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Biomedical subjects

Antonio Federico

Publications and source records attributed to Antonio Federico.

At least 37 records · Page 2Linked to original sources
PubMed2005

Systemic blood pressure profile in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic form of subcortical ischemic vascular dementia (SIVD). The most common vascular risk factors are unremarkable in CADASIL; however, studies on systemic blood pressure (BP) changes over time are substantially lacking. Because BP instability is a relevant risk factor for developing or worsening white matter changes in sporadic SIVD, we aimed to study the BP profile of CADASIL to investigate its relationship with cognitive decline and white matter injury. METHODS: Twenty-four-hour ambulatory BP monitoring was performed in a group of 14 CADASIL patients (12 males and 2 females) and in a group of 15 healthy age-matched control subjects. The following BP variables were compared between the 2 groups: mean daytime and nighttime systolic, diastolic, and mean arterial BP (SABPday, DABPday, and MABPday, and SABPnight, DABPnight, and MABPnight) and nocturnal percentage decline in arterial BP (%MABP reduction). Cognitive performances were tested by mini mental status examination (MMSE), and brain MRI was performed to extrapolate the T2-weighted lesion volume (LV) in each CADASIL patient. The 24-hour arterial BP variables were compared between CADASIL and controls. In addition, for CADASIL patients only, MMSE, LV, and age were compared with each pressure variable. RESULTS: Patients with CADASIL showed a significant reduction (P<0.05) of SABPday, DABPday, MABPday and %MABP decline with respect to controls. In addition, MMSE of CADASIL subjects correlated significantly (P<0.0001) with daytime MABP. CONCLUSIONS: The low systemic BP profile observed in CADASIL patients was specifically attributable to reduced diurnal BP values. This may further affect cerebral hemodynamics and increase the risk of cognitive impairment in these patients. The pathogenesis of abnormal BP profile in CADASIL remains to be clarified. It is likely that central and peripheral mechanisms controlling BP variations are involved.

Adolescent↗
PubMed2005

Magnetic resonance spectroscopy as a measure of brain damage in multiple sclerosis.

Recent MR studies have emphasised the importance of neuronal and axonal damage in multiple sclerosis. In this respect, proton MR spectroscopy (by monitoring levels of N-acetylaspartate, a putative marker of axonal integrity) has been particularly illuminating by showing indirect evidence of neurodegeneration in both lesional and non-lesional brain tissues from the earliest stages of the disease. The importance of these changes to patients' clinical disability argues for the primary role of neuronal pathology in the pathogenesis of the disease.

Aspartic Acid↗
PubMed2005

Peripheral neuropathy in CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary cerebral microangiopathy associated with mutations in the Notch 3 gene. The clinical phenotype is characterized by cerebral impairment even though typical microvascular changes are diffuse. OBJECTIVE: To assess peripheral neuropathy in patients with CADASIL. PATIENTS AND METHODS: We enrolled eleven CADASIL patients with variable phenotype including clinical signs of peripheral nerve involvement. In all patients electromyography and nerve conduction velocities were performed. Peripheral nerve biopsy was performed in three cases. RESULTS: We found sensory motor neuropathy in 7/11 patients. Nerve biopsy revealed axonal and demyelinated findings. CONCLUSION: Our findings suggest that peripheral neuropathy may be part of the CADASIL phenotype.

Action Potentials↗
PubMed2005

A novel heteroplasmic tRNA(Leu(CUN)) mtDNA point mutation associated with chronic progressive external ophthalmoplegia.

We have sequenced all mitochondrial tRNA genes from a patient with chronic progressive external ophthalmoplegia (CPEO) and mitochondrial myopathy, who had no detectable large mtDNA deletions. Direct sequencing failed to detect previously reported mutations and showed a heteroplasmic mutation at nucleotide 12,276 in the tRNA(Leu(CUN)) gene, in the dihydrouridine stem, which is highly conserved through the species during evolution. RFLP analyses confirmed that 18% of muscle mtDNA harbored the mutation, while it was absent from DNA of fibroblasts and lymphocytes of the proband and in 110 patients with other encephalomyopathies. To date, besides large and single nucleotide deletions, several point mutations on mitochondrial tRNA genes have been reported in CPEO patients, but only three were in the gene coding for tRNA(Leu(CUN)).

Animals↗
PubMed2005

Leber hereditary optic neuropathy in 2 of 4 siblings with 11778 mtDNA mutation: clinical variability or effect of toxic environmental exposure?

Although mitochondrial (mt) DNA mutation at nucleotide position 11778 accounts for most cases of Leber's hereditary optic neuropathy (LHON), the phenotypic expression may vary greatly even in different members of the same family. The possible influence of exogenous toxicity on phenotypic expression is still debated in LHON. Here we describe 4 siblings carrying the 11778 mtDNA mutation with a different phenotype. The index case developed an atypical optic neuropathy at the age of 60 years after a long history of occupational exposure to polycyclic aromatic hydrocarbons (PAHs). This report underlines a number of unanswered questions about phenotypic variability of LHON including the possible influence of PAH toxicity.

Aged↗
PubMed2005

Role of beta-galactosidase and elastin binding protein in lysosomal and nonlysosomal complexes of patients with GM1-gangliosidosis.

G(M1)-gangliosidosis is a lysosomal storage disorder caused by a deficiency of beta-galactosidase (GLB1). The GLB1 gene gives rise to the GLB1 lysosomal enzyme and to the elastin binding protein (EBP), involved in elastic fiber deposition. GLB1 forms a complex with protective protein cathepsin A (PPCA), alpha neuraminidase (NEU1), and galactosamine 6-sulphate sulfatase (GALNS) inside lysosomes, while EBP binds to PPCA and NEU1 on the cell surface. We investigated the function of the GLB1 and EBP mutated proteins by analyzing the clinical, genetic, and cellular data of 11 G(M1)-gangliosidosis patients. Their molecular analysis, followed by expression studies, lead to the identification of four new and 10 known GLB1 mutations. Some common amino acid substitutions [c.1445G>A (p.Arg482H), c.622C>T (p.Arg208His), c.175C>T (p.Arg59Cys) and c.176G>A (p.Arg59His)] were present in the GLB1 enzyme of several patients, all of Mediterranean origin, suggesting a common origin. Western blotting analyses against GLB1, EBP, and PPCA proteins showed that the identified mutations affect GLB1 enzyme activity and/or stability. The c.1445G>A (p.Arg482His), c.175C>T (p.Arg59Cys), c.733+2T>C, c.1736G>A (p.Gly579Asp), and c.1051C>T (p.Arg351X) GLB1 mutations, affect the stabilization of PPCA probably because they hamper the interaction between GLB1/EBP and PPCA within the multiprotein complex. The amount of EBP was normal, but the detection of impaired elastogenesis in such patients suggests an alteration in its function. We conclude that the presence of genetic lesions in both GLB1 and EBP coding region does not directly predict impaired elastogenesis and that elastic fiber assembly has to be evaluated specifically in each case. Nevertheless, the degree of EBP involvement may be linked to specific clinical findings.

Adult↗
PubMed2005

Isotopomer spectral analysis of intermediates of cholesterol synthesis in patients with cerebrotendinous xanthomatosis.

Four patients with cerebrotendinous xanthomatosis (CTX) and 2 healthy controls received a constant proximal intraduodenal infusion of 1- 13 C-acetate as a stable-isotope-labeled marker of sterol synthesis. One patient was treated with pravastatin (20 mg twice daily) and another patient with chenodeoxycholic acid (250 mg tid). Every hour, venous blood and duodenal samples were obtained. Stable-isotope enrichment of neutral and polar sterols in serum and bile was assessed by gas chromatography/mass spectrometry. Isotopomer spectral analysis was performed on cholesterol, lathosterol, Delta-8-cholesterol, methylsterol, and lanosterol. Stable-isotope labeling of cholestanol, bile acids, and bile alcohols was analyzed by assessing the change over time of the ratio of M + 3 to M + 0. Eleven hours after marker infusion, we found up to 50% newly synthesized lathosterol in serum and up to 80% in bile, with similar results for other cholesterol precursors. In cholesterol, stable-isotope labeling could be demonstrated in all study subjects with a more prominent labeling in bile than in serum. No stable-isotope labeling was detected in cholestanol. Only minor stable-isotope incorporation was detectable in polar sterols in some subjects. Therapy with pravastatin did not have any effect on fractional or absolute synthesis rates or on the concentrations of cholestanol or cholesterol precursors compared to untreated patients with CTX. In contrast, therapy with chenodeoxycholic acid markedly lowered the concentrations of cholestanol and cholesterol precursors, led to a disappearance of bile alcohols, and reduced absolute synthesis rates of lathosterol. Isotopomer spectral analysis proved to be a powerful method to assess the endogenous synthesis of cholesterol precursors in patients with CTX. Higher fractional synthesis in bile than in serum may be due to the size of the pools in bile vs serum. Cholestanol exhibits no marker uptake and is therefore probably synthesized from preformed cholesterol. Biliary cholesterol secretion in patients with CTX is decreased compared to healthy controls.

Adult↗
PubMed2004

Sequence analysis of the complete mitochondrial genome in patients with mitochondrial encephaloneuromyopathies lacking the common pathogenic DNA mutations.

The purpose of this study was to identify novel mitochondrial deoxyribonucleic acid (mtDNA) mutations in a series of patients with clinical and/or morphological features of mitochondrial dysfunction, but still no genetic diagnosis. A heterogeneous group of clinical disorders is caused by mutations in mtDNA that damage respiratory chain function of cell energy production. We developed a method to systematically screen the entire mitochondrial genome. The sequence-data were obtained with a rapid automated system. In the six mitochondrial genomes analysed we found 20 variants of the revised Cambridge reference sequence [Nat. Genet. 23 (1999) 147]. In skeletal muscle nineteen novel mtDNA variants were homoplasmic, suggesting secondary pathogenicity or co-responsibility in determination of the disease. In one patient we identified a novel heteroplasmic mtDNA mutation which presumably has a pathogenic role. This screening is therefore useful to extend the mtDNA polymorphism database and should facilitate definition of disease-related mutations in human mtDNA.

Adult↗
PubMed2004

Influence of apolipoprotein E epsilon4 genotype on brain tissue integrity in relapsing-remitting multiple sclerosis.

BACKGROUND: Recent clinical and imaging studies have raised the hypothesis that patients with multiple sclerosis (MS) and the apolipoprotein E (ApoE) epsilon4 allele may have a more severe disease course than those without the ApoE epsilon4 allele. This seems to be related to more extensive tissue destruction and less efficient neuronal maintenance and repair in ApoE epsilon4 carriers. OBJECTIVE: To evaluate the influence of different ApoE genotypes on brain tissue integrity in patients with relapsing-remitting MS (RRMS). DESIGN: We determined the ApoE genotype in 76 RRMS patients. Conventional T1-, T2-, and proton density-weighted magnetic resonance (MR) images were obtained for each patient and in a group of demographically matched healthy control subjects. On conventional T1-weighted MR images, an automated analysis tool was used to obtain total brain volumes normalized for head size (NBVs). Total brain lesion load was estimated on proton density- and T2-weighted MR images. RESULTS: From the whole group of RRMS patients, we identified 18 with and 58 without the epsilon4 allele. Both patient groups were not significantly different in age, age of disease onset, clinical disability, and disease duration. Carriers of the epsilon4 allele showed significantly (P =.01) lower NBVs than controls and non-epsilon4 allele carriers. When a similar analysis was performed on only those patients with both very short disease duration and absence of clinical disability, NBV values were still significantly lower in RRMS patients with the epsilon4 allele than in those without it (P =.02) and in controls (P =.007). In contrast, RRMS patients with different ApoE genotypes did not show significant differences in values of total brain T2-weighted lesion volumes. CONCLUSIONS: The presence of significant NBV decreases only in the group of RRMS patients with the ApoE epsilon4 genotype provides new evidence that links ApoE epsilon4-related impaired mechanisms of cell repair and severe tissue destruction in MS. Results of the present study suggest that this negative influence of the ApoE epsilon4 genotype might be active from the earliest disease stages.

Adult↗
PubMed2004

Acute unilateral visual loss as the first symptom of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND: Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is considered a cerebrovascular disorder with almost exclusively neurological symptoms, the arteriopathy is generalized and involves choroidal and retinal vasculature as demonstrated by fluorescein angiographic and ocular electrophysiological abnormalities. The occurrence of acute visual loss due to nonarteritic anterior ischemic optic neuropathy (NAION) has not previously been reported in CADASIL. OBJECTIVE: To describe acute visual loss due to NAION as a possible manifestation of CADASIL. PATIENTS AND METHODS: The patient was a 60-year-old man with subcortical diffuse leukoencephalopathy, multi-infarct dementia, tetraparesis, visual loss, and a family history of stroke. We performed clinical and neuro-ophthalmological evaluation, electrophysiological assessment, brain magnetic resonance imaging, and genetic screening for mutations or small deletions of the Notch3 gene, (causing CADASIL). RESULTS: The patient's first symptom was acute visual loss in the right eye due to NAION at age 27 years, in absence of the common cardiovascular risk factors and before any neurological impairment. The patient was reevaluated at age 60 years, and neuro-ophthalmological examination showed optic disc atrophy in the right eye with arteriolar narrowing and a reduction in visual acuity in the left eye. Fluorescein angiography of the right eye showed evidence of persistent peripapillary hypofluorescence with a retinal pigment epithelial windows defect in the inferior temporal area. Pattern reversal visual evoked potentials were abolished in the right eye. The P100 latency of the left eye was delayed and reduced in amplitude. The diagnosis of CADASIL was confirmed by molecular analysis (heterozygotes for the C406T mutation on exon 3 of the Notch3 gene). There was a family history of cerebrovascular disorders and ocular impairment. CONCLUSIONS: Visual loss due to transient or stable ischemic events involving the optic nerve head should be considered in the CADASIL phenotype. The possibility of CADASIL should also be evaluated in patients with NAION who do not have cardiovascular risk factors but do have a family history of stroke.

Blindness↗
PubMed2004

A novel NOTCH3 frameshift deletion and mitochondrial abnormalities in a patient with CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which leads to strokes and dementia, is caused by single missense mutations or, in a few cases, small deletions in the NOTCH3 gene. These mutations result in a gain or a loss of 1 (or, rarely, 3) cysteine residue in 1 of 34 epidermal growth factor-like repeats in the extracellular amino-terminal region of NOTCH3. OBJECTIVE: To describe a patient with a novel NOTCH3 mutation in whom clinical and laboratory findings of mitochondrial abnormalities were associated with a diagnosis of CADASIL. Patient A patient with a history of migraines, repeated transient ischemic attacks, and generalized fatigue underwent muscle biopsy, brain magnetic resonance spectroscopic imaging, and screening of mitochondrial DNA and NOTCH3. RESULTS: Molecular genetic analysis showed a NOTCH3 mutation (the first documented frameshift deletion in a patient with CADASIL) in exon 4. Although the screening of mitochondrial DNA did not show mitochondrial mutations, findings from muscle biopsy and brain magnetic resonance spectroscopic imaging showed signs of mitochondrial impairment (ultrastructural mitochondrial abnormalities and increased parenchymal brain lactate, respectively). CONCLUSIONS: A patient with CADASIL and a 5-base pair deletion leading to a frameshift mutation showed clinical and laboratory evidence of mitochondrial dysfunction. This adds to the previously reported hypothesis of a pathogenetic role of NOTCH3 or, less specifically, a microvascular pathologic effect on mitochondrial energy metabolism.

Base Sequence↗
PubMed2004

Hemodynamic evaluation of the optic nerve head in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND: Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is considered a cerebrovascular disorder with almost exclusively neurological symptoms, arteriopathy is generalized and also involves the choroid and retina. OBJECTIVE: To study optic nerve head microvascular function in CADASIL by assessing blood flow, volume, and velocity with a retina flowmeter. PATIENTS AND METHODS: Scanning laser Doppler flowmetry permits the noninvasive assessment of relative blood velocity, volume, and flow in a sample volume of either retina or anterior optic nerve head. Measurements were performed in a first group of 9 eyes of 5 patients with CADASIL and a second group of 8 eyes of 4 healthy subjects. Hemodynamic parameters were computed in 4 quadrants of the optic disc (superior nasal, superior temporal, inferior nasal, and inferior temporal). The Wilcoxon rank sum test was used to assess differences in relative flow, volume, and velocity in each quadrant and between the 2 groups and differences in overall optic nerve head blood flow, volume, and velocity. RESULTS: Patients with CADASIL had a significant decrease in overall blood flow and volume compared with healthy subjects (P<.05). The reduction in blood flow and volume was particularly significant in the superior and inferior temporal quadrants. No significant differences were found nasally between the patients and the control groups. CONCLUSION: Our results suggest that hemodynamic parameters are abnormal in the superficial nerve fiber layer of the optic nerve head of patients with CADASIL, especially in the temporal quadrants of the neuroretinal rim.

Adult↗
PubMed2004

Chorein detection for the diagnosis of chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is a severe, neurodegenerative disorder that shares clinical features with Huntington's disease and McLeod syndrome. It is caused by mutations in VPS13A, which encodes a large protein called chorein. Using antichorein antisera, we found expression of chorein in all human cells analyzed. However, chorein expression was absent or noticeably reduced in ChAc patient cells, but not McLeod syndrome and Huntington's disease cells. This suggests that loss of chorein expression is a diagnostic feature of ChAc.

Acanthocytes↗
PubMed2004

The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy.

A novel mitochondrial DNA (mtDNA) transition (3733G-->A) inducing the E143 K amino acid change at a very conserved site of the NADH dehydrogenase subunit 1 (ND1) was identified in a family with six maternally related individuals with Leber's hereditary optic neuropathy (LHON) and in an unrelated sporadic case, all negative for known mutations and presenting with the canonical phenotype. The transition was not detected in 1,082 control mtDNAs and was heteroplasmic in several individuals from both pedigrees. In addition, the mtDNAs of the two families were found to belong to different haplogroups (H and X), thus confirming that the 3733G-->A mutation occurred twice independently. Phosphorus magnetic resonance spectroscopy disclosed an in vivo brain and skeletal muscle energy metabolism deficit in the four examined patients. Muscle biopsy from two patients showed slight mitochondrial proliferation with abnormal mitochondria. Biochemical investigations in platelets showed partially insensitive complex I to rotenone inhibition. We conclude that the 3733G-->A transition is a novel cause of LHON and, after those at positions 3460 and 4171, is the third ND1 mutation to be identified in multiple unrelated families. This finding shows that, in addition to ND6, the ND1 subunit gene is also a mutational hot spot for LHON.

Adult↗
PubMed2004

A point mutation in the lariat branch point of intron 6 of NPC1 as the cause of abnormal pre-mRNA splicing in Niemann-Pick type C disease.

The lariat branch point sequence (BPS) is crucial for splicing pre-mRNA even if BPS mutations have infrequently been reported in human disease. In two siblings with Niemann-Pick type C (NPC) disease we identified two mutations of the NPC1 gene: i) one in exon 20 (c.2932C>T) (p.R978C) previously reported in NPC patients; ii) the other (c.882-28A>G) unreported, in the highly conserved adenosine of a putative lariat BPS of intron 6. Using RT-PCR we found that, besides the normally spliced mRNA, patients' fibroblasts contained minute amounts of an mRNA devoid of exon 7. The exon 6--exon 8 junction in this mRNA causes a frameshift and a premature stop codon, predicted to result in a truncated protein. To assess the effect of c.882-28A>G mutation we constructed two minigenes (wild type and mutant), spanning from intron 5 to intron 8, which were inserted into a pTarget vector and transfected in COS1 cells. The wild type minigene generated an mRNA of the expected size and sequence; the mutant minigene generated only an mRNA devoid of exon 7. This is the first example of a splicing defect due to a mutation in the lariat BPS in an intron of NPC1 found in NPC patients.

Adult↗
PubMed2004

Lymphoblastoid cell lines of Rett syndrome patients exposed to oxidative-stress-induced apoptosis.

Despite the identification of mutations in the methyl CpG binding protein 2 gene, the pathogenesis of Rett syndrome (RS) is still unknown. In order to clarify the role of apoptosis in this disorder, we studied lymphoblastoid cell lines in five classical RS patients and five controls, incubated with 2-deoxy-d-ribose (dRib), a reducing sugar that induces apoptosis in human cells, through oxidative damage. The apoptotic response was detected by flow cytometric analysis and agarose gel electrophoresis. The cells of RS patients showed a lower percentage of apoptosis in a routine condition than those of controls did, whereas, in the presence of dRib, the percentage of apoptotic cells in RS patients increased with time and reached the same percentage of those of controls at 72 h. The data observed here suggest that RS may have a low susceptibility or an increased resistance to the apoptotic cell death, which may be corrected only in the presence of a strong apoptotic stimulus.

Adolescent↗