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E Mazzone,
G Vasco,
M P Sormani,
Y Torrente,
A Berardinelli,
S Messina,
A D'Amico,
L Doglio,
L Politano,
F Cavallaro, [......],
M Pane,
S Gasperini, S Previtali,
S Napolitano,
D Martinelli,
C Bruno,
G Vita,
G Comi,
E Bertini,
E Mercuri
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ABSTRACT: The aim of the study was to assess different outcome measures in a cohort of ambulant boys with Duchenne muscular dystrophy (DMD) over 12 months in order to establish the spectrum of possible changes in relation to age and steroid treatment.
The study is a longitudinal multicentric cohort study. A total of 106 ambulant patients with DMD were assessed using the 6-minute walk test (6MWT) and North Star Ambulatory Assessment (NSAA) at baseline and 12 months. Clinical data including age and steroid treatment were collected.
During the 12 months of the study, we observed a mean decline of 25.8 meters in the 6MWT with a SD of 74.3 meters. On NSAA, the mean decline was 2.2 points with a SD of 3.7. Not all the boys with DMD in our cohort showed a decline over the 12 months, with young boys showing some improvement in their 6MWT and NSAA scores up to the age of 7. NSAA and the 6MWT had the highest correlation (r = 0.52, p < 0.001).
This study provides longitudinal data of NSAA and 6MWT over a 12-month period. These data can be useful when designing a clinical trial.
Neurology 07/2011; 77(3):250-6. · 8.31 Impact Factor
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Roberta Virgilio,
Dario Ronchi,
Georgios M Hadjigeorgiou,
Andreina Bordoni,
Francesca Saladino,
Maurizio Moggio,
Laura Adobbati,
Demetra Kafetsouli,
Evangelia Tsironi, Stefano Previtali,
Alexandros Papadimitriou,
Nereo Bresolin,
Giacomo P Comi
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ABSTRACT: Multiple deletions of mitochondrial DNA (mtDNA) are associated with different mitochondrial disorders inherited as autosomal dominant and recessive traits. Causative mutations have been found in five genes, mainly involved in mtDNA replication and stability. They include POLG1, the gene encoding the catalytic subunit of mtDNA polymerase (pol gamma), POLG2 encoding its accessory subunit, ANT1 coding the adenine nucleotide translocator and PEO1 which codes for Twinkle, the mitochondrial helicase. Finally OPA1 missense mutations are involved in phenotypes presenting optic atrophy as a major feature.To define the relative contribution of POLG1, POLG2, ANT1 and PEO1 genes to the mtDNA multiple deletion syndromes, we analysed them in a cohort of 67 probands showing accumulation of multiple mtDNA deletions in muscle. The patients were predominantly affected with a mitochondrial myopathy with or without progressive external ophthalmoplegia (PEO). Genetic analysis revealed that 1) PEO1 has a major role in determining familial PEO, since it accounts for 26.8% of familial cases, followed by ANT1 (14.6%) and POLG1 (9.8%); 2) no mutations in any of the known genes were found in 53.7% of probands of this series. Six novel missense mutations contributing to the mutational load of PEO1 gene (p.R334P, p.W315S, p. S426N, p.W474S, p.F478I, p.E479K) were associated with an adult onset PEO phenotype.
Journal of Neurology 07/2008; 255(9):1384-91. · 3.47 Impact Factor
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ABSTRACT: Docetaxel has been implicated as a causative agent in peripheral neuropathy, but pathological changes in peripheral nerve have not been described. During docetaxel treatment a 54-year-old man developed a sensorimotor polyneuropathy when the overall docetaxel dosage was 540 mg/m(2). Neurophysiological investigation revealed a sensorimotor axonal neuropathy. Fascicular sural nerve biopsy showed an axonal neuropathy with a preferentially loss of large myelinated fibers. There was evidence of considerable fiber regeneration. Sensory and motor symptoms progressively improved after docetaxel withdrawal.
Acta Neuropathologica 01/2000; 98(6):651-3. · 9.32 Impact Factor
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ABSTRACT: Normal peripheral nerve myelination depends on Schwann cell-basal lamina interactions. An important component of Schwann cell basal lamina is laminin--predominantly laminins 2 and 4. Mutations in the alpha 2 chain common to these two isoforms are associated with dysmyelination in mouse (dy) and man (congenital muscular dystrophy). Thus, laminin 2 and 4 receptors are also likely to be important for myelin formation. Several laminin 2/4 receptors are detected at the basal lamina surface of myelin-forming Schwann cells, namely, alpha 6 beta 4 and alpha 6 beta 1 integrins and dystroglycan. The evidence linking these receptors to myelination is suggestive, but not conclusive. Genetic studies have not yet confirmed a role for these molecules in myelin formation. Natural or targeted inactivation of alpha 6, beta 4, and beta 1 integrins and of dystroglycan have profound effects on other tissues causing embryonic or perinatal death before myelination. Therefore, to conditionally inactivate these receptors specifically in myelin-forming Schwann cells, we have constructed and initially characterized a P0-Cre transgene that activates Cre-mediated recombination of loxP-containing genes in peripheral nerve.
Annals of the New York Academy of Sciences 10/1999; 883:116-23. · 3.15 Impact Factor
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ABSTRACT: We have previously shown that increased dosage of the mouse protein zero gene (Mpz) causes a dysmyelinating neuropathy in transgenic (Tg80) mice. To ask whether the dysmyelination is dose dependent, we inbred one of the Tg80 lines and compared the resulting phenotype in homozygous and heterozygous mice. Whereas heterozygous mice (30% overexpression) have only transient peripheral nerve hypomyelination at two weeks after birth and normal myelin at four weeks after birth, homozygous mice demonstrated more severely hypomyelinated nerves. In the latter, many Schwann cells had achieved a one-to-one relationship with large axons but formed no myelin at four weeks after birth. Expression analysis confirmed a doubling of Mpz overexpression in the sciatic nerves of the homozygous mice. Thus, a threshold exists for Mpz overexpression, above which dysmyelination results. These data have important implications for replacement therapy in Charcot-Marie-Tooth 1B neuropathies due to loss of P0 function.
Annals of the New York Academy of Sciences 10/1999; 883:294-301. · 3.15 Impact Factor
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ABSTRACT: P0 glycoprotein, the most abundant protein in peripheral nerve, is expressed specifically in the Schwann cell lineage. Upstream of the rat P0 gene 1.1 kb of DNA can activate expression of cDNAs specifically in Schwann cells in transgenic mice. However, the expression of P0 promoter-based transgenes has been inconsistent. As much as 9 kb of 5' flanking sequence fused to lacZ never yielded detectable levels of beta-galactosidase in multiple lines of mice. We describe transgenic mice that express lacZ in peripheral nerve, using the complete mouse P0 gene, including 6 kb of 5' flanking sequence, all exons and introns, and the natural polyadenylation signal. This vector activated lacZ expression specifically in cultured Schwann cells, and myelin-forming Schwann cells in four out of six transgenic lines. Transgene expression paralleled that of the endogenous P0 gene, both during development and after Wallerian degeneration. lacZ expression was lower than endogenous P0 expression, and was not detected in neural crest or Schwann cell precursors, where low levels of P0 mRNA are present. However, when the same vector contained a small myc tag instead of the 3.2-kb lacZ insert, the resulting transgenic mRNA was expressed at levels comparable to endogenous P0 mRNA. These data suggest that intragenic or 3' flanking sequences are necessary to generate the remarkable levels of endogenous P0 gene expression.
European Journal of Neuroscience 06/1999; 11(5):1577-86. · 3.63 Impact Factor
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ABSTRACT: Schwann cell gene expression is dynamically regulated after peripheral nerve injury and during regeneration. We hypothesized that the changes in protein expression described after rat peripheral nerve injury could be used to identify single Schwann cell-axon units in human axonal neuropathy. Therefore, we performed immuno-fluorescence staining on sections of injured rat sciatic nerves compared with sections of neuropathic human sural nerves. We chose the markers beta 4 integrin, P0 glycoprotein, and glial fibrillary acidic protein (GFAP) to characterize Schwann cells, and neurofilament-heavy (NF-H) to recognize axons. Normal rat or human myelin-forming units demonstrated a sharp ring of beta 4 staining at their outer surface, P0 staining in the myelin sheath, and NF-H staining in the axon. Acutely denervated rat units transited from broken rings of beta 4 and P0 staining, to diffuse beta 4 and absent P0 and NF-H staining. Chronically denervated rat Schwann cells re-expressed beta 4 more highly, but in a diffuse, non-polarized pattern. In contrast, regenerating units re-expressed beta 4, P0, and NF-H; beta 4 staining was polarized to the outer surface of Schwann cells. Finally, GFAP staining increased progressively after injury and decreased during regeneration in the distal nerve stump. In neuropathic human sural nerves, we identified units exhibiting each of these beta 4, P0, and NF-H staining patterns; the proportion of each pattern correlated best with the extent and chronicity of axonal injury. Thus, synchronous injury of rat sciatic nerve predicts patterns of Schwann cell marker expression in human axonal neuropathy. In addition, the unique changes in the polarity of beta 4 integrin expression, in combination with changes in P0 and NF-H expression, may distinguish normal from denervated or reinnervated myelin-forming Schwann cells in human sural nerve biopsies.
Glia 09/1996; 17(4):294-306. · 4.82 Impact Factor
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ABSTRACT: Laminin may alter the biological behavior of gliomas. Therefore, we investigated the expression of two laminin receptors, alpha6 beta1 and alpha6 beta4 integrins in normal brain, astrogliotic brain, and astrocytomas as compared to other central nervous system (CNS) tumors. In most CNS tumors, the expression of these integrins was unchanged in neoplastic as compared to normal counterpart cells. In contrast, increased numbers of reactive and neoplastic astrocytes expressed beta4 integrin as compared to normal astrocytes, whereas alpha6 and beta1 integrin expression did not change. Conversely, lower numbers of astrocytoma blood vessels expressed beta4, whereas all blood vessels in normal brain expressed beta4. These data suggest that the profile of laminin receptors changes in neoplastic astrocytes and in astrocytoma blood vessels; this change may play an important role in astrocytoma pathogenesis.
Journal of Neuropathology and Experimental Neurology 05/1996; 55(4):456-65. · 4.26 Impact Factor
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ABSTRACT: Nine patients with chronic inflammatory demyelinating poliradiculoneuropathy (CIDP) were treated with intravenous immunoglobulin. All patients had been previously treated with prednisone and/or plasma exchange without effect. Objective improvement in clinical condition occurred in six patients. One patient became refractory after two treatment courses, two patients had no response. The results indicate that intravenous immunoglobulin has beneficial effects in a high percentage of patients with CIDP who are unresponsive to other treatments.
Journal of Neurology Neurosurgery & Psychiatry 12/1994; 57 Suppl:43-5. · 4.76 Impact Factor
