Biomedical subjects

A Simonati

Publications and source records attributed to A Simonati.

At least 19 recordsLinked to original sources

PubMed2007

The role of muscle biopsy in investigating isolated muscle pain.

OBJECTIVE: To evaluate the muscle biopsy findings from 240 patients who had isolated muscle pain. METHODS: Histopathology, immunohistochemistry for dystrophin, dystrophin-related proteins, major histocompatibility complex type I, and biochemical analysis of glycolytic and mitochondrial respiratory chain enzymes were performed on muscle biopsies. An attempt was made to correlate pathologic data and clinical findings (sex, age, quality and distribution of symptoms, serum CK levels, and EMG recording). RESULTS: We have described five groups of patients based on muscle biopsy findings: 51.6% had heterogeneous myopathic abnormalities; only 19% of them had a specific myopathic picture, i.e., central nuclei myopathy, central core disease, myopathy with tubular aggregates or with trabecular fibers or abnormalities of fiber typing; 20% had signs of respiratory chain dysfunction but only one patient had a probable mitochondrial disease; 7% had a neurogenic pattern; 2.4% had a metabolic myopathy (phosphorylase or phosphofructokinase deficiency); and 19% had normal muscle biopsy. No clear-cut correlation between muscle biopsy and clinical data was observed except for those patients with a metabolic myopathy. CONCLUSIONS: The probability that a patient complaining only of muscle pain and with a normal neurologic examination has a definite muscle pathology is 2%. Only patients with sole exercise-related muscle pain and sCK seven times higher than the normal value are strongly suspected of having a metabolic myopathy. A rigorous selection of patients is needed before performing a muscle biopsy.

Adolescent↗

PubMed2006

A novel missense mutation in the L1CAM gene in a boy with L1 disease.

A novel missense mutation of the L1CAM gene (Xq28) is described in an adult patient affected with severe mental retardation, spastic paraparesis, adducted thumbs, agenesis of corpus callosum and microcephaly (L1 disease). We detected a transition c2308G-->A in exon 18 that caused an amino acid change in codon 770. The patient's mother and two sisters were heterozygous for the same mutation. This newly described mutation predicts the substitution of an aspartate by asparagine (D770N) in the second fibronectin (Fn2) domain of the extracellular portion of the mature L1 protein. Even if amino acid substitution does not significantly change the physico-chemical properties of the Fn2 domain, it seems clear that the integrity of this domain is required to maintain the biological functions of the protein. The feature peculiar to this patient is the decelerated head growth post-natally, leading to microcephaly. Mutations of L1CAM associated with prolonged survival may hamper post-natal brain and head growth.

Abnormalities, Multiple↗

PubMed2003

MELAS: clinical phenotype and morphological brain abnormalities.

We describe the clinical and neuropathological findings of three unrelated autopsy cases of MELAS harboring the A3243G transition in the mitochondrial DNA (mtDNA). Using immunohistochemical techniques, we studied the expression of several subunits of the respiratory chain in various brain regions from the same cases. In all three cases there was a reduced immunocytochemical staining for mtDNA-encoded subunits of the respiratory chain, confirming the presence of a defective mitochondrial protein synthesis in this disease. Mitochondrial abnormalities were mostly confined to multiple areas of different size and shape, in agreement with the focal character of the brain pathology in MELAS, and were most prominent in the cerebral cortex, providing a morphological contribution to the explanation of the cognitive regression of the patients. Immunoreactivity for mtDNA-encoded subunits was reduced in the walls of many pial and intracerebral arterioles of different brain regions but there was no clear correlation between territories of affected vessels and distribution of the histological and immunohistochemical lesions. Cerebral focal lesions in MELAS might have a metabolic nature and several pathogenetic mechanisms might be involved in the genesis of stroke-like episodes when there is a local increased ATP demand.

Adenosine Triphosphatases↗

PubMed2002

Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3-q24.1.

It has been suggested that a genetic factor(s) or a familial predisposition may contribute to the clinical manifestations of disc herniation; moreover, no genetic linkage between spinal disc herniation and spastic paraplegia has ever been described. A family with consanguineous parents and four of eight sibs affected by multiple disc herniations and spastic paraplegia was clinically and genetically analysed. Surgery caused partial improvement in all of them. After the exclusion of type II collagen and vitamin D receptor genes and the recessive loci for HSPs, a genome wide search was performed with about 500 fluorescent markers. Positive lod score values were obtained for chromosome 6q22.31-q24.1, with evidence of three homozygous intervals. The maximum multipoint lod score of 3.28 was obtained in only one interval, between markers D6S1699 and D6S314. On the whole, a susceptibility locus for disc herniation and autosomal recessive spastic paraplegia was found on chromosome 6q23.3-q24.1. This is the first time that disc herniation and the associated neurological syndrome has been linked to a human chromosomal region.

Chromosome Mapping↗

PubMed2001

PMP22 related congenital hypomyelination neuropathy.

The peripheral myelin protein 22 (PMP22) is a tetraspan membrane protein which is localised in the compact myelin of the peripheral nerves. In fibroblasts, where it was originally identified as growth arrest related factor 3 (Gas3), PMP22 has been shown to modulate cell proliferation; in the peripheral nervous system its roles are still debated. The duplication of PMP22 is the most common cause of the demyelinating form of the autosomal dominant Charcot-Marie-Tooth neuropathy (CMT1A); rarer missense mutations of PMP22 also cause CMT1A or severe dehypomyelinating neuropathies of infancy grouped under the heading of Dejerine-Sottas syndrome (DSS). Here, a sporadic patient affected with DSS is described; nerve biopsy disclosed a picture of hypomyelination/amyelination with basal laminae onion bulbs and no florid demyelination and it was consistent with congenital hypomyelination neuropathy (CHN); molecular analysis disclosed a novel point mutation of PMP22 that causes a non-conservative arginine for cysteine substitution at codon 109, in the third transmembrane domain. CHN is the rarest and severest form of DSS and it is thought to reflect dysmyelination rather than demyelination. The reported case suggests that missense point mutations may alter a putative role of PMP22 in modulating Schwann cell growth and differentiation.

Adolescent↗

PubMed2000

A novel nonsense mutation (Q509X) in three Italian late-infantile neuronal ceroid-lipofuscinosis children.

We identified a novel nonsense CLN2 mutation (Q509X) in three Italian children with classical late-infantile neuronal ceroid lipofuscinosis (LINCL) from two unrelated families. The mutation introduced a premature stop codon in exon 12 of the CLN2 gene, resulting in a protein lacking the last 54 residues. Haplotype analysis suggested independent origin of the mutation in our families. The protein truncation test was employed to verify the functional consequences of the novel Q509X mutation. In Patient 1, the mutant alleles were transcribed but translated in a shorted peptide suggesting that the Q509X mutation is likely to interfere with CLN2p function. While expanding the list of genetic variants in LINCL, our findings represent the first molecular characterization of LINCL patients in South Europe.

Aminopeptidases↗

PubMed2000

Focally folded myelin in Charcot-Marie-Tooth neuropathy type 1B with Ser49Leu in the myelin protein zero.

Charcot-Marie-Tooth disease type 1 B (CMT1B) is a demyelinating neuropathy caused by mutations in the myelin protein zero (P0) gene (MPZ). A few cases of CMT1B were recently found to be characterized by focally folded myelin sheaths in nerve biopsy specimens; the significance of this association is unknown. Here, we describe two unrelated pedigrees harboring a heterozygous Ser49Leu substitution in P0ex. In both pedigrees, the mutation caused a late-onset, relatively mild CMT1B; in one pedigree, two patients had atrophy of peroneal muscles but hypertrophy of the gastrocnemius muscles. The sural nerve biopsy performed in the two index cases revealed an identical chronic demyelinating and remyelinating neuropathy dominated by focal foldings of the myelin sheath shaped either as tomacula or as out/infoldings. The report adds Ser49Leu to the mutations of P0ex associated with focally folded myelin and provides strong evidence that such a structural alteration of the myelin sheath reflects a distinct pathogenetic mechanism in a subgroup of CMT1B.

Amino Acid Substitution↗

PubMed2000

Neuronal ceroid lipofuscinoses: pathological features of bioptic specimens from 28 patients.

Clinical findings and pathological features of 28 patients affected with neuronal ceroid lipofuscinoses (NCL) are reviewed. The patient group included 15 children affected with the late-infantile form of NCL (LINCL), 10 patients affected with the juvenile form (JNCL), and 3 adult cases. Ultrastructural examinations of 50 biopsies from 6 tissues were consistent with clinical features in all LINCL and JNCL cases but one. The importance of electron microscopic (EM) examination of blood lymphocytes in these forms is outlined, particularly when combined with molecular analysis of the CLN2 or CLN3 genes, respectively. This approach leads to a definite diagnosis of LINCL and JNCL in a relatively short time. In adult NCL, diagnosis still relies on pathological grounds, and difficulties in interpreting the osmiophilic storage bodies in different tissues are outlined. EM investigation of blood lymphocytes was not helpful in any case of adult NCL. Results of one stereotactic brain biopsy are also reported.

Biopsy↗

PubMed2000

A CLN2 gene nonsense mutation is associated with severe caudate atrophy and dystonia in LINCL.

Clinical features and results of the blood DNA analysis are reported of a child affected with a distinct phenotype of the late infantile form of neuronal ceroid-lipofuscinosis (LINCL). He was affected by microcephaly and hypotonia since the fourth month of life; acquisition of motor and language abilities was severely impaired, and a disorder of communication with stereotyped movements followed. By age four, he developed signs and symptoms of progressive myoclonic encephalopathy along with motor and cognitive deterioration. Extrapyramidal signs were associated with neuroradiological findings of marked atrophy of the caudate nucleus. Specific curvilinear bodies were observed in blood lymphocytes and skin biopsy. Homozygous, nonsense mutation in the CLN2 gene was found giving origin to an Arg208stop, which produces an early transcription termination with loss of translation of about 50% of the gene product. Any relationship between the severe clinical features of our patient and the homozygous mutation here reported must be investigated on a larger number of LINCL patients bearing the same mutation.

Atrophy↗

PubMed1999

Myelin uncompaction in Charcot-Marie-Tooth neuropathy type 1A with a point mutation of peripheral myelin protein-22.

BACKGROUND: The peripheral myelin protein-22 (PMP22) gene has four transmembrane domains, two extracellular loops, and a short cytoplasmic tail. Its roles in the peripheral nervous system remain unclear. The most common cause of Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is a PMP22 gene duplication. Missense point mutations in the transmembrane domains are rare alternative causes that have undetermined pathogenetic mechanisms. OBJECTIVE: To investigate the phenotype-to-genotype correlations in a pedigree with unusual CMT1A. METHODS: We identified a pedigree with an autosomal dominant motor-sensory neuropathy and severely reduced nerve conduction velocities who did not have the PMP22 duplication. Specimens from sural nerve biopsies from two patients of different ages were evaluated morphometrically. By automated direct nucleotide sequencing we analyzed PMP22 and the gene of the major structural myelin protein zero (P0). RESULTS: Nucleotide 159 of PMP22 showed an A-to-T heterozygous mutation, predicted to cause an aspartate-to-valine substitution at codon 37 in the first extracellular loop of the protein. The mutation co-segregated with the disease in the pedigree and was absent in 80 healthy controls. The histopathologic phenotype was a de-remyelinating neuropathy with onion bulb formations, characterized by prominent uncompaction of the myelin sheath in the majority of fibers and by frequent tomacula. CONCLUSION: We have described a novel mutation in the first extracellular loop of PMP22 associated with an atypical CMT1A that overlaps pathologically with CMT1B caused by point mutations in the extracellular domain of P0.

Adult↗

PubMed1999

Cell proliferation and death: morphological evidence during corticogenesis in the developing human brain.

Cell proliferation and death account for the refinement of the cell number during corticogenesis. These processes have been investigated in the human developing telencephalon (12th-24th week of gestation) and cerebellum (16th-24th week). Only foetal brains, which had normal neuropathological examination, were utilised. Cell proliferation was analysed by classical histology and PCNA immunohistochemistry; cell death was investigated by the TUNEL method, which makes evident the different stages of apoptosis. High figures of mitotic nuclei were seen in the ventricular zone at the 12th-15th week of gestation, before sharply declining. The decrease of the proliferating cells occurs synchronously in both frontal and occipital germinal zones. Conversely, a slow increase of the number of the mitotic cells was observed in the more dorsal regions, probably due to the presence of proliferating glial elements. The amount of apoptotic nuclei was always remarkably low in the transient compartments of the wall of the telencephalon. The moderate number of apoptotic cells suggests that cellular mechanisms other than apoptosis are involved in the dissolution of the ventricular zone. Neither proliferating nor apoptotic cells were seen in the cortical plate. The topography of cell proliferation and death in the developing cerebellum did not account for a mutual relationship between the two events. The prolonged duration of the cell-cycle in the human developing CNS may explain its increased vulnerability to various DNA-damaging conditions, which can lead to either destructive lesions or malformations.

Cell Death↗

PubMed1999

Congenital hypomyelination neuropathy with Ser72Leu substitution in PMP22.

We describe a patient with congenital hypomyelination neuropathy. The pathological and morphometrical findings in the sural nerve biopsy were consistent with a defect of myelin formation and maintenance. Direct sequence analysis of the genomic regions coding the peripheral myelin proteins P0 and PMP22 disclosed a heterozygous missense point mutation that leads to a Ser72Leu substitution in the second transmembrane of PMP22. Codon 72 mutations of PMP22 are associated with different phenotypes encompassing the Dejerine-Sottas syndrome and including congenital hypomyelination neuropathy.

Amino Acid Substitution↗

PubMed1999

Neuroaxonal dystrophy with dystonia and pallidal involvement.

Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive disease of infantile onset, characterised by progressive clinical course, multi-systemic involvement and widespread presence of dystrophic axons in both the central and peripheral nervous system. Clinical, neurophysiological and neuroradiological criteria of the disease are established, but the occurrence of atypical cases is known. Since the availability of molecular markers is still lacking, diagnostic evidence in vivo is provided by the presence of specific axonal lesions distally in the peripheral nerve fibres. In two children who had a protracted course of the disease with dystonic postures of the upper limbs and showed dystrophic axons following sural nerve biopsy, bilateral pallidal hypointensity was observed after T2-weighted MRI scans. These findings are consistent with iron deposition, and are usually observed in Hallervorden-Spatz syndrome (HSS), a condition which is also characterised by dystrophic axons diffusely present in the central nervous system, but without peripheral nervous system involvement. These observations raise the issue of different phenotypes of INAD, and are consistent with the existence of intermediate forms between INAD and HSS. Altered mechanisms of iron storage and transport to and from the cellular compartments may play a role in the pathogenesis of the disease.

Axons↗

PubMed1999

Novel mutation of the P0 extracellular domain causes a Déjérine-Sottas syndrome.

A patient is described with a Déjérine-Sottas syndrome caused by a novel heterozygous Cys(98)Tyr mutation in the extracellular domain of the major peripheral myelin protein zero (P0ex). Homotypical interactions between P0ex tetramers of apposed extracellular faces of the Schwann cell membrane play a crucial part in myelin compaction. The amino acid change disrupts a unique disulphide bond that stabilises the immunoglobulin-like structure of P0ex and it is predicted to cause severe dehypomyelination through dominant negative effects on the wild type protein.

Adult↗

PubMed1998

Clinical and pathological correlations in Charcot-Marie-Tooth neuropathy type 1A with the 17p11.2p12 duplication: a cross-sectional morphometric and immunohistochemical study in twenty cases.

In a cross-sectional, clinical, and morphometric analysis we assessed the correlation between the clinical and pathological evolution of disease in 20 unrelated patients of various ages affected by Charcot-Marie-Tooth neuropathy type 1A (CMT1A) with the 17p11.2p12 (peripheral myelin protein 22, PMP22) duplication. The severity of neurologic deficits and slowing of motor conduction velocity at the median nerve did not vary significantly with the patients' age. The amount of demyelination was significantly higher below 15 years than in older age groups; in contrast, myelinated fiber and onion bulb densities were similar at all ages. The results indicate that in duplicated CMT1A, the pathological process develops early in life and progresses little during the course of the disease. Younger patients had lower g-ratio values, suggesting that the trigger of demyelination in early years could be a hypermyelination, resulting from PMP22 overexpression. Yet none of the 20 patients examined had immunohistochemical evidence of altered PMP22 expression. The early onset and development of the disorder make it difficult to detect PMP22 overdosage in nerve biopsies.

Adolescent↗

PubMed1998

Coeliac disease associated with peripheral neuropathy in a child: a case report.

Clinical features and pathological findings of sural nerve biopsy are reported of a 3-year-old child affected with coeliac disease who developed a progressive polyneuropathy, unresponsive to a gluten-free diet, nor to vitamin E and folic acid supply. There was no evidence of malabsorption, nor of blood factor deficiency, nor of metabolic abnormalities which might account for the neuropathy. A sural nerve biopsy showed marked loss of myelinated fibres without evidence of regenerative phenomena. Distal involvement and features of nerve pathology are consistent with a "dying-back" mechanism to underlie the nerve damage. The lack of response to a gluten-free diet suggests that direct toxicity of gliadin is not implicated.

Biopsy↗

PubMed1998

High-field magnetic resonance imaging of the developing human brain from the 10th to the 16th week of gestational Age.

In the present work, high-field magnetic resonance imaging (HF-MRI) was applied to study the developing human brain paying particular attention to the structures of interest in pathology of malformation. The aim of the work was to evaluate the possible application of HF-MRI to the analysis of brain development in the absence of some limits of conventional histological technique. Seven formalin-fixed human fetuses of 50, 65, 70, 85, 110, 116 and 125 mm crown/ rump length (corresponding to a gestational age ranging from 10 to 16 weeks) were examined in an imager-spectrometer equipped with a 4. 7-tesla horizontal magnet with a 33-cm bore. In the brain of all the fetuses the telencephalic, mesencephalic and rhombencephalic vesicles were recognizable and an easy quantitative evaluation of the brain curvatures in the absence of distortion due to dissection was possible. Comparing fetuses at different gestational ages, the spatial modification of the different vesicles was evident. In fetuses at 16 weeks of gestational age, stratified compartments of the telencephalic wall were evident. The germinal zone and the cortical plate were visible: the germinal layer was identifiable as a hypointensity in the periventricular area. The subplate zone and the intermediate zone emitted a strong intensity signal. Our study demonstrates that HF-MRI can contribute to the study of the complex developmental events in the human brain from the 10th to 16th week of gestational age in a submillimetric scale of resolution. This technique can provide information about the morphology of the encephalic vesicles and their relations with the bone cavity that cannot be obtained with conventional methods and may be a useful adjunct to histological techniques.

Anatomy, Cross-Sectional↗

PubMed1997

Botulinum toxin treatment of muscle cramps: a clinical and neurophysiological study.

Botulinum toxin is now widely used in the treatment of several hyperkinetic movement disorders. To evaluate its efficacy in treating muscle cramping syndromes, we studied clinical and neurophysiological variables before and after botulinum toxin injections into calf muscles and small flexor muscles of the foot in patients with an inherited benign cramp-fasciculation syndrome. At each assessment the clinical severity of cramp was scored and the cramp threshold frequency was measured with repetitive electrical peripheral nerve stimulation. Botulinum toxin injection significantly lowered our patients' clinical cramp severity scores (mean +/- SD: before, 3.80 +/- 0.44; after, 1.40 +/- 0.54), left muscle strength unchanged and significantly increased their cramp threshold frequencies (before, 4.22 +/- 2.26 Hz; after, 10.0 +/- 3.74 Hz). The clinical benefit induced by botulinum toxin lasted about 3 months. Botulinum toxin injections also significantly reduced fasciculation potentials in relaxed muscles (before, 0.86 +/- 0.19 fasciculations/sec; after, 0.45 +/- 0.11 fasciculations/sec). These findings show that local intramuscular injections of botulinum toxin provide effective, safe, and long-lasting relief of cramps possibly by reducing presynaptic cholinergic stimulation of motor nerve terminals and by impairing the input/output function of intrafusal and extrafusal motor end plates.

Adult↗