

BACKGROUND AND PURPOSE: Fabry disease is a multisystem X-linked disorder characterized clinically by angiokeratoma, corneal and lenticular abnormalities, acroparesthesia, and renal and cardiac dysfunction and stroke. We sought to describe novel neuroimaging characteristics of Fabry disease. METHODS: Neuroradiologic records of 104 hemizygous patients with Fabry disease evaluated between 1994 and 2002 were reviewed. In total, 94 MR studies consisting of T1- and T2-weighted images were examined for the presence of hyperintensity on the T1-weighted images. Additional CT, gradient-echo (T2*-weighted), and fat-suppression MR studies were reviewed to characterize further the T1 abnormality in selected patients. In some patients, cerebral blood flow (CBF) was quantified by using arterial spin tagging (AST). RESULTS: Overall, 22 patients ( approximately 23%) demonstrated pulvinar hyperintensity on T1-weighted images; the frequency increased with age to over 30% by age 50 years. Susceptibility-weighted T2* studies demonstrated a low-signal-intensity abnormality in the pulvinar in the more severe cases, whereas CT demonstrated the pulvinar to be mineralized. CT attenuation corresponded with an increasing signal intensity on T1-weighted images. Posterior circulation CBF was found to be elevated on individual AST studies, especially in the thalamus. CONCLUSION: Hyperintensity in the pulvinar on T1-weighted images is a common finding in Fabry disease, likely reflecting the presence of calcification. Although other minreralizing abnormalities may result in calcification of deep gray nuclei, exclusive involvement of the pulvinar may be distinctively characteristic to Fabry disease. Increased CBF in the posterior circulation, particularly the thalamus, suggests that the dystrophic calcification is secondary to cerebral hyperperfusion and selective vulnerability of the pulvinar and adjacent thalamic nuclei. The finding of isolated pulvinar hyperintensity on T1-weighted images should suggest Fabry disease, particularly when seen in conjunction with other nonspecific neuroradiologic manifestations of the disease.

Adolescent↗