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Biomedical subjects

A Federico

Publications and source records attributed to A Federico.

At least 145 records · Page 8Linked to original sources
PubMed1996

[Cerebrotendinous xanthomatosis. A case report].

We describe a patient with cerebrotendinous xanthomatosis (CTX) who saw a Rheumatologist because of joint and muscle pain in the lower limbs. Clinical examination did not reveal any classic joint disease; however, tendon lesions and clumsy gait were noted. The patient presented with a swollen Achilles tendon bilaterally and a parapareto-spastic gait; Babinski sign was positive on the right side, and hyperreflexia of both lower limbs could be demonstrated. As bilateral cataracts were present, we have interpreted the aforementioned signs as CTX with spinal involvement; mean plasma cholesterol was increased, thus confirming the diagnosis. The primary biochemical abnormality of this disease is a defect in the synthesis of bile acids; therefore, chenodeoxycholic acid (CDCA) has been tried, and beneficial effects following CDCA treatment, especially in the early stages of CTX, have been reported in the literature. We report this case because of the severity and the rarity of this disease, and also because of its hereditary transmission. Our aim is to underline the need of a precocious diagnosis, in order to prevent a further progression of the disease; this therapeutic goal can now be achieved, thanks to the therapeutic regimens recently developed.

Achilles Tendon↗
PubMed1996

Partial deletion of the gene encoding sterol 27-hydroxylase in a subject with cerebrotendinous xanthomatosis.

An Italian subject with cerebrotendinous xanthomatosis (CTX) was found to have a partial deletion of the gene encoding the enzyme sterol 27-hydroxylase (CYP27 gene). Southern blot analysis revealed that this deletion (approximately 2 kb) spans from intron 6 to the 3' flanking (3'FLK) region, eliminating exons 7-9, the last three exons of CYP27 gene. No sterol 27-hydroxylase mRNA was detected in proband cells, either by Northern blot analysis or by reverse transcription polymerase chain reaction (PCR). This suggests that the mutant mRNA devoid of the exon encoding the whole untranslated sequence (exon 9) might be rapidly degraded in the cytoplasm. We used inverse PCR to obtain a partial sequence of the 3'FLK region of the normal CYP27 gene; this allowed us to define the mechanism underlying the deletion. The established sequence was used to design suitable primers to perform step-wise sequences of a 1.7 kb segment of the 3'FLK region of the normal gene and of the deletion joint in the CTX patient. The analysis of the sequence data indicate that the deletion might result from a complex mechanism involving two intragenic recombinations between a) two 14 nucleotide complementary sequences, one in intron 6 and the other in the 3'FLK region: and b) AT-rich complementary sequences of the 3'FLK region, and a slipped mispairing between two 6 nucleotide direct repeats, one in intron 6 and the other in the 3'FLK region. Such repeats are brought close to each other by the formation of the stem-loops induced by the two intragenic recombinations. This is the first example of CTX caused by a rearrangement of CYP27 gene.

Adult↗
PubMed1996

Disappearance of skin lipofuscin storage and marked clinical improvement in adult onset coeliac disease and severe vitamin E deficiency after chronic vitamin E megatherapy.

A case of adult onset coeliac disease with IgA and severe vitamin E deficiencies, associated with cerebellar impairment and peripheral neuropathy, is described. Nerve conduction velocities, BAERs and SEP were altered. Brain nMR showed cortical atrophy mainly in the frontal and parietal regions. At ultrastructural examination, nerve biopsy showed a severe nerve fiber loss with presence of lipofuscin. Lipofuscin has been also found in skin and muscle biopsy. Duodenal biopsy showed villar atrophy with criptae hypoplasia. IgA, Apo A1 lipoprotein and cholesterol were decreased. Serum level of vitamin E was not detectable and its amount did not increase after an oral loading (2 g bolus). Parenteral vitamin E administration (900 mg/day) was able to normalize the plasma values only after 6 months of chronic administration of the drug in coincidence with a significant improvement of clinical and neurophysiological signs, and disappearance of lipofuscin storage in the skin biopsy.

Brain Diseases, Metabolic↗
PubMed1996

Cerebrotendinous xanthomatosis caused by two new mutations of the sterol-27-hydroxylase gene that disrupt mRNA splicing.

Cerebrotendinous xanthomatosis (CTX) is an inherited sterol storage disease associated with the accumulation of cholestanol and cholesterol in various tissues. CTX is caused by a deficiency of sterol-27-hydroxylase, a mitochondrial enzyme that oxidizes the side chain of cholesterol in the pathway leading to the formation of bile acids. In the present study we report two mutations of sterol-27-hydroxylase gene (CYP27 gene) found in Italian CTX patients. Proband T.C. is homozygous for a G-->A transition at the first nucleotide of intron 7. This mutation causes the formation of minute amounts of an abnormal mRNA, in which exon 6 joins directly to exon 8 with the skipping of exon 7. The exon 6-exon 8 junction results in a frame shift, downstream from the codon for Arg362, which generates a string of 28 novel amino acids preceding a premature termination codon. Proband C.U. is homozygous for a G-->C transversion at the last nucleotide of exon 3. This mutation, which changes the consensus sequence of the 5' donor splice site, is associated with barely detectable levels of sterol-27-hydroxylase mRNA, of normal size, in proband fibroblasts. As both mutations change the sites for two restriction enzymes, rapid methods were devised for the identification of the healthy carriers among the probands' family members and for the screening of these mutations in other CTX patients.

Adult↗
PubMed1996

Urinary excretion of mevalonic acid as an indicator of cholesterol synthesis.

Urinary excretion of mevalonic acid was investigated as an indicator of cholesterol synthesis. In normolipemic volunteers, excretion of mevalonic acid averaged 3.51 +/- 0.59 (SD) micrograms/kg x day1; (n = 24) and was not different from patients with hypercholesterolemia (3.30 +/- 0.92 micrograms/kg x day1; n = 24). In patients with cerebrotendineous xanthomatosis, the excretion was significantly higher (8.55 +/- 1.92 micrograms/kg x day1; n = 6, P < 0.001) but comparable to volunteers treated with cholestyramine (6.69 +/- 2.6 micrograms/kg x day1; n = 5). A significant correlation was found between 24-h excretion of mevalonic acid and cholesterol synthesis (r = 0.835; n = 35; P < 0.001). The coefficient of variation of excretion of mevalonic acid during 3 consecutive days was small (9.8%; n = 7). However, urinary output of mevalonic acid was significantly higher during the night (164 +/- 14 micrograms/12-h) than during the day (129 +/- 9 micrograms/12-h; n = 11; P < 0.05). In patients treated with simvastatin (40 mg/day) for 6 weeks, the ratio of mevalonic acid to creatinine in a morning urine sample decreased significantly compared to pretreatment values (110 +/- 25 micrograms/g vs. 66 +/- 25 micrograms/g; P < 0.001). Furthermore, the ratio of mevalonic acid to creatinine in a morning urine sample correlated with the ratio from the 24-h collection period (r = 0.714; n = 34; P < 0.001). The results indicate that the analysis of urinary mevalonic acid, either in 24-h collection or in a single morning sample, is an attractive method for evaluation of long and very short term changes of the rates of cholesterol synthesis.

Adult↗
PubMed1996

Skin and conjunctive biopsies as a useful diagnostic tool in tomaculous neuropathy.

In nerve fascicles from skin and conjunctive biopsies from two siblings with hereditary chronic sensory-motor neuropathy with tomaculous changes (tomaculous neuropathy) we describe similar abnormalities to those found in sural nerve, consisting in thickenings of nerve fibres, with redundant loops of myelin and concentric apposition of enormous number of myelin lamellae. Our data demonstrate that, as previously reported in many neurometabolic or other abiotrophic diseases of the nervous system, skin and conjunctival biopsies may be a useful diagnostic tool also in this disorder, mainly when the diagnosis has to be confirmed in other family members, after one has been fully investigated by nerve biopsy, and when less invasive molecular genetic analyses on peripheral blood DNA have failed to reveal any known mutation associated with the disease.

Biopsy↗
PubMed1995

Polarographic analyses of subsarcolemmal and intermyofibrillar mitochondria from rat skeletal and cardiac muscle.

We report the polarographic analysis of subsarcolemmal and intermyofibrillar mitochondria from rat skeletal and cardiac muscle, in order to detect possible biochemical and functional differences. Electron microscopic observation of isolated mitochondria showed normal aspect, with intact membranes. Respiratory control rate with different substrates and state 3 activity did not show differences between subsarcolemmal and intermyofibrillar mitochondria in skeletal muscle and heart.

Animals↗
PubMed1995

Mitochondrial enzyme deficiency in cerebrotendinous xanthomatosis.

We report reduced respiratory chain enzyme activity in isolated muscle mitochondria and high levels of serum and CSF pyruvate and lactate in a case of cerebrotendinous xanthomatosis. These findings raise the question of the pathogenetic role of mitochondrial dysfunction in this syndrome.

Adult↗
PubMed1995

Amiodarone induced lipidosis similar to Niemann-Pick C disease. Biochemical and morphological study.

Amiodarone is effective in the treatment of supraventricular and ventricular cardiac arrhythmia, however a high incidence of toxic side effects has been observed in various organs and tissues during chronic treatment. Ultrastructural observation of affected tissues reveals myelinoid inclusion bodies. The exact pathogenetic mechanism of these changes is still unknown. In this study we investigated the biochemical effects of this drug on lysosomal hydrolases and the alterations induced in subcellular organelles of fibroblasts cultured for 24 h with different concentrations of amiodarone in the medium. Of the enzyme activities assayed, we only observed a significant reduction in sphingomyelinase. Ultrastructural observation of fibroblasts showed swollen lysosomes and a few onionoid inclusion bodies at lower concentrations of the drug; at higher concentrations the lysosomal system was severely impaired. Cytochemical staining of unesterified cholesterol with filipin showed accumulation of cholesterol. We conclude that chronic amiodarone treatment in experimental conditions induces inhibition in sphingomyelinase activity through interaction with membrane lipids and modification of bilayer structure. Higher concentrations of the drug impair cholesterol transport and induce lipid accumulation. These results may be useful for understanding the pathogenesis of induced lipidosis in patients in chronic treatment with amiodarone.

Amiodarone↗
PubMed1995

Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex.

Human pyruvate dehydrogenase (PDH)-complex deficiency is an inborn error of metabolism that is extremely heterogeneous in its presentation and clinical course. In a study of 14 patients (7 females and 7 males), we have found a mutation in the coding region of the E1 alpha gene in all 14 patients. Two female patients had the same 7-bp deletion at nt 927; another female patient had a 3-bp deletion at nt 931. Another female patient was found to have a deletion of exon 6 in her cDNA. Two other female patients were found to have insertions, one of 13 bp at nt 981 and one of 46 bp at nucleotide 1078. Two male patients were found to have a 4-bp insertion at nucleotide 1163. The remaining six patients all had missense mutations. A male patient and a female patient both had an A1133G mutation. The other missense mutations were C214T, C615A, and C787G (two patients). Five of these mutations are novel mutations, five have been previously reported in other patients, and two were published observations in other patients in an E1 alpha-mutation summary. In the four cases where parent DNA was available, only one mother was found to be a carrier of the same mutation as her child.

Base Sequence↗
PubMed1995

Plasma levels of vitamin E in Parkinson's disease.

We report the analysis of plasma levels of vitamin E that has been found normal in 20 italian patients with Parkinson's disease (PD) confirming the previously reported results from other groups. We discuss the literature data about the possible protective effect of antioxidant agents in the PD and generally in the aging processes.

Aged↗
PubMed1994

Cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease): CT and MR findings.

PURPOSE: To describe the CT and MR findings in the brain and spinal cord of patients with cerebrotendinous xanthomatosis and to seek possible correlations between clinical, biochemical (cholestanol levels), and neuroimaging findings. METHODS: Ten patients with well-defined clinical and biochemical diagnoses of cerebrotendinous xanthomatosis were examined. Brain CT was performed in eight cases. In all patients MR was obtained using spin-echo and gradient-echo sequences. In eight patients spine MR was also performed. RESULTS: Neuroradiologic findings included diffuse cerebral and cerebellar atrophy. In half the cases, atrophy of the brain stem and corpus callosum was also found. In the majority of patients cerebellar bilateral focal lesions and mild white matter signal alterations were present. Spinal cord MR did not show signal abnormalities or atrophy. CONCLUSIONS: We found cranial alterations in patients with severe neurologic impairment, but there was no correlation with cholestanol plasma levels. No spinal cord abnormalities were present.

Adult↗
PubMed1994

Primary antiphospholipid syndrome: two case reports, one with histological examination of skin, peripheral nerve and muscle.

Two cases of primary antiphospholipid antibody syndrome are reported. One patient presented multiple abortions and epilepsy. The second patient was affected by a brain vascular accident, with a residual hemiparesis. Both cases showed livedo reticularis in arms, NMR evidence of diffuse lesions of the white matter, high serum levels of anticardiolipin antibodies and cardiopathy. Lupus anticoagulant was also found in the serum of the first patient, and cortisone and antiaggregants enabled her to reach term in a fifth pregnancy after four miscarriages. In the other case histological examination of specimens of skin, peripheral nerve and skeletal muscle revealed occlusive, non arteriosclerotic vasculopathy and an absence of inflammatory lesions. Histological study has rarely been performed in primary antiphospholipid syndrome but suggests that the mechanism of thrombosis is not vascular; in our subjects it revealed findings similar to those in Sneddon syndrome.

Adult↗