G. C. Guazzi

Interleukin-6 levels in the cerebrospinal fluid and serum of patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy

Clinical and experimental findings suggest that humoral factors, such as anti-peripheral nerve antibodies and cytokines, may be implicated in the immunopathogenesis of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Interleukin-6 (IL-6) is a multifunctional cytokine that promotes immunoglobulin synthesis by B lymphocytes. Increased IL-6 release is associated with autoantibody production in a number of immune-mediated and neoplastic disorders. To investigate the possible involvement of abnormal IL-6 release in inflammatory polyneuropathies, we assayed IL-6 levels in the cerebrospinal fluid (CSF) and serum of 23 patients with acute GBS and seven with CIDP. We also studied 69 patients with other non-inflammatory neurological diseases (NIND), 25 with other inflammatory neurological diseases (IND), four with brain tumors (BT), and 15 normal donors (serum alone) as controls. We found detectable levels of IL-6 in the CSF of 57% of GBS, 43% of CIDP, 60% of IND, 75% of BT, and 4% of NIND. In GBS patients, no correlation was found between CSF IL-6 values and other laboratory or clinical parameters, such as CSF total protein, CSF albumin, CSF IgG, CSF/serum albumin ratio, functional disability score, and time elapsed from disease onset. Serum IL-6 levels were increased in six of 23 (26%) GBS, in one of 39 (3%) NIND, and in one of seven (14%) IND, but in none of the CIDP or BT patients. There was no correlation between serum and CSF IL-6 values, but cytokine levels in GBS sera correlated with time elapsed from clinical onset.(ABSTRACT TRUNCATED AT 250 WORDS)

Axonal motor and sensory neuropathy in myotonic dystrophy

We report the neurophysiological findings from 24 subjects with myotonic dystrophy of Steinert and the histological findings in two of them. The conduction data is compared with that of a group of subjects with Landouzy‐Déjérine muscular dystrophy. In 46% of cases, the electrophysiological data revealed slight and generalized axonal neuropathy. Histological results of sural nerve confirmed axonal damage of sensory fibres. The neuropathy was not correlated with age of patients, duration or onset of the disease, nor with the state of the deep reflexes; it did not show signs of progressing and is probably one of the multisystemic manifestations of gene pleiotropism.

Atypical McLeod syndrome manifested as X-linked chorea-acanthocytosis, neuromyopathy and dilated cardiomyopathy: report of a family

We report a family with three members affected by a typically X-linked McLeod syndrome. In the proband a very weak positivity for antigens of the Kell group was detected. His sister showed a normal antigenic pattern. We emphasize the prominent neurological picture characterized by a choreic syndrome with atrophy of the caudate nucleus on MRI, psychiatric disturbances, peripheral nerve and muscle biopsy findings indicating slight neuromuscular involvement, and cardiac abnormalities. The differential diagnosis is discussed.

Charcot-Marie-Tooth disease: study of a large kinship with an intermediate form

SummaryA clinical, genetic, electrophysiological and ultrastructural study of a large kinship with peroneal muscular atrophy is reported. There was a noteworthy homogeneity in the phenotype as well as in the electrophysiological characteristics encountered in 15 affected members aged between 7 and 72 years. The symptoms appeared first in the second decade of life and stabilized by the fourth decade. There was no evidence of linkage of the neuropathy gene to the Duffy blood group locus on chromosome 1. The electrophysiological data in this family as well as the ultrastructural findings confirm that there is heterogeneity in hereditary motor and sensory neuropathy type I, and support the concept of an intermediate form of Charcot-Marie-Tooth disease.

The A to G transition at nt 3243 of the mitochondrial tRNALeu(UUR) may cause an MERRF syndrome.

OBJECTIVE--To verify the phenotype to genotype correlations of mitochondrial DNA (mtDNA) related disorders in an atypical maternally inherited encephalomyopathy. METHODS--Neuroradiological, morphological, biochemical, and molecular genetic analyses were performed on the affected members of a pedigree harbouring the heteroplasmic A to G transition at nucleotide 3243 of the mitochondrial tRNALeu(UUR), which is usually associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). RESULTS--The proband was affected by a fullblown syndrome of myoclonic epilepsy with ragged red fibres (MERRF), severe brain atrophy, and basal ganglia calcifications, without the MRI T2 hyperintense focal lesions which are pathognomonic of MELAS. Oligosymptomatic relatives were variably affected by lipomas, goitre, brain atrophy, and basal ganglia calcifications. Muscle biopsies in the proband and his mother showed a MELAS-like pattern with cytochrome c oxidase hyperreactive ragged red fibres and strongly succinate dehydrogenase reactive vessels. Quantification of the A3243G mutation disclosed 78% and 70% of mutated mtDNA in the muscle of the severely affected proband and of his oligosymptomatic mother respectively. Nucleotide sequencing of the mitochondrial tRNALeu(UUR) and tRNALys in the probands muscle failed to show any additional nucleotide change which could account for the clinical oddity of this pedigree by modulating the expression of the primary pathogenic mutation. CONCLUSION--So far, MERRF has been associated with mutations of the mitochondrial tRNALys, and MELAS with mutations of the mitochondrial tRNALeu(UUR). Now MERRF may also be considered among the clinical syndromes associated with the A to G transition at nt 3243 of the tRNALeu(UUR).

The clinical aspects of adult hexosaminidase deficiencies.

The authors describe the clinical phenotypes of hexosaminidase deficiencies (GM2 gangliosidosis). The symptoms, differently combined, include cerebellar ataxia, motor neuron disease, dystonia, psychosis, neurovegetative troubles with different severity. Morphological changes are evident in rectal, muscle or nerve biopsies. Minor clinical changes are described in carriers from a family. A chronic GM2 gangliosidosis has to be suspected in any atypical case with the above-mentioned symptoms with autosomal-recessive inheritance.

Localization of laminin α2 chain in normal human central nervous system: an immunofluorescence and ultrastructural study

Abstract Recently, a rare form of congenital muscular dystrophy has been shown to be associated with a deficiency of laminin α2 chain, a tissue-specific component of the basal lamina. Besides muscular dystrophy, children affected with this disorder also show electrophysiological and magnetic resonance imaging evidence of white matter involvement in the central nervous system (CNS). We have studied the precise localization of laminin α2 chain in normal human brain, using specific electron microscopic techniques including thin-section fracture labeling and cryoultramicrotomy, in parallel with immunohistochemical techniques. We found that this laminin chain was localized to the basal lamina of all cerebral blood vessels, whereas blood vessels of the choroid plexus did not show any reaction. No positive reaction was found in meningeal blood vessels either. We hypothesize that in normal brain, laminin α2 may be important for the selective filtration capability of the blood-brain barrier. The lack of laminin α2 in cerebral vessels of children with laminin α2-deficient congenital muscular dystrophy may cause impaired selective filtration, leading to leakage of plasma components and damage to the CNS. Further studies should be performed on patients affected by congenital muscular dystrophy associated with laminin α2 deficiency to test this hypothesis.

Hypoplasia of the corpus callosum in Niemann-Pick type C disease

In two unrelated patients with Niemann-Pick type C disease MRI showed symmetrical cerebral and cerebellar atrophy and hypoplasia of the corpus callosum. T2-weighted images in one showed high signal areas in the posterior white matter.

Early synthesis and correlation of serum anti-thyroid antibodies with clinical parameters in multiple sclerosis.

A high frequency of anti-thyroid antibodies has been demonstrated in multiple sclerosis (MS), but there is a lack of data on the possible association of thyroid autoimmunity with disease activity. To assess whether anti-thyroid antibodies are synthesized early in MS or are induced over the course of the disease and whether or not they are correlated with clinical findings, we assayed serum anti-peroxidase and anti-thyroglobulin antibodies in 129 relapsing-remitting MS patients at the time of diagnosis and prior to any immunosuppressive or immunomodulatory treatment. Anti-peroxidase antibodies were detected in 28/129 (21.7%) MS patients, compared to 12/130 (9.2%) neurological controls (P=0.006) and 8/152 (5.3%) normal healthy subjects (P<0.0001). High titres of anti-thyroglobulin antibodies were detected in 11/129 (8.5%) MS patients compared to 6/130 (4.6%) patients with other neurological diseases (P=0.22) and 5/152 (3.3%) normal healthy subjects (P=0.07). Anti-peroxidase antibodies were associated with initial relapse in 14 of 28 (50%) of the patients compared to 18/101 (18%) without antibodies (P=0.001). Similarly, anti-thyroglobulin antibodies were associated with first relapse in 8/11 (73%) of the patients compared to 11/118 (9.3%) of those without (P<0.0001). However, there was no correlation between anti-thyroid antibody titres and disease duration or CSF IgG index values. By contrast, a significant inverse correlation was found between anti-thyroglobulin antibody titres and EDSS score (r(s)=-0. 75; P=0.008). Our findings demonstrate that anti-peroxidase and anti-thyroglobulin antibodies are synthesized early in relapsing-remitting MS and are associated with early clinical disease activity. Furthermore, high titres of anti-thyroglobulin antibodies are associated with low disability scores, suggesting a possible protective role of these antibodies that deserves further investigation.

Clinicopathological and genetic studies of two further Italian families with cerebral autosomal dominant arteriopathy

Abstract We report on two Italian families with an early-adult onset autosomal dominant disorder, characterized by leukoencephalopathy, migraine, psychiatric disturbances, stroke and dementia. These findings fulfill the diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome. Moreover, to confirm the CADASIL gene location to 19p12, we performed a linkage analysis with four microsatellite markers. The results of the genetic study gave positive but not significant lod scores, indicating only weak evidence of a linkage with 19p12. In one autopsy case, we found extensive ischemic changes due to the selective involvement of the small muscular arteries of the cerebral white matter. The lesions consisted of a thickening of the media with deposition of granular eosinophilic material. Ultrastructural examination of the arterial walls showed graded damage to smooth muscle cells, mostly of the longitudinal layer, and an abnormal proliferation of basal lamina components. Immunocytochemical analysis showed strong reactivity using antibodies to collagen IV and smooth myosin proteins. The results suggest a primary involvement of the smooth muscle cells of small cerebral arteries, with a secondary alteration of basal lamina components and elastic tissue.