Uveitis and Fabry disease.
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Fabry Disease↗
Biomedical subjects
G Altarescu
Publications and source records attributed to G Altarescu.
Single-sperm analysis for haplotype construction of de-novo paternal mutations: application to PGD for neurofibromatosis type 1.
BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the neurofibromin gene. Approximately, 50% of cases are caused by de-novo mutations. Even when the NF1 mutation is known, accuracy of PGD is highly enhanced by simultaneous analysis of linked markers. In a childless couple referred to PGD, the male carried a de-novo mutation, precluding the possibility of typing relatives to establish the mutation-associated haplotype. We developed a single-sperm haplotype analysis strategy to establish the haplotype linked to the NF1 mutation. METHODS: Spermatozoa from freshly ejaculated semen were used as a substrate for multiplex PCR on single sperm. RESULTS: In addition to the NF1 mutation, six informative polymorphic markers flanking the NF1 gene (D17S1294, D17S1849, D17S841, D17S975, NF1TG2 and NF1AC5) were linked to individual alleles in single sperm from the affected male. CONCLUSIONS: Single-sperm analysis established the haplotypes of both mutant and wild-type NF1 alleles and enabled the implementation of a PGD protocol using polymorphic marker analysis. This method is generally applicable to PGD for any disease in which the haplotype of paternal mutations cannot be determined by typing relatives.
Adult↗
The interleukin-6 promoter polymorphism in Gaucher disease: a new modifier gene?
BACKGROUND: Individuals with Gaucher disease vary significantly with regard to degree of bone disease, but there are no predictive markers for severity of skeletal involvement. AIM: To determine the frequency of polymorphisms of interleukin-6 (IL-6) among patients with Gaucher disease, and the relationship to bone mineral density (BMD) and other markers of disease severity. DESIGN: Case-control study. METHODS: Genotyping for the 174G --> C promoter polymorphism of IL-6 was performed in adult patients with Gaucher disease for whom there was concurrent bone mineral density (BMD) data and in healthy Ashkenazi Jewish controls. RESULTS: The prevalence of allelic variants (58% G/G, 36% G/C, and 6% C/C) was similar in Ashkenazi Jewish adults with Gaucher disease as in Ashkenazi Jewish controls, but significantly different (p < 0.05) from that reported among Caucasians. No statistically significant correlation was found between IL-6 genotypes and BMD or markers of severity of Gaucher disease. Patients with the C/C genotype had relatively mild Gaucher disease. DISCUSSION: The IL-6 polymorphisms appear to be distributed differently in Ashkenazi Jews than among other Caucasians. In Gaucher disease, the C/C genotype may be associated with a milder Gaucher phenotype, and may serve as a mitigating genetic modifier.
Adolescent↗
The neurogenetics of mucolipidosis type IV.
BACKGROUND: Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor potential (TRP) gene family. OBJECTIVE: To comprehensively characterize the clinical and genetic abnormalities of MLIV. METHODS: Twenty-eight patients with MLIV, aged 2 to 25 years, were studied. Ten returned for follow-up every 1 to 2 years for up to 5 years. Standard clinical, neuroimaging, neurophysiologic, and genetic techniques were used. RESULTS: All patients had varying degrees of corneal clouding, with progressive optic atrophy and retinal dystrophy. Twenty-three patients had severe motor and mental impairment. Motor function deteriorated in three patients and remained stable in the rest. All had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had iron deficiency or anemia. Head MRI showed consistent characteristic findings of a thin corpus callosum and remained unchanged during the follow-up period. Prominent abnormalities of speech, hand usage, and swallowing were also noted. Mutations in the MCOLN1 gene were present in all patients. Correlation of the genotype with the neurologic handicap and corpus callosum dysplasia was found. CONCLUSIONS: MLIV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay diagnosis.
Adolescent↗
Plasma chitotriosidase activity in patients with beta-thalassemia.
Variable increases in chitotriosidase levels have been reported in Italian patients with beta-thalassemia major and intermedia. We measured plasma chitotriosidase levels in Israeli patients with beta-thalassemia to ascertain its use as a universal marker of disease and/or response to therapy. Chitotriosidase levels in 39 adults (16-53 years; 30 with beta-thalassemia major, 9 with intermedia), and in 14 children (0.7-15 years; 12 with beta-thalassemia major, 2 with intermedia) were compared with other measures of disease, such as ferritin, hemoglobin, liver function tests, and genotype. Plasma chitotriosidase levels were normal (0.37 +/- 0.04 mU/mL) in all children. Twelve adults (31%) had elevated levels (>1.33 mU/mL): 11 patients (37%) with thalassemia major and 1 patient (11%) with thalassemia intermedia. A significant correlation was only found between plasma chitotriosidase levels and ferritin levels, and with mean number of transfusions per year. The patient with the highest chitotriosidase (1,440 nmol/mL/hr) had the highest ferritin (5,175 microg/L), required the most transfusions per year (40), and had abnormal liver tests. Normal chitotriosidase levels in the pediatric cohort and increased levels in only some adults may reflect status of iron overload in macrophages; thus there may be a role for monitoring chitotriosidase in patients with beta-thalassemia. Our results confirm results of the Italian cohort; however, in the latter, a more universal correlation was noted and chitotriosidase levels were much higher.
Adolescent↗
Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabry disease: reversal by enzyme replacement therapy.
BACKGROUND: Fabry disease is an X-linked lysosomal deficiency of alpha-galactosidase A that results in cellular accumulation of galacto-conjugates such as globotriosylceramide, particularly in blood vessels. It is associated with early-onset stroke and kidney and heart failure. METHODS AND RESULTS: Using [(15)O] H(2)O and PET, we found increased resting regional cerebral blood flow in Fabry disease without evidence of occlusive vasculopathy or cerebral hypoperfusion. Because nitric oxide is known to play an important role in vascular tone and reactivity, we studied plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol levels by chemiluminescence. Skin biopsy specimens and archived brain tissue were also examined immunohistochemically for nitrotyrosine. Plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol were in the normal range; however, enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels. After a double-blind, placebo-controlled trial of alpha-galactosidase A therapy, the resting regional cerebral blood flow in the treated group was significantly reduced, with a notable decrease of nitrotyrosine staining in dermal blood vessels. CONCLUSIONS: These findings suggest a chronic alteration of the nitric oxide pathway in Fabry disease, with critical protein nitration that is reversible with enzyme replacement therapy.
Adult↗
Somatosensory evoked potentials as a marker of disease burden in type 3 Gaucher disease.
The authors compared stretch-evoked somatosensory evoked potentials (SEP) of 18 type 3 Gaucher disease (GD3) patients (two with progressive myoclonus epilepsy [PME]) with 22 age-matched normal controls and six patients with type 1 (nonneuronopathic) Gaucher disease (GD1). The mean P1-N2 SEP amplitude in GD3 patients was significantly larger than the SEP in controls and in GD1 patients, and there was a significant negative correlation between SEP amplitude and the IQ of GD3 patients. The authors conclude that abnormal cortical inhibition is a unifying feature of GD3 patients and correlates with the degree of cognitive deficit.
Adolescent↗
The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher's disease.
OBJECTIVE: To assess the long-term systemic and neurologic responses to enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher's disease. STUDY DESIGN: Patients with type 3 Gaucher's disease (n = 21), aged 8 months to 35 years, were enrolled in a prospective study. Enzyme dose was adjusted to control systemic manifestations. Clinical and laboratory evaluations were performed at baseline and every 6 to 12 months thereafter. Patients were followed up for 2 to 8 years. RESULTS: Significant improvement in hemoglobin levels, platelet count, and acid phosphatase values occurred. Liver and spleen volume markedly decreased, and bone structure improved. Nineteen patients had asymptomatic interstitial lung disease unresponsive to ERT. Supranuclear gaze palsy remained stable in 19 patients, worsened in one patient, and improved in one. Cognitive function remained unchanged or improved over time in 13 patients but decreased in 8 patients, 3 of whom developed progressive myoclonic encephalopathy accompanied by cranial magnetic resonance imaging and electroencephalographic deterioration. CONCLUSIONS: At relatively high doses, ERT reverses almost all the systemic manifestations in patients with type 3 Gaucher's disease. Most treated patients do not deteriorate neurologically. Novel therapeutic strategies are required to reverse the pulmonary and neuronopathic aspects of the disease.
Adolescent↗
Enhanced endothelium-dependent vasodilation in Fabry disease.
BACKGROUND AND PURPOSE: Fabry disease is an X-linked lysosomal storage disease secondary to deficiency of alpha-galactosidase A with resulting glycolipid accumulation, particularly globotriaosylceramide in arterial smooth muscle and endothelial cells. A systemic vasculopathy, including early-onset stroke, is prevalent without a clear pathogenesis. METHODS: Seventeen normotensive and normocholesterolemic hemizygous Fabry patients (aged 21 to 49 years) and 13 control subjects (aged 21 to 48 years) were investigated by venous plethysmography, allowing assessment of forearm blood flow. Plethysmographic measurements were obtained at baseline and during intra-arterial infusion of acetylcholine and sodium nitroprusside both with and without N(G)-monomethyl-L-arginine (L-NMMA). RESULTS: Forearm blood flow was significantly higher in patients than in control subjects at all 3 acetylcholine doses (P=0.014). Patients had a greater response to acetylcholine even after the addition of L-NMMA (P=0.036). CONCLUSIONS: These results demonstrate an increased endothelium-mediated vascular reactivity in Fabry disease. The increased vessel response to acetylcholine with and without L-NMMA suggests altered functionality of non-NO endothelium-dependent vasodilatory pathways.
Acetylcholine↗
Cutaneous silent periods in patients with Fabry disease.
We assessed the cutaneous silent period (CSP) in 24 patients with Fabry disease with small-fiber sensory neuropathy and 12 normal subjects to test the hypothesis that small-diameter afferents are responsible for producing the CSP. Sensory nerve conduction studies and quantitative sensory testing for cold and vibration detection thresholds were also measured. Overall, Fabry patients had impaired thermal, but not vibration, detection thresholds, with greatest impairment in the feet. In the upper extremity, CSP latencies, duration, and suppression of electromyographic activity (EMG) did not differ. In the lower extremity, patients had reduced suppression of EMG during the CSP compared to normal controls. CSP durations exhibited a bimodal distribution in patients, including a subset of seven patients with durations shorter than all controls. This subset had profound loss of thermal sensation in the feet, but this was also true of some patients who had normal CSPs. Patients with shortened CSPs had modestly elevated vibration thresholds and reduced sensory potentials in comparison to patients with normal CSPs. Reduced CSPs in Fabry patients are associated with, but not entirely explained by, the severity of small-fiber neuropathy as measured by quantitative sensory testing. The possibility that large-diameter fibers provide a minor contribution to producing the CSP should be considered.
Action Potentials↗
Comparative efficacy of dose regimens in enzyme replacement therapy of type I Gaucher disease.
Gaucher disease is caused by a deficiency of beta-glucocerebrosidase activity. The optimum dose and frequency of enzyme replacement therapy for Gaucher patients have not been determined. We set to compare the therapeutic effects of initiating treatment with macrophage-targeted glucocerebrosidase at a high dose followed by progressive dose reductions with that produced by initial treatment at a low dose in patients with type I Gaucher disease. The study included two parts: (i) Twelve patients received every 2 weeks enzyme replacement therapy at 60 IU/kg body wt for 24 months followed by sequential dose reduction every 6 months to 30 and then to 15 IU/kg body wt. (ii) Thirty-two patients received enzyme replacement therapy at 10 IU/kg every 2 weeks for 12 months. Hematologic parameters and liver and spleen volume were monitored in all patients. All patients had intact spleens. In patients who were started on high-dose enzyme replacement therapy, hemoglobin, acid phosphatase, and organ volume improved or remained unchanged at the end of each dose reduction. Platelet count decreased significantly when the dose of enzyme was reduced from 30 to 15 IU/kg body wt. Initiation of therapy at a low dose led to a significant improvement in all measured parameters at the end of 1 year. We conclude that the minimal effective dose for the nonskeletal manifestations of Gaucher disease can be achieved either by initiating enzyme replacement therapy with a high dose followed by a stepwise dose reduction or by starting treatment at the minimal dose. High dose provides a faster clinical response and should be considered for patients with more aggressive disease. The therapeutic threshold for macrophage-targeted glucocerebrosidase appears to be 10-15 IU/kg body wt every 2 weeks.
Adolescent↗
Profile of endothelial and leukocyte activation in Fabry patients.
Fabry disease is an X-linked recessive disorder resulting in the deposition of globotriaosylceramide in numerous cell types including vascular endothelial cells. Because this disease is associated with vascular injury and a high recurrence rate of thrombotic events, measurements of factors regulating endothelium and leukocyte interaction may provide insight into the mechanisms leading to a prothrombotic state. Twenty-five patients with Fabry disease and 25 control subjects participated in the study. Plasma from all 25 Fabry patients and 15 of the 25 controls were studied for multiple endothelial factors. Leukocyte integrins were measured by flow cytometry in 21 Fabry patients and 10 controls. The concentrations of soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, P-selectin, and plasminogen activator inhibitor were significantly higher and thrombomodulin was significantly lower in Fabry patients. Expression of the integrin CD11b on monocytes was also significantly higher in the Fabry patients. This study reveals measurable evidence for endothelium and leukocyte activation that is consistent with a prothrombotic state in Fabry patients compared with controls. Further investigations of these findings may help to understand the mechanism of stroke in Fabry disease and provide indicators (or markers) of efficacy of future therapeutic intervention.
Adult↗
Mucolipidosis type IV: characteristic MRI findings.
OBJECTIVE: The objective of this study is to characterize the brain abnormalities on head MRI of patients with mucolipidosis type IV. BACKGROUND: Mucolipidosis type IV is an autosomal recessive lysosomal storage disease of unknown etiology. Patients develop corneal clouding, retinal degeneration, spastic quadriparesis, and mental retardation. Patients with this disorder have not been studied systematically. METHODS: We studied prospectively 15 consecutive patients with mucolipidosis type IV using cranial MRI. RESULTS: Fourteen patients with these typical clinical findings had a hypoplastic corpus callosum with absent rostrum and a dysplastic or absent splenium, signal abnormalities on T1-weighted head MRI images in the white matter, and increased ferritin deposition in the thalamus and basal ganglia. Atrophy of the cerebellum and cerebrum was observed in older patients, which may reflect disease progression. One patient with a mild clinical variant had a normal corpus callosum. CONCLUSION: Patients with mucolipidosis type IV have characteristic cranial MRI findings that suggest that this disorder causes both developmental and neurodegenerative abnormalities.
Adolescent↗
Quality of sleep in the medical department.
The quality of sleep in 134 patients admitted to two medical departments and an intensive coronary care unit was studied by comparing pre- and post-admission sleeping scores. Four aspects of sleep have been evaluated: duration of sleep; number of awakenings; personal assessment of quality of sleep; and the need for using sleeping pills. Results were expressed in scores ranging from 1 (worst) to 4 (best). A significant reduction in the mean quality of sleep for the entire group was found for all scores employed (P < 0.01-P < 0.001). Of the 134 patients, 51% had a reduction in post-admission total sleep score (23 +/- 3%, mean +/- SE); 31% had no change or mixed trends in the various scores, with a change in total sleep score not exceeding 3 +/- 3%; and 18% had an improved total sleep score (16 +/- 2%). Of the individual scores, a deterioration was found in the following order of frequency: number of awakenings (37%); personal assessment of quality of sleep (32%); duration of sleep (31%); and the need for using sleeping pills (26%). Of the reasons specified for impaired quality of sleep, the most important were noise made by other patients or by the medical staff (47%), and the patient's own disease (30%). Significant differences in the quality of sleep between the two medical departments located in different hospitals have been encountered (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗