Acute motor conduction block neuropathy followed by axonal degeneration and poor recovery.
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Axons↗
Biomedical subjects
Antonino Uncini
Publications and source records attributed to Antonino Uncini.
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↗
Susceptibility to Guillain-Barré syndrome is associated to polymorphisms of CD1 genes.
Guillain-Barré syndrome (GBS) is the prototype of a postinfectious autoimmune neuropathy. Molecular mimicry between glycolipid antigens expressed by an infective antigen such as Campylobacter jejuni and the human peripheral nerve has been hypothesized to be the causative mechanism of GBS. However, only 1/1000 of C. jejuni enteritis develops GBS. This emphasizes the importance of host-related factors in the development of the disease. HLA studies in GBS failed to show an association or gave conflicting results but MHC class I and II process and present peptides to T lymphocytes making unlikely that the HLA system plays a role in GBS with autoantibodies against self-gangliosides. CD1 molecules are MCH-like glycoproteins specialized in capturing and presenting a variety of glycolipid to antigen-specific T cells. There are five closely linked CD1 genes in humans located in chromosome 1 (named CD1A, B, C, D, and E) all showing limited polymorphism in exon 2 which codifies for the alpha1 domain of CD1 molecules. The nucleotide substitutions in CD1B and CD1C are rare and reported to be silent. In 100 controls and 65 GBS patients (21 with a recent C. jejuni infection and 35 with anti-glycolipid antibodies) we used direct sequencing by polymerase chain reaction to genotype exon 2 of CD1A, CD1D and CD1E genes. CD1D is monomorphic in both controls and patients whereas CD1A and CD1E are biallelic in exon 2. Subjects with CD1E*01/01 genotype are 2.5 times more likely to develop GBS, whereas subjects with CD1A*01/02 or CD1E*01/02 have a reduced relative risk by 3.6 and 2.3 times respectively. The combination of CD1A*01/02 and CD1E*01/02 reduces by 5 times the risk of developing GBS. Although a correlation between CD1E*01/01 genotype and recent C. jejuni infection or presence of antiganglioside antibodies was not found the overall findings indicate that susceptibility to develop GBS is associated with polymorphisms of CD1E and CD1A genes.
Adolescent↗
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↗
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↗
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↗
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↗
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↗
Mutation finding in patients with dysferlin deficiency and role of the dysferlin interacting proteins annexin A1 and A2 in muscular dystrophies.
Mutations in the DYSF gene underlie two main muscle diseases: Limb Girdle Muscular Dystrophy (LGMD) 2B and Miyoshi myopathy (MM). Dysferlin is involved in muscle membrane-repair and is thought to interact with other dysferlin molecules and annexins A1 and A2 at the sarcolemma. We performed genotype/phenotype correlations in a large cohort of dysferlinopathic patients and explored the possible role of annexins as modifier factors in LGMD-2B and MM. In particular, clinical examination, expression of sarcolemmal proteins and genetic analysis were performed on 27 dysferlinopathic subjects. Expression of A1 and A2 annexins was investigated in LGMD-2B/MM subjects and in patients with other muscle disorders. We identified 24 different DYSF mutations, 10 of them being novel. We observed no clear correlation between mutation type and clinical phenotype, but MM patients were found to display muscle symptoms significantly earlier in life than LGMD subjects. Remarkably, dysferlinopathic patients and subjects suffering from other muscular disorders expressed higher levels of both annexins compared to controls; a significant correlation was observed between annexin expression levels and clinical severity scores. Also, annexin amounts paralleled the degree of muscle histopathologic changes. In conclusion, our data indicate that the pathogenesis of different inherited and acquired muscle disorders involves annexin overexpression, probably because these proteins actively participate in the plasmalemma repair process. The positive correlation between annexin A1 and A2 and clinical severity, as well as muscle histopathology, suggests that their level may be a prognostic indicator of disease.
Adolescent↗
Wide expressivity variation and high but no gender-related penetrance in two dopa-responsive dystonia families with a novel GCH-I mutation.
We describe the clinical and molecular correlates in two Italian families with dopa-responsive dystonia (DRD) and the same novel mutation of GTP-cyclohydrolase I (GCH-I) gene. Thirty-five subjects were examined and the genotype correlated to phenotype. Childhood onset foot dystonia is present in 7 subjects currently under the age of 40. In 1 patient bilateral foot dystonia was evident at birth suggesting that dystonia may be active as early as in utero. In another patient, dystonia spontaneously remitted in adolescence, to relapse 8 years later, as writer's cramp. Dystonia and parkinsonian signs are present in 5 other patients. In 2 subjects an isolated parkinsonism started over the age of 45. A 5-base pair insertion at codon 242 within exon 6 of GTP-cyclohydrolase I (GCH-I) gene that shifts the reading frame and results in a premature stop at codon 247 with truncation of the polypeptide has been detected in 21 subjects. Considering dystonia and parkinsonism the overall penetrance is 0.71 and not significantly different in men (0.69) and women (0.75). Genealogical studies seem to exclude that these families are related but haplotype analysis suggests a single founder. Our findings in subjects with the same mutation indicate a wide intrafamilial variation in expressivity and high penetrance in DRD but do not confirm the reported influence of gender on GCH-I gene mutation penetrance.
Adult↗
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↗
Interferon beta normalizes suppressor cell function in dysimmune neuropathies.
We found a defective suppressor cell function in vitro both in idiopathic chronic inflammatory demyelinating polyneuropathy and in paraproteinemic neuropathy with antibodies to sulfated glucuronyl paragloboside. In the presence of interferon beta, suppressor cell function was normalized. Our results suggest that a decreased suppressor cell function plays a pathogenetic role in dysimmune neuropathies. Interferon beta might represent an adjunctive therapy in CIDP both acting on a defective blood-nerve barrier and normalizing an otherwise defective suppressor cell function.
Adolescent↗
The "electrocuted" hippocampus.
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Epilepsy, Complex Partial↗