Biomedical subjects

Antonio Di Muzio

Publications and source records attributed to Antonio Di Muzio.

8 recordsLinked to original sources

PubMed2006

Spinal muscular atrophy genotyping by gene dosage using multiple ligation-dependent probe amplification.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord, causing symmetric proximal muscle weakness. SMA is classified in three clinical types, SMA I, SMA II, and SMA III, based on the severity of the symptoms and the age of onset. About 95% of SMA cases are caused by homozygous deletion of the survival motor neuron 1 (SMN1) gene (5q13), or its conversion to SMN2. The molecular diagnosis of this disease is usually carried out by a polymerase chain reaction-restriction fragment length polymorphism approach able to evidence the absence of both SMN1 copies. However, this approach is not able to identify heterozygous healthy carriers, which show a very high frequency in general population (1:50). We used the multiple ligation-dependent probe amplification (MLPA) approach for the molecular diagnosis of SMA in 19 affected patient and in 57 individuals at risk to become healthy carriers. This analysis detected the absence of the homozygous SMN1 in all the investigated cases, and allowed to discriminate between SMN1 deletion and conversion to SMN2 on the basis of the size showed by the peaks specific for the different genes mapped within the SMA critical region. Moreover, MLPA analysis evidenced a condition of the absence of the heterozygous SMN1 in 33 out of the 57 relatives of the affected patients, demonstrating the usefulness of this approach in the identification of healthy carriers. Thus, the MLPA technique represents an easy, low cost, and high throughput system in the molecular diagnosis of SMA, both in affected patients and in healthy carriers.

Adult↗

PubMed2006

Experimental axonopathy induced by immunization with Campylobacter jejuni lipopolysaccharide from a patient with Guillain-Barré syndrome.

New Zealand white rabbits were immunized with a lipopolysaccharide (LPS) extracted from a Campylobacter jejuni HS:19 strain isolated from a GBS patient expressing GM1 and GD1a-like epitopes, Freund's adjuvant (group I) and Freund's adjuvant plus keyhole lympet hemocyanin (KLH) (group II). Both groups showed high titers of anti-LPS and anti-GM1 and lower titers of anti-GD1b and anti-GD1a antibodies. Weakness and axonal degeneration in sciatic nerves was detected in 1/11 of group I and 6/7 of group II. This model replicates, at least in part, the pathogenetic process hypothesized in the human axonal GBS with antiganglioside antibodies post C. jejuni infection and indicates that KLH plays an additional role in neuropathy induction.

Animals↗

PubMed2006

Lewis-Sumner syndrome in hepatitis C virus infection: a possible pathogenetic association with therapeutic problems.

A patient with chronic hepatitis from hepatitis C virus (HCV) infection developed Lewis-Sumner syndrome (LSS). The neuropathy worsened after intravenous immunoglobulins, remitted after intravenous methylprednisolone, relapsed during interferon-alpha, but responded again to steroids continued for 68 weeks with clinical remission and without worsening of hepatitis. We are not aware of other reports of HCV infection and LSS. This association may be coincidental or related to a virus-triggered immune-mediated process. Although the coexistence of a dysimmune neuropathy with hepatitis makes problematic the choice of treatment, we emphasize that the patient's condition during treatment with steroids and the 46 following weeks without therapy has been excellent.

Adult↗

PubMed2006

Familial idiopathic hyper-CK-emia: an underrecognized condition.

Persistent elevation of serum creatine kinase (CK) in individuals with normal neurological and laboratory examinations has been called idiopathic hyperCKemia (IH). IH has been reported in rare families and was recently ascribed to caveolin-3 gene mutations. We retrospectively found that IH was familial in 13 of 28 subjects in whom serum CK was measured in relatives. These 13 families had a total of 41 subjects with IH, including six over 60 years of age. In eight families there was male-to-male transmission and a higher prevalence of males with hyperCKemia. Muscle biopsy in one member of all families was normal or showed minimal, nonspecific changes. Morphometric examination disclosed different patterns of changes in fiber size and distribution. Caveolin-3 expression was normal and in five families molecular genetics excluded caveolin-3 gene mutations. Our findings suggest that IH is familial in 46% of cases. Familial IH is a benign genetically heterogeneous condition that is autosomal-dominant in at least 60% of cases, with a higher penetrance in men.

Adolescent↗

PubMed2005

Both laminin and Schwann cell dystroglycan are necessary for proper clustering of sodium channels at nodes of Ranvier.

Nodes of Ranvier are specialized axonal domains, at which voltage-gated sodium channels cluster. How axons cluster molecules in discrete domains is mostly unknown. Both axons and glia probably provide constraining mechanisms that contribute to domain formation. Proper sodium channel clustering in peripheral nerves depends on contact from Schwann cell microvilli, where at least one molecule, gliomedin, binds the sodium channel complex and induces its clustering. Furthermore, mice lacking Schwann cell dystroglycan have aberrant microvilli and poorly clustered sodium channels. Dystroglycan could interact at the basal lamina or at the axonglial surface. Because dystroglycan is a laminin receptor, and laminin 2 mutations [merosin-deficient congenital muscular dystrophy (MDC1A)] cause reduced nerve conduction velocity, we asked whether laminins are involved. Here, we show that the composition of both laminins and the dystroglycan complex at nodes differs from that of internodes. Mice defective in laminin 2 have poorly formed microvilli and abnormal sodium clusters. These abnormalities are similar, albeit less severe, than those of mice lacking dystroglycan. However, mice lacking all Schwann cell laminins show severe nodal abnormalities, suggesting that other laminins compensate for the lack of laminin 2. Thus, although laminins are located at a distance from the axoglial junction, they are required for proper clustering of sodium channels. Laminins, through their specific nodal receptors and cytoskeletal linkages, may participate in the formation of mechanisms that constrain clusters at nodes. Finally, abnormal sodium channel clusters are present in a patient with MDC1A, providing a molecular basis for the reduced nerve conduction velocity in this disorder.

Animals↗

PubMed2005

Identification of deletions and duplications of the DMD gene in affected males and carrier females by multiple ligation probe amplification (MLPA).

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused in the majority of cases by deletions of the DMD gene and are readily detectable in affected males by multiplex polymerase chain reaction (PCR). However, different approaches must be used for the identification of female carriers, in which deletions are not detectable by PCR, because of the presence of a normal X chromosome. In this study, we used the multiple ligation probe amplification (MLPA) tool for the identification of female carriers of DMD deletions or duplications in 12 families with a single affected male, 10 of which were previously diagnosed as carriers of a DMD rearrangement, and the remaining two as having an unknown disease-causing mutation. In all the investigated affected males, MLPA analysis confirmed the presence of a DMD rearrangement, and in six of them allowed the refinement of the breakpoints. In 12 female relatives of the affected patients, MLPA analysis showed a DMD deletion or duplication, confirming their carrier status. Two of these were the mother and the sister of a patient whose disease-causing mutation was not known. MLPA analysis thus proved to be an useful tool for the analysis of both affected males and females carriers of DMD rearrangements in cases in which the disease-causing mutation in the affected male was not known, providing useful information for the genetic counselling of the family.

Chromosomes, Human, X↗

PubMed2002

Peripheral nerve extracellular matrix remodeling in Charcot-Marie-Tooth type I disease.

Charcot-Marie-Tooth type 1 disease (CMT1) is a group of inherited demyelinating neuropathies caused by mutations in genes expressed by myelinating Schwann cells. Rather than demyelination per se, alterations of Schwann cell-axon interactions have been suggested as the main cause of motor-sensory impairment in CMT1 patients. In an attempt to identify molecules that may be involved in such altered interactions, the extracellular matrix (ECM) remodeling occurring in CMT1 sural nerves was studied. For comparison, both normal sural nerves and sural nerves affected by neuropathies of different origin were used. The study was performed by immunohistochemical analysis using antibodies against collagen types I, III, IV, V, and VI and the glycoproteins fibronectin, laminin, vitronectin and tenascin. Up-regulation of collagens, fibronectin and laminin was commonly found in nerve biopsy specimens from patients affected by CMT1 and control diseases, but higher levels of overexpression were usually observed in CMT1 cases. On the other hand, vitronectin and tenascin appeared preferentially induced in CMT1 compared to other pathologies investigated here. Vitronectin, whose expression in normal nerves was limited to perineurial layers and to the walls of epineurial and endoneurial vessels, became strongly and diffusely expressed in the endoneurium in most CMT1 biopsy specimens. The expression of tenascin, confined to the perineurium, to vessel walls and to the nodes of Ranvier in normal nerves, was displaced and extended along the internodes of several nerve fibers in the majority of CMT1 nerves. Thus, compared with our pathological controls CMT1 seemed to determine the most extensive remodeling of peripheral nerve ECM.

Adolescent↗

PubMed2002

Can electrophysiology differentiate polyneuropathy with anti-MAG/SGPG antibodies from chronic inflammatory demyelinating polyneuropathy?

OBJECTIVES: Patients with polyneuropathy and antibodies to myelin-associated glycoprotein (MAG) and sulphated glucuronyl paragloboside (SGPG) differ from chronic inflammatory demyelinating polyneuropathy (CIDP) because of a slower, progressive course, symmetrical and predominantly sensory involvement of legs, predominantly distal slowing of motor conductions, and poorer response to therapy. We studied whether a wide set of electrophysiologic parameters may differentiate these two neuropathies. METHODS: We reviewed the electrophysiological studies of 10 patients with anti-MAG/SGPG antibodies and 22 with CIDP examining: (1) motor conduction velocity and distal compound muscle action potential amplitude; (2) conduction block (CB) and temporal dispersion; (3) distal motor latency and terminal latency index (TLI); (4) F wave and proximal conduction time; and (5) sensory conduction and occurrence of abnormal median with normal sural sensory potential. RESULTS: Anti-MAG/SGPG neuropathies showed: (1) more severe involvement of peroneal nerves; (2) more frequent disproportionate distal slowing of motor conductions (TLI< or =0.25) and absent sural potential, and (3) no CB. However 3/22 CIDP patients also had at least two nerves with TLI< or =0.25 and no CB. CONCLUSIONS: Electrophysiologic findings suggest in anti-MAG/SGPG neuropathy a length-dependent process with a likely centripetal evolution. A disproportionate slowing of conduction in distal segments of motor nerves suggests the diagnosis of anti-MAG/SGPG neuropathy, although it is not pathognomonic.

Adult↗